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 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).
Gardner
N M
NM
Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cathays Park, Cardiff, UK.
Broadley
K J
KJ
D015761:4-Aminopyridine / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D026902:Potassium Channel Blockers; D011433:Propranolol / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D012110:Reserpine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D026902:Potassium Channel Blockers; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; C064885:8-(3-sulfophenyl)theophylline; C048599:N(6)-cyclopentyladenosine; D012110:Reserpine; D011433:Propranolol; D015761:4-Aminopyridine; D013806:Theophylline; D000241:Adenosine