Direct vasodilators with unknown modes of action: the nitro-compounds and hydralazine.
Several aspects of the mode of action of direct vasodilators are discussed. Nitro-compounds probably act via an intracellular formation of S-nitrosothiols, which stimulate cellular guanylate cyclase. Doubts, however, arise with regard to a generalization of this concept, e.g., methylene blue, an inhibitor of guanylate cyclase, interferes potently with the vasorelaxant action of nitroglycerin, but not with that of nitroprusside and sodium nitrite in KCl-stimulated rabbit aorta. Nitro-compounds do not interfere with transmembrane calcium movements. Hyperpolarization of the vascular smooth-muscle membrane, although reported to occur with nitroprusside, does not seem to be a common feature of the nitro-compounds. On the other hand, all nitro-compounds tested interfered with the noradrenaline-induced increase in 36-Cl steady-state exchange in rabbit aorta, and this effect could be mimicked by 8-Br-cGMP. Chemically skinned vascular smooth muscle was relaxed by pure cGMP-dependent protein kinase, but this effect requires confirmation. The action of hydralazine is augmented in chemically sympathectomized arteries and blocked by purines, such as adenosine, pointing to modulating role of purine-like compounds released from sympathetic nerve endings. The direct vasodilator action of hydralazine consists of a predominantly inhibitory effect on pharmacomechanical coupling. Membrane hyperpolarization with hydralazine has been reported. In addition to having direct effects on vascular smooth muscle, hydralazine can interfere with transmitter release by a prejunctional mechanism, and part of its vasorelaxant action seems to depend on the integrity of the endothelium in vascular smooth muscle.
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D006152:Cyclic GMP / Q000502:physiology; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009124:Muscle Proteins / Q000502:physiology; D009574:Nitro Compounds / Q000494:pharmacology*; D005996:Nitroglycerin / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D012977:Sodium Nitrite / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D009124:Muscle Proteins; D009574:Nitro Compounds; D009603:Nitroso Compounds; D014665:Vasodilator Agents; D009599:Nitroprusside; D006830:Hydralazine; D005996:Nitroglycerin; D006152:Cyclic GMP; D012977:Sodium Nitrite; D002118:Calcium