Suppression of proliferation of human coronary artery smooth muscle cells by the nitric oxide donor, S-nitrosoglutathione, is cGMP-independent.
Nitric oxide (NO), delivered by a single addition of S-nitrosoglutathione (GSNO, IC(50) = 60-75 microM), causes the prolonged, multi-day suppression of proliferation of asynchronous, logarithmically growing human (hCASMC, two cell strains), and porcine (porCASMC) coronary artery smooth muscle cells. The inhibition is not cytotoxic, but cytostatic and reversible. Transient exposure (>4-12 h) to GSNO is sufficient to elicit prolonged suppression, but a less than 4 h exposure produces little or no inhibition. Unlike porCASMC and rat and rabbit aortic SMC, hCASMC synthesize little cGMP in response to GSNO stimulation, suggesting loss of NO responsive guanylate cyclase in vitro. The guanylate cyclase inhibitor, ODQ, blocks the slight cGMP synthesis induced by GSNO in hCASMC, but does not prevent GSNO suppression of proliferation. These data support a cGMP independent mechanism for NO induced suppression of hCASMC proliferation which may be significant in the treatment of proliferative coronary artery diseases.
Young
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NitroMed, Inc., Bedford, Massachusetts, 01730, USA. dyoung@hitromed.com
Serebryanik
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Janero
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Tam
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D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects*; D006152:Cyclic GMP / Q000378:metabolism*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D026422:S-Nitrosoglutathione; D013552:Swine
D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D026422:S-Nitrosoglutathione; D005978:Glutathione; D006152:Cyclic GMP