PRONOUNCED DIRECT INHIBITORY-ACTION MEDIATED BY ADENOSINE A(1)RECEPTOR AND PERTUSSIS-TOXIN-SENSITIVE G-PROTEIN ON THE FERRET VENTRICULAR CONTRACTION

An adenosine A1 receptor agonist R-N6-phenylisopropyladenosine (R-PIA) elicited a pronounced negative inotropic effect with the EC50 value o f 0.69 mumol/l in the presence of a beta-adrenoceptor blocking agent b upranolol (0.3 mumol/l) in the isolated ferret papillary muscle. The n egative inotropic effect of R-PIA was not associated with changes in c yclic AMP level. Adenosine and other A1 receptor agonists also elicite d a negative inotropic effect. DPCPX (1,3-dipropyl-8-cyclopentyl xanth ine) antagonized the negative inotropic effect of R-PIA in a competiti ve manner (pA2 value = 8.4). The inhibitory action of R-PIA was marked ly attenuated in the ventricular muscle preparation isolated from ferr ets pretreated with pertussis toxin that caused ADP-ribosylation of 39 kDa proteins in the membrane fraction. In the membrane fraction deriv ed from the ferret ventricle, [H-3]-DPCPX bound to a single binding si te in a saturable and reversible manner with high affinity (K(d) value = 1.21 +/- 0.41 nmol/l; B(max) = 12.8 +/- 3.02 fmol/mg protein; n = 7 ). The binding characteristics of [H-3]-DPCPX in the rat ventricle (K( d) value = 1.51 +/- 0.09 nmol/l; B(max) = 12.7 +/- 1.47 fmol/mg protei n; n = 5) were similar to those in the ferret. On the other hand, the content of GO, a major pertussis toxin-sensitive G protein in the ferr et heart, was much higher in the ferret than in the rat ventricle. The present results indicate that adenosine receptors may play an importa nt role in the inhibitory regulation of ventricular contractility in t he ferret in contrast to other mammalian species. The signal transduct ion process subsequent to agonist binding to A1 receptors including th e pertussis toxin-sensitive G protein and ion channels may be responsi ble for the unique inhibitory action of adenosine in this species.