Pharmacological evidence for alpha(1D)-adrenoceptors in the rabbit ventricular myocardium: analysis with BMY 7378.

1. It was examined by means of BMY 7378, a selective antagonist of alpha 1D-adrenoceptors, whether alpha 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 nM shifted the concentration-response curve (CRC) for the PIE of phenylephrine to the right and downward and at 100 nM to 1 microM it antagonized the PIE in a competitive manner, the slope of Schild plot being 0.93 and the pA2 being 7.17 +/- 0.09. 3. The inhibitory action of BMY 7378 at 1-10 nM is ascribed to the selective action on alpha 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 nM WB 4101, the antagonistic action of BMY 7378 at 1-10 nM remained unchanged but the antagonistic action of BMY 7378 at 100-300 nM disappeared. The antagonistic action of BMY 7378 at 1 nM was unaffected by 100 nM (+)-niguldipine. 5. Following pretreatment with chloroethyldonidine, BMY 7378 at 1 nM inhibited the maximal response to phenylephrine but the pD2 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 nM BMY 7378 but it was shifted to the right by BMY 7378 at 300 nM. 6. Stimulation of PI hydrolysis induced by phenylephrine was not affected by BMY 7378 up to 10 nM but it was reduced significantly by BMY 7378 at higher concentrations (100 nM to 1 microM). 7. BMY 7378 inhibited the [3H]prazosin specific binding to the rabbit ventricular membrane fraction in a monophasic manner with a pKi value of 7.53 +/- 0.09. 8 The results indicate that in rabbit ventricular muscle, BMY 7378 at 1-10 nM suppressed the maximal response to phenylephrine (probably mediated by alpha 1D-adrenoceptors) and at 10-100 nM it inhibited the negative inotropic effect of phenylephrine, the mechanisms of which remain to be characterized. At higher concentrations (100 nM to 1 microM) BMY 7378 antagonized the functional and biochemical response via a presumed interaction mainly with the alpha 1D-adrenoceptor and partially with the alpha 1A-adrenoceptor.