Modulatory Effects of Carbon Monoxide on Baroreflex Activation in Nucleus Tractus Solitarii of Rats

Abstract

Abstract-Recent studies suggest that carbon monoxide (CO), which is produced in significant quantities in many brain regions, may function as a neurotransmitter. Heme oxygenase catalyzes the metabolism of heme to CO and biliverdin; however, the physiological role of CO in central cardiovascular regulation was not well understood. In the present study, we evaluated the baroreflex response of CO in the nucleus tractus solitarii (NTS) of rats. Male Sprague-Dawley rats were anesthetized with urethane, and blood pressure and heart rate were monitored intra-arterially. Unilateral microinjection (60 nL) of hematin, a heme molecule cleaved by heme oxygenase to yield CO, into the NTS produced prominent dose-related depressor and bradycardic effects. Baroreflex responses were elicited by increasing doses of phenylephrine (10 to 30 g/kg IV) before and after intra-NTS administration of zinc deuteroporphyrin 2,4-bis-glycol (ZnDPBG) (1 nmol), an inhibitor of heme oxygenase activity, or vehicle alone. The reflex bradycardia elicited by phenylephrine was significantly inhibited by pretreatment with ZnDPBG. Furthermore, the inhibitory effect of ZnDPBG on baroreflex activation was dose dependent. These results suggest CO formed by brain heme oxygenase plays a significant role in central cardiovascular regulation and that inhibition of heme oxygenase attenuated baroreflex activation. (Hypertension. 2000;35:1253-1257.)Key Words: bradycardia Ⅲ brain Ⅲ baroreflex C arbon monoxide (CO), previously thought to be a toxic gas and biological waste product, is now being considered a likely candidate in the new class of gaseous neural messengers. 1 In animals, the predominant source of CO generation is heme degradation. Heme oxygenase (HO) is the rate-limiting enzyme responsible for the catabolism of heme and subsequent production of CO and bilirubin. Two forms of HO have been identified. HO-1 is enriched in spleen and liver and is induced by heme and numerous oxidative stressors. In contrast, HO-2 is a constitutive enzyme and is present abundantly in the brain and testis. 2 Recent studies have suggested that CO stimulates soluble guanylate cyclase activity and promotes elevation of cGMP in neural and cardiovascular tissues. [3][4][5][6][7][8] These results have implicated the HO-CO system as a potential regulator of various neural 5,6 and cardiovascular functions. 4,7,8 HO is widely expressed in the brain and is responsible for the impressive CO-generating ability of the brain, including brain stem. 3,6 Zinc deuteroprophyrin 2,4-bis-glycol (ZnDPBG) is an inhibitor of HO activity. 5,9,10 ZnDPBG has been shown to inhibit endogenous CO production in rats 11 and thus has been applied in in vivo studies of the physiological actions of HO.In the central nervous system, the nucleus of the solitary tract (NTS) is the site where afferent fibers arising from arterial baroreceptor, chemoreceptors, cardiopulmonary receptors, and other visceral receptors make the first central synapses 12 and thus play an important role in the integration of autonomic ...

Interaction of Carbon Monoxide and Adenosine in the Nucleus Tractus Solitarii of Rats

“…8 We have previously reported that unilateral microinjection of hematin, a heme molecule cleaved by HO to yield CO, into the NTS of anesthetized rat produce dose-related depressor and bradycardic effects. 9 On the other hand, systemic administration or direct microinjection into the NTS of HO inhibitor zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) attenuates the baroreceptor reflex. 8,9 Taken together, these findings suggest that CO within the NTS may play an important role in the regulation of cardiovascular function.…”

“…9 On the other hand, systemic administration or direct microinjection into the NTS of HO inhibitor zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) attenuates the baroreceptor reflex. 8,9 Taken together, these findings suggest that CO within the NTS may play an important role in the regulation of cardiovascular function.Adenosine has been known to be a potent vasodilator acting through purinergic receptors both on vascular smooth muscle and endothelial cells. This endogenous nucleoside has been studied for its potential role as a neuromodulator in a number of autonomic functions.…”

“…These results were in agreement with our previous findings. 9,18 One report has shown that administration of an HO inducer such as heme-L-arginate or heme-L-lysinate causes a marked decrease in BP in spontaneously hypertensive rats (SHR). 23 Furthermore, there is evidence that HO inhibitors increase BP and peripheral resistance, suggesting that endogenous CO subserves a tonic vasodepressor function.…”

“…9 On the other hand, systemic administration or direct microinjection into the NTS of HO inhibitor zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) attenuates the baroreceptor reflex. 8,9 Taken together, these findings suggest that CO within the NTS may play an important role in the regulation of cardiovascular function.…”

Role of Carbon Monoxide in Blood Pressure Regulation

“…These studies were significant in that they provided the first experimental evidence that CO produced by HO may play a role in central regulation of blood pressure. Additional studies by Lo et al 38 also demonstrated that direct injection of ZnDBPG into the NTS decreased baroreflex sensitivity. It should again be noted that the use of metalloporphyrins as HO inhibitors is not without controversy.…”