Inhibition of vasoconstrictor mechanisms by dazoxiben in the rat mesenteric vasculature

Sympathetic neurotransmission can be modulated by prostaglandins in a number of tissues, but it is not known whether thromboxane A₂ also influences neurotransmission. In this study, vasoconstrictor responses to electrical stimulation of the sympathetic nerves and to injection of noradrenaline were examined in the blood perfused mesentry of the rat in situ. The thromboxane synthetase inhibitor dazoxiben, infused into the perfusion circuit at 10–100 μmol/l, significantly inhibited constrictor responses to nerve stimulation and to injected noradrenaline and vasopressin. The cyclo-oxygenase inhibitor indomethacin (28 μmol/kg intravenously) had no effect on responses to nerve stimulation or noradrenaline, but pretreatment with indomethacin abolished the inhibitory effect of dazoxiben vasoconstrictor responses. The thromboxane-mimetic (U46619, 10 nmol/l) slightly reduced responses to nerve timulation (but not to noradrenaline), whereas prostacyclin (3–10 nmol/l) and PGE₂ (3 nmol/l) markedly reduced responses both to nerve stimulation and to injections of noradrenaline. These prostanoids did not alter perfusion pressure at these concentrations. The data suggest that the inhibitory effect of dazoxiben on sympathetic neurotransmission is unlikely to be due directly to inhibition of thromboxane synthesis. Inhibition might result from diversion of endoperoxide metabolism to endogenous prostanoids that, in turn, inhibit activation of vasoconstrictor mechanisms.