86Rubidium efflux and negative inotropy induced by P1- and muscarinic-receptor agonists in guinea-pig left atria. Effects of potassium channel blockers.
Guinea-pig isolated left atria, paced at 2 Hz were incubated with 86rubidium (86Rb) for 120 min. They were then washed every 2 min for 2 hr, each sample being retained for scintillation counting. Left atrial isometric tension was recorded simultaneously. A concentration-response curve for the muscarinic agonist carbachol or the P1-receptor agonists adenosine and L-N6-phenyl-isopropyladenosine (L-PIA) was obtained. Antagonists were present from 20 min before agonist exposure. The rate constant (k) for 86Rb efflux was calculated for each 2 min sample and the mean increase for each concentration of agonist determined. In the absence of drugs there was no significant alteration in the rate constant during the 2 hr experimental period. Adenosine, L-PIA and carbachol produced concentration-related increases in rate constant for 86Rb efflux. The adenosine and L-PIA concentration-response curves were virtually superimposed upon the curves for the negative inotropic responses. The 86Rb efflux induced by adenosine was antagonized in an apparently parallel manner by 8-phenyltheophylline (8-PT) indicating involvement of P1-receptors. Alone, the putative potassium channel blockers, 4-aminopyridine (4-AP) and bromobenzoylmethyladamantylamine (BMA) caused, respectively, no change and a reduction in resting 86Rb efflux immediately prior to the agonist exposure. 4-AP reduced the L-PIA- and adenosine-induced increases in 86Rb efflux and, to a lesser extent, the negative inotropic response to adenosine. BMA caused "flattening" of the dose-response curves for 86Rb efflux induced by L-PIA, adenosine and carbachol with a significant reduction in response at the highest concentrations of adenosine and carbachol. The negative inotropic response to adenosine was also reduced. These results suggest that 4-AP and BMA block the P1-receptor-linked potassium channels and that BMA interacts with common K+ channels linked to P1- and muscarinic receptors. The negative inotropic responses of the guinea-pig left atrium to P1- and muscarinic agonists can be attributed, at least in part, to the opening of outward K+ channels.
Urquhart
R A
RA
Department of Pharmacology, Welsh School of Pharmacy, University of Wales College of Cardiff, U.K.
Rothaul
A L
AL
Broadley
K J
KJ
D015761:4-Aminopyridine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000547:Amantadine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004347:Drug Interactions; D006168:Guinea Pigs; D006207:Half-Life; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010277:Parasympathomimetics / Q000494:pharmacology*; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D012414:Rubidium Radioisotopes / Q000493:pharmacokinetics; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
D010277:Parasympathomimetics; D015221:Potassium Channels; D012414:Rubidium Radioisotopes; D010660:Phenylisopropyladenosine; C036548:4-bromobenzoyl-methyladamantylamine; D002217:Carbachol; D000547:Amantadine; D015761:4-Aminopyridine; D013806:Theophylline; C028322:8-phenyltheophylline; D000241:Adenosine; D011188:Potassium