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Modulation of guinea-pig cardiac L-type calcium current by nitric oxide synthase inhibitors

Maria Pia Gallo, Dario Ghigo *, Amalia Bosia *, Giuseppe Alloatti ¹, Costanzo Costamagna *, Claudia Penna and Renzo C. Levi ¹

1. Electrophysiological (whole-cell clamp) techniques were used to study the effect of NO synthase (NOS) inhibitors on guinea-pig ventricular calcium current (I_Ca), and biochemical measurements (Western blot and citrulline synthesis) were made to investigate the possible mechanisms of action.

2. The two NOS inhibitors, N ^G-monomethyl-L-arginine (L-NMMA, 1 mM) and N ^G-nitro-L-arginine (L-NNA, 1 mM), induced a rapid increase in I_Ca when applied to the external solution. D-NMMA (1 mM), the stereoisomer of L-NMMA, which has no effect on NOS, did not enhance I_Ca.

3. Western blot experiments gave no indication of the presence of inducible NOS protein (iNOS) in our cell preparation, neither immediately after dissociation nor after more than 24 h. Statistically, there was no significant difference between electrophysiological experiments performed on freshly dissociated cells and experiments performed the next day. Moreover cells prepared and kept in the presence of dexamethasone (3 µM), to inhibit the expression of iNOS, gave the same response to L-NMMA as control cells.

4. The stimulatory effect of L-NMMA (1 mM) on basal I_Ca was reversed by competition with higher doses (5 mM) of externally applied L-arginine, the natural substrate of NOS. The effect of L-NMMA was also eliminated by L-arginine in the patch pipette solution.

5. Intracellular perfusion with GDPS (0·5 mM), which stabilizes the G-proteins in the inactive state, did not affect the L-NMMA-induced stimulation of I_Ca.

6. Carbachol (1 µM) reduced the I_Ca previously stimulated by L-NMMA, and intracellular cGMP (10 µM) prevented L-NMMA enhancement.

7. Simultaneous treatment with L-NMMA and isoprenaline (1 µM) induced a non-cumulative enhancement of I_Ca that could not be reversed by carbachol (1 µM).

8. NO synthesis, measured by the formation of [³H]citrulline from L-[³H]arginine during a 15 min incubation, showed a relatively high basal NO production, which was inhibited by L-NMMA but not affected by carbachol.

9. These results suggest that inhibitors of NOS are able to modulate the basal ventricular I_Ca in the absence of a receptor-mediated pathway, and that NO might be required for the muscarinic reduction of I_Ca under isoprenaline stimulation, even if NO production is not directly controlled by the muscarinic pathway.

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