| 1. |
- Zygmunt, P.M., et al.
(author)
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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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In: British Journal of Pharmacology. - : Wiley. - 0007-1188. ; 110:4, s. 1285-1290
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Journal article (peer-reviewed)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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| 2. |
- Zygmunt, P M, et al.
(author)
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Calcium channels at the adrenergic neuroeffector junction in the rabbit ear artery
- 1993
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In: Naunyn-Schmiedeberg's Archives of Pharmacology. - 0028-1298. ; 347:6, s. 23-617
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Journal article (peer-reviewed)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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| 3. |
- ZYGMUNT, P. M., et al.
(author)
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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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In: Acta Physiologica Scandinavica. - : Wiley. - 0001-6772 .- 1365-201X. ; 152:1, s. 107-114
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Journal article (peer-reviewed)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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| 4. |
- ZYGMUNT, P. M., et al.
(author)
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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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In: Acta Physiologica Scandinavica. - : Wiley. - 0001-6772 .- 1365-201X. ; 152:2, s. 137-143
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Journal article (peer-reviewed)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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| 5. |
- ZYGMUNT, P. M., et al.
(author)
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The endothelium mediates a nitric oxide‐independent hyperpolarization and relaxation in the rat hepatic artery
- 1994
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In: Acta Physiologica Scandinavica. - : Wiley. - 0001-6772 .- 1365-201X. ; 152:4, s. 375-384
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Journal article (peer-reviewed)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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