UBC Theses and Dissertations
A structural characteriztion of the dog myocardial adrenergic receptors Hughson, Richard Lee
The chronotropic and inotropic responses to isoprenaline and salbutamol were determined in the chloralose anaesthetized dog. The myocardium was denervated, sympathetically and parasympathetically to prevent direct neural influence on the heart rate and myocardial contractility. The heart rate was determined from the E.C.G. Myocardial contractility was indicated by the change in the maximum rate of rise of left ventricular pressure (dP/dt max) at a constant electrically paced heart rate. The structure-activity relationships for salbutamol and isoprenaline were determined from dose-response curves and by plotting the change in contractility (ΔdP/dt max) against the change in heart rate (ΔHR). The data obtained from this series of experiments indicated that the only difference between the effects of the agonists on the inotropic and chronotropic responses of the myocardium was the lower affinity of salbutamol for the adrenergic receptor as indicated by the 100 times greater concentration required to produce the same response level. Previously reported in vitro studies with the guinea pig atrium and dog papillary muscle had indicated that a smaller inotropic response to salbutamol should have been expected. To test this discrepancy between the present in vivo experimentation, and the previous in vitro work, studies were designed to test the guinea pig atrium and the dog papillary muscle in vitro. The effects of the agonists were studied on the isolated guinea pig atrium in a manner that paralleled the in vivo dog study. With the organ bath at 25°C, the chronotropic response, measured by the change in free contraction rate (ΔR), and the inotropic response, determined from the change in peak tension developed (ΔT) during electrical stimulation at 2 Hz, to a single randomly ordered dose of salbutamol or isoprenaline were determined. Salbutamol acted as a partial agonist, that is, had a lower efficacy than isoprenaline. However, the relative effect of each drug on the inotropic and chronotropic responses was almost identical. In the isolated dog papillary muscle, salbutamol displayed a much lower efficacy, producing only 20% of the maximum isoprenaline increase in peak tension developed to the cummulative addition of agonist. The affinity of salbutamol for the adrenergic receptor in this preparation was much lower than that observed in vivo when compared with isoprenaline, 5,000:1 and 100:1 respectively. The structure-activity relationships for salbutamol and isoprenaline showed that the relative effects of these agonists on the in vivo denervated dog myocardial inotropic and chronotropic responses were similar. This observation indicates that the adrenergic receptors of the dog myocardium mediating the inotropic and chronotropic responses are structurally similar at a site complementary to the phenyl ring of the agonist molecule. However,, a definite conclusion regarding the adrenergic receptors responsible for the inotropic response cannot be made because of the unexplained difference in inotropic response observed with ventricular muscle in vivo and in vitro. Examination of the structure-activity relationships for salbutamol and isoprenaline in the in vitro guinea pig atrium indicates that, in this preparation also, the adrenergic receptors involved in the two measured responses are probably structurally similar.
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