Cholera Toxin Accentuates the Antagonism by Acetylcholine of Higenamine-Induced Positive Chronotropy in Isolated Right Atria of Mice

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(±)-Higenamine (demethylcoclaurine), a cardiotonic principle from aconite root, has positive chronotropic and inotropic actions mediated through β_1-adrenergic receptors. We have investigated the influence of cholera toxin (CTX), a G_s-protein activator, and pertussis toxin (PTX), a G_i-protein inhibitor on the chronotropic interaction between higenamine and a muscarinic agonist, acetylcholine (ACh) in the isolated right atria of mice. CTX (100 nM, 1h) pretreatment accentuated the inhibitory responses to cumulative applications of ACh (30 nM-30 μM) for the positive chronotropic effects induced by higenamine (100 nM), isoproterenol (3 and 10 nM) or dobutamine (100 nM). In normal atria (CTX-untreated), ACh physiologically antagonized the positive chronotropic effects of these β-adrenergic agonists. Pretreatment with PTX (150μg/kg, i.p., 3d) abolished the CTX (100 nM, 1h)-induced accentuation in the inhibitory effect of ACh against higenamine. PTX pretreatment also attenuated the physiological antagonism by ACh against higenamine in normal atria. The negative chronotropic effect of ACh was not affected by a submaximal concentration of forskolin (1μM). These results suggest an accentuated antagonism between higenamine and ACh in CTX-treated, but not in untreated, isolated right atria of mice, which may occur through a functional interaction between the β_1-adrenergic-G_s and muscarinic-G_i systems.
公益社団法人日本薬学会の論文
1995-11-15

Cholera Toxin Accentuates the Antagonism by Acetylcholine of Higenamine-Induced Positive Chronotropy in Isolated Right Atria of Mice

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