The mechanism of hypothermia-induced supersensitivity of guinea pig left atria to carbachol.
Hypothermia has previously been demonstrated to induce supersensitivity (defined as a decrease in the ED50) of guinea pig left atria to the negative inotropic effect of carbachol. In the present investigation, the dissociation constant (pKA or -log KA) for carbachol, determined using benzilylcholine mustard, was found to be significantly increased at 25 degrees C compared to 37 degrees C. However, the increase in pD2 (-log ED50) for carbachol at 25 degrees C was much less than would be predicted from the increase in pKA. Increasing the extracellular Ca2+ concentration or the frequency of stimulation, both of which, like hypothermia, are believed to increase Ca2+ influx into cardiac cells, resulted in a decrease in sensitivity to carbachol. Carbachol had no significant effect on cAMP or cGMP levels at either 37 degrees C or at 25 degrees C. These results suggest that the hypothermia-induced increase in sensitivity of left atria to carbachol can be explained by an increase in the affinity of the muscarinic receptor for this agonist. However, the expression of this increased affinity appears to be limited. This may be due to a concurrent decrease in the efficacy of the carbachol muscarinic receptor complex.
MacLeod
K M
KM
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology; D007035:Hypothermia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism
D011976:Receptors, Muscarinic; D002217:Carbachol; D000242:Cyclic AMP; D006152:Cyclic GMP; D002118:Calcium