Desensitization of depolarization-mediated contractile pathways does not necessarily regulate receptor-mediated excitation-contraction coupling in longitudinal smooth muscle of guinea pig ileum.

1. Activation of G(q) protein-coupled receptors, such as muscarinic M(3) and histamine H(1) receptors, induces smooth muscle contraction through activation of voltage-dependent Ca channels. 2. To evaluate roles of depolarization-mediated contractile pathways in the desensitization of receptor-mediated contraction, we compared the development of carbachol-induced desensitization to receptor agonists, carbachol and histamine, and to receptor-bypassed stimulation of voltage-dependent Ca channels with depolarizing high K in longitudinal smooth muscle of guinea pig ileum. 3. Under Ca-containing physiological conditions, pretreatment with 10(-4) mol/L carbachol for 15 s-30 min induced desensitization to carbachol as well as to high K, whereas contractile responses to histamine remained normal. 4. In contrast, under Ca-free conditions containing 0.2 mmol/L EGTA, carbachol pretreatment induced desensitization to high K in a manner similar to that induced under Ca-containing physiological conditions, whereas contractile responses to carbachol and histamine remained normal. 5. Thus, it was shown that contractile responses to carbachol and histamine were not necessarily desensitized, even under conditions where contractile responses to high K were desensitized. These results suggest that desensitization of depolarization-mediated contractile pathways might not necessarily regulate excitation-contraction coupling through muscarinic M(3) and histamine H(1) receptors in longitudinal smooth muscle of guinea pig ileum.