The influence of chronic treatment with the angiotensin I converting enzyme (ACE) inhibitor enalapril on blood pressure, kidney function, and survival was examined in stroke-prone spontaneously hypertensive rats (SHRSP). Male SHRSP that were fed a Japanese rat chow plus a 1% NaCl drinking solution beginning at 7-8 weeks of age developed severe hypertension and stroke; 14 of 18 untreated control SHRSP died by 14 weeks of age and exhibited evidence of cerebrovascular lesions. When enalapril (15 mg/kg/day) was included in the drinking solution of 15 SHRSP, blood pressure was initially reduced by only a slight degree, whereas survival unproved markedly; only one of 10 SHRSP died before the rest were killed at 18 to 21 weeks. The remaining five enalapril-treated SHRSP lived beyond 36 weeks and on histological examination exhibited no evidence of cerebrovascular lesions. Chronic enalapril treatment also prevented the greater urinary excretion of protein and severe renal lesions observed in untreated SHRSP but did not affect urinary salt and water excretion. In anesthetized rats, glomerular filtration rate and tubular reabsorption of water were lower hi untreated control SHRSP when compared with enalapril-treated SHRSP. Mean arterial pressure was comparable in both groups. These data support a possible role for ACE inhibition in the prevention of stroke and maintenance of kidney function independent of any marked change in blood pressure of SHRSP. Whether the protective effects of ACE inhibition relate to reduced angiotensin H formation, increased tissue kinins, or another mechanism remains to be determined. {Hyper-tension 1989;13:115-121) I n 1974 Okamoto and coworkers 1 reported the development of a stroke-prone substrain of the spontaneously hypertensive rat (SHRSP). These animals developed severe hypertension and a high incidence (80%) of cerebrovascular hemorrhage or infarction after 15 weeks of age. The pial arteries of SHRSP showed cellular hyperplasia or proliferation of adventitial cells and fibrinoid necrosis, 1 which resulted in microinfarction. 2 Parenchymal brain lesions were noted that were thought to be the result of vascular leakage.34 Similar abnormalities were observed in the microvasculature of the heart, kidney, and other organs. SHRSP From the Departments of Pharmacology, Pathology, and Medicine, New York Medical College, Valhalla, New York.Portions of this work were previously published in abstract form (FedProc 1987 ;46:1290).Supported by Grant HL-35522 (to C.T.S.) from the National Institutes of Health, Bethesda, Maryland.Address for reprints: Charles T. Stier Jr., PhD, Department of Pharmacology, Basic Science Building, New York Medical College, Valhalla, NY 10595.Received February 5, 1988; accepted October 14, 1988. fed a Japanese rat chow exhibited a higher incidence of stroke than SHRSP fed an American rat chow (88% vs. 30% by 9 months of age). 5 Elevation of sodium intake (by replacing normal drinking water with a 1% NaCl solution) also increased blood pressure and accelerated the onset ...

In the present study we examined whether the angiotensin I converting enzyme inhibitor, captopril, would protect stroke-prone spontaneously hypertensive rats (SHRSP) from stroke and renal pathology over a 26-week period. In the control group of six untreated SHRSP fed Stroke-Prone Rodent Diet and 1% NaCl drinking solution, all animals developed severe hypertension and stroke by 16.1 weeks of age. In eight salt-loaded SHRSP treated with oral captopril (50 mg/kg/day) beginning at 8.4 weeks of age, systolic blood pressure was slightly but temporarily suppressed and then continued to rise; by 12 weeks of age systolic blood pressure reached levels of severe hypertension, 240 +/- 8 mm Hg, and did not differ from that of untreated SHRSP. No deaths or brain lesions were noted in captopril-treated SHRSP despite severe hypertension maintained through 26 weeks of age when the study ended. Captopril treatment prevented increases in urinary protein excretion (14 +/- 2 v 63 +/- 16 mg/day at 11.7 weeks of age, P less than .01) and the severe brain, renal, and cardiac vascular lesions observed in untreated SHRSP. When maintained on Stroke-Prone Rodent Diet and saline, plasma renin activity of untreated SHRSP surviving until 14.5 weeks of age was markedly increased (29.1 +/- 9.4 ng Ang I/mL/h) compared with either untreated SHRSP (9.2 +/- 2.5 ng Ang I/mL/h, P less than .01) or Wistar-Kyoto rats (3.5 +/- 1.0 ng Ang I/mL/h, P less than .01) maintained on standard diet and water.(ABSTRACT TRUNCATED AT 250 WORDS)

1. The effects of two vasodilator polypeptides, bradykinin and eledoisin, were studied in isolated blood-perfused canine kidneys before and after administration of indomethacin, an inhibitor of prostaglandin synthesis, Bradykinin, but not eledoisin, releases renal prostaglandins. 2. Before administration of indomethacin, bradykinin decreased urinary osmolality and increased free qater clearance, whereas eledoisin did not affect the excretion of solute-free water. After administration of indomethacin, the renal vasodilator action of bradykinin was reduced but the vasodilator action of eledoisin was unaffected. 3. Fractional excretion of sodium was not affected by bradykinin before but was increased after administration of indomethacin. Reduction in glomerular filtration rate contributed to changes in sodium excretion produced by bradykinin and eledoisin. 4. The release of prostaglandins from the kidney by bradykinin amplifies the renal vasodilator action of the kinin and possibly mediates its effect on excretion of solute-free water.

Inhibition of prostaglandin synthesis in chloralose-anesthetized dogs reduced renal blood flow, and this reduction closely correlated (r = 0.92, P<0.01) with a decline in the renal efflux of a substance having the properties of PGE 2 . We used solvent extraction and thin-layer chromatography coupled with parallel bioassay to identify and assay the PGE-and PGF-like substances (expressed as PGE 2 and PGF 2a equivalents). Either of two antunflaiunatory acids, indomethacin or meclofenamate, that inhibited conversion of 14 C-arachidonic acid to prostaglandins in renal homogenates decreased the basal concentration of a PGE-like substance in renal venous blood to 0.06 ±0.02 ng/ml from a mean control value of 0.34 ±0.10 ng/ml (P<0.01). This change was associated with a mean reduction in renal blood flow of 45% in spite of increased renal perfusion pressure. Femoral blood flow and cardiac output were variably and insignificantly affected. Changes in the renal efflux of a PGF-like substance induced by indomethacin were unrelated to the decline in renal blood flow. Changes in the efflux of a PGE-like substance from the femoral vascular bed were unrelated to the small and variable changes in femoral blood flow. Extrarenal factors, i.e., humoral, nervous, or cardiopulmonary factors, did not account for the decline in renal blood flow produced by the inhibitors of prostaglandin synthesis, since the inhibitors produced identical effects in the isolated blood-perfused canine kidney. We concluded that PGE 2 participates in maintaining renal vascular tone which heretofore has been ascribed to autonomous, intrinsic renal arteriolar activity.

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