Autonomic dysregulation in ob/ob mice is improved by inhibition of angiotensin-converting enzyme

Abstract

The leptin deficient ob/ob mice are insulin resistant and obese. However, the control of blood pressure in this model is not well defined. The goal of this study was to evaluate the role of leptin and of the renin-angiotensin system in the cardiovascular abnormalities observed in obesity using a model lacking leptin. To this purpose, we measured blood pressure in ob/ob and control animals by radiotelemetry combined with fast Fourier transformation before and after both leptin and enalapril treatment. Autonomic function was assessed pharmacologically. Blood pressure during daytime was slightly higher in the ob/ob compared to control mice while no difference in heart rate was observed. Blood pressure response to trimetaphane and heart rate response to metoprolol were greater in ob/ob mice than in control littermates indicating an activated sympathetic nervous system. Heart rate response to atropine was attenuated. Baroreflex sensitivity and heart rate variability were blunted in ob/ob mice, while low frequency of systolic blood pressure variability was found increased. Chronic leptin replacement reduced blood pressure and reversed the impaired autonomic function observed in ob/ob mice. Inhibition of angiotensin converting enzyme by enalapril treatment had similar effects, prior to the loss of weight. These findings suggest that the renin-angiotensin system is involved in the autonomic dysfunction caused by the lack of leptin in ob/ob mice and support a role of this interplay in the pathogenesis of obesity, hypertension, and metabolic syndrome.

Angiotensin AT1A receptors on leptin receptor–expressing cells control resting metabolism

“…Indeed, i.c.v. administration of leptin leads to elevated AT 1A receptor expression in the ARC, and ob/ob mice have decreased expression and activity of angiotensin-converting enzyme (ACE) (15,37,38). Further, administration of leptin to ob/ob mice enhances plasma RAS expression (37,38), and angiotensinogen is expressed in AgRP neurons of the ARC (21).…”

Effect of Tulbaghia violacea on the blood pressure and heart rate in male spontaneously hypertensive Wistar rats

“…Angiotensin II diminishes the sensitivity of this reflex by synaptically inhibiting it in the nucleus tractus solitarii, by increasing sympathetic nerve activity while decreasing the vagal tone to the heart. It also directly stimulates the myocardium, thus, shifting the operating 'set-point' for regulation of sympathetic outflow to higher BP (Isaacson & Reid, 1990;Kumagai & Reid, 1994;Averill, 2000;Averill & Diz, 2000;Bader et al, 2001;Balt et al, 2003;Diz et al, 2008;Smith et al, 2008;Hilzendeger et al, 2010;Arnold et al, 2011). This may explain the reductions in HR observed with the two highest doses of ang II given alone (figure 4.15).…”

Mecanismos associados ao desenvolvimento das complicações do diabetes tipo 2 em camundongos fêmeas ob/ob: papel preventivo do treinamento físico dinâmico aeróbio, resistido ou combinado

“…Outros autores também tem relatado o aumento na resistência à insulina e diminuição da tolerância à glicose (COLEMAN, 1978;LORD & ATKINS, 1985). Somado a essas alterações, podemos observar neuropatia periférica (DREL et al, 2006), autonômica e diminuição da sensibilidade barorreflexa nesse modelo (HILZENDEGER et al, 2010).…”

“…Em camundongos ob/ob, a inibição da enzima conversora de angiotensina (ECA), diminui a modulação simpática e melhora a sensibilidade barorreflexa, sugerindo que a angiotensina II está associada ao desequilíbrio da modulação autonômica em camundongos com deficiência de leptina (HILZENDEGER et al, 2010). Além disto, há evidências de que a angiotensina II diminui a biodisponibilidade de óxido nítrico, diminuindo as defesas antioxidantes do organismo e induz aumento na produção de NADPH no pâncreas.…”

“…Disfunções na modulação autonômica e na sensibilidade barorreflexa também podem estar relacionadas a maior ativação do eixo constritor do sistema renina angiotensina (HILZENDEGER et al, 2010). A ativação desse eixo além de estar relacionada à modulação simpática e sensibilidade barorreflexa, também contribui para o estabelecimento da obesidade e da resistência à insulina (MASSIERA et al, 2001 treinamento físico induz benefícios na razão angiotensina 2/ angiotensina 1-7 tanto em ratos normotensos, como em ratos SHR.…”