Tajima T, Tsuji Y, Brown J H, Pappano A J
Circ Res. 1987 Sep;61(3):436-45. doi: 10.1161/01.res.61.3.436.
Muscarinic agonists can stimulate rather than inhibit cardiac muscle in some preparations. In left atria from hatched chicks, treatment with pertussis toxin reversed the membrane action of carbachol from hyperpolarization to depolarization and reversed the inotropic effect of carbachol from negative to positive. Acetylcholine also depolarized the membrane and increased the force of contraction in atria from pertussis-toxin-treated chicks although oxotremorine did not. These cholinergic responses were blocked by atropine but not by adrenoceptor antagonists, suggesting that they are mediated via muscarinic receptors and are not due to actions of endogenously released catecholamines. Muscarinic receptor stimulation leads to two distinct biochemical responses in chick atria: inhibition of adenylate cyclase and activation of phosphoinositide (PI) hydrolysis. The former is lost in atria from pertussis-toxin-treated chicks, whereas the PI response persists. The pharmacologic characteristics of the PI response resemble those of the depolarization and positive inotropic response. Both are insensitive to blockade by pertussis toxin, require high concentrations of carbachol, and are elicited by acetylcholine but not by oxotremorine. The present study suggests that muscarinic agonist-induced PI turnover may be responsible for the membrane depolarization and positive inotropic effects of carbachol and acetylcholine; that an increase in Na+ conductance underlies these responses; and that it is stimulated either by an increase of intracellular calcium mobilized by inositol triphosphate and/or by activation by protein kinase C.
在某些实验制剂中，毒蕈碱激动剂可刺激而非抑制心肌。在刚孵出雏鸡的左心房中，用百日咳毒素处理可使卡巴胆碱的膜作用由超极化转变为去极化，并使卡巴胆碱的变力作用由负性变为正性。乙酰胆碱也可使经百日咳毒素处理的雏鸡心房的膜去极化并增强收缩力，而氧化震颤素则无此作用。这些胆碱能反应可被阿托品阻断，但不能被肾上腺素能受体拮抗剂阻断，这表明它们是通过毒蕈碱受体介导的，而非内源性释放的儿茶酚胺的作用。毒蕈碱受体刺激在雏鸡心房中导致两种不同的生化反应：抑制腺苷酸环化酶和激活磷脂酰肌醇（PI）水解。前者在经百日咳毒素处理的雏鸡心房中消失，而PI反应持续存在。PI反应的药理学特征类似于去极化和正性变力反应。两者均对百日咳毒素的阻断不敏感，需要高浓度的卡巴胆碱，且由乙酰胆碱而非氧化震颤素引发。本研究表明，毒蕈碱激动剂诱导的PI转换可能是卡巴胆碱和乙酰胆碱的膜去极化和正性变力作用的原因；这些反应的基础是Na+电导增加；并且它要么由肌醇三磷酸动员的细胞内钙增加所刺激，要么由蛋白激酶C激活所刺激。
