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We have evaluated the effects of different doses of an angiotensin-converting enzyme (ACE) inhibitor, enalapril (ENA) and of an angiotensin II type 1 receptor blocker olmesartan (OLM), on extracellular matrix of the heart, kidney, aorta and mesenteric artery of spontaneously hypertensive rats (SHR). Forty SHR and eight Wistar–Kyoto controls (WKY) were included in the study. Eight SHR were treated with high-dose OLM 15 mg/kg per day, eight with high-dose ENA 25 mg/kg per day, eight with low-dose OLM 1 mg/kg per day and eight with low-dose ENA (2 mg/kg per day). Eight SHR and eight WKY were kept untreated as controls. Treatment was from age 4 to 12 weeks. Systolic blood pressure (SBP) was measured non-invasively every week. The left ventricular weight to body weight (RLVM) was measured, and the cardiac, aortic and glomerular interstitial collagen content was evaluated using Sirius red staining and image analysis. Mesenteric small arteries were dissected and mounted on a micromyograph, and the media:lumen ratio (M/L) was calculated. Collagen subtypes were evaluated by polarized light microscopy. The SHR treated with high-dose OLM or ENA showed a normalization of SBP. The RLVM was significantly increased in untreated SHR compared with untreated WKY, whereas significantly lower values were observed in the groups of SHR treated with high-dose OLM or ENA. A significant increase in cardiac and glomerular collagen content was observed in untreated SHR. Both high- or low-dose OLM and ENA normalized collagen content in the heart and the kidney. Both high-dose OLM and high-dose ENA normalized M/L ratio; however, OLM proved to be more effective than ENA in normalizing collagen pattern. In fact, aortic collagen content was normalized by both high-dose and low-dose OLM, but only by high-dose ENA. In conclusion, both OLM and ENA were significantly and equally effective in the prevention of cardiac and renal damage in SHR, whereas OLM was more effective than ENA in terms of effects on vascular extracellular matrix. [ABSTRACT FROM AUTHOR]

We have evaluated the effects of an ACE inhibitor, enalapril (ENA) and of an angiotensin II receptor blocker, losartan (LOS), administered either at hypotensive or non-hypotensive dosage, on the cardiac and renal structure of spontaneously hypertensive rats (SHR). Forty-eight rats were included in the study: eight SHR were treated with low-dose (ld, 1 mg/kg/day) ENA; eight with low-dose (ld, 0.5 mg/kg/day) LOS; eight with high-dose (hd, 25 mg/kg/day) ENA; eight with high-dose (hd, 15 mg/kg/day) LOS; while eight Wistar–Kyoto (WKY) and eight SHR were kept untreated (unt). Treatment was given from the 4th to the 12th week of age. Systolic blood pressure (SBP) was measured non-invasively every week. The left ventricular weight to body weight (RLVM) and the left + right kidney weight (RKW) to body weight was measured, and the cardiac and glomerular interstitial collagen content was evaluated using sirius red staining and image analysis. In addition, cardiac metalloproteinases activity (43 kDa MMP, MMP-2, and MMP-9) was evaluated by zymography. A significant reduction in RLVM was observed in SHR given ENA hd or LOS hd. Cardiac collagen was significantly reduced in SHR ENA hd and SHR LOS hd as well as in SHR LOS ld, but not in SHR ENA ld. The 43 kDa MMP collagenase activity was greater in WKY unt compared with SHR unt, being normalized only in SHR ENA hd. The gelatinase activity of MMP-9 showed a trend similar to 43 kDa MMP, but differences between SHR and WKY unt were only of borderline statistical significance. No difference among groups was observed in MMP-2 activity. No significant differences in RKW was observed between groups. However, the collagen content in the glomerular perivascular space was significantly reduced in all treated groups, including those given ld, compared with SHR unt. In conclusion, LOS and ENA showed a similar preventive effect on the increase of RLVM in SHR, but, at least in part, different effects on the extracellular matrix in different organs, being cardiac collagen less sensitive to low dose (ld) ACE inhibition. [ABSTRACT FROM AUTHOR]

Objective: The aim of our study was to investigate contractile responses to endothelin-1 in the presence or absence of selective blockers of ETA or ETB receptors in subcutaneous small resistance arteries of normotensive subjects and of patients with essential hypertension. Methods: Twenty-four subjects (eight normotensives aged 50 ± 4 years, and 16 with essential hypertension aged 53 ± 4 years) were included in the study. All subjects were submitted to a biopsy of the subcutaneous fat. Small resistance arteries (internal diameter 160-280 µm) were dissected and mounted on a micromyograph as a ring preparation (Mulvany's technique). The media-to-lumen ratio was calculated. A concentration-response curve to endothelin-1 was then performed in the presence or absence of FR 139317, (a selective blocker of ETA receptors) or of BQ 788, (a selective blocker of ETB receptors). Results: The media-to-lumen ratio was lower in normotensives compared with those subjects with essential hypertension (0.08 ± 0.02 vs. 0.12 ± 0.05, p < 0.01). The vasoconstriction induced by endothelin-1 was greater in normotensives than in patients with essential hypertension. In normotensives, almost all the vasoconstriction induced by endothelin-1 was blocked by the addition of FR 139317, while in subjects with essential hypertension the effect was smaller. The selective blocker of ETB was devoid of effect in both groups. Conclusions: The vasoconstrictor effect of endothelin-1 in small resistance arteries of normotensive subjects and, in part, also in hypertensive patients is mediated by ETA receptors, while ETB receptors play a minor role, if any. It is, however, possible that a vasoconstrictor effect mediated by ETB receptors located on vascular smooth muscle cells may be masked by the simultaneous stimulation of endothelial ETB receptors which may induce a vasodilation mediated by nitric oxide. [ABSTRACT FROM AUTHOR]