TUMOR NECROSIS FACTOR(ALPHA) INHIBITS CONTRACTIONS TO SYMPATHETIC-NERVE STIMULATION BY A NITRIC OXIDE-DEPENDENT MECHANISM

Gram-negative sepsis and administration of tumor necrosis factor(alpha ) (TNFalpha) are associated with hypotension and peripheral neuropathi es suggestive of Impaired sympathetic neurotransmission. We examined t he effect of TNFalpha on the responses of the bovine pulmonary artery (BPA) to transmural sympathetic nerve stimulation (SNS). BPA contracte d to SNS (0.5-32 Hz, 5-10 V, 2-msec duration, 2-msec delay) in a frequ ency-dependent manner. The contractions of the BPA to SNS were mediate d by norepinephrine and activation of postsynaptic alpha(1)-adrenocept ors, since they were attenuated by prazosin. Maximum contraction of th e BPA to SNS was significantly enhanced (148 +/- 37% increase, n = 6) after inhibition of nitric oxide synthase with L-N-G-monomethylarginin e (LNMMA, 500 mu M), an effect abrogated by L-arginine (1 mM). TNFalph a (0.0042, 0.042, and 0.42 mu g/ml) selectively inhibited contractions of the BPA to SNS without affecting the contraction of the BPA to exo genous norepinephrine. In BPA incubated with LNMMA (5-500 mu M), TNFal pha facilitated rather than inhibited SNS. TNFalpha increased the form ation of amperiometrically measured free nitric oxide in bovine adrena l chromaffin cells in primary culture. The data show that in the absen ce of LNMMA, TNFalpha releases free nitric oxide from a sympathetic ne uron and selectively inhibits the contractions of the BPA to SNS. In B PA in which nitric oxide synthase I is inhibited by LNMMA, TNFalpha am plifies the contractions to SNS, even in the absence of endothelium. T hus, TNFalpha can modify vascular smooth muscle tone by affecting SNS. TNFalpha inhibits SNS at the level of the neuron by a mechanism invol ving the L-arginine-nitric oxide pathway. TNFalpha-induced suppression of SNS and neurotransmission may contribute to the hypotension and pe ripheral neuropathy of sepsis.