Enantiomers of dobutamine increase the force of contraction via beta adrenoceptors, but antagonize competitively the positive inotropic effect mediated by alpha-1 adrenoceptors in the rabbit ventricular myocardium.
Experiments were carried out to characterize the pharmacological properties of enantiomers and racemic mixture of dobutamine to modulate the myocardial contractility through alpha and beta adrenoceptors in the rabbit papillary muscle. Dobutamine caused the concentration-dependent positive inotropic effect: the rank order of potency was R-(+)- greater than (+/-) - greater than S-(-)-dobutamine. The positive inotropic effect of (+)-, (-)- and (+/-)-dobutamine was antagonized by a beta adrenoceptor antagonist, (+/-)-bupranolol in a competitive manner, but was not affected by an alpha-1 adrenoceptor antagonist, prazosin. The concentration-response curve for (-)-phenylephrine mediated by alpha adrenoceptors in the presence of 10(-6) M (+/-)-bupranolol was shifted by enantiomers of dobutamine to the right in a concentration-dependent manner. Thus, enantiomers of dobutamine antagonized the positive inotropic effect of (-)-phenylephrine in a competitive manner, and pA2 values [negative logarithm of the dissociation constant (KB)] for (+)- and (-)-dobutamine were 6.67 and 5.99, respectively. The specific binding of [3H]prazosin to membrane fractions of rabbit ventricular myocardium was displaced by dobutamine with a high potency: the -log Ki values for (+)- and (-)-dobutamine were 6.43 and 5.97, respectively, which correspond well with pA2 values of these compounds for functional modification. These findings indicate that enantiomers of dobutamine elicit the positive inotropic effect through activation of beta adrenoceptors, whereas both enantiomers behave as the competitive antagonist of myocardial alpha adrenoceptors mediating the positive inotropic effect in the isolated rabbit papillary muscle.
Ishihata
A
A
Department of Pharmacology, Yamagata University School of Medicine, Japan.
Kushida
H
H
Endoh
M
M
D000818:Animals; D001667:Binding, Competitive; D002046:Bupranolol / Q000494:pharmacology; D004280:Dobutamine / Q000494:pharmacology*; D007536:Isomerism; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013268:Stimulation, Chemical
D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D010656:Phenylephrine; D004280:Dobutamine; D002046:Bupranolol; D011224:Prazosin