Central blockade of nitric oxide synthesis reduces moxonidine‐induced hypotension

Abstract

1 Nitric oxide (NO) and a 2 -adrenoceptor and imidazoline agonists such as moxonidine may act centrally to inhibit sympathetic activity and decrease arterial pressure. 2 In the present study, we investigated the effects of pretreatment with L-NAME (NO synthesis inhibitor), injected into the 4th ventricle (4th V) or intravenously (i.v.), on the hypotension, bradycardia and vasodilatation induced by moxonidine injected into the 4th V in normotensive rats. 3 Male Wistar rats with a stainless steel cannula implanted into the 4th V and anaesthetized with urethane were used. Blood flows were recorded by use of miniature pulsed Doppler flow probes implanted around the renal, superior mesenteric and low abdominal aorta. 4 Moxonidine (20 nmol), injected into the 4th V, reduced the mean arterial pressure (À4273 mmHg), heart rate (À2277 bpm) and renal (À62715%), mesenteric (À4178%) and hindquarter (À5078%) vascular resistances. 5 Pretreatment with L-NAME (10 nmol into the 4th V) almost abolished central moxonidineinduced hypotension (À1073 mmHg) and renal (À1074%), mesenteric (À1174%) and hindquarter (À1376%) vascular resistance reduction, but did not affect the bradycardia (À1878 bpm). 6 The results indicate that central NO mechanisms are involved in the vasodilatation and hypotension, but not in the bradycardia, induced by central moxonidine in normotensive rats.

Brainstem Phosphorylated Extracellular Signal-Regulated Kinase 1/2-Nitric-Oxide Synthase Signaling Mediates the Adenosine A2A-Dependent Hypotensive Action of Clonidine in Conscious Aortic Barodenervated Rats

“…L-NAME (4 g i.c.) had no effect on baseline MAP and HR (Table 1), which agrees with reported findings (Moreira et al, 2004). Pretreatment with L-NAME, compared with aCSF, virtually abolished clonidine-evoked hypotension (Figs.…”

“…Our finding that central NOS inhibi- jpet.aspetjournals.org tion (i.c. L-NAME) attenuated clonidine-evoked hypotension fully agrees with the latter study (Moreira et al, 2004). More importantly, we demonstrated the preservation of clonidineevoked enhancement of RVLM pERK1/2 generation in L-NAME-pretreated rats in spite of the abolition of the hypotensive response (Figs.…”

“…However, these findings did not elucidate the cellular events downstream of pERK1/2. We reasoned that pERK1/2 would activate downstream NOS-NO signaling based on an established signaling pathway in cultured cells (Wyatt et al, 2002;Vá squez et al, 2004), and the following in vivo findings: 1) NOS-derived NO in the RVLM mediates sympathoinhibition and hypotension in rats (Chan et al, 2001), and 2) central NOS inhibition (L-NAME) attenuated moxonidine-evoked hypotension (Moreira et al, 2004). Our finding that central NOS inhibi- jpet.aspetjournals.org tion (i.c.…”

“…The chosen dose of L-NAME had no effect on baseline BP and heart rate, but it attenuated moxonidine (selective I 1 receptor agonist)-evoked hypotension when administered centrally (i.c.v.) (Moreira et al, 2004). pERK1/2 was measured in the RVLM in all groups of rats sacrificed at a time that coincides with the maximal hypotensive response elicited by i.c.…”

Envolvimento da região comissural do núcleo do trato solitário nas respostas cardiovasculares e simpáticas promovidas pela injeção do anti-hipertensivo de ação central moxonidina em ratos.

“…A moxonidina é classicamente classificada como um antihipertensivo de ação central com uma elevada afinidade sobre os receptores imidazolícos localizados na região RVL/C1 e com baixa afinidade para receptores adrenérgicos α 2 . No entanto, nossos e outros resultados mostraram que moxonidina foi capaz de produzir hipotensão e simpatoinibição por uma ação nos neurônios pré-simpáticos localizados na região RVL/C1 e também na região do NTScom (HEAD, 1999;MOREIRA et al, 2004MOREIRA et al, , 2007presentes resultados Embora a região RVL/C1 se apresente como o principal local de ação para a simpatoinibição de fármacos anti-hipertensivos de ação central (HEAD, 1999), os presentes dados mostram claramente que a moxonidina pode estar atuando em outra região encefálica para promover a redução dos neurônios pré-motores simpáticos da região RVL/C1, promovendo uma redução da atividade simpática eferente e consequente queda de pressão arterial. Dessa maneira, acreditamos que a moxonidina promova uma inibição pré-sináptica nos neurônios localizados no…”