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Muscarinic inhibitory and stimulatory regulation of the L-type Ca²⁺ current is not altered in cardiac ventricular myocytes from mice lacking endothelial nitric oxide synthase

Andriy E. Belevych and Robert D. Harvey

1. Using conventional and perforated patch-clamp techniques, the inhibitory and stimulatory effects of acetylcholine (ACh) on -adrenergic regulation of the L-type Ca²⁺ current (I_Ca) were studied in ventricular myocytes from wild-type mice (WT) and from mice lacking endothelial nitric oxide synthase (eNOS or NOS3; NOS3-KO mice).

2. To validate the direct comparison of ACh effects on -adrenergic responses, the sensitivity of I_Ca to the -adrenergic agonist isoprenaline (Iso) was studied in both WT and NOS3-KO mouse myocytes. I_Ca sensitivity to Iso was not found to be significantly different in WT and NOS3-KO myocytes: Iso increased I_Ca with an EC₅₀ of 4·9 and 3·7 nM in WT and NOS3-KO myocytes, respectively.

3. ACh-induced inhibition of I_Ca did not significantly differ in ventricular myocytes from WT and NOS3-KO mice. ACh (10 µM) inhibited the stimulatory effect of 3 nM Iso by 39 and 35 % in WT and NOS3-KO myocytes, respectively.

4. Exposure to and subsequent washout of ACh in the continuous presence of submaximally stimulating concentrations of Iso (1-3 nM) resulted in a transient rebound stimulation of I_Ca in both WT and NOS3-KO mouse myocytes. The magnitude of the stimulatory effect of ACh did not significantly differ in WT and NOS3-KO mice.

5. These results indicate that nitric oxide (NO) generated by NOS3 does not significantly affect the -adrenergic responsiveness of I_Ca. The results also confirm previous work indicating that NO generated by NOS3 is not obligatory for muscarinic inhibition of the -adrenergically regulated I_Ca in ventricular myocytes. Finally these results demonstrate for the first time that NO generated by NOS3 is not involved in muscarinic rebound stimulation of I_Ca in ventricular myocytes.

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