| 1. |
- Streng, T., et al.
(författare)
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Distribution and Function of the Hydrogen Sulfide-Sensitive TRPA1 Ion Channel in Rat Urinary Bladder
- 2008
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 53:2, s. 391-400
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To investigate the distribution of the transient receptor potential (TRP) A1 ion channel in the rat urinary bladder, and to study the effects of hydrogen sulfide (H2S) and known TRPA1 activators on micturition in conscious rats and on heterologously expressed ion channels. Methods: The expression of TRPA1 in urinary bladder was studied with fluorescence immunohistochemistry and real-time PCR in female Sprague-Dawley rats. Cystometric investigations were performed in conscious animals subjected to intravesical administration of sodium hydrogen sulfide (NaHS, donor of H2S), allyl isothiocyanate (AI), and cinnamaldehyde (CA). Fluorometric calcium imaging was used to study the effect of NaHS on human and mouse TRPA1 expressed in CHO cells. Results: TRPA1 immunoreactivity was found on unmyelinated nerve fibres within the urothelium, suburothelial space, and muscle layer as well as around blood vessels throughout the bladder. All TRPA1 immunoreactive nerves fibres also expressed TRPV1 immunoreactivity and vice versa. TRPA1 was also detected in urothelial cells at both transcriptional and protein levels. AI increased micturition frequency and reduced voiding volume. CA and NaHS produced similar changes in urodynamic parameters after disruption of the urothelial barrier with protamine sulfate. NaHS also induced calcium responses in TRPA1-expressing CHO cells, but not in untransfected cells. Conclusions: The expression of TRPA1 on C-fibre bladder afferents and urothelial cells together with the finding that intravesical TRPA1 activators initiate detrusor overactivity indicate that TRPA1 may have a role in sensory transduction in this organ. The study also highlights H2S as a TRPA1 activator potentially involved in inflammatory bladder disease. © 2007.
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| 2. |
- Zygmunt, P.M., et al.
(författare)
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Effects of ω‐conotoxin on adrenergic, cholinergic and NANC neurotransmission in the rabbit urethra and detrusor
- 1993
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188. ; 110:4, s. 1285-1290
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Tidskriftsartikel (refereegranskat)abstract
- The effects of ω‐conotoxin GVIA (an inhibitor of N‐type voltage‐operated calcium channels; VOCCs) were compared on adrenergic, cholinergic and non‐adrenergic, non‐cholinergic (NANC) responses induced by electrical field stimulation (EFS) in the rabbit urethra and detrusor. EFS induced a relaxation in urethral smooth muscle and lamina propria precontracted by arginine vasopressin (AVP). The relaxation was abolished by tetrodotoxin (TTX) or the nitric oxide (NO) synthase inhibitor Nω‐nitro‐l‐arginine. ω‐Conotoxin inhibited the relaxation induced by EFS, but not that elicited by the NO donor 3‐morpholino‐sydnonimin. The inhibition, however, decreased with increasing frequencies of stimulation. Nimodipine, tetramethrin and nickel did not affect the ω‐conotoxin‐resistant relaxation in lamina propria, suggesting that neuronal L or T VOCCs were not involved in the response. EFS contracted urethral smooth muscle at resting tension. The contractions were virtually abolished by TTX or prazosin. ω‐Conotoxin effectively inhibited the contractile responses to EFS, but not those to exogenous noradrenaline. An ω‐conotoxin‐resistant contraction was, however, observed at high frequencies of stimulation. The detrusor responded with frequency‐dependent contractions upon EFS. A TTX‐resistant contraction less than 10% of controls remained at 30 Hz stimulation. At a stimulation frequency of 10 Hz, scopolamine reduced the EFS‐induced contraction by 71%. ω‐Conotoxin inhibited the responses in both the absence and presence of scopolamine. The inhibition decreased with increasing frequencies of stimulation (examined in the absence of scopolamine). ω‐Conotoxin did not affect the contractile responses to carbachol or adenosine 5′‐triphosphate. The adrenergic contraction (25 Hz) and NANC relaxation (10 Hz) in the urethra, and cholinergic and NANC contractions (10 Hz) in the detrusor were inhibited concentration‐dependently by ω‐conotoxin. The adrenergic contraction in the urethra was 10 times and the cholinergic contraction in the detrusor was three times more sensitive to ω‐conotoxin than the NANC responses. These results suggest that NANC neurotransmission is less inhibited by ω‐conotoxin than transmission mediated by adrenergic and cholinergic nerves in the rabbit lower urinary tract. In the urethra a marked ω‐conotoxin‐resistant component of the NANC relaxation was observed which increased with increasing stimulation frequencies and was unaffected by inhibitors of L and T type VOCCs. This raises the question whether VOCCs of a type other than L, T, and N is involved in the mediation of this response. 1993 British Pharmacological Society
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| 3. |
- Bautista, D M, et al.
(författare)
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Pungent products from garlic activate the sensory ion channel TRPA1
- 2005
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 102:34, s. 12248-12252
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Tidskriftsartikel (refereegranskat)abstract
- Garlic belongs to the Allium family of plants that produce organosulfur compounds, such as allicin and diallyl disulfide (DADS), which account for their pungency and spicy aroma. Many health benefits have been ascribed to Allium extracts, including hypotensive and vasorelaxant activities. However, the molecular mechanisms underlying these effects remain unknown. Intriguingly, allicin and DADS share structural similarities with allyl isothiocyanate, the pungent ingredient in wasabi and other mustard plants that induces pain and inflammation by activating TRPA1, an excitatory ion channel on primary sensory neurons of the pain pathway. Here we show that allicin and DADS excite an allyl isothiocyanate-sensitive subpopulation of sensory neurons and induce vasodilation by activating capsaicin-sensitive perivascular sensory nerve endings. Moreover, allicin and DADS activate the cloned TRPA1 channel when expressed in heterologous systems. These and other results suggest that garlic excites sensory neurons primarily through activation of TRPA1. Thus different plant genera, including Allium and Brassica, have developed evolutionary convergent strategies that target TRPA1 channels on sensory nerve endings to achieve chemical deterrence.
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| 4. |
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| 5. |
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| 6. |
- Grundemar, L, et al.
(författare)
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Characterization of vascular neuropeptide Y receptors
- 1992
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188. ; 105:1, s. 45-50
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Tidskriftsartikel (refereegranskat)abstract
- 1. In the present study we compared neuropeptide Y (NPY) and NPY-related analogues for their ability to activate or bind to vascular NPY receptors in four experimental set-ups. Previous results have suggested the existence of different receptor subtypes, Y1 receptors requiring full-length NPY (1-36) or [Pro34]-NPY, and Y2 receptors recognizing also N-terminally truncated forms of NPY but not [Pro34]-NPY. 2. NPY 1-36 and [Pro34]-NPY dose-dependently increased arterial pressure in the anaesthetized rat with a similar magnitude and potency. NPY 2-36 was much less potent than NPY 1-36. NPY 4-36 and NPY 11-36 were inactive even at a dose as high as 10 nmol kg-1. 3. NPY 1-36, [Pro34]-NPY, NPY 2-36 and NPY 5-36 concentration-dependently increased the coronary resistance in the Langendorff preparation of the rat. NPY 1-36 and [Pro34]-NPY were equipotent, while NPY 2-36 and NPY 5-36 were about 7 and 20 times less potent. At 0.3 microM, NPY 11-36, NPY 20-36 and NPY 22-36 induced a slight contraction while NPY 23-36 was inactive. 4. NPY 1-36, [Pro34]-NPY, NPY 2-36, NPY 4-36, NPY 5-36 and NPY 11-36 evoked concentration-dependent contractions in the isolated inferior caval vein of the rat and guinea-pig. [Pro34]-NPY was more potent than NPY 1-36. NPY 2-36 was equipotent with NPY 1-36, while NPY 4-36, NPY 5-36 and NPY 11-36 were approximately 30 times less potent.5. [Pro34]-NPY was equipotent with NPY 1-36 in displacing the '25I-labelled gut hormone peptide([1251]-PYY) from rat aortic smooth muscle cells, while NPY 2-36 and shorter forms of NPY were much less potent or inactive.6. In caval vein smooth muscle cells of the rat, the displacement pattern was more complex than in aortic smooth muscle cells, in that both [Pro34]-NPY and NPY 13-36 effectively displaced the radioligand,albeit none of them completely.7. In conclusion, the NPY-evoked pressor response in the whole rat and coronary vessels seems to be mediated by vascular Y1 receptors and the binding characteristics of the NPY-related peptides in the aortic smooth muscle cells correspond to a population of such receptors. In the caval vein, the profile of the bioactivity and the binding affinity of the NPY-related peptides suggest a mixed population of Y1/Y2 receptors.
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| 7. |
- Grundemar, L, et al.
(författare)
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Vascular effects of helodermin, helospectin I and helospectin II : a comparison with vasoactive intestinal peptide (VIP)
- 1990
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188. ; 99:3, s. 526-528
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Tidskriftsartikel (refereegranskat)abstract
- 1. Helodermin, helospectin I and helospectin II, peptides recently isolated from the salivary gland venom of Heloderma suspectum, were compared to vasoactive intestinal peptide (VIP) with respect to effects on systemic blood pressure and on isolated femoral arteries in the rat. 2. They all reduced blood pressure in a dose-dependent manner; helodermin was less effective than VIP. However, at doses higher than 1 nmol kg-1 all four peptides reduced blood pressure to about the same extent. 3. The half-life of the hypotensive effect of VIP was longer than that of helodermin and the helospectins. 4. VIP and helodermin were equally potent in relaxing femoral arteries precontracted with phenylephrine or prostaglandin F2 alpha. 5. Helospectin I and II relaxed phenylephrine-contracted vessels to the same extent as VIP but with a lower potency. 6. Addition of VIP 1 microM to preparations exposed to helodermin 1 microM or to either of the helospectins did not produce a further relaxation. 7. The findings indicate that VIP, helodermin and helospectin I and II have a similar profile of action and therefore may act on a common receptor.
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| 8. |
- Häggman Henrikson, Birgitta, et al.
(författare)
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Pharmacological treatment of oro-facial pain : health technology assessment including a systematic review with network meta-analysis
- 2017
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Ingår i: Journal of Oral Rehabilitation. - Hoboken : John Wiley & Sons. - 1365-2842 .- 0305-182X. ; 44:10, s. 800-826
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Forskningsöversikt (refereegranskat)abstract
- This health technology assessment evaluated the efficacy of pharmacological treatment in patients with oro-facial pain. Randomised controlled trials were included if they reported pharmacological treatment in patients >= 18 years with chronic (>= 3 months) oro-facial pain. Patients were divided into subgroups: TMD-muscle [ temporomandibular disorders (TMD) mainly associated with myalgia]; TMD-joint (TMD mainly associated with temporomandibular joint pain); and burning mouth syndrome (BMS). The primary outcome was pain intensity reduction after pharmacological treatment. The scientific quality of the evidence was rated according to GRADE. An electronic search in PubMed, Cochrane Library, and EMBASE from database inception to 1 March 2017 combined with a handsearch identified 1552 articles. After screening of abstracts, 178 articles were reviewed in full text and 57 studies met the inclusion criteria. After risk of bias assessment, 41 articles remained: 15 studies on 790 patients classified as TMD-joint, nine on 375 patients classified as TMD-muscle and 17 on 868 patients with BMS. Of these, eight studies on TMD-muscle, and five on BMS were included in separate network meta-analysis. The narrative synthesis suggests that NSAIDs as well as corticosteroid and hyaluronate injections are effective treatments for TMD-joint pain. The network meta-analysis showed that clonazepam and capsaicin reduced pain intensity in BMS, and the muscle relaxant cyclobenzaprine, for the TMD-muscle group. In conclusion, based on a limited number of studies, evidence provided with network meta-analysis showed that clonazepam and capsaicin are effective in treatment of BMS and that the muscle relaxant cyclobenzaprine has a positive treatment effect for TMD-muscle pain.
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| 9. |
- Zygmunt, P M, et al.
(författare)
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Calcium channels at the adrenergic neuroeffector junction in the rabbit ear artery
- 1993
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Ingår i: Naunyn-Schmiedeberg's Archives of Pharmacology. - 0028-1298. ; 347:6, s. 23-617
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Tidskriftsartikel (refereegranskat)abstract
- Neurotransmitter release is dependent on influx of Ca2+ through voltage-operated calcium channels (VOCCs). These channels may be divided into L, N, T and P subtypes. To investigate the subtypes of VOCC involved in transmitter release from adrenergic nerves in the isolated rabbit ear artery, the effects of some subtype selective VOCC antagonists were examined on contractile responses induced by electrical field stimulation (EFS), and exposure to an isosmolar (low Na+, normal Cl- content) or a hyperosmolar (normal Na+, high Cl- content) 60 mM K+ solution. Tetrodotoxin (TTX) and the L channel blocker nimodipine were present in the latter experiments to inhibit sodium-dependent action potential discharge and the direct contractile effect of K+ depolarization on the smooth muscle cells. Prazosin abolished the contractile effect of EFS, indicating that the response was elicited by activation of adrenergic nerves. The EFS-induced contractions were concentration-dependently inhibited by the N channel blocker omega-conotoxin (pIC50 = 9.0) and the proposed L channel blocker T-cadinol (pIC50 = 4.5), while nimodipine and the T channel blocker tetramethrin had no effect. The isosmolar and hyperosmolar K+ solutions induced a prazosin-sensitive contraction, amounting to 46% and 10% of the response to 10(-5) M noradrenaline (NA), respectively. omega-Conotoxin inhibited the contractile response to the hyperosmolar K+ solution, but not that to the isosmolar K+ solution. T-cadinol preferentially inhibited the response to the hyperosmolar K+ solution. Tetramethrin had no effect on contractions induced by either type of K+ solution.(ABSTRACT TRUNCATED AT 250 WORDS)
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| 10. |
- ZYGMUNT, P. M., et al.
(författare)
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Endothelium‐dependent relaxation resistant to N/ω‐nitro‐L‐arginine in the rat hepatic artery and aorta
- 1994
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Ingår i: Acta Physiologica Scandinavica. - : Wiley. - 0001-6772 .- 1365-201X. ; 152:1, s. 107-114
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Tidskriftsartikel (refereegranskat)abstract
- Nitric oxide (NO)‐independent pathways contributing to acetylcholine (ACh)‐induced relaxation were examined in the rat isolated hepatic artery and aorta at low and high levels of precontraction induced by phenylephrine (PhE). In the hepatic artery, the ACh‐induced relaxation was unaffected by the NO synthase inhibitors Nw‐nitro‐L‐arginine (L‐NOARG, 0.3 mM) and Nω‐nitro‐L‐arginine methyl ester (0.1 mM) at either level of pre‐contraction. In the aorta, L‐NOARG virtually abolished the ACh‐induced relaxation at a high level, but only partially reduced the response at a low level of precontraction. Methylene blue (10 μM) and indomethacin (10 μM) did not affect the ACh‐induced relaxation in the hepatic artery. L‐NOARG completely inhibited the cGMP and cAMP increases induced by ACh in both types of artery. In the presence of L‐NOARG, ACh was unable to relax the hepatic artery precontracted by K+. The sensitivity to PhE was increased less by L‐NOARG (threefold) than after endothelial denudation (tenfold) in the hepatic artery, whereas no such difference was observed in the aorta. The relaxation induced by the NO donor 3‐morpholino‐sydnonimin did not differ between the arteries after endothelial denudation. These results are compatible with the existence of an endothelium‐dependent inhibitory pathway distinct from the NO and cyclooxygenase pathways. This pathway seems to contribute more to the ACh‐induced relaxation in the hepatic artery than in the aorta, whereas the opposite appears to be true for the NO pathway.
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| 11. |
- ZYGMUNT, P. M., et al.
(författare)
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Light–dependent effects of zinc protoporphyrin IX on endothelium–dependent relaxation resistant to NoM–nitro–L–arginine
- 1994
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Ingår i: Acta Physiologica Scandinavica. - : Wiley. - 0001-6772 .- 1365-201X. ; 152:2, s. 137-143
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Tidskriftsartikel (refereegranskat)abstract
- Acetylcholine (ACh) induces an Nω–nitro–L–arginine (L–NOARG)–resistant relaxation and hyperpolarization in the rat isolated hepatic artery. The possibility that carbon monoxide (CO) produced by haem oxygenase (HO) is an endogenous mediator of this response was investigated. Exogenously applied CO evoked a concentration–dependent relaxation, and the CO ‘scavenger’ oxyhaemoglobin (10μM) reduced the maximum ACh–induced relaxation by 25%. The HO inhibitor zinc protoporphyrin IX (ZnPP, 10 μM virtually abolished the ACh–induced relaxation in experiments carried out under ordinary light conditions. However, ZnPP did not affect the ACh–induced relaxation under dark conditions, even after exposure of ZnPP to intense light before the preincubation period. Biliverdin (0.1 mM), a feedback inhibitor of HO, was also inactive under dark conditions, and the HO substrate haematin (0.1 mM) did not facilitate the ACh–induced relaxation. The relaxation induced by the nitric oxide (NO) donor 3–morpholino–sydnonimin was not affected by ZnPP in the presence of light. However, ZnPP inhibited the relaxation evoked by the potassium channel opener levcromakalim and the tonic component of the contractile response to 60 mM potassium, indicating that ZnPP has effects distinct from HO inhibition in the presence of light. ZnPP should therefore be protected from light when used to inhibit HO–mediated CO formation. The results do not suggest that CO generated by HO mediates the endothelium–dependent, L–NOARG–resistant relaxation induced by ACh in the rat hepatic artery.
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| 12. |
- ZYGMUNT, P. M., et al.
(författare)
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Regional differences in endothelium‐dependent relaxation in the rat : contribution of nitric oxide and nitric oxide‐independent mechanisms
- 1995
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Ingår i: Acta Physiologica Scandinavica. - : Wiley. - 0001-6772 .- 1365-201X. ; 155:3, s. 257-266
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Tidskriftsartikel (refereegranskat)abstract
- Relaxant effects of acetylcholine (ACh), histamine, calcitonin gene‐related peptide (CGRP) and the calcium ionophore A23187 were examined in rat femoral (Ø ≅ 0.2 mm), mesenteric (0.2 mm), intrarenal (0.2 mm) and hepatic (0.3 mm) arteries, and aorta (2 mm). Acetylcholine elicited an endothelium‐dependent relaxation in all arteries. Histamine induced an endothelium‐dependent relaxation in aorta, and mesenteric and intrarenal arteries, whereas a partly endothelium‐dependent and mainly endothelium‐independent relaxation was observed in hepatic and femoral arteries, respectively. In hepatic, mesenteric and intrarenal arteries, CGRP induced an endothelium‐independent relaxation, whereas either small or no relaxation was obtained in aorta and femoral arteries respectively. A23187 induced an endothelium‐dependent relaxation in the aorta and hepatic artery, whereas A23187 had no relaxant effect in femoral, mesenteric and intrarenal arteries. Nω‐nitro‐l‐arginine (l‐NOARG, 0.3 mM) reduced the maximum ACh‐induced relaxation (in the presence of 10 μM indomethacin) by 66% in the aorta, and abolished the relaxation in femoral and intrarenal arteries. A marked l‐NOARG/indomethacin‐resistant relaxation was obtained in mesenteric and hepatic arteries. Levcromakalim induced a concentration‐dependent and almost complete relaxation in all arteries. When contracted by a 60 mM K+ solution, all arteries responded to ACh with a relaxation that was abolished by l‐NOARG. These results demonstrate marked regional differences with regard to the vascular effects of ACh, histamine, CGRP and A23187. Whereas nitric oxide appears to mediate endothelium‐ dependent relaxation regardless of the vascular region, an l‐NOARG/indomethacin‐resistant relaxation, presumably mediated by an endothelium‐derived hyperpolarizing factor, was observed only in mesenteric and hepatic arteries, and aorta.
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| 13. |
- ZYGMUNT, P. M., et al.
(författare)
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The endothelium mediates a nitric oxide‐independent hyperpolarization and relaxation in the rat hepatic artery
- 1994
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Ingår i: Acta Physiologica Scandinavica. - : Wiley. - 0001-6772 .- 1365-201X. ; 152:4, s. 375-384
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Tidskriftsartikel (refereegranskat)abstract
- The rat hepatic artery responds to acetylcholine (ACh) with an endothelium‐dependent relaxation, which is unaffected by nitric oxide (NO) synthase and cyclooxygenase inhibition. The purpose of this study was to investigate whether the NO‐independent relaxation is caused by hyperpolarization of the smooth muscle cells. In vessels with endothelium ACh induced a hyperpolarization in the presence of 0.3 mM Nw‐nitro‐l‐arginine (l‐NOARG) and 10μm indomethacin. The hyperpolarization, which slowly decayed after an initial maximum, generally lasted for at least 20 min. ACh in contrast to levcromakalim failed to hyperpolarize the smooth muscle cells in endothelium‐denuded vessels. In vessels contracted by phenylephrine (PhE) ACh caused a concentration‐dependent hyperpolarization and relaxation, and both events occurred over the same concentration interval. Curve fitting using the Hill equation showed a close correlation between the hyperpolarization and the relaxation. Exposure to a 30 mM K+ solution abolished the hyperpolarization and suppressed the relaxation induced by ACh. Nimodipine did not affect the ACh‐induced hyperpolarization, whereas the relaxation induced by ACh and levcromakalim, but not that evoked by the NO donor 3‐morpholino‐sydnonimin, were attenuated. Glibenclamide had no effect on the ACh‐induced hyperpolarization and relaxation, but abolished the corresponding responses to levcromakalim. The results demonstrate a NO‐independent hyperpolarization and relaxation in the rat hepatic artery. The hyperpolarization and relaxation were endothelium‐dependent, and apparently causally related to each other, since interference with the hyperpolarization or the subsequent effector pathway inhibited the relaxation.
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