J. Gen. Physiol., Volume 111, Number 1, January 1, 1998 113-125

Nitric Oxide Signaling Mediates Stimulation of L-Type Ca²⁺ Current Elicited by Withdrawal of Acetylcholine in Cat Atrial Myocytes

Yong G. Wang, Christine E. Rechenmacher, and Stephen L. Lipsius

From the Department of Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153

A perforated-patch whole-cell recording method was used to determine whether nitric oxide signaling participates in acetylcholine (ACh)-induced regulation of basal L-type Ca²⁺ current (I_Ca,L) in cat atrial myocytes. Exposure to 1 µM ACh for 2 min inhibited basal I_Ca,L (21 ± 3%), and withdrawal of ACh elicited rebound stimulation of I_Ca,L above control (80 ± 13%) (n = 23). Stimulation of I_Ca,L elicited by withdrawal of ACh (but not ACh-induced inhibition of I_Ca,L) was blocked by either 50 µM hemoglobin; 30 µM ODQ or 10 µM methylene blue, inhibitors of soluble guanylate cyclase; 10 µM W-7, a calmodulin inhibitor; or 10 µM L-NIO, an inhibitor of constitutive NO synthase (NOS). In cells incubated in 5 mM l-arginine, ACh-induced rebound stimulation of I_Ca,L was enhanced compared with control responses. Histochemical assay (NADPH diaphorase) indicated that atrial myocytes express constitutive NOS. NO-donor, spermine/NO (SP/NO), >1 µM stimulated basal I_Ca,L. SP/NO-induced stimulation of I_Ca,L was inhibited by 50 µM hemoglobin, 30 µM ODQ, or 5 µM H-89, an inhibitor of PKA, and was unchanged by 50 µM MnTBAP, a peroxynitrite scavenger. When I_Ca,L was prestimulated by 10 µM milrinone, an inhibitor of cGMP-inhibited phosphodiesterase (type III) activity, SP/NO failed to further increase I_Ca,L. In cells incubated in pertussis toxin (3.4 µg/ml for 6 h; 36°C), ACh failed to affect I_Ca,L, but 100 µM SP/NO or 10 µM milrinone still increased basal I_Ca,L. These results indicate that in cat atrial myocytes NO signaling mediates stimulation of I_Ca,L elicited by withdrawal of ACh but not ACh-induced inhibition of basal I_Ca,L. NO activates cGMP-induced inhibition of phosphodiesterase (type III) activity. Upon withdrawal of ACh, this mechanism allows cAMP to recover to levels above control, thereby stimulating I_Ca,L. Pertussis toxin-sensitive G-proteins couple M₂ muscarinic receptors to NO signaling. NO-mediated stimulation of I_Ca,L elicited by withdrawal of ACh may be an important mechanism that rapidly restores cardiac pacemaker and contractile functions after cholinergic suppression of atrial activity.

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