Carbon monoxide induces vasodilation and nitric oxide release but suppresses endothelial NOS

The vascular effects of carbon monoxide (CO) resemble those of nitric oxide (NO), but it is unknown whether the two messengers converge or exhibit rec iprocal feedback regulation. These questions were examined in microdissecte d perfused renal resistance arteries (RRA) studied using NO-sensitive micro electrodes. Perfusion of RRA with buffers containing increasing concentrati ons of CO resulted in a biphasic release of NO. The NO response peaked at 1 00 nM CO and then declined to virtually zero at 10 mu M When a series of 50 -s pulses of 100 nM CO were applied repeatedly (150 s interval), the amplit ude of consecutive NO responses was diminished. NO release from RRA showed dependence on L-arginine but not D-arginine, and the responses to CO were i nhibited by pretreatment with N-G-nitro-L-arginine methyl ester (L-NAME), a n inhibitor of NO synthases (NOS). CO (100 nM) also suppressed NO release i nduced by 100 mu M: carbachol, a potent agonist for endothelial NOS (eNOS). RRA from rats in which endogenous CO production from inducible HO was elev ated (cobalt chloride 12 h prior to study) also showed suppressed responses to carbachol. Furthermore, responses consistent with these findings were o btained in juxtamedullary afferent arterioles perfused in vitro, where the vasodilatory response to CO was biphasic and the response to acetylcholine was blunted. Collectively, these data suggest that the CO-induced NO releas e could be attributed to either stimulation of eNOS or to NO displacement f rom a cellular storage pool. To address this, direct in vitro measurements with an NO-selective electrode of NO production by recombinant eNOS reveale d that CO dose-dependently inhibits NO synthesis. Together, the above data demonstrate that, whereas high levels of CO inhibit NOS activity and NO gen eration, lower concentrations of CO induce release of NO from a large intra cellular pool and, therefore, may mimic the vascular effects of NO.