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.