Carbachol depolarizes and accelerates pacemaker activity in the sinoatrial node of chicks treated with pertussis toxin.
Carbachol hyperpolarized the membrane of sinoatrial (SA) node cells from saline-treated chicks in a concentration-dependent fashion (10(-8)-10(-4) M). The rate of spontaneous impulse generation diminished in the presence of carbachol; complete inhibition (arrest) occurred at 10(-6) M. The hyperpolarization and negative chronotropic effect of carbachol (10(-8)-10(-6) M) were prevented by pretreatment of chicks with islet activating protein. Treatment with islet activating protein, which inactivates the guanine nucleotide binding proteins Gi and Go unmasked "stimulant" effects at high (greater than or equal to 10(-5) M) concentrations of carbachol. The stimulant effects included membrane depolarization and an acceleration of spontaneous impulse generation detected at 10(-5) and 10(-4) M carbachol, respectively. Because the depolarization and acceleration produced by carbachol occurred in the presence of propranolol, they are independent of endogenous catecholamines. As with the inhibition of the SA node, the stimulation by carbachol was mediated by muscarinic receptors and prevented by atropine. We speculate that the depolarization of SA node cells by carbachol, as in left atrium, may be mediated by products of phosphoinositide metabolism because phosphoinositide hydrolysis is activated at the same concentrations (greater than or equal to 10(-5) M). The ionic mechanism for the carbachol-induced depolarization and acceleration in SA node cells is not known. By analogy with results in left atrial cells from islet activating protein-treated animals, the mechanism would involve an increased intracellular Na+ activity and stimulation of Na-Ca exchange.
Agnarsson
U
U
Department of Pharmacology, University of Connecticut Health Center, Farmington.
Tajima
T
T
Pappano
A J
AJ
D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D002645:Chickens; D006339:Heart Rate / Q000187:drug effects*; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D037342:Pertussis Toxin; D011188:Potassium / Q000378:metabolism; D012849:Sinoatrial Node / Q000187:drug effects* / Q000502:physiology; D014700:Verapamil / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D007295:Inositol Phosphates; D010566:Virulence Factors, Bordetella; D015544:Inositol 1,4,5-Trisphosphate; D002217:Carbachol; D014700:Verapamil; D037342:Pertussis Toxin; D011188:Potassium