Heterologous desensitization of smooth muscle to K+ depolarization: retarded stimulus-[Ca2+]i coupling

To understand the phenomenon of postreceptor heterologous desensitization, we exposed porcine carotid media to 40 mM KCl physiological saline solution both before and after intervening treatment with histamine. Increasing histamine concentration or duration of exposure or decreasing the interval between histamine exposure and KCl progressively slowed the contractile responses to K+ depolarization. A delay in initiation and a slower rate of rise of KCl-induced stress in histamine-pretreated muscle were preceded by a slower rate of rise of aequorin-estimated myoplasmic Ca2+ concentration ([Ca2+]i), myosin regulatory light chain (MRLC) phosphorylation, and tissue stiffness, with no detectable change in the Ca2+ sensitivity of MRLC phosphorylation. This heterologous desensitization was not a diminished steady-state force but instead a profound slowing of contraction rates. This slowing was a manifestation of retardation of the rate at which [Ca2+]i rises to the level appropriate for the stimulus. The lack of rapid initial [Ca2+]i and cross-bridge phosphorylation transients as a consequence of histamine pretreatment resulted in very slow cross-bridge cycling rates and rates of force development (latch).