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Regulation of cardiac calcium current by NO and cGMP-modulating agents

M P Gallo1, D Malan, I Bedendi

  • 1Dipartimento di Biologia Animale e dell'Uomo e INFM Unità TO Uni, Università di Torino, Italy.

Pflugers Archiv : European Journal of Physiology
|April 11, 2001
PubMed

Insights

Nitric oxide (NO) tonically inhibits L-type calcium current (ICa) in guinea pig ventricular cells. Blocking NO signaling or its downstream cGMP pathway increases ICa, suggesting NO regulates calcium handling.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Nitric Oxide Signaling

Background:

  • Nitric oxide (NO) plays a role in regulating cardiac function, including calcium handling.
  • The precise mechanisms by which NO influences L-type calcium current (ICa) in cardiomyocytes remain controversial.
  • Previous studies suggested a stimulatory effect of nitric oxide synthase (NOS) inhibitors on ICa in guinea pig ventricular cells.

Purpose of the Study:

  • To investigate the intracellular mechanisms underlying the inhibitory role of NO on basal ICa in ventricular cells.
  • To elucidate the signaling pathway involved in NO-mediated regulation of cardiac calcium current.

Main Methods:

  • Whole-cell voltage-clamp experiments to measure L-type calcium current (ICa) in guinea pig ventricular cells.
  • Application of NOS inhibitors (L-NMMA), NO scavengers (PTIO), soluble guanylate cyclase inhibitor (ODQ), and phosphodiesterase inhibitor (EHNA).
  • Calcium transient measurements and experiments with carbachol (CCh) to assess functional effects and pathway reversibility.

Main Results:

  • NOS inhibition (L-NMMA) and NO scavenging (PTIO) increased peak ICa, particularly after L-arginine preincubation.
  • Inhibition of soluble guanylate cyclase (ODQ) and cGMP-hydrolysis (EHNA) mimicked the stimulatory effect of NO removal on ICa.
  • Carbachol (CCh) reversed the stimulatory effects of PTIO, ODQ, and EHNA, indicating involvement of the cGMP pathway.

Conclusions:

  • A tonic inhibitory effect of NO on basal ICa in guinea pig ventricular cells is proposed.
  • The NO-cGMP signaling cascade, involving soluble guanylate cyclase, plays a role in the basal control of ventricular calcium current.
  • Understanding this NO-mediated regulation is crucial for comprehending cardiac calcium handling and potential therapeutic interventions.

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