SPECIFIC AND NON-SPECIFIC DESENSITIZATION OF GUINEA-PIG ILEAL SMOOTH MUSCLE

The effects of cis-2-methyl-4-dimethylaminomethyl-1-3-dioxolane methiodide (CD), a muscarinic agonist, histamine, substance P and K+-stimulation on the mechanical responses, Ca2+-dependence and desensitization in guinea-pig ileal longitudinal smooth muscle have been studied. The mechanical responses to all four stimulants are highly dependent upon extracellular Ca2+(Ca2+EXT) and are blocked by the Ca2+ channel antagonist nicardipine. The tonic (slow) components of response are more dependent on Ca2+EXT and are more sensitive to nicardipine (IC50 values 5.0 X 10(-8) - 2.5 X 10(-9)M) than are the phasic (fast) components of response. Tissue exposure to CD (5 X 10(-7)M, 10 min) or histamine (3 X 10(-6)M and 3 X 10(-4)M, 10 min) produces short term nonspecific desensitization but substance P (5 X 10(-8)M, 10 min) produces only specific desensitization. K+-induced responses neither desensitize nor are desensitized. Desensitization is concentration- and time-dependent for both specific and nonspecific processes. Nonspecific desensitization is protected by elevation of K+ concentration (5.36mM) in the incubating medium, by dithiothreitol and by inhibitors (mepacrine,p-bromophenacyl bromide and phenylgloxal) of phospholipase A2 and is potentiated by mellitin, an activator of phospholipase A2. Desensitization produced by the muscarinic agonist CS is protected by Gpp(NH)p (10(-4)M), but histamine-induced desensitization is unaffected. There is no loss of muscarinic receptors, measured by [3H]QNB binding following tissue exposure to low concentrations of CD (5.0 X 10(-7)M) for up to 72 h. However, an apparent loss of receptors (20-30%) is measured following 10-90 min exposure of tissue to 10(-3)M CD. It is suggested that contractions of guinea-pig ileal longitudinal smooth muscle elicited by CD, histamine, substance P or K+ mobilize a common pool of Ca2+ through a Ca2+ channel antagonist (nicardipine) sensitive pathway. However, the existence of short term nonspecific desensitization (CD and histamine), specific desensitization (substance P) or no desensitization (K+ stimulation) indicates that significant differences exist in the pathways linking initial stimulus to mechanical response. The ability of elevated K+ to protect against nonspecific desensitization suggest that post stimulus membrane hyperpolarization may represent one contributing component to nonspecific desensitization. Products of phospholipid degradation may also contribute to desensitization since i