Pharmacodynamic modeling of theEmphasis Type="Ita

Authors: TsangBin Tzeng HoLeung Fung

Publish Date: 1992/06/01

Volume: 20, Issue: 3, Pages: 227-251

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Abstract

The in vitrodoserelaxation curves of four isomeric organic mononitrates Lisoidide mononitrate LIIMN isosorbide2mononitrate IS2MN isomannide mononitrate IMMN and isosorbide5mononitrate IS5MN were determined with rat aorta rings These mononitrates relaxed vascular tissue in a concentrationdependent manner Based upon the EC50obtained from the Hill equation the relative potency of LIIMN IS2MN IMMN IS5MN was 432122231 The Hill exponential coefficients were identical value of about 15 in these four isomeric mononitrates suggesting that they are likely to have a common mechanism of action For all four isomers relaxation was fairly immediate after addition of the tested compound into the tissue bath with a 2 to 3 mindelay to reach steadystate effect The rates of relaxation were then used to construct a pharmacodynamic model that described the time course of relaxation for these compounds This theoretical analysis suggested that in vitronitrate action is mediated by a catenary process consistent with published biochemical evidence that suggests a series of reactions involving metabolic activation to nitric oxide production of cyclic GMP and myosin lightchain phosphorylation to produce relaxation Via this pharmacodynamic model the halflives of nitric oxide and cGMP in the smooth muscle cells were estimated to be 152 and 231 sec respectively consistent with literature reports Results from the present study indicated the potential use of in vitropharmacodynamic modeling in confirming mechanisms of drug action obtained through biochemical or other methods

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