Comparison of the effects of nitric oxide synthase inhibition and guanylate cyclase inhibition on vascular contraction in vitro and in vivo in the rat.
Naunyn Schmiedebergs Arch Pharmacol 1997 Oct;356(4):481-7 Unique Identifier : AIDSLINE 98007791 Abdullah K; Cawley T; Connolly C; Ruiz E; Docherty JR; Department of Physiology, Royal College of Surgeons in Ireland, Dublin; 2.
Abstract:
We have investigated the differences between the nitric oxide synthase inhibitor (NOSI), L-NMMA, and the guanylate cyclase inhibitors (GCI), methylene blue and LY 83583, in their abilities to increase vasoconstrictor responses in vitro and in vivo. In rat small mesenteric arterial rings, 1 h exposure to the NOSI, L-NMMA (100 microM), and the GCI, methylene blue (10 microM), alone or in combination with L-NMMA, caused a significant reduction in the maximum relaxation to ACh in mesenteric arteries pre-contracted with the thromboxane mimetic U46619 (10 microM). Hence, both NOSI and GCI inhibit endothelium-dependent relaxations to ACh in rat small mesenteric artery. However, 1 h exposure to L-NMMA and L-NNA (both 100 microM), but not methylene blue (10 microM), significantly increased the contractile response to U- 46619 (10 microM) in rat small mesenteric artery. It was decided to investigate further this difference between NOSI and methylene blue. In rat small mesenteric arterial rings, L-NMMA (10 microM) and LY 83583 (1- 10 microM) significantly increased the contractile response to KCl (40 mM) or to noradrenaline (10 microM), when administered during the contraction. However, methylene blue (1-10 microM) increased the contractile response to KCl but not noradrenaline. In rat aortic rings, L-NMMA (100 microM), methylene blue (1-10 microM) and LY 83583 (1-10 microM) significantly increased the contractile response to KCl (40 mM) or to noradrenaline (1 microM). In the pithed rat preparation, L-NMMA (40.3 micromol kg(-1), i.v.) significantly increased the pressor response both to bolus injection of noradrenaline (3.13 nmol kg[-1]) and to spinal pressor nerve stimulation. However, methylene blue (3.13- 15.6 micromol kg[-1]) or LY 83583 (4.0-40.0 micromol kg[-1]), failed to affect pressor responses to either NA or pressor nerve stimulation. Hence, there are differences between NOSI and GCI in their abilities to increase vasoconstrictor responses, especially when comparing responses in vitro and in vivo. This suggests that nitric oxide has actions in addition to activation of guanylate cyclase to modulate vasoconstrictor responses, presumably by membrane hyperpolarisation, and that this action may be more important in vivo.
Keywords: JOURNAL ARTICLE omega-N-Methylarginine/pharmacology Acetylcholine/pharmacology Aminoquinolines/pharmacology Animal Aorta/drug effects Comparative Study Endothelium, Vascular/drug effects/physiology Enzyme Inhibitors/pharmacology Guanylate Cyclase/*antagonists & inhibitors In Vitro Male Mesenteric Arteries/drug effects Methylene Blue/pharmacology Muscle Contraction/drug effects Muscle, Smooth, Vascular/*drug effects Nitric-Oxide Synthase/*antagonists & inhibitors Nitroarginine/pharmacology Rats Rats, Wistar Support, Non-U.S. Gov't Vasoconstriction/*drug effects
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