Nitric oxide inhibits human and canine pulmonary vascular tone via a postjunctional, nonelectromechanical, cGMP-dependent pathway.
We examined nitric oxide mediated regulation of pulmonary arterial and venous smooth muscle (PASM and PVSM, respectively): whether this inhibition is mediated via prejunctional receptors on adrenergic nerve endings; whether NO is neuronally derived; the relationship between degree of inhibition and vessel size; and identification of the signalling mechanisms involved. Canine pulmonary vascular tissues were generally quiescent, while human PASM exhibited spontaneous phasic activity. The nitric oxide (NO) synthesis inhibitor Nomega-nitro-L-arginine (L-NNA; 10(-4) M) increased tone and enhanced phasic activity. Electrical field stimulation (EFS) evoked contractions were markedly enhanced by L-NNA in an endothelium-dependent fashion, and antagonized by the NO donor S-nitroso-N-acetylpenicillamine (SNAP; 10(-7) to 10(-5) M). 8-Bromo-cGMP mimicked the effects of SNAP on basal tone and EFS contractions, while an inhibitor of soluble guanylate cyclase mimicked those of L-NNA. While mechanical responses to exogenously added norepinephrine (10(-9)-10(-4) M) were also enhanced by L-NNA and suppressed by SNAP, EFS-evoked excitatory junction potentials were unaffected by SNAP. We conclude that, in human and canine PASM and PVSM, there is a tonic generation of NO originating within the endothelium that does not mediate a prejunctional effect, but which acts postjunctionally to activate a cGMP-dependent pathway within the smooth muscle.
Janssen
L J
LJ
Department of Medicine, McMaster University, Hamilton, ON, Canada. janssenl@fhs.csu.mcmaster.ca
Mardi
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Netherton
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Betti
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D000818:Animals; D006152:Cyclic GMP / Q000502:physiology*; D004285:Dogs; D004558:Electric Stimulation; D004730:Endothelium, Vascular / Q000502:physiology; D006162:Guanylate Cyclase / Q000502:physiology; D006801:Humans; D009569:Nitric Oxide / Q000502:physiology*; D019335:Nitroarginine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011651:Pulmonary Artery / Q000502:physiology*; D011667:Pulmonary Veins / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects
C110881:S-nitro-N-acetylpenicillamine; D019335:Nitroarginine; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D010396:Penicillamine; D006152:Cyclic GMP; D009638:Norepinephrine