Mechanism of inhibitory effect of calcium on negative inotropic activity of acetylcholine in guinea pig atria.

The mechanism of inhibition of negative inotropic effect (NIE) of acetylcholine (ACh) by high extracellular calcium concentration ([Ca2+]0) has been studied in isolated guinea pig atria. Atropine (10(-10) - 10(-7) M) as well as enhanced [Ca2+]0 (3.26 - 13.6 X 10(-3) M) caused a concentration dependent inhibition of NIE indicating a competitive antimuscarinic effect of these agents. The observed dose ratio of ACh in the presence of atropine and high [Ca2+]0 together was greater than the theoretically expected value. D600 (10(-7) - 10(-6) M), a calcium channel blocker, potentiated NIE of ACh, reduced its dose ratio and antagonised the antimuscarinic effect of excess [Ca2+]0. It is concluded that the present observations support the suggestion that NIE of ACh is primarily due to inhibition of calcium channel by muscarinic receptor activation. In addition, high [Ca2+]0 inhibits the NIE of ACh by acting on multiple sites, e.g. muscarinic receptors, calcium channel and other sites, sensitive to variations in [Ca2+]0.