Use of tension measurements to delineate the mode of action of vasodilators.

Direct experimental procedures to delineate the modes of inhibition of drugs on vascular smooth muscle contractility are described. In isolated rabbit aortic strips, high concentrations of KCl and norepinephrine induce sustained contractions that depend upon Ca2+ influx mediated by selective activation of voltage-dependent and receptor-linked Ca2+ channels, respectively. In the absence of external Ca2+, norepinephrine also induces a transient contraction that is dependent upon release of cellular bound Ca2+. The contractile responses are differentially susceptible to vasodilators acting on different mechanisms. The Ca2+ channel blockers selectively inhibit KCl-induced contraction. The selective inhibitors of norepinephrine-induced contraction include nitro compounds, atrial natriuretic peptide, acetylcholine and other stimulants of endothelium-derived relaxing factor, beta-adrenergic agonists, forskolin, adenosine, and metabolic inhibitors. The nonselective inhibitors of these contractions include the inhibitors of contractile filaments, such as calmodulin inhibitors, and the inhibitors with multiple sites of action, such as papaverine. Although the inhibitors of Ca2+ release from storage site, such as ryanodine, may not inhibit these contractions, these inhibitors inhibit the norepinephrine-induced transient contraction in Ca2+-free solution. Thus, primary evaluation (screening) of drugs affecting vascular smooth muscle contraction can be performed by analyzing their effects on contractile responses of isolated rabbit aorta. Furthermore, methods to define more detailed sites of action of drugs are also described.