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

Abstract

The vascular effects of carbon monoxide (CO) resemble those of nitric oxide (NO), but it is unknown whether the two messengers converge or exhibit reciprocal feedback regulation. These questions were examined in microdissected perfused renal resistance arteries (RRA) studied using NO-sensitive microelectrodes. Perfusion of RRA with buffers containing increasing concentrations of CO resulted in a biphasic release of NO. The NO response peaked at 100 nM CO and then declined to virtually zero at 10 microM. When a series of 50-s pulses of 100 nM CO were applied repeatedly (150-s interval), the amplitude 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 inhibited by pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthases (NOS). CO (100 nM) also suppressed NO release induced by 100 microM carbachol, a potent agonist for endothelial NOS (eNOS). RRA from rats in which endogenous CO production from inducible HO was elevated (cobalt chloride 12 h prior to study) also showed suppressed responses to carbachol. Furthermore, responses consistent with these findings were obtained 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 release could be attributed to either stimulation of eNOS or to NO displacement from a cellular storage pool. To address this, direct in vitro measurements with an NO-selective electrode of NO production by recombinant eNOS revealed that CO dose-dependently inhibits NO synthesis. Together, the above data demonstrate that, whereas high levels of CO inhibit NOS activity and NO generation, lower concentrations of CO induce release of NO from a large intracellular pool and, therefore, may mimic the vascular effects of NO.

ERK5 Activation Inhibits Inflammatory Responses via Peroxisome Proliferator-activated Receptor δ (PPARδ) Stimulation

“…The next possible mechanism is down-regulation of iNOS expression by degradation of heme, as an essential cofactor for iNOS protein assembly and activity. Finally, CO, the other product of HO-1, has a protective role and inhibits NO synthase activity (42) or JNK activity and suppresses pro-inflammatory cytokine production (43). In this study, we found that both HO-1 induction and a CO-releasing compound, [Ru(CO) 3 Cl 2 ] 2 , activated ERK5/PPAR␦.…”

Interaction Among Heme Oxygenase, Nuclear Factor-κB, and Transcription Activating Factors in Cardiac Hypertrophy in Hypertension

“…Because cardiac fibrosis is difficult to study in human patients, other than its therapeutic relevance, our findings may have diagnostic implications, because the DOCA-salt model displays distinct fibrotic characteristics. 6 Although the HO system is cytoprotective, 9 -11 some reports indicate that carbon monoxide may interfere with NO-induced vasodilation, 35 causing endothelium-dependent vasoconstriction. 36 These studies suggest that carbon monoxide may have a biphasic effect, and, therefore, the specific conditions under which different experiments are done may be critical to the observed effect.…”

Heme Oxygenase-1 Modulates Fetal Growth in the Rat

“…Deficiency of HO in a human has been described (Yachie et al, 1999) and, as with the HO-1 null mutant mice (Poss and Tonegawa, 1997), there was growth restriction. An effect of HO-1 on cell proliferation (Clark et al, 1997;Deramaudt et al, 1998), vasodilatation (Thorup et al, 1999;Zhang et al, 2001), and postnatal growth (Sabaawy et al, 2001) has been documented. Gene transfer of hHO-1 into coronary endothelial cells promoted angiogenesis (Deramaudt et al, 1998) and inhibitors of HO increased placental resistance (Lyall et al, 2000).…”