EFFECT OF TEMPERATURE REDUCTION ON RESPONSIVENESS TO CHOLINOMIMETICS IN THE TAENIA CECI OF THE GUINEA-PIG

1 The effect of temperature reduction on the interaction of carbachol (CCh) and McN-A-343 (McN) with muscarinic receptors in the guinea-pig taenia caeci was investigated. 2 McN, a partial agonist, acted on the smooth muscle to produce contraction. The response was unaffected by tetrodotoxin and the pK(B) for inhibition by pirenzepine was 6.8, indicating that ganglionic M1 receptors were not involved in the response. 3 Reduction in temperature from 37-degrees-C to 18-degrees-C for 3 h led to a marked reduction in the contractile response to McN (2-200-mu-M) but no reduction in the response to CCh (0.1-3-mu-M). 4 The reduction in temperature was not accompanied by any change in the affinity of McN or CCh for muscarine receptors in binding experiments with [H-3]-QNB. 5 The K(A) value for CCh determined after irreversible receptor inactivation with propylbenzilylcholine mustard followed by ca 60-min wash-out was 7.6-mu-M, a value similar to that obtained in binding experiments. 6 The EC50 for McN in producing contraction at 37-degrees-C (2.1-mu-M) was similar to the K(A) value for the partial agonist obtained in experiments with the irreversible antagonist phenoxybenzamine (2.5-mu-M). It was also similar to the K(B) value determined at 18-degrees-C (3.4-mu-M) when McN could be used as an antagonist of contractions to CCh. 7 At 18-degrees-C, phosphatidylinositol (PI) hydrolysis by CCh was reduced to 23% of that at 37-degrees-C. 8 It is concluded that reduction of muscarinic receptor activation of the PI pathway by cholinomimetics with lowering of the temperature could account for the findings with McN on contractility.