Torill Berg

• Berg, Torill (2018). Kv7(KCNQ)-K+-Channels Influence Total Peripheral Resistance in Female but Not Male Rats, and Hamper Catecholamine Release in Hypertensive Rats of Both Sexes. Frontiers in Physiology.  ISSN 1664-042X.  9, s 1- 13 . doi: 10.3389/fphys.2018.00117 Full text in Research Archive. Show summary

  K+-channels of the Kv7/KCNQ-family hyperpolarize and stabilize excitable cells such as autonomic neurons and vascular smooth muscle cells (VSMC). Kv7 may therefore play a role in blood pressure (BP) homeostasis, and prevent a high total peripheral vascular resistance (TPR), a hallmark of hypertensive disease. The present study analyzed if Kv7 channels influence catecholamine release and TPR in normotensive (WKY) and spontaneously hypertensive rats (SHR), and if theymay contribute to the antihypertensive protection seen in young, female SHR. Tyramine-stimulated norepinephrine release evokes an adrenergic cardiovascular response, and also allows modulation of release to be reflected in the overflow to plasma. The experiment itself activated some secretion of epinephrine. The results show: (1) XE-991 (Kv7.1-7.4-inhibitor), but not chromanol 293B (Kv7.1-inhibitor), increased tyramine-stimulated norepinephrine overflow and epinephrine secretion in both sexes in SHR, but not WKY. (2) Surprisingly, the Kv7-openers retigabine (Kv7.2-7.5) and ICA-27243 (Kv7.2-7.3-preferring) increased catecholamine release in female SHR. (3) The rise in TPR following tyramine-stimulated norepinephrine release was increased by XE-991 but not chromanol in the female WKY only. (4) Retigabine and ICA-27243 reduced the TPR-response to tyramine in the female SHR only. These results suggested: (1) Up-regulation of Kv7.2-7.3 function in sympathetic neurons and chromaffin cells hampered catecholamine release in SHR of both sexes. (2) The increase catecholamine release observed after channel openers in the female SHR may possibly involve reduced transmission in cholinergic neurons which hamper catecholamine release. These two mechanisms may serve to counter-act the hyperadrenergic state in SHR. (3) Kv7.4, most likely in the vasculature, opposed the tension-response to norepinephrine in the female WKY. (4) Vascular Kv7.4-7.5 could be stimulated and then opposed norepinephrine-induced vasoconstriction in the female SHR. (5) Vascular Kv7 channels did not counter-act norepinephrine induced vasoconstriction in male rats, possibly due to different Kv7 channel regulation. Kv7 channels may represent a novel target for antihypertensive therapy.

• Stahl, Katja; Rahmani, Soulmaz; Prydz, Agnete; Skauli, Nadia; MacAulay, Nanna; Mylonakou, Maria-Niki; Torp, Reidun; Skare, Øivind; Berg, Torill; Leergaard, Trygve Brauns; Paulsen, Ragnhild Elisabeth; Ottersen, Ole Petter & Amiry-Moghaddam, Mahmood (2018). Targeted deletion of the aquaglyceroporin AQP9 is protective in a mouse model of Parkinson's disease. PLOS ONE.  ISSN 1932-6203.  13(3) . doi: 10.1371/journal.pone.0194896 Full text in Research Archive. Show summary

  More than 90% of the cases of Parkinson’s disease have unknown etiology. Gradual loss of dopaminergic neurons of substantia nigra is the main cause of morbidity in this disease. External factors such as environmental toxins are believed to play a role in the cell loss, although the cause of the selective vulnerability of dopaminergic neurons remains unknown. We have previously shown that aquaglyceroporin AQP9 is expressed in dopaminergic neurons and astrocytes of rodent brain. AQP9 is permeable to a broad spectrum of substrates including purines, pyrimidines, and lactate, in addition to water and glycerol. Here we test our hypothesis that AQP9 serves as an influx route for exogenous toxins and, hence, may contribute to the selective vulnerability of nigral dopaminergic (tyrosine hydroxylase-positive) neurons. Using Xenopus oocytes injected with Aqp9 cRNA, we show that AQP9 is permeable to the parkinsonogenic toxin 1-methyl-4-phenylpyridinium (MPP+). Stable expression of AQP9 in HEK cells increases their vulnerability to MPP+ and to arsenite—another parkinsonogenic toxin. Conversely, targeted deletion of Aqp9 in mice protects nigral dopaminergic neurons against MPP+ toxicity. A protective effect of Aqp9 deletion was demonstrated in organotypic slice cultures of mouse midbrain exposed to MPP+ in vitro and in mice subjected to intrastriatal injections of MPP+ in vivo. Seven days after intrastriatal MPP+ injections, the population of tyrosine hydroxylase-positive cells in substantia nigra is reduced by 48% in Aqp9 knockout mice compared with 67% in WT littermates. Our results show that AQP9 –selectively expressed in catecholaminergic neurons—is permeable to MPP+ and suggest that this aquaglyceroporin contributes to the selective vulnerability of nigral dopaminergic neurons by providing an entry route for parkinsonogenic toxins. To our knowledge this is the first evidence implicating a toxin permeable membrane channel in the pathophysiology of Parkinson’s disease.

• Berg, Torill (2017). b- and a2-adrenoceptor control of vascular tension and catecholamine release in female normotensive and spontaneously hypertensive rats. Frontiers in Neurology.  ISSN 1664-2295.  8 . doi: 10.3389/fneur.2017.00130 Full text in Research Archive.
• Berg, Torill (2016). M-currents (Kv7.2-7.3/KCNQ2-3) are responsible for dysfunctional autonomic control of heart rate and catecholamine release in hypertensive rats. Frontiers in Physiology.  ISSN 1664-042X.  7 (584) . doi: 10.3389/fphys.2016.00584 Full text in Research Archive. Show summary

  Autonomic dysfunctions play important roles in hypertension, heart failure and arrhythmia, often with a detrimental and fatal effect. The present study analysed if these dysfunctions involved M-channels (members of the Kv7/KNCQ family) spontaneously hypertensive rats (SHR). Cardiac output and heart rate (HR) were recorded by a flow probe on the ascending aorta in anesthetized SHR and normotensive rats (WKY), and blood pressure (BP) by a femoral artery catheter. Total peripheral vascular resistance (TPR) was calculated. XE-991 (Kv7.1-7.4-inhibitor) reduced resting HR in WKY but only after reserpine in SHR. XE-991 increased TPR and BP baseline in both strains. Retigabine (Kv7.2-7.5-opener) reduced HR, TPR and BP, also after reserpine. Depolarization induced by 3,4-diaminopyridine (3,4-DAP), a voltage-sensitive K+ channel (Kv) inhibitor, activated release of both acetylcholine and norepinephrine, thus activating an initial, cholinergic bradycardia in SHR, followed by sustained, norepinephrine-dependant tachycardia in both strains. XE-991 augmented the initial 3,4-DAP-induced bradycardia and eliminated the late tachycardia in SHR, but not in WKY. The increased bradycardia was eliminated by hexamethonium and methoctramine (M2muscarinic receptor antagonist) but not reserpine. Retigabine eliminated the increased bradycardia observed in reserpinized SHR. XE-991 also increased 3,4-DAP-stimulated catecholamine release, but not after hexamethonium or reserpine. Conclusions: M-currents hampered parasympathetic ganglion excitation and, through that, vagal control of HR, in SHR but not WKY. M-currents also opposed catecholamine release in SHR but not in WKY. M-currents represented a vasodilatory component in resting TPR-control, with no strain-related difference detected. Excessive M-currents may represent the underlying cause of autonomic dysfunctions in hypertension.

• Berg, Torill (2016). α<sub>2</sub>-adrenoreceptor constraint of catecholamine release and blood pressure is enhanced in female spontaneously hypertensive rats. Frontiers in Neuroscience.  ISSN 1662-4548.  10 . doi: 10.3389/fnins.2016.00130 Show summary

  α2-adrenoceptors (α2AR) lower central sympathetic output and peripheral catecholamine release, and may therefore prevent sympathetic hyperactivity and hypertension. The α2AR are dysfunctional in male spontaneously hypertensive rats (SHR). Premenopausal females are less hypertensive than males. The purpose of this study was to test if this difference could be explained by functional α2AR in the female SHR. A 15-min tyramine-infusion was used to stimulate norepinephrine release through the re-uptake transporter, consequently preventing re-uptake. Presynaptic control of vesicular release will therefore be reflected as differences in overflow to plasma. The surgical trauma activates secretion of epinephrine, also subjected to α2AR auto-inhibition. Blood pressure was monitored through a femoral artery catheter and cardiac output by ascending aorta flow in 12-14 weeks-old (early hypertension) SHR and normotensive rats (WKY). Total peripheral vascular resistance (TPR) was calculated. Female SHR, unlike male, were close to normotensive. Pre-treatment with none-selective (clonidine) or non-A-selective (ST-91) α2AR agonist reduced, and none-selective α2AR antagonist (L-659,066) increased tyramine-induced norepinephrine overflow in female and WKY and SHR. L-659,066 also increased secretion of epinephrine. The L-659,066-induced increase in catecholamine release was further enhanced by additional pre-treatment with ST-91 or angiotensin AT1 receptor antagonist (losartan) in SHR only. L-659,066 eliminated the tyramine-induced rise in TPR in both strains in female rats. Conclusion: α2AR-mediated control of catecholamine release and vascular tension was therefore functional in female SHR, unlike that previously observed in male SHR. Functional α2AR is likely to have a protective function and may explain the lack of hypertension in the young female SHR.

• Berg, Torill (2015). Altered beta1-3-adrenoceptor influence on alpha2-adrenoceptor-mediated control of catecholamine release and vascular tension in hypertensive rats. Frontiers in Physiology.  ISSN 1664-042X.  6, s 1-12 . doi: 10.3389/fphys.2015.00120
• Berg, Torill (2015). Voltage-sensitive K+ channels inhibit parasympathetic ganglion transmission and vagal control of heart rate in hypertensive rats. Frontiers in Neurology.  ISSN 1664-2295.  6(260), s 1- 13 . doi: 10.3389/fneur.2015.00260 Full text in Research Archive.
• Berg, Torill (2014). beta1-blockers Lower Norepinephrine Release by Inhibiting Presynaptic, Facilitating beta1-Adrenoceptors in Normotensive and Hypertensive Rats. Frontiers in Neurology.  ISSN 1664-2295.  5(51) . doi: 10.3389/fneur.2014.00051 Show summary

  Peripheral norepinephrine release is facilitated by presynaptic β-adrenoceptors (AR), believed to involve the β2-subtype exclusively. However, β1-selective blockers are the most commonly used β-blockers in hypertension. Here I tested the hypothesis that β1AR may function as presynaptic, release-facilitating auto-receptors. Since β1AR-blockers are injected during myocardial infarction, their influence on the cardiovascular response to acute norepinephrine release was also studied. By a newly established method, using tyramine-stimulated release through the norepinephrine transporter (NET), presynaptic control of catecholamine release was studied in normotensive and spontaneously hypertensive rats. β1AR-selective antagonists (CGP20712A, atenolol, metoprolol) reduced norepinephrine overflow to plasma equally efficient as β2AR-selective (ICI-118551) and β1+2AR (nadolol) antagonists in both strains. Neither antagonist lowered epinephrine secretion. Atenolol, which does not cross the blood-brain barrier, reduced norepinephrine overflow after adrenalectomy, adrenalectomy+ganglion blockade, losartan or nephrectomy. Atenolol and metoprolol reduced resting cardiac work load. During tyramine-stimulated norepinephrine release, they had little effect on work load, and increased the transient rise in total peripheral vascular resistance, particularly atenolol when combined with losartan. In conclusion, β1AR, like β2AR, stimulated norepinephrine but not epinephrine release, independent of adrenal catecholamines, ganglion transmission, or renal renin release/angiotensin AT1-receptor activation. β1AR therefore functioned as a peripheral, presynaptic, facilitating auto-receptor. Like tyramine, hypoxia may induce NET-mediated release. Augmented tyramine-induced vasoconstriction, as observed after injection of β1AR-blocker, particularly atenolol combined with losartan, may hamper organ perfusion, and may have clinical relevance in hypoxic conditions such as myocardial infarction.

• Berg, Torill (2014). β3-adrenoceptors inhibit stimulated norepinephrine release in spontaneously hypertensive rats. Frontiers in Physiology.  ISSN 1664-042X.  5:499 . doi: 10.3389/fphys.2014.00499 Full text in Research Archive. Show summary

  Here, the influence of β3-adrenoceptors on catecholamine release in normotensive and spontaneously hypertensive rats was analyzed. Blood pressure was recorded through a femoral artery catheter, and cardiac output by ascending aorta flow. Time from onset of flow to maximum rise in flow indicated inotropy. Total peripheral vascular resistance (TPR) was calculated. Norepinephrine release was stimulated with tyramine, which allowed presynaptic release-control to be reflected as changes in the plasma norepinephrine concentration. β3-adrenoceptor agonist (BRL37344) reduced baseline vascular resistance, the tyramine-stimulated norepinephrine overflow and the positive inotropic response to tyramine in hypertensive but not normotensive rats. β3-adrenoceptor antagonist (SR59230A) reduced tyramine-stimulated norepinephrine release in both strains and the secretion of epinephrine in hypertensive rats. SR59230A reduced tyramine-induced tachycardia in normotensive rats, and prevented down-regulation of the tyramine-induced rise in resistance in hypertensive rats. It was concluded that the contradicting results obtained by agonist vs. antagonist, could be explained by their interaction with two different β-adrenoceptors: The BRL37344-dependent inhibition of stimulated norepinephrine release and positive inotropic response to tyramine was compatible with stimulation of β3-adrenoceptor coupling to inhibitory G-protein. This was observed only in hypertensive rats during stimulated, high levels of circulating catecholamines. The effect of BRL37344 on baseline vascular resistance was compatible with activation of β3-adrenoceptor coupling to endothelial nitric oxide synthase. The inhibitory effect of SR59230A on tyramine-stimulated norepinephrine release in both strains, the increased TPR-response to tyramine in hypertensive rats and tachycardia in normotensive rats may result from inhibition of the low-affinity-state β1-adrenoceptor, also known as the putative β4-adrenoceptor.

• Berg, Torill (2013). Angiotensin AT1 - alpha2Cadrenoceptor interaction disturbs alpha2A-autoinhibition of catecholamine release in hypertensive rats. Frontiers in Neurology.  ISSN 1664-2295.  4 . doi: 10.3389/fneur.2013.00070 Full text in Research Archive.
• Berg, Torill & Jensen, Jørgen (2013). Tyramine reveals failing alpha2-adrenoceptor control of catecholamine release and total peripheral vascular tension in hypertensive rats. Frontiers in Neurology.  ISSN 1664-2295.  4 . doi: 10.3389/fneur.2013.00019 Full text in Research Archive. Show summary

  α2-adrenoceptor-activation lowers central sympathetic output, peripheral, vesicular norepinephrine release, epinephrine secretion and modulates vascular tension. We previously demonstrated that α2-adrenoceptor-mediated inhibition of basal norepinephrine release was not reflected in plasma unless re-uptake through the norepinephrine transporter (NET) was blocked. Tyramine activates reverse norepinephrine transport through NET. Here we tested the hypothesis that tyramine, by engaging NET in release, also blocks re-uptake and therefore allows manipulation of pre-junctional α2-adrenoceptors to directly regulate norepinephrine overflow to plasma. We compared in anaesthetised spontaneously hypertensive rats (SHRs) and normotensive controls (WKYs), the effect of α2-adrenoreceptor antagonist (L-659,066) and/or agonist (clonidine) on norepinephrine overflow and increase in total peripheral vascular resistance (TPR) evoked by tyramine infusion (1.26 μmol/min/kg, 15 min) and epinephrine secretion activated by the surgical stress. TPR was computed as cardiac output, recorded as ascending aortic flow, divided by blood pressure. Plasma catecholamine concentrations after tyramine were higher in SHRs than WKYs. Pre-treatment with L-659,066 increased the catecholamine concentrations in WKYs, but only if combined with clonidine in SHRs. Clonidine alone reduced tyramine-induced norepinephrine overflow in SHRs, and epinephrine in both strains. Tyramine-induced increase in TPR was not different after clonidine, eliminated after L-659,066 and L-659,066+clonidine in WKYs, but only after L-659,066+clonidine in SHRs. We conclude that tyramine infusion does allow presynaptic regulation of vesicular release to be accurately assessed by measuring differences in plasma norepinephrine concentration. Our results indicate that pre-synaptic α2-adrenoceptor regulation of norepinephrine release from nerve vesicles and epinephrine secretion is dysfunctional in SHRs, but can be restored by clonidine.

• Berg, Torill; Walaas, S. Ivar; Roberg, Bjørg Åse; Ngoc-Trang, Thi Huynh & Jensen, Jørgen (2012). Plasma norepinephrine in hypertensive rats reflects alpha2-adrenoceptor release control only when re-uptake is inhibited. Frontiers in Neurology.  ISSN 1664-2295.  3 . doi: 10.3389/fneur.2012.00160 Full text in Research Archive. Show summary

  α2-adrenoceptors (AR) lower central sympathetic output and peripheral catecholamine release, thereby protecting against sympathetic hyperactivity and hypertension. Norepinephrine re-uptake–transporter effectively (NET) removes norepinephrine from the synapse. Overflow to plasma will therefore not reflect release. Here we tested if inhibition of re-uptake allowed presynaptic α2AR release control to be reflected as differences in norepinephrine overflow in anesthetized hypertensive spontaneously hypertensive rats (SHR) and normotensive rats (WKY). We also tested if α2AR modulated the experiment-induced epinephrine secretion, and a phenylephrine-induced, α1-adrenergic vasoconstriction. Blood pressure was recorded through a femoral artery catheter, and cardiac output by ascending aorta flow. After pre-treatment with NET inhibitor (desipramine), and/or α2AR antagonist (yohimbine, L-659,066) or agonist (clonidine, ST-91), we injected phenylephrine. Arterial blood was sampled 15 min later. Plasma catecholamine concentrations were not influenced by phenylephrine, and therefore reflected effects of pre-treatment. Desipramine and α2AR antagonist separately had little effect on norepinephrine overflow. Combined, they increased norepinephrine overflow, particularly in SHR. Clonidine, but not ST-91, reduced, and pertussis toxin increased norepinephrine overflow in SHR and epinephrine secretion in both strains. L-659,066 + clonidine (central α2AR-stimulation) normalized the high blood pressure, heart rate, and vascular tension in SHR. α2AR antagonists reduced phenylephrine-induced vasoconstriction equally in WKY and SHR. Conclusions: α2AAR inhibition increased norepinephrine overflow only when re-uptake was blocked, and then with particular efficacy in SHR, possibly due to their high sympathetic tone. α2AAR inhibited epinephrine secretion, particularly in SHR. α2AAR supported α1AR-induced vasoconstriction equally in the two strains. α2AR malfunctions were therefore not detected in SHR under this basal condition.

• Berg, Torill & Jensen, Jørgen (2011). Simultaneous parasympathetic and sympathetic activation reveals altered autonomic control of heart rate, vascular tension, and epinephrine release in anesthetized hypertensive rats. Frontiers in Neurology.  ISSN 1664-2295.  2 . doi: 10.3389/fneur.2011.00071 Full text in Research Archive. Show summary

  Sympathetic hyperactivity and parasympathetic insufficiency characterize blood pressure (BP) control in genetic hypertension. This shift is difficult to investigate in anesthetized rats. Here we present a pharmacological approach to simultaneously provoke sympathetic and parasympathetic transmitter release, and identify their respective roles in the concomitant cardiovascular response. To stimulate transmitter release in anesthetized normotensive (WKY) and spontaneously hypertensive rats (SHR), we injected intravenously 4-aminopyridine (4-AP), a voltage-sensitive K+ channel (KV) inhibitor. A femoral artery catheter monitored BP, an ascending aorta flow-probe recorded cardiac output and heart rate (HR). Total peripheral vascular resistance (TPVR) was calculated. 4-AP-induced an immediate, atropine (muscarinic antagonist)- and hexamethonium (ganglion blocker)-sensitive bradycardia in WKY, and in both strains, a subsequent, sustained tachycardia, and norepinephrine but not epinephrine release. Reserpine (sympatholytic), nadolol (β-adrenoceptor antagonist) or right vagal nerve stimulation eliminated the late tachycardia, adrenalectomy, scopolamine (central muscarinic antagonist) or hexamethonium did not. 4-AP increased TPVR, transiently in WKY but sustained in SHR. Yohimbine (α2-adrenoceptor antagonist) prevented the TPVR down-regulation in WKY. Reserpine and prazosin (α1-adrenoceptor antagonist) eliminated the late vasoconstriction in SHR. Plasma epinephrine overflow increased in nadolol-treated SHR. Through inhibition of KV, 4-AP activated parasympathetic ganglion transmission and peripheral, neuronal norepinephrine release. The sympathetic component dominated the 4-AP–HR-response in SHR. α2-adrenoceptor-dependent vasodilatation opposed norepinephrine-induced α1-adrenergic vasoconstriction in WKY, but not SHR. A βAR-activated, probably vagal afferent mechanism, hampered epinephrine secretion in SHR. Thus, 4-AP activated the autonomic system and exposed mechanisms relevant to hypertensive disease.

• Berg, Torill; Piercey, Bruce William & Jensen, Jørgen (2010). Role of beta(1-3)-Adrenoceptors in Blood Pressure Control at Rest and During Tyramine-Induced Norepinephrine Release in Spontaneously Hypertensive Rats. Hypertension.  ISSN 0194-911X.  55(5), s 1224- U240 . doi: 10.1161/HYPERTENSIONAHA.109.149286 Show summary

  β-Adrenoceptors contribute to hypertension in spite of the fact that β-adrenoceptor agonists lower blood pressure. We aimed to differentiate between these functions and to identify differences between spontaneously hypertensive and normotensive rats. β-Adrenoceptor antagonists with different subtype selectivity or the ability to cross the blood-brain barrier were used to demonstrate β-adrenoceptor involvement in resting blood pressure and the response to tyramine-induced peripheral norepinephrine release. The centrally acting propranolol (β1+2[+3]), CGP20712A (β1), ICI-118551 (β2), and SR59230A (β3), as well as peripherally restricted nadolol (β1+2) and atenolol (β1), were administered intravenously, separately, or in combinations. Blood pressure, cardiac output, heart rate, total peripheral vascular resistance, and plasma catecholamine concentrations were evaluated. β-Adrenoceptor antagonists had little effect on cardiovascular baselines in normotensive rats. In hypertensive rats, antagonist-induced hypotension paralleled reductions in resistance, except for atenolol, which reduced cardiac output. The resistance reduction involved primarily neuronal catecholamine, central β1-adrenoceptors, and peripheral β2-adrenoceptors. Tyramine induced a transient, prazosin-sensitive vascular resistance increase. Inhibition of nerve-activated, peripheral β1/3-adrenoceptors enhanced this α1-adrenoceptor–dependent vasoconstriction in normotensive but not hypertensive rats. In hypertensive rats, return to baseline was eliminated after inhibition of the central β1-adrenoceptor, epinephrine release (acute adrenalectomy), and peripheral β2/3-adrenoceptors. Adrenalectomy eliminated β-adrenoceptor–mediated vasodilation in hypertensive rats, and tyramine induced a prazosin-sensitive vasoconstriction, which was inhibited by combined blockade of central β1- and peripheral β2-adrenoceptors. In conclusion, nerve-activated β1- and β3-adrenoceptor–mediated vasodilation was not present in hypertensive rats, whereas epinephrine-activated β2- and β3-adrenoceptor–mediated vasodilation was upregulated. There was also a hypertensive, nerve-activated vasoconstrictory mechanism present in hypertensive rats, involving central β1- and peripheral β2-adrenoceptors combined.

• Berg, Torill; Degerman, Eva & Tasken, Kjetil (2009). Increased cAMP Signaling Can Ameliorate the Hypertensive Condition in Spontaneously Hypertensive Rats. Journal of Vascular Research.  ISSN 1018-1172.  46(1), s 25- 35 . doi: 10.1159/000135662 Show summary

  Background/Aim: Augmented adrenergic control of total peripheral vascular resistance (TPVR) in spontaneously hypertensive rats (SHR) may result from deficiencies in vasodilatory system(s). Here, we studied the effect of cyclic AMP (cAMP) on TPVR-baseline and adrenergic vasoconstriction in SHR and normotensive controls (WKY). Methods: Blood pressure and cardiac output were monitored in anaesthetized rats, and TPVR calculated. Results: cAMP-analogue (8CPT-cAMP) and phosphodiesterase (PDE) 3 inhibitor (milrinone) reduced TPVR in both strains. Gi inactivator (pertussis toxin) lowered TPVR but not in all SHR. ∆TPVR induced by α1-adrenoceptor agonist (phenylephrine) was reduced by 8CPT-cAMP and milrinone in both strains. They also clearly reduced the response to endogenous noradrenaline release (tyramine) in SHR but had little effect in WKY. When pertussis toxin reduced baseline, it also eliminated the tyramine TPVR-response. Propranolol did not change the effect of milrinone on the phenylephrine- or tyramine-response. Strain-related differences in aorta, femoral arteries or skeletal muscle PDE-activity (total/PDE3/PDE4) were absent. Conclusions: cAMP-signalling down-stream of cAMP was functional in SHR, and opposed α1-adrenoceptor vasoconstriction in both strains. Gi-activity greatly influenced TPVR baseline and adrenergic TPVR-response, and its activity appeared increased in SHR. Therapeutics aiming to increase signalling through this pathway, may turn out valuable in the treatment of hypertension.

• Berg, Torill (2005). Increased counteracting effect of eNOS and nNOS on an alpha(1)-adrenergic rise in total peripheral vascular resistance in spontaneous hypertensive rats. Cardiovascular Research (CVR).  ISSN 0008-6363.  67, s 736- 744
• Berg, Torill (2003). The vascular response to the K+ channel inhibitor 4-aminopyridine in hypertensive rats. European Journal of Pharmacology.  ISSN 0014-2999.  466, s 301- 310
• Berg, Torill (2002). Analysis of the pressor response to the K+ channel inhibitor 4-aminopyridine. European Journal of Pharmacology.  ISSN 0014-2999.  452(3), s 325- 337 Show summary

  The cardiovascular response to the K(+) channel inhibitor 4-aminopyridine in anaesthetized rats was analysed. 4-Aminopyridine produced a biphasic pressor response. First, it increased blood pressure, total peripheral vascular resistance, cardiac output and stroke volume. Nitric oxide synthase (NOS) inhibitor augmented the tension response; reserpine, phentolamine, propranolol, scopolamine, atropine, adrenalectomy, indomethacin, angiotensin AT(1) and endothelin ET(A) receptor antagonists had no effect. Subsequently, heart rate increased, but total peripheral vascular resistance was no longer elevated. Reserpine and propranolol abolished the tachycardia. An elevated late tension occurred after propranolol and NOS inhibitor but not reserpine or phentolamine+NOS inhibitor. The peripherally acting 3,4-diaminopyridine produced similar responses. 4-Aminopyridine contracted isolated aortic rings also after denudation. These results are compatible with that the immediate tension response resulted from closure of vascular smooth muscle K(+) channels, and that closure of presynaptic K(+) channels in peripheral sympathetic nerves subsequently activated noradrenaline release, beta-adrenoceptors and tachycardia, while nitric oxide counter-acted a concomitant alpha-adrenergic vasoconstriction.

• Berg, Torill & Koteng, Ø. (1997). Signalling pathways in bradykinin- and nitric oxide-induced hypotension in the normotensive rat; role of K+-channels. British Journal of Pharmacology.  ISSN 0007-1188.  121, s 1113- 1120
• Bjørnstad-Østensen, Anniken; Holte, Hege Ruge & Berg, Torill (1997). Amplification of Kinin-Induced Hypotension by Nitric Oxide Synthesis in Spontaneously Hypertensive Rats. Hypertension.  ISSN 0194-911X.  29(1), s 53- 57
• Holte, H.; Bjørnstad-Østensen, A. & Berg, Torill (1996). The role of endogenous bradykinin in blood pressure homeostasis in spontaneously hypertensive rats. British Journal of Pharmacology.  ISSN 0007-1188.  118, s 1925- 1930
• Holte, Hege Ruge & Berg, Torill (1996). The role of nephrectomy and proadifen in blood pressure homeostasis following an acute kinin-induced hypotension in normotensive rats. British Journal of Pharmacology.  ISSN 0007-1188.  117, s 1516- 1520
• Berg, Torill & Schøyen, H. (1995). Immunohistochemical localization of rK9, an enzyme of the kallikrein gene family, in the rat ventral prostate. Journal of Histochemistry and Cytochemistry.  ISSN 0022-1554.  43, s 61- 65
• Wassdal, I.; Hull, R.; Gerskowitch, V.P. & Berg, Torill (1995). Kallikrein rK10 induced kinin-independent, direct activation of NO-formation and relaxation of rat isolated aortic rings. British Journal of Pharmacology.  ISSN 0007-1188.  115, s 356- 360
• Bjørnstad-Østensen, A. & Berg, Torill (1994). The role of nitric oxide, adrenergic activation and kinin-degradation in blood pressure homeostasis following an acute kinin-induced hypotension. British Journal of Pharmacology.  ISSN 0007-1188.  113, s 1567- 1573
• Jensen, Janicke Liaaen; Xu, T.; Lamkin, MS; Brodin, Pål; Aars, Harald; Berg, Torill & Oppenheim, FG (1994). Physiological regulation of the secretion of histatins and statherins in human parotid saliva. Journal of Dental Research.  ISSN 0022-0345.  73(12), s 1811- 1817
• Jørgensen, P.E.; Nexø, E.; Poulsen, S.S.; Almendingen, M. & Berg, Torill (1994). Processing of rat epidermal growth factor by five members of the rat kallikrein family. Growth Factors.  ISSN 0897-7194.  11, s 113- 123
• Schøyen, Hege; Wassdal, Irene; Toft, Kim; Almendingen, M. & Berg, Torill (1994). Purification of enzymes of the kallikrein gene family (rK8 and rK9) from the rat prostate. Biochemical Journal.  ISSN 0264-6021.  302, s 229- 235
• Berg, Torill; Bradshaw, R.A.; Carretero, O.A.; Chao, J.; Chao, L; Clements, J.A.; Fahnestock, M; Fritz, H.; Gauthier, F.; MacDonald, R.J.; Margolius, H.S.; Morris, B.J.; Richards, R.I. & Scicli, A.G. (1992). A common nomenclature for members of the tissue (glandular) kallikrein gene families. AGENTS AND ACTIONS SUPPLEMENTS.  ISSN 0379-0363.  38/1, s 19- 25
• Berg, Torill; Schøyen, Hege; Wassdal, Irene; Hull, Robert; Gerskowitch, V. Paul & Toft, Kim (1992). Characterization of a new kallikrein-like enzyme (KLP-S3) of the rat submandibular gland. Biochemical Journal.  ISSN 0264-6021.  281, s 819- 828
• Berg, Torill; Schøyen, Helle; Wassdal, I. & Bjørnstad-Østensen, A. (1992). Identification of proteins of the kallikrein family by isoelectrofocusing and immunoblotting. AGENTS AND ACTIONS SUPPLEMENTS.  ISSN 0379-0363.  38/1, s 51- 58
• Berg, Torill; Wassdal, I. & Sletten, K. (1992). Immunohistochemical localization of rat submandibular gland esterase B (homologous to the RSKG-7 kallikrein gene) in relation to other serine proteases of the kallikrein family. Journal of Histochemistry and Cytochemistry.  ISSN 0022-1554.  40, s 83- 92
• Berg, Torill; Wassdal, I.; Mindroiu, T.; Sletten, K.; Scicli, G.; Carretero, O.A. & Scicli, A.G. (1991). T-kininogenase activity of the rat submandibular gland is predominantly due to the kallikrein-like serine protease antigen gamma. Biochemical Journal.  ISSN 0264-6021.  280, s 19- 25
• Jensen, Janicke Liaaen; Brodin, Pål; Berg, Torill & Aars, Harald (1991). Parotid secretion of fluid, amylase and kallikrein during reflex stimulation under normal conditions and after acute administration of autonomic blocking agents in man. Acta Physiologica Scandinavica.  ISSN 0001-6772.  143(3), s 321-329
• Berg, Torill; Johansen, L. & Poulsen, K. (1990). Exocrine and endocrine release of kallikrein after reflex-induced submandibular gland secretion. Acta Physiologica Scandinavica.  ISSN 0001-6772.  139, s 29- 37
• Berg, Torill; Carretero, O.A.; Scicli, A.G.; Tilley, B. & Stewart, J.M. (1989). The role of kinin in the regulation of rat submandibular gland blood flow. Hypertension.  ISSN 0194-911X.  14, s 73- 80
• Berg, Torill; Schlichting, E.; Ishida, H. & Carretero, O.A. (1989). Kinin antagonist does not protect against the hypotensive response to endotoxin, anaphylaxis, or acute pancreatitis. Journal of Pharmacology and Experimental Therapeutics.  ISSN 0022-3565.  251, s 731- 734
• Berg, Torill (1988). Immunohistochemical viewing of kallikrein in tissues. Methods in Enzymology.  ISSN 0076-6879.  163, s 143- 159
• Berg, Torill; Ørstavik, D. & Zachrison, Y.O. (1988). Secretory regulation and calcium dependency of bacterial agglutinins in rat salivary glands. Acta Odontologica Scandinavica.  ISSN 0001-6357.  46, s 141- 149
• Johansen, L.; Berg, Torill; Bergundhaugen, H.; Nustad, K.; Scicli, A.G. & Carretero, O.A. (1987). Excess antibody immunoassay for the measurement of tonin in rat tissues and plasma. JIM - Journal of Immunological Methods.  ISSN 0022-1759.  98, s 257- 265
• Johansen, L.; Bergundhaugen, H. & Berg, Torill (1987). Rapid purification of tonin, esterase B, antigen gamma, and kallikrein from rat submandibular gland by fast protein liquid chromatography. Journal of Chromatography A.  ISSN 0021-9673.  387, s 347- 359
• Keilen, J.C.J.; Brodin, P.; Aars, H. & Berg, Torill (1987). Parotid salivary flow in response to mechanical and gustatory stimulation in man. Acta Physiologica Scandinavica.  ISSN 0001-6772.  131, s 169- 175
• Messelt, E.B. & Berg, Torill (1987). Effect of autonomic nerve stimulation on bleb formation in rat submandibular gland striated duct. Acta Odontologica Scandinavica.  ISSN 0001-6357.  45, s 275- 281
• Soffer, R.L.; Berg, Torill & Sulner, J. (1987). Pulmonary and testicular angiotensin converting isoenzymes. Clinical and experimental hypertension (1993, Print).  ISSN 1064-1963.  A9, s 229- 234
• Ørstavik, Torill Berg; Holck, M. & Johansen, L. (1987). Isolation, characterization, and localization of antigen gamma, a serine protease of the "kallikrein-family" in the rat submandibular gland. Biological chemistry.  ISSN 1431-6730.  368, s 1455- 1467
• Berg, Torill; Sulner, J.; Lay, C.Y. & Soffer, R.L. (1986). Immunohistochemical localization of two angiotensin I converting isoenzymes in the reproductive tract of the male rabbit. Journal of Histochemistry and Cytochemistry.  ISSN 0022-1554.  34, s 753- 760
• Berg, Torill; Johansen, L.; Bergundhaugen, H.; Hansen, L.J.; Reddy, J.K. & Poulsen, K. (1985). Demonstration of kallikrein in rat pancreatic acinar cell carcinoma. Cancer Research.  ISSN 0008-5472.  45, s 226- 234
• Berg, Torill; Johansen, L. & Brekke, I.B. (1985). Insulin potentiates cholecystokinin (CCK)-induced secretion of pancreatic kallikrein. Acta Physiologica Scandinavica.  ISSN 0001-6772.  123, s 89- 95
• Berg, Torill; Johansen, L. & Nustad, K. (1985). Enzymatic activity of rat submandibular gland kallikrein released into blood. American Journal of Physiology. Heart and Circulatory Physiology.  ISSN 0363-6135.  249, s H1134- H1143
• Johansen, L.; Nustad, K.; Berg, Torill & Pierce, J.V. (1984). Excess antibody immunoassay for rat glandular kallikrein. Measurement of kallikrein in complex with inhibitors and plasma. JIM - Journal of Immunological Methods.  ISSN 0022-1759.  69, s 253- 266
• Arnold, W.; Ørstavik, Torill Berg & Holck, M. (1983). A 4-methoxy-2naphtyl-amide substrate of esterproteases in the submandibular gland of the rat. The Histochemical Journal.  ISSN 0018-2214.  15, s 139- 146
• Arnold, W.H.; Ørstavik, Torill Berg & Johansen, L. (1983). A biochemical and morphological study of kallikrein in the rat submandibular gland and plasma after duct ligation, In G.L. Haberland; J.W. Rohen; H. Fritz & P. Huber (ed.),  Kininogenases Kallikrein VI.  Schattauer Verlag.  ISBN 3-7945-0551-4.  Kapittel.  s 105 - 114
• Carretero, O.A.; Ørstavik, Torill Berg; Rabito, S.F. & Scicli, A.G. (1983). Interference of converting enzyme inhibitors with the kallikrein-kinin system. Clinical and experimental hypertension (1993, Print).  ISSN 1064-1963.  A5, s 1277- 1285
• Johansen, L.; Nustad, Kjell; Ørstavik, Torill Berg; Ugelstad, J.; Berge, A. & Ellingsen, T. (1983). Excess antibody immunoassay for rat glandular kallikrein. Monosized polymer particles as the preferred solid phase material. JIM - Journal of Immunological Methods.  ISSN 0022-1759.  59, s 255- 264
• Johansen, Liv; Ørstavik, Torill Berg; Nustad, Kjell & Holck, M. (1983). Excess antibody immunoassays for rat glandular kallikreins. Measurement of kallikrein from different organs in the presence of crossreacting antigens. JIM - Journal of Immunological Methods.  ISSN 0022-1759.  59, s 315- 326
• Rabito, S.F.; Ørstavik, Torill Berg; Scicli, A.G.; Schork, A. & Carretero, O.A. (1983). Role of the autonomic nervous system in the release of rat submandibular gland kallikrein into the circulation. IEEE Transactions on Circuits and Systems - II - Express Briefs.  ISSN 1549-7747.  52, s 635- 641
• Scicli, A.G.; Ørstavik, Torill Berg; Rabito, S.F. & Carretero, O.A. (1983). Possible role of the submandibular gland in the regulation of circulating kinins. Hypertension.  ISSN 0194-911X.  5, s l101- l106
• Ørstavik, Torill Berg (1983). Cellular origin of pancreatic kallikrein. - A review. Advances in Experimental Medicine and Biology.  ISSN 0065-2598.  156A, s 347- 356
• Ørstavik, Torill Berg; Carretero, O.A. & Johansen, Liv (1983). A role of glandular kallikreins in blood pressure regulation. Journal of Internal Medicine.  ISSN 0954-6820.  s 52
• Ørstavik, Torill Berg & Johansen, L. (1983). The glandular kallikrein-kinin system in local blood flow regulation and blood pressure homeostasis, In G.L. Haberland; J.W. Rohen; H. Fritz & P. Huber (ed.),  Kininogenases Kallikrein VI.  Schattauer Verlag.  ISBN 3-7945-0551-4.  Kapittel.  s 75 - 83
• Bendayan, M. & Ørstavik, Torill Berg (1982). Immunohistochemical localization of kallikrein in the rat exocrine pancreas. Journal of Histochemistry and Cytochemistry.  ISSN 0022-1554.  30, s 58- 66
• Lund, T.; Vuust, J.; Bravo, R.; Boel, E.; Ørstavik, Torill Berg & Poulsen, K. (1982). In vitro studies on the conversion of the biosynthetic precursor of renin. Clinical and experimental hypertension (1993, Print).  ISSN 1064-1963.  A4, s 1965- 1972
• Ørstavik, Torill Berg (1982). A role of glandular kallikreins in local blood flow and blood pressure regulation. Acta Chirurgica Scandinavica.  ISSN 0001-5482.  s 137
• Ørstavik, Torill Berg; Carretero, O.A.; Hayashi, H.; Scicli, A.G. & Johansen, L. (1982). Immunohistochemical localization of tonin and its relation to kallikrein in rat salivary glands. Journal of Histochemistry and Cytochemistry.  ISSN 0022-1554.  30, s 1123- 1129
• Ørstavik, Torill Berg; Carretero, O.A.; Johansen, L. & Scicli, A.G. (1982). Role of kallikrein in the hypotensive effect of captopril after sympathetic stimulation of the rat submandibular gland. Circulation Research.  ISSN 0009-7330.  51, s 385- 390
• Ørstavik, Torill Berg; Carretero, O.A. & Scicli, A.G. (1982). Kallikrein-kinin system in regulation of submandibular gland blood flow. American Journal of Physiology. Heart and Circulatory Physiology.  ISSN 0363-6135.  242, s H1010- H1014
• Ørstavik, Torill Berg & Inagami, T. (1982). The localization of kallikrein in the rat kidney and its anatomical relationship to renin. Journal of Histochemistry and Cytochemistry.  ISSN 0022-1554.  30, s 385- 390
• Ørstavik, Torill Berg; Brandtzæg, P.; Nustad, Kjell & Pierce, J.V. (1981). Effects of tissue processing methods on the immunohistochemical localization of kallikrein in the pancreas. Journal of Histochemistry and Cytochemistry.  ISSN 0022-1554.  29, s 985- 988
• Ørstavik, Torill Berg; Brekke, I.B.; Alumets, J. & Carretero, O.A. (1981). Kallikrein in rat pancreas tissue after beta cell destruction or acinar cell atrophy. Journal of Histochemistry and Cytochemistry.  ISSN 0022-1554.  29, s 1431- 1436
• Ørstavik, Torill Berg; Brandtzæg, P.; Nustad, Kjell & Pierce, J.V. (1980). Immunohistochemical localization of kallikrein in human pancreas and salivary glands. Journal of Histochemistry and Cytochemistry.  ISSN 0022-1554.  28, s 557- 562
• Ørstavik, Torill Berg; Nustad, K. & Brandtzæg, P. (1980). Localization of glandular kallikreins in rat and man, In F. Gross & H.G. Vogel (ed.),  Enzymatic release of vasoactive peptides.  Raven Press.  ISBN 0-89004-458-9.  Kapittel.  s 137 - 149
• Gautvik, Kaare M; Svindahl, K.; Nustad, Kjell & Ørstavik, Torill Berg (1980). Isolation of rat glandular kallikreins using immunosorption chromatography. Biochemical Journal.  ISSN 0264-6021.  189, s 153- 159
• Gautvik, Kaare M; Ørstavik, Torill Berg & Svindahl, K. (1980). Release of glandular kallikreins, In F. Gross & H.G. Vogel (ed.),  Enzymatic release of vasoactive peptides.  Raven Press.  ISBN 0-89004-458-9.  Kapittel.  s 287 - 300
• Nustad, K.; Johansen, L.; Ørstavik, Torill Berg & Pierce, J.V. (1980). Submandibular gland kallikreins: biochemistry, origin and function, In F. Gross & H.G. Vogel (ed.),  Enzymatic release of vasoactive peptides.  Raven Press.  ISBN 0-89004-458-9.  Kapittel.  s 89 - 100
• Ørstavik, Torill Berg (1980). The kallikrein-kinin system in exocrine glands. Journal of Histochemistry and Cytochemistry.  ISSN 0022-1554.  28, s 881- 889
• Ørstavik, Torill Berg; Gautvik, Kaare M & Nustad, Kjell (1980). Intraglandular transport of 125I-kallikrein in the rat submandibular gland. Acta Physiologica Scandinavica.  ISSN 0001-6772.  109, s 315- 323
• Ørstavik, Torill Berg; Nustad, Kjell & Brandtzæg, P. (1979). Origin of kallikrein in the rat and human exocrine glands and kidney. Clinical Science.  ISSN 0143-5221.  57, s 239- 241
• Nustad, Kjell; Gautvik, Kaare M & Ørstavik, Torill Berg (1979). Radioimmunoassay of rat submandibular gland kallikrein and the detection of immunoreactive antigen in blood. Advances in Experimental Medicine and Biology.  ISSN 0065-2598.  120A, s 225- 234
• Ørstavik, Torill Berg; Nustad, Kjell & Gautvik, Kaare M (1979). Localization of glandular kallikreins and secretion of kallikrein from salivary glands. Advances in Experimental Medicine and Biology.  ISSN 0065-2598.  120A, s 439- 450
• Nustad, K; Ørstavik, Torill Berg & Gautvik, Kaare M (1978). Radioimmunological measurement of rat submandibular gland kallikrein (RSK) in tissue and serum. Microvascular Research.  ISSN 0026-2862.  15, s 115
• Nustad, Kjell; Ørstavik, Torill Berg; Gautvik, Kaare M & Pierce, J.V. (1978). Glandular kallikreins. General Pharmacology.  ISSN 0306-3623.  9, s 1- 9
• Ørstavik, Torill Berg (1978). An immunohistochemical study of kallikrein in the rat parotid and exorbital lacrimal glands. Archives of Oral Biology.  ISSN 0003-9969.  23, s 1023- 1025
• Ørstavik, Torill Berg (1978). Localization of kallikrein and its relation to other trypsin-like esterases in the rat pancreas. A study in comparison with the submandibular gland. Acta Physiologica Scandinavica.  ISSN 0001-6772.  103, s 384- 393
• Ørstavik, Torill Berg (1978). The distribution and secretion of kallikrein in some exocrine organs of the rat. Acta Physiologica Scandinavica.  ISSN 0001-6772.  104, s 431- 442

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• Berg, Torill & Jensen, Jørgen (2010). Nicotinic Receptors Suppress Beta-Adrenoceptor Contribution and Vagal Interaction in Tachycardia Following 4-Aminopyidine-Induced Noradrenaline Release in Hypertensive Rats (Shr). Journal of Hypertension.  ISSN 0263-6352.  28, s E529- E529
• Jensen, J.L.; Xu, T.; Lamkin, MS; Brodin, P; Aars, H; Berg, Torill & Oppenheim, F.G. (1994). Secretory patterns of human parotid statherins and histatins. Journal of Dental Research.  ISSN 0022-0345.  73 Spec Issue, s 192
• Jensen, J.L.; Brodin, P. & Berg, Torill (1991). Influence of autonomic blocking agents on human salivary secretion. Journal of Dental Research.  ISSN 0022-0345.  70, s 406
• Berg, Torill; Carretero, O.A. & Stewart, J. (1987). The effect of bradykinin antagonist in rat submandibular gland blood flow regulation. Journal of Physiology.  ISSN 0022-3751.  110P
• Jensen Keilen, J.C.; Brodin, P.; Aars, H. & Berg, Torill (1987). Human parotid salivation in response to differential mechanical and gustatory stimulation. Acta Physiologica Scandinavica.  ISSN 0001-6772.  129, s 51A
• Jensen Keilen, J.C.; Brodin, P.; Aars, H. & Berg, Torill (1987). Mean and instantaneous changes in human parotid flow rate following chewing and citric acid stimulation. Caries Research.  ISSN 0008-6568.  22, s 116
• Jensen Keilen, J.C.; Brodin, P.; Aars, H. & Berg, Torill (1987). Reflex stimulated human parotid saliva; water, amylase, and kallikrein secretion. Journal of Dental Research.  ISSN 0022-0345.  66, s 221
• Ørstavik, Torill Berg (1985). Spyttkjertlenes og salivas fysiologi, I: J.J. Holst & S.B. Jensen (red.),  Nordisk klinisk odontologi: Oral fysiologi.  A/S Forlaget for faglitteratur.  ISBN 87-573-01107.  Kapittel 5-I.  s 1 - 29
• Messelt, Edvard Berger & Ørstavik, Torill Berg (1983). Ultrastructural localization of intracellular kallikrein in rat submandibular gland striated duct. Journal of Dental Research.  ISSN 0022-0345.  62, s 493
• Zachrison, Y.O.; Ørstavik, Torill Berg & Ørstavik, Dag (1983). Bacterial agglutinins in rat salivary secretion. Journal of Dental Research.  ISSN 0022-0345.  62, s 494
• Ørstavik, Torill Berg; Johansen, L. & Nustad, K (1983). Release of submandibular kallikrein into blood. Journal of Dental Research.  ISSN 0022-0345.  62, s 93
• Rabito, SF; Scicli, AG; Ørstavik, Torill Berg & Carretero, OA (1982). Role of sympathetic nervous system in the release of rat submandibular gland kallikrein and kinins into the circulation. Fed Proc.  (41:472)
• Ørstavik, Torill Berg; Carretero, O.A.; Johansen, L. & Scicli, A.G. (1982). Role of kallikrein in the hypotensive effect of captopril after sympathetic stimulation of the rat submandibular gland. The Physiologist.  ISSN 0031-9376.  25, s 4
• Bendayan, M. & Ørstavik, Torill Berg (1981). Ultrastructural localization of kallikrein in rat pancreatic acinar cells. Proc Can Fed Biol Soc.
• Ørstavik, Torill Berg (1979). The kallikrein-kinin system; biochemistry and physiology. Scandinavian Journal of Clinical and Laboratory Investigation.  ISSN 0036-5513.  39, s 17
• Ørstavik, Torill Berg (1978). Glandular kallikreins. Origin and secretion in some exocrine organs of the rat.

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