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We examined the influence of chronic treatment with ANG-(1–7) on development of hypertension and end-organ damage in spontaneously hypertensive rats (SHR) chronically treated with the nitric oxide synthesis inhibitor l-NAME (SHR-l-NAME). l-NAME administered orally (80 mg/l) for 4 wk significantly elevated mean arterial pressure (MAP) compared with SHR controls drinking regular water (269 ± 10 vs. 196 ± 6 mmHg). ANG-(1–7) (24 μg·kg−1·h−1) or captopril (300 mg/l) significantly attenuated the elevation in MAP due to l-NAME (213 ± 7 and 228 ± 8 mmHg, respectively), and ANG-(1–7) + captopril completely reversed the l-NAME-dependent increase in MAP (193 ± 5 mmHg). l-NAME-induced increases in urinary protein were significantly lower in ANG-(1–7)-treated animals (226 ± 6 vs. 145 ± 12 mg/day). Captopril was more effective (96 ± 12 mg/day), and there was no additional effect of captopril + ANG-(1–7) (87 ± 5 mg/day). The abnormal vascular responsiveness to endothelin-1, carbachol, and sodium nitroprusside in perfused mesenteric vascular bed of SHR-l-NAME was improved by ANG-(1–7) or captopril, with no additive effect of ANG-(1–7) + captopril. In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischemia was significantly better in ANG-(1–7)- or captopril-treated SHR-l-NAME, with additive effects of combined treatment. The beneficial effects of ANG-(1–7) on MAP and cardiac function were inhibited when indomethacin was administered with ANG-(1–7), but indomethacin did not reverse the protective effects on proteinuria or vascular reactivity. The protective effects of the ANG-(1–7) analog AVE-0991 were qualitatively comparable to those of ANG-(1–7) but were not improved over those of captopril alone. Thus, during reduced nitric oxide availability, ANG-(1–7) attenuates development of severe hypertension and end-organ damage; prostaglandins participate in the MAP-lowering and cardioprotective effects of ANG-(1–7); and additive effects of captopril + ANG-(1–7) on MAP, but not proteinuria or endothelial function, suggest common, as well as different, mechanisms of action for the two treatments. Together, the results provide further evidence of a role for ANG-(1–7) in protective effects of angiotensin-converting enzyme inhibition and suggest dissociation of factors influencing MAP and those influencing end-organ damage.

The aim of this study was to test the hypothesis that treatment with angiotensin-(1–7) [ANG-(1–7)] or ANG-(1–7) nonpeptide analog AVE-0991 can produce protection against diabetes-induced cardiovascular dysfunction. We examined the influence of chronic treatment (4 wk) with ANG-(1–7) (576 μg·kg−1·day−1 ip) or AVE-0991 (576 μg·kg−1·day−1 ip) on proteinuria, vascular responsiveness of isolated carotid and renal artery ring segments and mesenteric bed to vasoactive agonists, and cardiac recovery from ischemia-reperfusion in streptozotocin-treated rats (diabetes). Animals were killed 4 wk after induction of diabetes and/or treatment with ANG-(1–7) or AVE-0991. There was a significant increase in urine protein (231 ± 2 mg/24 h) in diabetic animals compared with controls (88 ± 6 mg/24 h). Treatment of diabetic animals with ANG-(1–7) or AVE-0991 resulted in a significant reduction in urine protein compared with vehicle-treated diabetic animals (183 ± 16 and 149 ± 15 mg/24 h, respectively). Treatment with ANG-(1–7) or AVE-0991 also prevented the diabetes-induced abnormal vascular responsiveness to norepinephrine, endothelin-1, angiotensin II, carbachol, and histamine in the perfused mesenteric bed and isolated carotid and renal arteries. In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischemia was significantly better in ANG-(1–7)- or AVE-0991-treated animals. These results suggest that activation of ANG-(1–7)-mediated signal transduction could be an important therapeutic strategy to reduce cardiovascular events in diabetic patients.

Quantitative studies of endogenous lysozyme (low molecular weight protein) were performed in rats. Urine and plasma concentrations of lysozyme and inulin were measured spectrophotometrically. An improved lysozyme assay (standard curve established by using egg white-lysozyme) enabled us to determine the mean plasma concentration of endogenous lysozyme (4.4 µg· ml-1) and the urinary concentrations of endogenous lysozyme (between 0.1 and 3.8 µg · ml-1. The urinary concentrations of endogenous lysozyme were found to be dependent on urinary flow rate. High urinary concentrations (ULy) were found at low urinary flow rates (V). The excreted amount of endogenous lysozyme (ULy·V) was independent of urinary flow rate and yielded a constant value of 0.02µg·min-I. Mean glomerular filtration rate (GFR) was 1.2 ml- min-1 while clearance of endogenous lysozyme averaged 0.0039 ml · min-1. Inhibition of endogenous lysozyme reabsorption by cytochrome c was used to estimate the glomerular sieving coefficient of endogenous lysozyme in clearance experiments. CLy/GFR increased from a mean value of 0.0053 in control rats to 0.8 at maximal inhibition of tubular reabsorption of endogenous lysozyme by cytochrome c. Knowing the glomerular sieving coefficient, GFR and the lysozyme concentrations in plasma and urine samples, the filtered, excreted and reabsorbed lysozyme amounts could be calculated: 0.5% excreted and 99.5% reabsorbed. Reabsorbed endogenous lysozyme is stored in the kidney in high amounts (1,983 µg · g-1 kidney).