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Gardner NM, Broadley KJ: Resistance to antagonism of atrial P (1) purinoceptor responses in the presence of K (+) channel blockade. Eur J Pharmacol. 1999 Oct 27;383(2):143-53.
The rate of onset of the negative inotropic responses of guinea-pig isolated paced atria to the adenosine receptor agonist, N (6)-cyclopentyladenosine, was significantly slowed by the K (+) channel inhibitor, 4-aminopyridine (10 mM). The concentration-dependent inhibition of developed tension by N (6)-cyclopentyladenosine, however, was unaffected by 4-aminopyridine (10 mM). Thus, K (+) efflux only governs the speed of onset of the negative inotropic response and does not appear to be a major component in the negative inotropy produced by the adenosine A (1) receptor agonist. The P (1) purinoceptor antagonist, 8 (p-sulfophenyl) theophylline (1 x 10 (-5) M) significantly shifted the concentration-response curve for N (6)-cyclopentyladenosine to the right (concentration-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 curve. At the IC (35) there was no significant shift, whereas at the IC (75) 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 biphasic concentration-response curve which was significantly shifted to the right by 8 (p-sulfophenyl) theophylline (1 x 10 (-5 ) M). In the presence 4-aminopyridine, however, there was no shift of the APNEA concentration-response curve by 8 (p-sulfophenyl) theophylline. These results show that when K (+) channels are blocked by 4-aminopyridine, the residual response is resistant to antagonism by the P (1) purinoceptor antagonist, 8 (p-sulfophenyl) theophylline. This residual component may involve L-type Ca (2+) channels, the adenosine A (1) receptor being possibly coupled to the two transduction pathways for negative inotropism via the different components of the G protein (receptor-transducer promiscuity). |
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