Eeffects of angiotensin converting ensyme inhibitors, peroxisome prolieferators activated receptor-α and γ agonists, and statins on a rat model of hypertension

Abstract

Background: Hypertension is a common and complex human disease that causes significant morbidity and mortality worldwide. The role of endothelial dysfunction as an early event of pathophysiologic importance has been recently delineated. Nitric oxide (NO) is an important vasodilator and a potent regulator of inflammation, and mitogenesis. Therefore, inhibition of NO synthesis provided an interesting model of hypertension with specific cardiovascular alterations in which different events of the disease process could be traced. Aim: The aim of this work was to study the cardiovascular abnormalities in a rat model of hypertension induced by administration of the NO synthase inhibitor, N?-nitro-L-arginine methyl ester (L-NAME). In addition, the effects of short and long term administration of an angiotensin converting enzyme inhibitor (Lisinopril), a peroxisome proliferators activated receptor (PPAR)-a agonist (Fenofibrate), a PPAR-? agonist (Pioglitazone) and a statin (Atorvastatin) were studied. Methods: The study was conducted on 128 rats divided into groups and received the studied drugs. Arterial blood pressure and TGF-ß1 were recorded. The animals were then sacrificed and the heart weight/body weight (HW/BW) ratio was calculated. Routinely processed hearts and aortae were examined to assess degree of inflammation or fibrosis. This was followed by immunohistochemical detection of CD68 and PCNA and histochemical staining using Masson trichrome stain. Evaluation was done by computerized image analysis. Results: Short term administration of L-NAME was associated with a significant increase in blood pressure associated with marked myocardial inflammatory response (mostly CD68 positives macrophages) and increased proliferative activity. Long term administration of L-NAME resulted in a significant aggravation of hypertension accompanied by myocardial hypertrophy and significant increase in HW/BW ratio. Extensive fibrosis and a significant increase in plasma TGF-ß1 level were noted. Short term administration of the studied drugs showed that only Lisinopril showed a significant decrease in blood pressure. The inflammatory and proliferative changes were attenuated by short term administration of the studied drugs, yet with different degrees. Long term administration of all drugs except Fenofibrate led to a significant reduction of blood pressure, HW/BW ratio, fibrosis and plasma TGF-ß1. Conclusions: Disturbances of NO production are likely to be major determinants of endothelial dysfunction, hypertension and their pathological consequences; hence, directing therapy towards conserving endothelial NO bioavailability seems to be of paramount importance. The tested drugs were capable of modulating the different aspects of the disease whether the early or late changes, though their profiles were different. Among the studied classes of drugs, Lisinopril was superior in modulating alterations associated with hypertension.

Key words: Rat Model of Hypertension, Angiotensin Converting Enzyme Inhibitors, PPAR-a and ? Agonists, Statins.