Pharmacological evidence for α 1D ‐adrenoceptors in the rabbit ventricular myocardium: analysis with BMY 7378

1 It was examined by means of BMY 7378, a selective antagonist of α 1D ‐adrenoceptors, whether α 1D ‐adrenoceptors contribute to the regulation of myocardial contractility and hydrolysis of phosphoinositide (PI) in rabbit ventricular muscle. 2 BMY 7378 had a biphasic antagonistic action on the positive inotropic effect (PIE) of phenylephrine depending on the concentration. BMY 7378 at 1–10 n m shifted the concentration–response curve (CRC) for the PIE of phenylephrine to the right and downward and at 100 n m to 1 μ m it antagonized the PIE in a competitive manner, the slope of Schild plot being 0.93 and the pA 2 being 7.17±0.09. 3 The inhibitory action of BMY 7378 at 1–10 n m is ascribed to the selective action on α 1 ‐adrenoceptors because the PIE of neither isoprenaline nor endothelin‐3 and angiotensin II was affected by this compound over this concentration range. 4 In the presence of 100 n m WB 4101, the antagonistic action of BMY 7378 at 1–10 n m remained unchanged but the antagonistic action of BMY 7378 at 100–300 n m disappeared. The antagonistic action of BMY 7378 at 1 n m was unaffected by 100 n m (+)‐niguldipine. 5 Following pretreatment with chloroethylclonidine, BMY 7378 at 1 n m inhibited the maximal response to phenylephrine but the pD 2 value for phenylephrine was increased in the presence of BMY 7378. The CRC for phenylephrine was shifted to the left in the presence of 10–100 n m BMY 7378 but it was shifted to the right by BMY 7378 at 300 n m . 6 Stimulation of PI hydrolysis induced by phenylephrine was not affected by BMY 7378 up to 10 n m but it was reduced significantly by BMY 7378 at higher concentrations (100 n m to 1 μ m ). 7 BMY 7378 inhibited the [ 3 H]prazosin specific binding to the rabbit ventricular membrane fraction in a monophasic manner with a p K i value of 7.53±0.09. 8 The results indicate that in rabbit ventricular muscle, BMY 7378 at 1–10 n m suppressed the maximal response to phenylephrine (probably mediated by α 1D ‐adrenoceptors) and at 10–100 n m it inhibited the negative inotropic effect of phenylephrine, the mechanisms of which remain to be characterized. At higher concentrations (100 n m to 1 μ m ) BMY 7378 antagonized the functional and biochemical response via a presumed interaction mainly with the α 1B ‐adrenoceptor and partially with the α 1A ‐adrenoceptor.