1-substituted tetrahydroisoquinoline analogs: beta adrenoceptor blocking agents in the isolated perfused rabbit heart.

The 1-benzyl and 1-methyl congeners of trimetoquinol were tested for antagonism of receptors which mediate inotropy and chronotropy in the isolated perfused rabbit heart. 1-Benzyltrimetoquinol was found to be a blocker of resting, isoproterenol- and dobutamine-stimulated inotropy at concentrations (10^?7?10^?5M) which did not significantly affect chronotropy ( > 10^?5M). 1-Methyltrimetoquinol was found to be a partial agonist in the resting myocardium, weakly blocking inotropy and chronotropy at doses of 10^?7?10^?5M. At a concentration of 10^?4M, 1-methyltrimetoquinol was an agonist of both chronotropy and inotropy. These stimulatory properties appear to be direct (not affected by prior reserpinization) and antagonized by propranolol. In the isoproterenol-stimulated heart, 1-methyltrimetoquinol was a specific negative inotropic agent at doses (10^?7?10^?5M) above which agonist properties were manifest. At 10^?4M, 1-methyltrimetoquinol acted synergistically with isoproterenol to produce positive inotropy and chronotropy significantly greater than that of isoproterenol alone. Currently, it is believed that the receptors which mediate inotropy and chronotropy are $\text{beta}$ adrenergic in nature. Thus, it would appear that 1-benzyltrimetoquinol is a specific antagonist of those $\text{beta}$-receptors which mediate inotropy, while 1-methyltrimetoquinol is a partial agonist of both inotropic and chronotropic $\text{beta}$-receptors. Further, the response to these compounds does not appear to be proportionate in various regions of the myocardium.