saralasin and Hydronephrosis

We have previously shown that rats with congenital, unilateral hydronephrosis exhibit a reduction in GFR that returns to normal when either the renin angiotensin system or thromboxane A2 (TxA2) is blocked. The current study defines the single nephron defect in congenital, unilateral hydronephrosis and evaluates the roles of angiotensin II (Ang II) and TxA2 in this renal derangement. Renal micropuncture experiments were performed on the right kidney of rats from an inbred colony with unilateral right-sided hydronephrosis (HYDRO), or non-affected litter mates (CONTROL). In addition, four separate groups of hydronephrotic animals were treated with either the TxA2 receptor antagonist SQ-29548 (SQ), one of two Ang II receptor antagonists [saralasin (SAR) or DuP-753 (DUP)]; or combined treatment with DuP-753 and SQ-29,548 (S&D). SNGFR was significantly reduced (P < 0.05) in HYDRO compared to CONTROL (17.6 +/- 2.0 vs. 35.9 +/- 3.7 nl/min, respectively). Treatment with SQ-29,548 normalized SNGFR (29.0 +/- 3.0 nl/min), while saralasin and DuP-753 resulted in only a partial recovery of function (25.6 +/- 1.6 and 27.8 +/- 1.4 nl/min, respectively). Combined SQ-29,548 and DuP-753 treatment resulted in full recovery of SNGFR to 32.9 +/- 4.4 nl/min. The glomerular ultrafiltration coefficient (Kf) was reduced (P < 0.05) approximately 45% in HYDRO compared to CONTROL (1.64 +/- .08 vs. 2.84 +/- .22 nl/min/mm Hg, respectively). Kf returned to control levels in SAR, DUP and SQ, and increased above control in S&D (5.58 +/- 1.6 nl/min/mm Hg). There were no differences (P > 0.05) in hydrostatic or oncotic pressures across the glomerular capillary between any of the groups studied. The observation that Kf increases above CONTROL with combined blockade of TxA2 and Ang II suggests that these regulatory hormones decrease Kf via independent mechanisms. These data indicate that the reduction in SNGFR in congenital, unilateral hydronephrosis is a result of a marked fall in Kf that is mediated by both Ang II and TxA2.

Topics: Angiotensin II; Animals; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Fatty Acids, Unsaturated; Glomerular Filtration Rate; Hydrazines; Hydronephrosis; Imidazoles; Kidney Glomerulus; Losartan; Male; Rats; Rats, Inbred Strains; Rats, Wistar; Saralasin; Tetrazoles; Thromboxane A2

A technique for the measurement of GFR without collection of urine in rats was experimentally validated and applied to experiments designed to: (1) evaluate the degree of reduction of GFR in rats with congenital, unilateral hydronephrosis; and (2) to determine if the reduction in renal function is mediated by angiotensin II and/or thromboxane A2 mechanisms. Simultaneous measurements of GFR by a constant-infusion technique and the traditional inulin clearance technique in rats with either one or two normal kidneys were highly correlated (r = 0.934; P < 0.001; N = 17). GFR was approximately 24% lower (P < 0.001) in rats with congenital unilateral hydronephrosis than in rats with a normal kidney. The GFR in rats with hydronephrosis infused with a receptor blocker for either angiotensin II or thromboxane A2 was greater than the GFR in hydronephrotic kidneys without blockade and was not significantly different (P > 0.05) from that in rats with normal kidneys. These results indicate that a constant inulin infusion technique without urine collections can be used to accurately measure GFR in congenitally hydronephrotic kidneys, rendering values free from possible residual pelvic volume artifact. In addition, these results also indicate that a significant 24% reduction in GFR occurs in congenital unilateral hydronephrosis and is mediated by angiotensin II and thromboxane A2 mechanisms.

Topics: Angiotensin Receptor Antagonists; Animals; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Glomerular Filtration Rate; Hydrazines; Hydronephrosis; Male; Rats; Rats, Wistar; Receptors, Angiotensin; Receptors, Thromboxane; Saralasin

The hydronephrotic rat kidney with intact circulation and innervation was split and spread out as a thin sheet in a tissue bath. The microvasculature was observed in vivo via television microscopy. We quantitated the effects of increasing concentrations (10(-9) to 10(-5) M) of saralasin (angiotensin II antagonist) applied locally in the tissue bath on microvascular diameters and on relative glomerular blood flow (measured using fluorescent labeled RBCs). Saralasin produced an increase in preglomerular diameters which was largest (37 +/- 11%) in the interlobular artery (there was no dilation in the afferent arteriole near the glomerulus), an increase in postglomerular diameters which was largest (17 +/- 4%) in the efferent arteriole near the glomerulus, and an increase in blood flow (19 +/- 4%). If these types of findings would hold for the normal kidney, it would suggest a role for angiotensin II in the control of total renal blood flow, in the regional distribution of flow, and in the control of filtration fraction. We also made control micropressure measurements using the servo-nulling approach. Pressures measured were: afferent arteriole, 65 +/- 5 mm Hg; intraglomerulus, 50 +/- 5 mm Hg; and efferent arteriole, 19 +/- 3 mm Hg. These data indicate that there is major vascular resistance near the glomerulus, especially in the efferent arteriole.

Topics: Angiotensin II; Animals; Arterioles; Blood Pressure; Dose-Response Relationship, Drug; Female; Hydronephrosis; Kidney Glomerulus; Microcirculation; Rats; Rats, Inbred Strains; Renal Circulation; Saralasin; Vasodilation