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Research ArticleCARDIOVASCULAR

Effects ofN G-Monomethyl-l-arginine on Ca2+ Current and Nitric-Oxide Synthase in Rat Ventricular Myocytes

Shigeji Matsumoto, Toshiaki Takahashi, Mizuho Ikeda, Toshimi Nishikawa, Shinki Yoshida and Tomoyuki Kawase
Journal of Pharmacology and Experimental Therapeutics July 2000, 294 (1) 216-223;
Shigeji Matsumoto
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Toshiaki Takahashi
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Mizuho Ikeda
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Toshimi Nishikawa
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Shinki Yoshida
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Tomoyuki Kawase
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Abstract

The effects ofNG-monomethyl-l-arginine (l-NMMA), a nitric-oxide synthase (NOS) inhibitor, on the L-type Ca2+ current (ICa) and NO effects on NOS were determined in rat ventricular myocytes. l-NMMA (10 and 100 μM) had no significant effect on basal ICa, but in a cAMP-stimulated condition due to forskolin (1 μM) or milrinone (10 μM), a cGMP-inhibited cAMP-phosphodiesterase (PDE), l-NMMA (10 and 100 μM) concentration dependently augmented ICa. The enhancing effects of l-NMMA (10 and 100 μM) on ICa were not seen in the presence of either a nonselective inhibitor of PDE, 3-isobutyl-1-methylxanthine (20 μM), resulting in a stimulated ICa condition or a cGMP-dependent protein kinase activator, 8-bromo-cGMP (200 μM). 8-Bromo-cGMP (200 μM) inhibited 100 μMl-NMMA-induced ICa increase in the simultaneous application of forskolin (1 μM). Acetylcholine (ACh; 1 and 3 μM) inhibited 1 μM forskolin-stimulated ICa in a concentration-dependent manner, but this inhibitory action of ACh was significantly attenuated by the additional application of l-NMMA (100 μM). In the continuing presence of both l-NMMA (100 μM) and forskolin (1 μM), ACh (6 μM) had no inhibitory effect on ICa. In another series of experiments with isolated ventricular myocytes, we obtained both the positive staining of NADPH-diaphorase activity and the expression of the endothelial isoform of NOS. These data suggest that the effect of l-NMMA on ICa in a cAMP-stimulated condition with or without cholinergic inhibition is due to inhibition (acute effects) of a cGMP-stimulated cAMP-PDE via inhibition of the endothelial isoform of NOS.

Footnotes

  • Send reprint requests to: Dr. Shigeji Matsumoto, Department of Physiology, Nippon Dental University, School of Dentistry at Tokyo, 1-9-20 Fujimi, Chiyoda-ku, Tokyo 102-8159, Japan.

  • Abbreviations:
    NO
    nitric oxide
    cNOS
    constitutive NO synthase
    iNOS
    inducible NOS
    ecNOS
    constitutive endothelial NOS
    l-NMMA
    NG-monomethyl-l-arginine
    PKG
    cGMP-dependent protein kinase
    PDE
    phosphodiesterase
    ICa
    calcium current
    SIN-1
    3-morpholine-syndnonimine
    8-Br-cGMP
    8-bromo-cGMP
    IBMX
    3-isobutyl-l-methyl-xanthine
    ACh
    acetylcholine
    I-V
    current-voltage
    • Received December 21, 1999.
    • Accepted April 5, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 1
1 Jul 2000
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Research ArticleCARDIOVASCULAR

Effects ofN G-Monomethyl-l-arginine on Ca2+ Current and Nitric-Oxide Synthase in Rat Ventricular Myocytes

Shigeji Matsumoto, Toshiaki Takahashi, Mizuho Ikeda, Toshimi Nishikawa, Shinki Yoshida and Tomoyuki Kawase
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 216-223;

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Research ArticleCARDIOVASCULAR

Effects ofN G-Monomethyl-l-arginine on Ca2+ Current and Nitric-Oxide Synthase in Rat Ventricular Myocytes

Shigeji Matsumoto, Toshiaki Takahashi, Mizuho Ikeda, Toshimi Nishikawa, Shinki Yoshida and Tomoyuki Kawase
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 216-223;
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