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Characteristics of nitric oxide-mediated cholinergic modulation of calcium current in rabbit sino-atrial node

X. Han *, L. Kobzik *, D. Severson ¹ and Y. Shimoni ²

1. We have previously shown that nitric oxide (NO) production is essential for cholinergic inhibition of the -adrenergic stimulated L-type calcium current (I_Ca-L) in rabbit pacemaker (sino-atrial node (SAN)) cells. The present experiments demonstrate the presence of constitutive nitric oxide synthase (cNOS) in SAN cells, and characterize the NO-mediated cholinergic response.

2. Immunohistochemical staining, using an antibody prepared against endothelial cNOS, demonstrated that this enzyme was present in single myocytes obtained from the SAN.

3. The activation of cNOS is known to be Ca²⁺ and calmodulin dependent. Strongly buffering intracellular Ca²⁺ with the membrane-permeable chelator BAPTA-AM (10 µM) significantly reduced (and in some cases abolished) the attenuation of I_Ca-L by the muscarinic agonist carbamylcholine (CCh). In contrast, the CCh-induced activation of an outward K⁺ current, I_K,ACh, was unaffected by buffering of [Ca²⁺]_i. The calmodulin inhibitor 48/80 (20 µM) also abolished the attenuation of I_Ca-L by CCh, with no change in the activation of I_K,ACh.

4. Neither thapsigargin nor ryanodine (5-10 µM), agents which deplete intracellular Ca²⁺ stores, significantly changed the attenuation of I_Ca-L by CCh.

5. Pertussis toxin (PTX) completely abolished both the inhibitory action of CCh on I_Ca-L and the activation of I_K,ACh. This establishes that a PTX-sensitive GTP-binding protein links the muscarinic receptor to NO synthase activation in SAN cells.

6. Our hypothesis is that NO leads to activation of a cyclic GMP (cGMP)-activated phosphodiesterase (PDE II) as a mechanism for enhanced cyclic AMP breakdown and I_Ca-L attenuation. This was supported by showing that a specific inhibitor of PDE II, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), blocks the effect of CCh on I_Ca-L, but not on I_K,ACh. Using reverse transcriptase-polymerase chain reaction techniques, we have established that PDE II is the dominant cyclic nucleotide phosphodiesterase isoform in SAN cells.

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