Submitted on June 28, 2007
Accepted on October 2, 2007
Enhanced nitric oxide-mediated chemoreceptor inhibition and altered cyclic GMP signaling in rat carotid body following chronic hypoxia
Liang He1, Jia Chen1, Xuemei Liu1, Bruce Dinger1*, and Salvatore Fidone1
1 Physiology, University of Utah, Salt Lake City, Utah, United States
* To whom correspondence should be addressed. E-mail: b.dinger{at}utah.edu.
Multiple studies have shown that CH elicits a time-dependent up-regulation of carotid body chemoreceptor sensitivity in mammals. In the present study we demonstrate that enhanced excitation is accompanied by a parallel increase of nitric oxide-(NO)-dependent inhibition, which acts via a CH-induced modification of the normal mechanism in O2-sensitive type I cells. The nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), elicits a progressively larger increase in carotid sinus nerve (CSN) chemoreceptor activity following incremental increases in CH exposure lasting 1-16 days. The inhibitory effect of the NO donor, S-nitroso-N-acetyl-penicillamine (SNAP), on CSN activity is enhanced following CH. However, the activation of soluble guanylate cyclase (sGC) by SNAP, assessed via production of cGMP, is impaired, along with decreased expression of sGC mRNA transcript. Inhibition of hypoxia-evoked Ca2+-responses by SNAP is mediated via a cGMP/PKG-dependent mechanism in normal type I cells which is sensitive to the protein kinase G (PKG) inhibitor KT5823, but following CH inhibitory responses are minimally sensitive to PKG inhibition. The data are consistent with the hypothesis that CH hampers cGMP-mediated inhibition of type I cells in favor of an alternative mechanism.
