Substance P elicits thromboxane-induced contraction of canine pulmonary veins

The effect of substance P on isolated rings of dog pulmonary vein was examined using tissue bath techniques. Substance P (10^-8-10^-6M) had no effect on baseline tone but equally potentiated matched contractions induced by exogenous norepinephrine (NE) and electrical field stimulation (ES). Potentiations produced by substance P were blocked by the substance P antagonist, [D-Arg¹, D-Pro², D-Tryp^7,9, Leu¹¹] substance P as well as by indomethacine, the thromboxane synthetase inhibitor dazoxiben, and the thromboxane receptor antagonist SQ 29,548. Removal of the endothelium did not alter the substance P potentiation of NE-induced contractions but greatly enhanced the response to exogenous NE. There was marked desensitization to substance P but not to the thromboxane receptor agonist U-46619. We conclude that substance P enhances NE-induced contractions of pulmonary veins by stimulating the production and release of thromboxane A₂ from non-endothelial cells. Thromboxane appears to exert a direct effect on smooth muscle cells rather than enhancing NE release from intramural neurons because the responses to NE and ES were potentiated equally. Desensitization probably resulted from down regulation of substance P receptors or depletion of thromboxane A₂ rather than an effect on thromboxane A₂ receptors.