Abstract.
Several effects of nitric oxide (NO) on the control of L-type calcium current (I Ca) and of calcium handling in cardiomyocytes have been described. Cardiomyocytes have been shown to express in different conditions all types of nitric oxide synthases (NOS), but the role of NO in the regulation of calcium current remains controversial. Previously, we have shown in guinea pig ventricular cells a stimulatory effect of NOS inhibitors on I Ca. Here we investigate the intracellular mechanisms involved in the putative inhibitory role of NO on basal I Ca in ventricular cells. The stimulatory effect of the NOS inhibitor N G-monomethyl-L-arginine (L-NMMA) (1 mM) was present also in calcium transient measurements, but only after a preincubation with L-arginine (L-arg, 0.1 mM). The nitric oxide scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO, 0.5 mM) increased peak I Ca in a similar manner to NOS inhibitors in whole-cell voltage-clamp experiments. Also ODQ (1H-[1,2,4]oxidiazolo[4,3-a]quinoxaline-1-one, 0.1 mM), a specific inhibitor of a target of NO, the soluble guanylate cyclase, was able to stimulate I Ca. The block of type II phosphodiesterase (cGMP-activated) by EHNA (erythro-9-[2-hydroxy-3-nonyl]adenine, 30 µM) exerted a similar effect on I Ca as PTIO and ODQ. Carbachol (CCh, 1 µM) was able to revert the stimulatory effect on I Ca observed with PTIO, ODQ, and EHNA. We propose that the increase of basal I Ca in guinea pig cardiomyocytes previously observed with L-NMMA depends on the removal of a tonic NO inhibition. This increase of I Ca is mimicked by blocking at different steps the cGMP-cascade activated by NO, suggesting a NO-guanylate cyclase mechanism in the basal control of ventricular calcium current.
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Received after revision: 11 October 2000
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Gallo, M., Malan, D., Bedendi, I. et al. Regulation of cardiac calcium current by NO and cGMP-modulating agents. Pflügers Arch - Eur J Physiol 441, 621–628 (2001). https://doi.org/10.1007/s004240000475
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DOI: https://doi.org/10.1007/s004240000475