Alpha 1-adrenergic control of contractility and coronary flow in the perfused rat heart

Prazosin inhibition of phenylephrine plus propranolol (alpha 1-adrenergic agonist combination)-mediated inotropy, oxygen uptake, and coronary vasoconstriction of the perfused rat heart were compared with prazosin binding under identical conditions. Binding studies for the perfused heart indicated a population of high-affinity sites (Kd, 0.41 nM; Bmax, 13.2 pmol/g wet wt). Phenylephrine (50 microM) plus dl-propranolol (10 microM) did not significantly alter binding of 3.9 nM prazosin. The alpha 1-agonist combination mediated a dose-dependent increase in tension development and oxygen uptake and a decrease in coronary flow, each of which was inhibited by prazosin. The concentration of prazosin required for half-maximal inhibition of inotropy and oxygen uptake produced by 50-100 microM phenylephrine was 30-40 nM; no inhibition occurred at 2-3 nM prazosin concentration when binding sites were saturated. One nanomolar prazosin was required for half-maximal inhibition of the flow decrease produced by 10 microM phenylephrine. It is concluded that less than 1% of the alpha 1-binding sites are required for full development of inotropy and that this may result from an excess of binding sites or a small population of low-affinity receptors.