The mechanism of hypothermia-induced supersensitivity of guinea pig left atria to carbachol

Abstract

Hypothermia has previously been demonstrated to induce supersensitivity (defined as a decrease in the ED 50) of guinea pig left atria to the negative inotropic effect of carbachol. In the present investigation, the dissociation constant (pK A or −log K A) for carbachol, determined using benzilylcholine mustard, was found to be significantly increased at 25°C compared to 37°C. However, the increase in pD 2 (−log ED 50) for carbachol at 25°C was much less than would be predicted from the increase in pK A. Increasing the extracellullar Ca 2+ concentration or the frequency of stimulation, both of which, like hypothermia, are believed to increase Ca 2+ 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°C or at 25°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.