The role of nitric oxide in carotid chemoreception.

Immunocytochemical and histochemical studies of cat and rat carotid bodies have revealed a plexus of nitric oxide synthase (NOS)-positive nerve fibers associated with lobules of chemosensory type I cells as well as with the carotid body vasculature. NOS-positive fibers originate from (1) autonomic neurons located in the carotid body and distributed along the carotid sinus nerve (CNS) and IXth cranial nerve which terminate in the adventitial layer of carotid body blood vessels, and (2) from unipolar sensory neurons of the petrosal (IXth nerve) ganglion. Carotid bodies incubated with the NO precursor, 3H-arginine, yield 3H-citrulline, the detectable coproduct of NO synthesis. Furthermore, electrical stimulation of the CNS or exposure of carotid bodies to hypoxic incubation media elevates 3H-citrulline formation. Millimolar concentrations of L-arginine inhibit chemoreceptor activity evoked by hypoxia, an effect which is reversed by the specific NOS antagonist, L-NG-nitroarginine methylester (L-NAME, 0.1 mM). Electrical stimulation of CNS C fibers elevates cyclic GMP in the carotid body vasculature and lobules of type I cells. Cyclic GMP production is reduced during stimulation in the presence of L-NAME, a finding consistent with the known ability of NO to activate a soluble form of guanylate cyclase. Further studies showed that brief (< 1 min) stimulation of CNS C fibers inhibits basal chemoreceptor discharge in a perfused/superfused in vitro carotid body preparation, whereas prolonged (> 5 min) stimulation is required to inhibit the response to hypoxia. The inhibitory effect is reversed by L-NAME. Our combined anatomical, neuropharmacological and electrophysiological data suggest that NO plays a dual role in mediating CNS inhibition, one via its actions on the organ's vasculature and the other through direct effects on the chemosensory type I cells. The former pathway involves cholinergic/NOS presumptive parasympathetic autonomic neurons, while the latter may be mediated by axon reflex or primary affarent depolarization of chemosensory nerve terminals.