sq-29548 and Hydronephrosis

Evidence indicates that prostaglandin E(2) (PGE(2)) preferentially affects preglomerular renal vessels. However, whether this is limited to small-caliber arterioles or whether larger vessels farther upstream also respond to PGE(2) is currently unclear. In the present study, we first investigated the effects of PGE(2) along the preglomerular vascular tree and subsequently focused on proximal interlobular arteries (ILAs). Proximal ILAs in hydronephrotic rat kidneys as well as isolated vessels from normal kidneys constricted in response to PGE(2), both under basal conditions and after the induction of vascular tone. By contrast, smaller vessels, i.e., distal ILAs and afferent arterioles, exhibited PGE(2)-induced vasodilation. Endothelium removal and pretreatment of single, isolated proximal ILAs with an EP1 receptor blocker (SC51322, 1 micromol/l) or a thromboxane A(2) receptor blocker (SQ29548, 1 micromol/l) did not prevent vasoconstriction to PGE(2). Furthermore, in the presence of SC51322, responses of these vessels to PGE(2) and the EP1/EP3 agonist sulprostone were superimposable, indicating that PGE(2)-induced vasoconstriction is mediated by EP3 receptors on smooth muscle cells. Immunohistochemical staining of proximal ILAs confirmed the presence of EP3 receptor protein on these cells and the endothelium. Adding PGE(2) to normal isolated kidneys induced a biphasic flow response, i.e., an initial flow increase at PGE(2) concentrations

Topics: Angiotensin II; Animals; Arteries; Bridged Bicyclo Compounds, Heterocyclic; Dinoprostone; Endothelium, Vascular; Fatty Acids, Unsaturated; Hydrazines; Hydronephrosis; In Vitro Techniques; Kidney Cortex; Male; Muscle, Smooth, Vascular; Norepinephrine; Perfusion; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP3 Subtype; Receptors, Thromboxane A2, Prostaglandin H2; Renal Circulation; Vasoconstriction; Vasoconstrictor Agents

The influence of hydronephrosis (6-10 wk) on the renal vascular response to arginine vasopressin (AVP) was assessed, using isolated perfused normal and hydronephrotic rat kidneys. In normal kidneys, AVP (0.3 nM) reduced renal perfusate flow (RPF) by 55 +/- 7% (P < 0.01). AVP-induced decrements in RPF were reversed partially by diltiazem (10 microM) and completely by 10 nM of an AVP (V1)-receptor antagonist (AVPX). In hydronephrotic kidneys, AVP reduced RPF by 81 +/- 2% (P < 0.01) and constricted afferent (AA) and efferent arterioles (EA) by 33 +/- 3 (P < 0.01) and 33 +/- 5% (P < 0.01), respectively. The addition of diltiazem altered neither RPF nor vessel diameters. Administration of AVPX recovered RPF, AA, and EA diameters. When hydronephrotic kidneys were pretreated with thromboxane (Tx) inhibitors, AVP reduced RPF by 62 +/- 5% (P < 0.01) and constricted AAs and EAs by 26 +/- 2 (P < 0.01) and 17 +/- 3% (P < 0.05), respectively. Under Tx blockade, diltiazem partially reversed the AVP-induced reduction in RPF and restored the decrements in AA diameter. Subsequent addition of AVPX returned RPF and EA diameter. Our data indicate that AVP elicits substantial renal microvascular constriction and suggest that AVP stimulates Tx production in hydronephrotic kidneys, thereby altering renal vascular responsiveness to this peptide.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Arterioles; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Enzyme Inhibitors; Fatty Acids, Unsaturated; Hydrazines; Hydronephrosis; In Vitro Techniques; Male; Rats; Rats, Sprague-Dawley; Reference Values; Renal Circulation; Thromboxane-A Synthase; Thromboxanes; Vasoconstriction

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