Acute coadministrations of an inhibitor of endopeptidase 24.11 (thiorphan) and a ligand (SC-46542) selective for the non-guanylate cyclase-llnked atriopeptin binding sites increases urinary sodium excretion to a greater degree in conscious spontaneously hypertensive rats than in normotensive Wistar-Kyoto rats. In the present study, we examined the effects of chronic 10-day intravenous infusions of SC-46542 (desIPhe'^Gly'^Ala^Gln" 6 ] atriopeptin-(103-126)) (0.1 mg/kg/hr), thiorphan (1.5 mg/kg/hr), and atriopeptin-(103-126) (100 ng/hr) alone or in combination on direct recording of mean arterial pressure in conscious spontaneously hypertensive rats. During an 11-day time-control infusion of isotonic saline vehicle (100 /tl/hr), mean arterial pressure remained stable. Chronic infusion of atriopeptin-(103-126) decreased mean arterial pressure progressively over the first 3 days; then mean arterial pressure progressively rose to control level over the following 3 days and remained at control level for the remainder of the experiment Similarly, coinfusions of atriopeptin-(103-126) and SC-46542 or thiorphan, SC-46542 and thiorphan, or the triple infusion of atriopeptin-(103-126), SC-46542, and thiorphan had only transient effects on mean arterial pressure during 10-day infusions. SC-46542 alone had no effect on mean arterial pressure. Similarly, thiorphan alone had no effect on mean arterial pressure except at doses that blocked the acute pressor response to angiotensin I. Chronic infusions of atriopeptin-(103-126), SC-46542, and thiorphan alone or in combination are not effective long-term treatments for hypertension in spontaneously hypertensive rats. (Hypertension 1990; 16:642-647)

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Angiotensin II (ANG II) is believed to promote progressive renal injury via augmented glomerular capillary hydraulic pressure (PGC). Acute volume reduction secondary to diuretic administration increases circulating ANG II and augments PGC, yet the hemodynamic effects of sustained diuretic administration are unknown. Therefore, glomerular micropuncture studies were performed in male Munich-Wistar rats after 6–8 wk of treatment with daily furosemide (F, 40 mg/day), furosemide plus the AT1 receptor antagonist, losartan (F + L, 5 mg/day), or no therapy (C, control). Renal weight was increased in F rats (1.23 ± 0.7 g) vs. C (1.00 ± 0.06 g) or F + L (0.97 ± 0.01 g). In addition, PGC was elevated in F animals (52.1 ± 1.5 mmHg) vs. C (43.7 ± 1.5) or F + L-treated rats (41.3 ± 1.7). F-treated rats were also characterized by a relative increase in efferent arteriolar resistance and filtration fraction. The latter was markedly attenuated in F + L-treated animals. Collectively, these findings are consistent with an ANG II-mediated alteration in intrarenal hemodynamics. In contrast to acute volume manipulations, however, chronic furosemide augmented renal growth, whereas losartan administration completely arrested this phenomenon. Further studies are warranted to determine whether the hemodynamic and growth adaptations elicited by chronic F administration induce or accelerate renal injury.