Pronounced direct inhibitory action mediated by adenosine A1 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 of 0.69 mumol/l in the presence of a beta-adrenoceptor blocking agent bupranolol (0.3 mumol/l) in the isolated ferret papillary muscle. The negative inotropic effect of R-PIA was not associated with changes in cyclic AMP level. Adenosine and other A1 receptor agonists also elicited a negative inotropic effect. DPCPX (1,3-dipropyl-8-cyclopentyl xanthine) antagonized the negative inotropic effect of R-PIA in a competitive manner (pA2 value = 8.4). The inhibitory action of R-PIA was markedly attenuated in the ventricular muscle preparation isolated from ferrets pretreated with pertussis toxin that caused ADP-ribosylation of 39 kDa proteins in the membrane fraction. In the membrane fraction derived from the ferret ventricle, [3H]-DPCPX bound to a single binding site in a saturable and reversible manner with high affinity (Kd value = 1.21 +/- 0.41 nmol/l; Bmax = 12.8 +/- 3.02 fmol/mg protein; n = 7). The binding characteristics of [3H]-DPCPX in the rat ventricle (Kd value = 1.51 +/- 0.09 nmol/l; Bmax = 12.7 +/- 1.47 fmol/mg protein; n = 5) were similar to those in the ferret. On the other hand, the content of G(o), a major pertussis toxin-sensitive G protein in the ferret heart, was much higher in the ferret than in the rat ventricle. The present results indicate that adenosine receptors may play an important role in the inhibitory regulation of ventricular contractility in the ferret in contrast to other mammalian species. The signal transduction process subsequent to agonist binding to A1 receptors including the pertussis toxin-sensitive G protein and ion channels may be responsible for the unique inhibitory action of adenosine in this species.
Endoh
M
M
Department of Pharmacology, Yamagata University School of Medicine, Japan.
Takanashi
M
M
Norota
I
I
Kawabata
Y
Y
Asano
T
T
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000818:Animals; D002046:Bupranolol / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D005289:Ferrets; D019204:GTP-Binding Proteins / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects; D007118:Immunoassay; D015151:Immunoblotting; D066298:In Vitro Techniques; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D037342:Pertussis Toxin; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D016276:Ventricular Function; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*; D014970:Xanthines / Q000494:pharmacology
D008565:Membrane Proteins; D018047:Receptors, Purinergic P1; D010566:Virulence Factors, Bordetella; D014970:Xanthines; D000246:Adenosine Diphosphate Ribose; D010660:Phenylisopropyladenosine; D002046:Bupranolol; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins