Summary
The ability of LY83583 to antagonize vascular smooth muscle relaxation elicited by a number of vasodilators was examined in rings of rat aorta. LY83583 (0.3–10 μM) inhibited relaxant responses to acetylcholine, calimycin (A23187), adenosine triphosphate (ATP) and sodium nitroprusside, whereas responses to atriopeptin III an activator of particulate guanylate cyclase, and papaverine were unaffected. For acetylcholine and calimycin the major effect of LY83583 (0.3–10 μM) was to reduce the maximal response without appreciably altering the EC50 values whereas for ATP the EC50 values were markedly increased by low concentrations of LY83583 (0.3–1 μM) with depression of maximal responses occurring at higher concentrations (10 μM) of the antagonist. In contrast LY83583 produced nonparallel rightward shifts of the curve for sodium nitroprusside without altering the maximal response. In addition, LY83583 (10 μM) reduced basal levels of cyclic GMP and prevented acetylcholine and sodium nitroprusside-induced elevations of cyclic GMP, in parallel with reductions in the relaxant responses. In the presence of LY83583 (10 μM) higher concentrations of sodium nitroprusside restored both the relaxant response and the elevation of cyclic GMP. The results of this study show that LY83583 antagonises only those vasodilators which are thought to act via stimulation of soluble guanylate cyclase. The nonsurmountable inhibition of relaxation to acetylcholine, calimycin and ATP probably reflects a limited maximal capacity of the endothelium to release EDRF in response to these agents.
Similar content being viewed by others
References
Angus JA, Campbell GRCocks TM, Manderson JA (1983) Vasodilatation by acetylcholine is endothelium-dependent: a study by sonomicrometry in canine femoral artery in vivo. J Physiol (Lond) 344:209–222
Diamond J (1986) Effects of quinacrine, NDGA and LY83583 on acetylcholine induced elevation of cyclic GMP and relaxation of rabbit aortic rings. Proc West Pharmacol Soc 29:105–108
Diamond J, Chu EB (1985) A novel cyclic GMP-lowering agent, LY83583, blocks carbachol-induced cGMP elevation in rabbit atrial strips without blocking the negative inotropic effects of carbachol. Can J Physiol Pharmacol 63:908–911
Dusting GJ, Read MA, Stewart AG (1987) Endothelium derived relaxing factor released from cultured cells: differentiation from nitric oxide. Clin Exp Pharmacol Physiol 14: in press
Förstermann U (1986) Properties and mechanisms of production and action of endothelium-derived relaxing factor. J Cardiovase Pharmacol 8 (Suppl 10):S45-S51
Grace GC, Dusting GJ, Kemp B, Martin TJ (1987) Endothelium and the vasodilator action of rat calcitonin gene-related peptide (CGRP). Br J Pharmacol 91:729–733
Hunt NH, Smith B, Pembury R (1980) Cyclic nucleotide excretion in human malignancies. Clin Ser 58:463–467
Ignarro LJ, Gruetter CA, Hyman AL, Kadowitz PJ (1984) Molecular mechanisms of vasodilation. In: Paste G, Crooke ST (eds) Dopamine receptor agonists. Plenum Press, New York, pp 259–288
Ignarro LJ, Kadowitz PJ (1985) The pharmacological and physiological role of cyclic GMP in vascular smooth muscle relaxation. Annu Rev Pharmacol Toxicol 25:171–191
Macleod KM, Diamond J (1986) Effects of the cyclic GMP lowering agent LY83583 on the interaction of carbachol with forskolin in rabbit isolated cardiac preparations. J Pharmacol Exp Ther 238:313–318
Macleod KM, Ng DDW, Harris KH, Diamond J (1987) Evidence that cGMP is the mediator of endothelium-dependent inhibition of contractile response of rat arteries to α-adrenoceptor stimulation. Mol Pharmacol 32:59–64
Martin W, Furchgott RF, Villani GM, Jothianandan D (1986) Phosphodiesterase inhibitors induce endothelium-dependent relaxation of rat and rabbit aorta by potentiating the effects of spontaneously released endothelium-derived relaxing factor. J Pharmacol Exp Ther 237:539–547
McPherson GA, Molenaar P, Raper C, Malta E (1983) Analysis of dose-response curves and calculation of agonist dissociation constants using a weighted nonlinear curve fitting programme. J. Pharmacol Methods 10:231–241
Murad F, Rapoport RM, Fiscus R (1985) Role of cyclic-GMP in relaxations of vascular smooth muscle. J Cardiovasc Pharmacol 7 (Suppl 3):S111–5118
Palmer RMJ, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526
Rapoport RM, Murad F (1983) Endothelium-dependent and nitrovasodilator-induced relaxation of vascular smooth muscle: role of cyclic GMP. J Cyclic Nucleotide Protein Phosphor Res 9:281–296
Rapoport RM, Waldman SA, Schwartz K, Winquist RJ, Murad F (1985) Effects of atrial natriuretic factor, sodium nitroprusside, and acetylcholine on cyclic GMP levels and relaxation in rat aorta. Eur J Pharmacol 115:219–229
Scheffé H (1967) The one-way layout. Multiple comparison. In: Scheffé H (ed) The analysis of variance. John Wiley, New York, pp 55–89
Schmidt MJ, Sawyer BD, Truex LL, Marshall WS, Fleisch JH (1985) LY83583: an agent that lowers intracellular levels of cyclic guanosine 3′,5′-monophosphate. J Pharmacol Exp Ther 232:764–769
Author information
Authors and Affiliations
Additional information
Send offprint requests to E. Malta
Rights and permissions
About this article
Cite this article
Malta, E., Macdonald, P.S. & Dusting, G.J. Inhibition of vascular smooth muscle relaxation by LY83583. Naunyn-Schmiedeberg's Arch Pharmacol 337, 459–464 (1988). https://doi.org/10.1007/BF00169540
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00169540