The present study examines the effects of prolonged angiotensin II antagonism in spontaneously hypertensive rats by using an angiotensin II receptor antagonist (DuP 753) that is devoid of agonistic properties and selective for the subtype 1 of the angiotensin II (AT,) receptor. The antihypertensive effects of DuP 753 and its effects on circulating parameters of the reninangiotensin system were compared with those of a converting enzyme inhibitor (benazeprilat). To minimize any influence of differences in the pharmacokinetic properties of the two blockers, administration was by continuous intravenous infusion. The experiments were performed in conscious, freely moving rats with continuous 24-hour monitoring of blood pressure. DuP 753 (10 or 30 mg/kg/day) lowered mean arterial pressure to the same extent as benazeprilat (3 or 10 mg/kg/day) during a 48-hour period. The antihypertensive effect was sustained when the treatment was extended to 7 days (DuP 753,10 mg/kg/day, benazeprilat, 3 mg/kg/day). Neither of the compounds affected the baseline or diurnal rhythm of heart rate. Plasma concentrations of renin and angiotensin II were increased sevenfold and 10-fold, respectively, in the rats treated with DuP 753. In rats treated with benazeprilat, plasma renin concentration increased threefold, whereas angiotensin II was unchanged. Heart weights were significantly reduced to a similar extent by DuP 753 and benazeprilat Both compounds also induced a smaller but significant decrease in blood pressure in Wistar-Kyoto rats. Our results indicate that the antihypertensive effects of converting enzyme inhibitors in spontaneously hypertensive rats are mainly due to the blockade of the renin-angiotensin system. In this rat model, angiotensin II appears to play an important role in the maintenance of hypertension that is mediated via the AT, receptor. {Hypertension 1991;18:278-288) T he spontaneously hypertensive rat (SHR) is an inbred strain that develops high blood pressure with increasing age and is widely used as a model of human essential hypertension.1 Similar to most patients with essential hypertension, SHR have normal or decreased plasma renin activity (PRA) and are not considered to be a renin-dependent model of hypertension. Nevertheless, angiotensin I converting enzyme (ACE) inhibitors lower blood pressure in SHR and in patients with essential hypertension. 2ÂCE inhibitors not only completely prevent the development of hypertension in SHR, if administered from an early age, but also lower blood pressure in adult SHR with established hypertension. In contrast to ACE inhibitors, peptidic angiotensin II (Ang II) antagonists 4 and Ang II antibodies 5 do not consistently lower blood pressure in SHR. In addition, the plasma renin-angiotensin system (RAS) is not elevated in SHR; these observations suggest that the effects of ACE inhibitors could be due to non-Ang II-mediated mechanisms.2 -3 However, there is also evidence indicating that the effects of ACE blockade are mediated mainly via Ang II. The antihypertensive effect...
Inhibitors of the renin-angiotensin system lower blood pressure of spontaneously hypertensive rats, although plasma renin is not elevated. To test the hypothesis that the actions of angiotensin II within the kidney may contribute to the high blood pressure in spontaneously hypertensive rats, we infused valsartan, a subtype 1 angiotensin II receptor antagonist, via the suprarenal artery into the right kidney of conscious, freely moving, unilaterally nephrectomized (left) spontaneously hypertensive rats (12 to 14 weeks old). Valsartan (03 mg/kg per day for 48 hours) lowered blood pressure (change in blood pressure, -7 ± 3 , -1 9 ± 4 , and -2 6 ± 4 mm Hg, n = l l , at 12, 24, and 48 hours) after intrarenal administration but had no significant effect on blood pressure after intravenous administration (change in blood pressure, 1±5, -3 ± 4 , and 10±5 mm Hg, n=l, at 12, 24, and 48 hours). Infusion of vehicle (0.9% saline) intrarenally had no significant effect on blood pressure (change in blood pressure, 2±5, -1 ± 6 , and 0±7 mm Hg, n = l l , at 12, 24, and 48 hours). The maximum fall in blood pressure reached after intrarenal administration of this dose of valsartan was similar to the maximum fall induced after intravenous administration of higher doses (change in blood pressure, -1 4 ± 5 , -27±4, and -3 2 ± 5 mm Hg, n=7, at 12,24, and 48 hours after 3 mg/kg per day i.v.). Thus, endogenous angiotensin II acting within the kidney appears to play an important role in the maintenance of high blood pressure in spontaneously hypertensive rats. Renal function studies have shown that renal hemodynamic abnormalities may be involved in the initiation of hypertension in SHR. Young SHR (4 to 6 weeks) are moderately hypertensive and have a reduced glomerular filtration rate and renal blood flow and an increased renal vascular resistance compared with the normotensive Wistar-Kyoto control strain. 2 -3 Moreover, an exaggerated salt and water retention has been detected in young SHR. 2 As the hypertension develops, renal hemodynamic abnormalities become normalized (after 12 to 14 weeks of age). The low renal blood flow and glomerular filtration rate in young SHR may be a stimulus for BP to increase and return renal perfusion to normal. SHR have a normal to low plasma renin activity 4 -5 and have not generally been considered to be a renindependent model of hypertension. 6 However, the antihypertensive efficacy of renin inhibitors, 7 angiotensin converting enzyme (ACE) inhibitors, 7 " 9 and angiotensin II (Ang II) receptor antagonists 510 in SHR implicates an involvement of the renin-angiotensin system in the pathogenesis of hypertension in this animal model. Treatment of SHR with an ACE inhibitor normalizes glomerular filtration rate, renal blood flow, renal vascular resistance, and BP, 9 suggesting a role for Ang II in both the renal hemodynamic abnormalities and development of hypertension. The observation that the antihypertensive response induced by renin inhibition, ACE inhibition, or Ang II receptor antagonism in SHR is abol...
Converting enzyme inhibitors impair renal function of the kidney beyond a stenosis of the renal artery in humans and induce histologlcal lesions in the clipped kidney of renal hypertensive rats. In two-kidney, one clip hypertensive rats, we compared the time course and magnitude of the biochemical effects of angiotensin converting enzyme inhibition on the plasma renin-angiotensin system, cardiac hypertrophy, renal lesions, and 24-hour blood pressure decrease induced by either intermittent angiotensin converting enzyme inhibition administration (benazepril PO, 10 mg/kg once a day, n=93) or continuous administration (benazeprilat, 3 mg/kg per day via osmotic pumps, n=92). Control rats (n=91) received the drug vehicle intermittently or continuously. Mortality was significantly reduced by both intermittent (n=3/93) and continuous (n=3/92) inhibition compared with controls (n=18/91) (P<.001). Changes in the plasma renin-angiotensin system and blood pressure were parallel. A continuous suppression of the activity of the plasma renin-angiotensin system was associated with a 24-hour decrease in blood pressure with continuous inhibition, whereas intermittent inhibition induced a similar fall in blood pressure only for the first hours after gavage. Heart weight (5.12±0.12, 3.98±0.09, 4_32±0.12 g/kg in controls [n=8], continuous inhibition [n=18], and intermittent inhibition [n=18], respectively) was significantly reduced to the same extent by both treatments (P<.0001), and clipped kidney weight (3.28±0.11, 1.83±0.12, 2.20±0.15 g/kg in controls [n=8], continuous inhibition [n=18], and intermittent inhibition [n=18], respectively) was significantly reduced in both groups of treated rats (P<.0001). After removal of the undipped kidney, plasma creatinine was significantly increased in both treatment groups (7 > <.0001) compared with nephrectomized hypertensive control rats but to a significantly greater extent in the continuously inhibited rats (117±39, 317±8, 260±8 /u.mol/L in controls [n=8], continuous inhibition [n=18], and intermittent inhibition [n = 18]; P<.0001). Therefore, changes in blood pressure and the plasma renin-angiotensin system were parallel after either continuous or intermittent inhibition. It was possible to decrease blood pressure continuously during 24 hours only with continuous inhibition. Both treatments reduced heart weight to a similar extent. Damage to the clipped kidney, as revealed by elevated plasma creatinine levels after nephrectomy of the undipped kidney, was slightly reduced but not avoided by the intermittent inhibition. (Hypertension 1993^2:188-196) KEY WORDS • hypertension, renovascular • angiotensin converting enzyme inhibition • angiotensin II • rat studies T he intrarenal renin-angiotensin system (RAS) plays a major role in sustaining glomerular filtration rate in situations in which the system has been stimulated, such as sodium depletion, renal artery stenosis, or congestive heart failure.1 ' 2 Under these circumstances, angiotensin I converting enzyme (ACE) inhibition impairs rena...
A radioinhibitor binding assay and an enzyme inhibition assay have been developed to measure plasma levels of CGP 38 560, a potent human renin inhibitor. The detection limit of the assays was between 0.5 and 1 pmol/ml. There was a good correlation (r=0.989) between the two assays for the measurement of human plasma spiked with CGP 38 560 in concentrations from 1.9 nM to 12 fiM. Intra-assay variability was 6.1-17.3% and 4.4-27.2% for the radioinhibitor binding assay and the enzyme inhibition assay, respectively. Interassay variability was 6.0-28.2% and 3.8-28.4% for the radioinhibitor binding assay and the enzyme inhibition assay, respectively. Blood samples were collected during a pharmacological study performed in normotensive human volunteers on an unrestricted diet who were infused during a 30-minute period with T he renin-angiotensin system plays a major role in the regulation of blood pressure and in the maintenance of sodium and volume homeostasis. The enzymatic cleavage of angiotensinogen by human renin (EC 3.4.23.15) generates a decapeptide, angiotensin I, which is immediately hydrolyzed by a carboxydipeptidyl hydrolase, the angiotensin converting enzyme (EC 3.4.15.1), to the octapeptide angiotensin II, a potent vasoconstrictor. Renin has only one known substrate, angiotensinogen, and therefore provides an interesting target for the design of specific blockers of the renin-angiotensin system. During recent years, several specific and potent inhibitors of primate renin have been synthesized and characterized in vitro and in vivo. The in vitro studies have demonstrated the potency and specificity of the compounds against renin from different species and other aspartic proteinases, 1 and the in vivo studies have demonstrated the effects of renin inhibitors on blood
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