Brainstem Phosphorylated Extracellular Signal-Regulated Kinase 1/2-Nitric-Oxide Synthase Signaling Mediates the Adenosine A_2A-Dependent Hypotensive Action of Clonidine in Conscious Aortic Barodenervated Rats

Abstract

The cellular mechanisms that underlie the enhancement of clonidine-evoked hypotension in aortic barodenervated (ABD) rats and its dependence on central adenosine A 2A receptor ( virtually abolished clonidine-evoked hypotension, clonidine-evoked enhancement of RVLM pERK1/2 production was only abrogated by SCH58261 pretreatment. These findings suggest that interventions that act centrally to increase RVLM neuronal pERK1/2 production elicit hypotension via the activation of downstream NOS-NO signaling. The findings also yield insight into a cellular mechanism that might explain the dependence of centrally (clonidine)-mediated hypotension on central A 2A R signaling in the ABD rat.Clonidine-evoked hypotension is enhanced in the aortic barodenervated (ABD) rat, which exhibits normal blood pressure compared with the sham-operated (SO) rat, despite a persistent baroreflex dysfunction and enhanced sympathetic tone (Osborn and England, 1990;Abdel-Rahman, 1992). The latter seems to contribute to the enhanced hypotensive response elicited by clonidine in ABD rats (Abdel-Rahman, 1992). Furthermore, in the same model, pharmacological blockade of central adenosine, and particularly the A 2A , receptor virtually abolished clonidine-evoked hypotension (Nassar and Abdel-Rahman, 2006a). These findings, which established a link between the molecular targets for clonidine, ␣ 2A R, and/or I 1 receptor, and central adenosine receptor signaling, are consistent with the physiological role of central A 2A R. It is noteworthy that in the RVLM, the major neuroanatomical target of clonidine, activation of the adenosine A 2A R causes hypotension (Thomas et al., 2000). However, the cellular mechanism implicated in the hypotension mediated by the activation of central adenosine A 2A R has not been investigated.In the RVLM, pERK1/2 is implicated in decreases or increases in blood pressure, depending on the experimental conditions and the preparation used (Seyedabadi et al., 2001;Springell et al., 2005;Zhang and Abdel-Rahman, 2005). In cell culture studies, A 2A R activation leads to This study was supported in part by National Institutes of Health Grant 2R01 AA07839.Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. , intracisternal; L-NAME, N -nitro-L-arginine methyl ester; BP, blood pressure; HR, heart rate; aCSF, artificial cerebrospinal fluid; MAP, mean arterial pressure; ANOVA, analysis of variance; PD98059, 2Ј-amino-3Ј-methoxyflavone; ir, immunoreactive.

Brainstem Adenosine A1 Receptor Signaling Masks Phosphorylated Extracellular Signal-Regulated Kinase 1/2-Dependent Hypotensive Action of Clonidine in Conscious Normotensive Rats

“…Our findings link central adenosine A 2A R signaling in the brainstem to clonidine-evoked hypotension in conscious ABD rats (Nassar and Abdel-Rahman, 2008) and A 1 R signaling to baroreceptor function in conscious normotensive rats. Compared with sham-operated (SO) rats, ABD rats exhibit up-regulation of the adenosine A 2A R in the RVLM, the major neuroanatomical target of clonidine (Nassar and Abdel-Rahman, 2008). On the other hand, adenosine A 1 R knockdown in the brainstem, by antisense against A 1 R, reduced baroreflex sensitivity in conscious normotensive rats (Mao et al, 1994) to a level comparable with that reported in ABD rats and SHRs (Judy et al, 1976Judy and Farrell, 1979; AbdelRahman, 1992;Prados et al, 1998).…”

“…However, the cellular mechanisms that explain these findings remain unclear. Our findings link central adenosine A 2A R signaling in the brainstem to clonidine-evoked hypotension in conscious ABD rats (Nassar and Abdel-Rahman, 2008) and A 1 R signaling to baroreceptor function in conscious normotensive rats. Compared with sham-operated (SO) rats, ABD rats exhibit up-regulation of the adenosine A 2A R in the RVLM, the major neuroanatomical target of clonidine (Nassar and Abdel-Rahman, 2008).…”

“…In contrast, central A 1 R blockade had no influence on the hypotensive response or the increase in RVLM pERK1/2 elicited by clonidine in ABD rats. These findings support the hypothesis that central adenosine A 1 R signaling opposes the adenosine A 2A R-mediated (pERK1/ 2-dependent) hypotensive response and yield insight into a cellular mechanism that explains the absence of clonidineevoked hypotension in conscious normotensive rats.Clonidine-evoked hypotension is minimal or absent in conscious normotensive rats (Abdel-Rahman, 1992;Ricci et al, 1992;Medvedev et al, 1998) in contrast to animal preparations that exhibit baroreflex dysfunction such as anesthetized (Borkowski and Finch, 1979;Sannajust et al, 1992;Su et al, 2002;Sato et al, 2005) and hypertensive (Judy et al, 1976Judy and Farrell, 1979;Prados et al, 1998) rats and after surgically induced baroreceptor dysfunction [aortic barodenervation (ABD)] (Abdel-Rahman, 1992; Nassar and Abdel-Rahman, 2006, 2008. However, the cellular mechanisms that explain these findings remain unclear.…”

Neuronal Nitric Oxide Synthase–Dependent Elevation in Adiponectin in the Rostral Ventrolateral Medulla Underlies G Protein–Coupled Receptor 18–Mediated Hypotension in Conscious Rats

“…This is important because the role of the phosphoinositide 3-kinase (PI3K)-Akt-ERK1/2 pathway in modulating the redox state in the RVLM and subsequently BP is controversial. Enhanced ERK1/2 phosphorylation and elevated NO levels in the RVLM mediate a pressor (Ibrahim and Abdel-Rahman, 2012a,b;Chan and Chan, 2014) or hypotensive (Zhang and Abdel-Rahman, 2005;Nassar and Abdel-Rahman, 2008;Chan and Chan, 2014) response. Furthermore, enhanced brainstem ERK1/2 phosphorylation by activation of angiotensin II receptor 1 leads to reactive oxygen species (ROS) generation and BP elevation (Kishi et al, 2004;Chan et al, 2007;Hirooka, 2008).…”

Enhancement of Rostral Ventrolateral Medulla Neuronal Nitric-Oxide Synthase–Nitric-Oxide Signaling Mediates the Central Cannabinoid Receptor 1-Evoked Pressor Response in Conscious Rats

“…For example, CB 1 R activation in CA1 hippocampal pyramidal neurons leads to nNOS-NO-dependent suppression of GABAergic neurotransmission (Makara et al, 2007); further, nNOS-derived NO in the brainstem is involved in central blood pressure regulation (Martins-Pinge et al, 1999, 2007Mayorov, 2007;Nassar and Abdel-Rahman, 2008). It is noteworthy that our previous studies implicated the inhibition of GABAergic neurotransmission in the central CB 1 R-mediated sympathoexcitation/ pressor response in conscious rats (Ibrahim and Abdel-Rahman, 2011), and reduced GABA release in the RVLM, caused by nNOS-derived NO, was associated with a pressor response (Chan et al, 2003;Martins-Pinge et al, 2007).…”