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

Abstract

Abstract-Carbon monoxide has been identified as an endogenous biological messenger in the brain. Heme oxygenase catalyzes the metabolism of heme to carbon monoxide and biliverdin. Previously, we have shown the involvement of carbon monoxide in central cardiovascular regulation, baroreflex modulation, and glutamatergic neurotransmission in the nucleus tractus solitarii of rats. We also showed that adenosine increased the release of glutamate in the nucleus tractus solitarii. In this study, we investigated the possible interactions of carbon monoxide and adenosine in the nucleus tractus solitarii. Male Sprague-Dawley rats were anesthetized with urethane, and blood pressure were monitored intra-arterially. Unilateral microinjection of increasing doses of hemin (0.01 to 3.3 nmol), a heme molecule cleaved by heme oxygenase to yield carbon monoxide, produced a significant decrease in blood pressure and heart rate in a dose-dependent manner. In addition, similar cardiovascular effects were observed after injection of adenosine (2.3 nmol). These cardiovascular effects of hemin were attenuated by prior administration of the adenosine receptor antagonist 1,3-dipropyl-8-sulfophenylxanthine. Similarly, pretreatment of the heme oxygenase inhibitor zinc protoporphyrin IX or zinc deuteroporphyrin 2,4-bis glycol also attenuated the depressor and bradycardic effects of adenosine.These results indicate that the interaction between carbon monoxide and adenosine may contribute to the activation of heme oxygenase in central cardiovascular regulation. Key Words: central nervous system Ⅲ blood pressure Ⅲ adenosine Ⅲ heart rate Ⅲ neuroregulators T he gaseous compound carbon monoxide (CO), a new neuromodulator agent, has been shown to play a role as a neurotransmitter. 1 In animals, the predominant source of CO generation is from heme degradation. Heme oxygenase (HO) is the rate-limiting enzyme responsible for the catabolism of heme and subsequent production of CO and biliverdin. Three isoforms of HO have been identified. HO-1, induced by heme and numerous oxidative stressors, is enriched in spleen and liver. HO-2 is present abundantly in the brain and testis as a constitutive enzyme. HO-3 has been identified in brain, heart, kidney, liver, testis, and spleen. 1 Studies have suggested that CO arising from heme through metabolism by HO stimulates soluble guanylate cyclase (sGC) activity and promotes an increase in cGMP in neural and cardiovascular tissues. [2][3][4] These results implicate the HO/CO system as a potential regulator of various neural and cardiovascular functions.HO is widely expressed in the brain and is responsible for the CO-generating ability of the brain, including brain stem. 2,5 In the central nervous system (CNS), the nucleus of the solitary tract (NTS) is the site where afferent fibers arising from arterial baroreceptor, chemoreceptors, cardiopulmonary receptors, and other visceral receptors form the first central synapses 6 and thus play an important role in the integration of autonomic control of the cardiovascul...

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

“…1, A and B). These results were similar to our previous findings (Lo et al, 2000;Lin et al, 2003). It has been 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 (Johnson et al, 1996).…”

“…In agreement with our previous finding, intra-NTS microinjection of hemin (1 nmol), a heme molecule cleaved by HO to yield CO, resulted in hypotension and bradycardia (Lo et al, 2000;Lin et al, 2003). The administration of vehicle (30% 0.1 N NaOH) itself elicited only slight cardiovascular effects, and the pattern of response was different from that of hemin.…”

“…It has been reported that CO formed within the NTS subserves a vasodepressor mechanism that is tonically active in awake rats (Johnson et al, 1997). Furthermore, we have shown that unilateral microinjection of hemin or hematin, a heme molecule cleaved by HO to yield CO, into the NTS produce dose-related depressor and bradycardic effects (Lo et al, 2000;Lin et al, 2003). On the other hand, either systemic administration (Johnson et al, 1997) or direct microinjection of HO inhibitor zinc deuteroporphyrin 2,4-bis glycol into the NTS attenuates the baroreceptor reflex (Lo et al, 2000).…”

Interactions of Carbon Monoxide and Metabotropic Glutamate Receptor Groups in the Nucleus Tractus Solitarii of Rats

“…It has recently been pointed out that carbon monoxide formed within the nucleus tractus solitarii subserves a vasodepressor mechanism that is tonically active in awake rats (Johnson et al, 1997). We have previously reported that unilateral microinjection of hemin or hematin, a heme molecule cleaved by heme oxygenase to yield carbon monoxide, into the nucleus tractus solitarii of anesthetized rat produces dose-related depressor and bradycardic effects (Lo et al, 2002;Lin et al, 2003). On the other hand, prior administration of the heme oxygenase inhibitor zinc protoporphyrin IX or zinc deuteroporphyrin 2,4-bis gly-col (ZnDPBG) attenuated the depressor and bradycardic effects of hemin (Lin et al, 2003).…”

Adenosine Modulates Cardiovascular Functions Through Activation of Extracellular Signal-Regulated Kinases 1 and 2 and Endothelial Nitric Oxide Synthase in the Nucleus Tractus Solitarii of Rats

“…These results were consistent with our previous findings. 7,8 Pretreatment with PD98059 did not elicit significant cardiovascular responses ( Figure 1A). Interestingly, the depressor and bradycardic responses of the same dose of adenosine in the NTS were attenuated 10 minutes after PD98059 treatment (Ϫ37.9Ϯ2.9 versus Ϫ21.7Ϯ3.1 mm Hg and Ϫ78.6Ϯ13.2 versus Ϫ52.9Ϯ12.0 bpm, respectively; PϽ0.05, paired t test; nϭ6; Figure 1A and 1B).…”