Induction of Heme Oxygenase-1 Is Involved in Carbon Monoxide-Mediated Central Cardiovascular Regulation

Abstract

Carbon monoxide (CO) has been identified as an endogenous biological messenger in the brain. Heme oxygenase (HO) catalyzes the metabolism of heme to CO and biliverdin. Previously, we have shown the involvement of CO in central cardiovascular regulation, baroreflex modulation, and glutaminergic neurotransmission in the nucleus tractus solitarii (NTS) of rats. In this study, we examined which HO isoform could be induced after hemin injection in the NTS. We also investigated their in situ distributions in the NTS after induction. Male Sprague-Dawley rats were anesthetized with urethane, and blood pressure was monitored intra-arterially. Unilateral microinjection of hemin (1 nmol), a heme molecule cleaved by HO to yield CO, produced significant decrease in blood pressure and heart rate. These cardiovascular effects of hemin were attenuated by prior administration of HO inhibitor zinc protoporphyrin IX (ZnPPIX). Microinjection of hemin into NTS resulted in significant induction of HO-1 protein expression in situ. Pretreatment of ZnPPIX significantly inhibited the HO-1 induction after hemin injection. No significant changes of HO-2 expression were found after hemin injection and ZnPPIX pretreatment. The in situ inductions of the HO-1 protein expression were further confirmed to be in glial cells and neurons after hemin injections into the NTS. These results indicated HO-1 but not HO-2 might be responsible for the generation of CO and contribute to central control of cardiovascular effects.

Role of Carbon Monoxide in Blood Pressure Regulation

“…Direct injection of hematin into the NTS consistently lowers blood pressure and heart rate. 40,41 The depressor effects of hematin injection into the NTS are similar to those observed with injection of the excitatory amino acid glutamate. Glutamate is the principle neurotransmitter of baroreceptor afferent fibers, which terminate in the NTS.…”

Enhanced Hemeoxygenase Activity in the Rostral Ventrolateral Medulla Mediates Exaggerated Hemin-Evoked Hypotension in the Spontaneously Hypertensive Rat

“…Few studies have directly shown that central HO-CO signaling in the nucleus tractus solitarius (NTS) exerts a tonic restraining influence on sympathetic activity and blood pressure (Johnson et al, 1997;Lo et al, 2006). Although the NTS modulates sympathetic activity and blood pressure, at least partly, via projections to the RVLM (Guyenet et al, 1990), there are no reports on the role of the RVLM HO in blood pressure regulation.…”

“…To this end, ZnPPIX (1 nmol; dissolved in 35% dimethyl sulfoxide in aCSF), in a dose used to inhibit HO-1 in the NTS in conscious normotensive rats (Lo et al, 2006), was microinjected into the RVLM of conscious SHRs or WKY rats 30 min before hemin. It is noteworthy that compared with aCSF microinjection of a similar concentration of dimethyl sulfoxide in aCSF into rat brainstem had no impact on baseline blood pressure or its response to subsequent pharmacologic interventions (Tsukamoto et al, 2002).…”

“…In the first experiment, the HO substrate hemin (1 nmol) was microinjected into the RVLM of conscious SHRs or WKY rats (n ϭ 5 each); the dose was based on reported intra-NTS hemin in normotensive rats (Lo et al, 2006). As a control for hemin and other treatments (see below), equal volume of aCSF (123 mM NaCl, 0.86 mM CaCl 2 , 3 mM KCl, 0.89 mM MgCl 2 , 25 mM NaHCO 3 , 0.5 mM NaH 2 PO 4 , and 0.25 mM Na 2 HPO 4 , pH 7.4) was microinjected into the RVLM of control groups (n ϭ 5 each).…”

“…Mounting evidence implicates carbon monoxide (CO) in blood pressure regulation both centrally and peripherally (Lo et al, 2006;Lee and Yen, 2009;Peterson et al, 2009). Whereas CO could be generated through non-HO pathways, the majority of endogenous CO is generated by HO, which catalyzes heme degradation to CO and biliverdin (Lee and Yen, 2009).…”