Resistance to antagonism of atrial P-1 purinoceptor responses in the presence of K+ channel blockade

The rate of onset of the negative inotropic responses of guinea-pig isolate d paced atria to the adenosine receptor agonist, N-6-cyclopentyladenosine, was significantly slowed by the K+ channel inhibitor, 4-aminopyridine (10 m M). The concentration- dependent inhibition of developed tension by N-6-cyc lopentyladenosine, however, was unaffected by 4-aminopyridine (10 mM). Thus , K+ efflux only governs the speed of onset of the negative inotropic respo nse and does not appear to be a major component in the negative inotropy pr oduced by the adenosine A, receptor agonist. The P-1 purinoceptor antagonis t, 8(p-sulfophenyl)theophylline (1 x 10(-5) M) significantly shifted the co ncentration-response curve for N-6-cyclopentyladenosine to the right (conce ntration-ratio, 7.1 +/- 1.5). In the presence of 4-aminopyridine (10 mM), 8 (p-sulfophenyl)theophylline caused a non-parallel rightwards shift of the c urve. At the IC35 there was no significant shift, whereas at the IC75 there was a small significant displacement of the curve. The adenosine A(1)/A(3) receptor agonist, N-6-2-(4-aminophenyl)ethyladenosine (APNEA) yielded a bi phasic concentration- response curve which was significantly shifted to the right by 8(p-sulfophenyl)theophylline (1 x 10(-5) M). In the presence 4-am inopyridine, however, there was no shift of the APNEA concentration-respons e curve by 8(p-sulfophenyl)theophylline. These results show that when K+ ch annels are blocked by 4-aminopyridine, the residual response is resistant t o antagonism by the P-1 purinoceptor ant agonist, 8(p-sulfophenyl)theophyll ine. This residual component may involve L-type Ca2+ channels, the adenosin e A(1) receptor bring possibly coupled to the two transduction pathways for negative inotropism via the different components of the G protein (recepto r-transducer promiscuity). (C) 1999 Elsevier Science B.V. All rights reserv ed.