Response of large and small vessels to α and β adrenoceptor stimulation in heart failure: effect of angiotensin converting enzyme inhibition

Abstract

The increased sympathetic drive in chronic heart failure (CHF) might provoke vascular adrenoceptor desensitization, which, together with endothelial dysfunction, could contribute to the altered vasomotor tone seen in CHF. We investigated 1) whether CHF alters the responses mediated by alpha and beta adrenoceptors in small and large peripheral arteries, and 2) the effect of angiotensin-converting enzyme (ACE) inhibition. Rats with CHF (coronary artery ligation) were treated with placebo or the ACE inhibitor lisinopril (10 mg/kg/d) starting 7 days after ligation. Responses to phenylephrine (alpha 1 agonist), salbutamol (beta 2 agonist) as well as acetylcholine (endothelium-dependent), were assessed after 3 months in isolated and pressurized segments of the abdominal aorta, the femoral and the mesenteric arteries. In animals with hemodynamic signs of CHF, neither the vasoconstrictor responses to phenylephrine nor the vasodilator response to salbutamol were affected. In contrast, the dilator response to acetylcholine of both small arteries, but not that of the aorta, was impaired. Furthermore, CHF did not modify vessel structure. While lisinopril did not modify the responses to adrenergic agonists, it normalized the response to acetylcholine. Furthermore, ACE inhibition reduced vascular media cross sectional area and collagen density. Thus, the unchanged arterial responsiveness to adrenoceptor agonists does not indicate any vascular adrenoceptor desensitization, while endothelial dependent vasodilation of small arteries is impaired in CHF. ACE inhibition does not modify the response to adrenergic stimuli, prevents endothelial dysfunction and induces both cardiac and vascular remodeling, which probably contribute to the effect ACE inhibitors have on exercise tolerance and survival.

Impaired neuronal and vascular responses to angiotensin II in a rabbit congestive heart failure model

“…Functional studies addressing the vascular responsiveness to many vasoactive substances in HF have yielded conflicting outcomes. [30][31][32][33] Factors involved may be receptor desensitisation and endothelial integrity/function, in addition to vascular structure adaptations. The decreased aortic contractility probably involves structural changes, such as remodelling and collagen accumulation, secondary to either increased pressure or neurohumoral changes associated with HF (highly activated RAS and SNS), as was previously suggested.…”

MECHANISM OF INCREASED Α1‐ADRENOCEPTOR‐MEDIATED CONTRACTION IN SMALL RESISTANCE ARTERIES OF RATS WITH HEART FAILURE

“…In heart failure, increased responses to the α 1 ‐AR agonist phenylephrine have been reported 3,4 . However, other studies have reported no change 5,6 or a decrease 7 in α 1 ‐AR reactivity in heart failure. Therefore, changes in α 1 ‐AR signalling in heart failure arteries remain unclear.…”

Estudo da função em artérias de resistência de ratos pós-infarto do miocárdio.

“…Já nas células de músculo liso vascular, a estimulação do receptor β-adrenérgico promove vasodilatação pela ativação da via adenilato ciclase/ AMPc/ PKA, a qual promove hiperpolarização e diminui a sensibilidade dos miofilamentos ao cálcio (Rembold, Chen, 1998;Ferro et al, 2004). Existem relatos na literatura de que o relaxamento mediado pela ativação dos receptores β-adrenérgicos está preservado nas artérias da musculatura esquelética de ratos com insuficiência cardíaca após o infarto do miocárdio (Mulder et al, 1997) e de cães com insuficiência cardíaca induzida por marcapasso ectópico (Frey et al, 1989). Enquanto que, na aorta e na artéria pulmonar de ratos com insuficiência induzida por infarto do miocárdio (Nasa et al, 1996;Toyoshima et al, 1998;Gaballa et al, 2001;Spooner et al, 2004), assim como, na artéria pulmonar e na artéria coronária de cães com insuficiência cardíaca induzida por marcapasso ectópico (Mathew et al, 1993;Larosa, Foster, 1996), observa-se redução do relaxamento mediado pela ativação dos receptores β-adrenérgicos.…”