Kinetics of relaxation responses to vasorelaxants in isolated rabbit aorta

Transient responses of isolated tissues to drugs are best studied by application of non-steady-state protocols in which the data collected are analyzed using kinetic models. The time dependence of the relaxation response of the adventitia- and endothelium-denuded rabbit aorta to four vasorelaxants (nitroglycerin, sodium nitroprusside, 5'-N-ethylcarboxamidoadenosine and isoproterenol) was analyzed by an exploratory kinetic model. A rapid relaxation (t1/2 = 1-3 min) was elicited by all vasorelaxants. An apparent desensitization or fade of the relaxation response to nitroglycerin or isoproterenol was visualized as the partial regaining of tissue tone (t1/2 = 2-3 min). The relaxation responses to sodium nitroprusside or 5'-N-ethylcarboxamidoadenosine were stable for at least 60 min and did not exhibit an apparent regaining of tension. Tissues rendered desensitized by either isoproterenol or nitroglycerin responded fully to sodium nitroprusside or 5'-N-ethylcarboxamidoadenosine. The rate constant for relaxation was vasorelaxant concentration-dependent and saturable for all vasorelaxants. For isoproterenol, nitroglycerin, and 5'-N-ethylcarboxamidoadenosine the rate constant for relaxation was inversely proportional to the contractile stimulus, as was the magnitude of relaxation for all vasorelaxants. Although the magnitude and rate constant of the fade was not concentration-dependent for isoproterenol, it was inversely proportional to the nitroglycerin concentration. The rate constant of the fade was proportional to the contractile stimulus for isoproterenol and nitroglycerin, and the magnitude of the fade was proportional to the contractile stimulus for nitroglycerin. We propose that kinetic studies of responses in isolated vasculature supersede studies performed under steady-state conditions, for they extend our knowledge of the manner by which the steady-state is achieved and allow for a quantitative analysis of the time-dependent changes which should assist in elucidating the biochemical basis of the observed physiological response.