Tumor Necrosis Factorα Inhibits Contractions to Sympathetic Nerve Stimulation by a Nitric Oxide-Dependent Mechanism

Summary

Abstract. Gram-negative sepsis and administration of tumor necrosis factorα (TNFα) are associated with hypotension and peripheral neuropathies suggestive of impaired sympathetic neurotransmission. We examined the effect of TNFα on the responses of the bovine pulmonary artery (BPA) to transmural sympathetic nerve stimulation (SNS). BPA contracted to SNS (0.5-32 Hz, 5-10 V, 2-msec duration, 2-msec delay) in a frequency-dependent manner. The contractions of the BPA to SNS were mediated by norepinephrine and activation of postsynaptic α₁-adrenoceptors, since they were attenuated by prazosin. Maximum contraction of the BPA to SNS was significantly enhanced (148 ± 37% increase, n = 6) after inhibition of nitric oxide synthase with L-N^G-monomethylarginine (LNMMA, 500 μM), an effect abrogated by L-arginine (1 mM). TNFα (0.0042, 0.042, and 0.42 μg/ml) selectively inhibited contractions of the BPA to SNS without affecting the contraction of the BPA to exogenous norepinephrine. In BPA incubated with LNMMA (5-500 μM), TNFα facilitated rather than inhibited SNS. TNFα increased the formation of amperiometrically measured free nitric oxide in bovine adrenal chromaffin cells in primary culture. The data show that in the absence of LNMMA, TNFα releases free nitric oxide from a sympathetic neuron and selectively inhibits the contractions of the BPA to SNS. In BPA in which nitric oxide synthase I is inhibited by LNMMA, TNFα amplifies the contractions to SNS, even in the absence of endothelium. Thus, TNFα can modify vascular smooth muscle tone by affecting SNS. TNFα inhibits SNS at the level of the neuron by a mechanism involving the L-arginine-nitric oxide pathway. TNFα-induced suppression of SNS and neurotransmission may contribute to the hypotension and peripheral neuropathy of sepsis.