Chronic administration of furosemide augments renal weight and glomerular capillary pressure in normal rats.

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.

Chronic atriopeptin regulation of arterial pressure in conscious hypertensive rats.

Acute coadministrations of an inhibitor of endopeptidase 24.11 (thiorphan) and a ligand (SC-46542) selective for the non-guanylate cyclase-linked 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 (des[Phe106,Gly107,Ala115,Gln116] 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 microliters/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.

Atriopeptin regulation and renal function in conscious spontaneously hypertensive rats.

We examined the interaction of a non-guanylate cyclase-linked atriopeptin (AP) binding site ligand, SC-46542 (des[Phe106,Gly107,Ala115,Gln116]AP-(103-126], and an endopeptidase 24.11 inhibitor, thiorphan, on mean arterial pressure, urinary sodium excretion, urinary cyclic guanosine monophosphate (cGMP) excretion, plasma cGMP concentration, and plasma AP immunoreactivity (ir) in conscious spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Compared to vehicle control rats, coadministration of SC-46542 and thiorphan increased urinary sodium excretion in SHR from 2.1 +/- 0.3 to 11.6 +/- 0.7 microEq/min/100 g body weight and in WKY from 1.6 +/- 0.4 to 4.4 +/- 0.4 microEq/min/100 g body weight, and increased urinary cGMP excretion in SHR from 2.7 +/- 0.5 to 79.0 +/- 17.5 pmol/min/100 g body weight and in WKY from 7.0 +/- 3.0 to 72.4 +/- 10.6 pmol/min/100 g body weight. The change in urinary sodium excretion was greater in SHR than WKY. The coadministration of SC-46542 and thiorphan had greater effects on urinary sodium excretion and urinary cGMP excretion than administration of either compound alone. Coadministration of thiorphan and SC-46542 had no effect on glomerular filtration rate or plasma cGMP concentration, suggesting that the urinary cGMP excretion response was nephrogenous. Compared to vehicle control rats, plasma APir was increased during coadministration of SC-46542 and thiorphan in both SHR (998 +/- 76 v 5.10 +/- 116 pg/mL) and WKY (775 +/- 36 v 414 +/- 36 pg/mL).(ABSTRACT TRUNCATED AT 250 WORDS)

Interaction of non-guanylate cyclase-linked atriopeptin receptor ligand and endopeptidase inhibitor in conscious rats.

We examined the interaction of SC-46542 [des(Phe106, Gly107, Ala115, Gln116)-AP(103-126)], a non-guanylate cyclase-linked atriopeptin (AP) binding site ligand, with thiorphan, an inhibitor of endopeptidase 24.11, on mean arterial pressure, urine flow, urinary sodium excretion and plasma AP immunoreactivity in conscious rats. The coadministration of SC-46542 (16 micrograms/kg/min) and thiorphan (30 mg/kg i.v. bolus) produced a greater diuresis and natriuresis (but had no effect on mean arterial pressure) than administration of either compound alone; plasma APir increased 2-fold during coadministration of SC-46542 and thiorphan (from 325 +/- 46 to 676 +/- 86 pg/ml). Administration of SC-46542 or thiorphan alone had small or no effects on mean arterial pressure, urine flow, urinary sodium excretion or plasma APir. Converting enzyme inhibition did not contribute to the effects of thiorphan since coadministration of captopril plus SC-46542 produced effects similar to SC-46542 alone. When a near threshold infusion of AP(103-126) was combined with the coadministration of SC-46542 and thiorphan, there was a potentiation of the depressor, diuretic and natriuretic responses. Neither SC-46542 nor thiorphan alone had these effects. SC-46542 potentiated the depressor but not diuretic or natriuretic responses to low dose AP(103-126) infusion; thiorphan had little or no effect on the responses to low dose AP(103-126). We conclude that blockade of non-guanylate cyclase-linked AP binding sites with SC-46542 combined with inhibition of AP degradation by endopeptidase 24.11 with thiorphan increases diuresis and natriuresis more than inhibition of either system alone.(ABSTRACT TRUNCATED AT 250 WORDS)