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• W2095755785 abstract "We have previously shown that nitric oxide (NO) production is essential for cholinergic inhibition of the β‐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. Immunohistochemical staining, using an antibody prepared against endothelial cNOS, demonstrated that this enzyme was present in single myocytes obtained from the SAN. The activation of cNOS is known to be Ca 2+ and calmodulin dependent. Strongly buffering intracellular Ca 2+ 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 [Ca 2+ ] 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 . Neither thapsigargin nor ryanodine (5‐10 μM), agents which deplete intracellular Ca 2+ stores, significantly changed the attenuation of I Ca‐L by CCh. 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. 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." @default.
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• W2095755785 date "1998-06-01" @default.
• W2095755785 modified "2023-10-15" @default.
• W2095755785 title "Characteristics of nitric oxide-mediated cholinergic modulation of calcium current in rabbit sino-atrial node" @default.
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• W2095755785 doi "https://doi.org/10.1111/j.1469-7793.1998.741bm.x" @default.
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