Reversal of cardiovascular remodelling with candesartan

Abstract

Cardiovascular remodelling, defined as ventricular and vascular hypertrophy together with fibrosis, characterises hypertension following inhibition of the production of the endogenous vasodilator, nitric oxide (NO). This study has determined whether the cardiovascular remodelling following chronic NO synthase inhibition can be reversed by administration of the selective angiotensin II AT 1 -receptor antagonist, candesartan. Male Wistar rats were treated with L-nitroarginine methyl ester (L-NAME, 400 mg/l in drinking water) for eight weeks and with candesartan cilexetil (2 mg/kg/day by oral gavage) for the last four weeks. L-NAME-treated rats became hypertensive with systolic blood pressure increasing from 110±4 mmHg (control) to 170±10 mmHg. Rats developed left ventricular hypertrophy (control 1.70±0.06; L-NAME 2.10±0.04 mg/kg body wt) with markedly increased deposition of perivascular and interstitial collagen. Candesartan returned blood pressure, left ventricular weights and collagen deposition to control values. Echocardiographic assessment showed concentric hypertrophy with an increased fractional shortening; this was reversed by candesartan treatment. Heart failure was not evident. In the isolated Langendorff heart, diastolic stiffness increased in L-NAME-treated rats while the rate of increase in pressure (+dP/dt) increased after eight weeks only; candesartan reduced collagen deposition and normalised +dP/dt. In isolated left ventricular papillary muscles, the potency (negative log EC 50 ) of noradrenaline as a positive inotropic compound was unchanged, (control 6.56±0.14); maximal increase in force before ectopic beats was reduced from 5.0±0.4 mN to 2.0±0.2 mN. Noradrenaline potency as a vasoconstrictor in thoracic aortic rings was unchanged, but maximal contraction was markedly reduced from 25.2±2.0 mN to 3.0±0.3 mN; this was partially reversed by candesartan treatment. Thus, chronic inhibition of NO production with L-NAME induces hypertension, hypertrophy and fibrosis with increased toxicity and significant decreases in vascular responses to noradrenaline. These changes were at least partially reversible by treatment with candesartan, implying a significant role of AT 1 -receptors in L-NAME-induced cardiovascular changes.

The streptozotocin-diabetic rat as a model of the chronic complications of human diabetes

“…Blood glucose concentrations were monitored every 4 weeks by a MediSense Precision Plus kit (Abbott Diagnostics, Melbourne, Victoria, Australia): rats with values ≥15 mmol/L were considered diabetic. Systolic blood pressure was measured every 4 weeks by a tail‐cuff method 17 . Echocardiography was performed every 4 weeks to non‐invasively assess left ventricular size, wall thickness and systolic function 18 …”

“…However, if displacement occurred, then the results of a subsequent impalement were accepted provided the data fitted the above criteria. Collagen deposition in the heart was visualised following picrosirius red staining 16,17 and quantified using laser confocal microscopy.…”

Effect of simvastatin on remodeling of the left ventricle and aorta in L-NAME-induced hypertension

“…Thus, a number of drugs are being tested with the aim to disclose their potential to prevent the development of or reverse left ventricular hypertrophy (LVH) (Brown et al, 2001;Pereira and Mandarim-de-Lacerda, 2002;Simko, 1994;Simko, 1996;Simko et al, 2002). According to recent data, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) seem to protect against pathological myocardial growth.…”

Electrophysiological, Vasoactive, and Gastromodulatory Effects of Stevia in Healthy Wistar Rats

“…Following excision of the heart after euthanasia, the thoracic aorta was promptly removed and placed in gassed (95% O 2 , 5% CO 2 ) Tyrodeʼs physiological salt solution [31]. The aortic vessels were then cleaned of adipose tissue, cut into 4-mm segments and suspended in 25 mL Tyrodeʼs filled organ baths with a resting tension of 10 mN to equilibrate for 30 minutes.…”