Renal actions of endothelin-1 under endothelin receptor blockade by BE-18257B.

PURPOSE: Endothelin-1 (ET-1), a peptide produced by the vascular endothelium, causes profound renal vasoconstriction by binding to ET-A receptors. The present study examined the renal actions of ET-1 after ET-A receptors were blocked by BE-18257B to unmask the functions of ET-B receptors. MATERIALS AND METHODS: Renal hemodynamics and clearance measurements were obtained in anesthetized dogs after intrarenal infusion of BE-18257B at 100 ng./kg./min. (Group 1), after intrarenal infusion of ET-1 at 2 ng./kg./min. (Group 2), or after intrarenal infusion of ET-1 superimposed on BE-18257B (Group 3). RESULTS: In Group 1, BE-18257B infusion did not alter arterial pressure, renal blood flow (RBF), GFR or tubular function. In Group 2, ET-1 infusion led to a significant decrease in RBF and GFR (37 and 40%, respectively) without altering arterial pressure. Urinary volume and sodium excretion were not changed but osmolality decreased significantly. In Group 3, BE-18257B infusion significantly attenuated the decrease in RBF caused by ET-1 and increased GFR by 40% without altering arterial pressure, associated with significant diuresis and natriuresis. CONCLUSION: Renal vasoconstriction caused by ET-1 is attenuated by ET-A receptor blockade with BE-18257B, which unmasks the hemodynamic and tubular actions of ET-B receptors. As a result, it limits the ET-1 induced decrease in RBF and raises GFR, and leads to a diuresis and natriuresis.

Activation of endothelium-derived relaxing factor system in acute unilateral ureteral obstruction.

PURPOSE: To investigate the effects of 1-arginine, a substrate for nitric oxide (NO) synthase, on renal hemodynamics in acute ureteral obstruction (UUO). MATERIALS AND METHODS: Renal blood flow (RBF) and ureteral pressure (UP) were measured in anesthetized dogs with or without UUO. RESULTS: In 9 dogs (Group 1), RBF was 212 +/- 13 ml./min. before UUO, and significantly increased to 302 +/- 18 and 268 +/- 9 ml./min. at 90 and 140 min. post-UUO, respectively, associated with a marked increase in UP from 3 +/_ 1 mm. Hg to 73 +/- 5 and 83 +/-2 mm. Hg at 90 and 140 min. post-UUO, respectively. In 6 dogs (Group 2) prostaglandin synthesis was inhibited with meclofenamate (5 mg./kg., i.v.). After UUO, RBF did not change significantly and the increase in UP was markedly attenuated when compared with Group 1, as UP rose only to 27 +/-3 and 34 +/- 4 mm. Hg at 90 and 140 min. post-UUO, respectively. In 6 dogs pre-treated with meclofenamate, L-arginine was infused into the renal artery at 5 mg./kg./min. at 90 min. after UUO (Group 3). Prostaglandin synthesis inhibition prevented renal vasodilation after UUO and significantly attenuated the increase in UP. Upon infusion of L-arginine, RBF and UP rose sharply from 202 +/- 16 ml./min. and 24 +/- 6 mm. Hg to 264 +/- 22 ml./min. and 70 +/- 4 mm. Hg, respectively, at 140 min. post-UUO (p <0.001), values approaching those in Group 1. In sham-operated dogs, L-arginine infusion did not alter RBF in dogs with or without pretreatment with meclofenamate. CONCLUSION: In UUO the L-arginine-NO pathway is activated, contributing to renal vasodilation and a marked increase in UP.

Contribution of endothelin-1 to renal vasoconstriction in unilateral ureteral obstruction: reversal by verapamil.

PURPOSE: In unilateral ureteral obstruction (UUO) vasoconstriction occurs both during and after release of UUO. ET-1, an endogenous peptide, causes marked vasoconstriction mediated by an increase in cytosolic calcium. We measured renal output of endothelin-1 (ET-1) in dogs with UUO and examined if the renal vasoconstriction that persisted after release of UUO could be reversed by a calcium antagonist, verapamil. MATERIALS AND METHODS: Hemodynamic and clearance experiments were performed in anesthetized mongrel dogs in three groups. Group I consisted of 9 dogs with sham-operation. Group 2 consisted of 7 dogs in whom ureteral obstruction was released 1.9 hours after UUO. Group 3 consisted of 5 dogs in whom verapamil was infused into the renal artery at two doses (5 and 10 microg./min., respectively) after release of UUO of 19-hour duration. ET-1 concentrations (measured by radioimmunoassay) were determined for renal venous and arterial plasma. RESULTS: In Group 1 renal venous plasma ET-1 level was 16.7 +/- 2.2, significantly lowered than 22.8 +/- 3.2 pg./ml. in arterial plasma, indicating a net clearance of ET-1. In Group 2 and 3, renal venous plasma ET-1 levels (28.2 +/- 5.2 and 27.2 +/- 2.4 pg./ml., respectively) were significantly greater than those in arterial plasma (24.2 +/- 5.7 and 17.4 +/- 0.8 pg./ml., respectively), indicating a net output of ET-1 in the kidney, In addition, renal vasoconstriction occurred in Groups 2 and 3 as indicated by significantly lower renal blood flow and GFR than those in Group 1. In Group 3, intrarenal infusion of verapamil at two doses did not change arterial pressure but caused an ipsilateral, significant increase in RBF (from 132 +/- 4 17 to 1.84 +/- 19 and 180 +/- 16 ml./min., respectively) and dose-dependent increases in GFR (from 12 +/- 2 to 25 +/- 3 and 38 +/- 7 ml./min., respectively), associated with a profound dose-dependent ipsilateral diuresis and natriuresis. CONCLUSION: Profound renal vasoconstriction in UUO was associated with an increase in renal production of ET-1, possibly contributing to renal vasoconstriction, and was reversed by intrarenal infusion of verapamil.

Renal hemodynamics in acute unilateral ureteral obstruction: contribution of endothelium-derived relaxing factor.

The increase in ureteral pressure after acute unilateral ureteral obstruction (UUO) is associated with an initial increase in renal blood flow (RBF). The present study examines the role of nitric oxide, a major endothelium-derived relaxing factor (EDRF), in UUO-induced renal hyperemia in anesthetized dogs. In Group 1, vehicle solution was infused into the left renal artery. In Group 2, nitric oxide formation from L-arginine was competitively inhibited by intrarenal infusion of N omega-monomethyl-L-arginine (L-NMMA) (50 micrograms/kg./min.) before UUO. In Group 3, L-arginine (2 mg./kg./min.) was infused together with L-NMMA (50 micrograms/kg./min.) into the renal artery. After UUO, ureteral pressure increased in all groups, averaging 69 mm.Hg. In Group 1, RBF at 10 and 20 minutes after UUO increased 7.9 +/- 1.6% and 16.5 +/- 5.2%, respectively, significantly greater than in Group 2 (1.2 +/- 1.6% and 2.4 +/- 1.5%). After L-NMMA was discontinued in Group 2, RBF increased 17%, reaching a level similar to that in Group 1. In Group 3, L-arginine infusion abolished the effects of L-NMMA, and RBF was similar to that in Group 1 at all postobstructive intervals. Our data indicate that release of nitric oxide in the kidney is augmented by UUO and mediates the early renal hyperemia induced by UUO.

Volume expansion enhances the recovery of renal function and prolongs the diuresis and natriuresis after release of bilateral ureteral obstruction: a possible role for atrial natriuretic peptide.

Plasma atrial natriuretic peptide (ANP) levels are elevated in patients with bilateral ureteral obstruction (BUO). To further evaluate the role of ANP in postobstructive diuresis, natriuresis and recovery of renal function, 3 groups of dogs were studied: Group 1, 6 dogs that underwent 48 hours of unilateral ureteral obstruction (UUO); Group 2, 6 dogs that underwent 48 hours of BUO; and Group 3, 6 dogs volume replete with normal saline during 48 hours of BUO. All 3 groups underwent hourly hemodynamic and clearance studies for 15 hours after the release of obstruction. Group 1 experienced no increase in either urine output or sodium excretion from the ipsilateral or contralateral kidney after release of obstruction. Groups 2 and 3 both experienced an initial diuresis and natriuresis after BUO (p < 0.01). However, in Group 2 diuresis and natriuresis after BUO ceased at 5 and 2 hours, respectively, while in Group 3 both persisted for 10 and 9 hours, respectively. Before obstruction the GFR was similar in all three groups. In Group 1 the GFR decreased significantly in the ipsilateral kidney (34.5 +/- 1.4 to 14.48 +/- 1.5 ml. per minute, (p < 0.01)) and increased significantly in the contralateral kidney (32.4 +/- 2.8 to 44.4 +/- 2.0 ml. per minute, (p < 0.05)) and remained so throughout the postobstruction period. The GFR in Groups 2 and 3 decreased to a similar level 1 hour after release (13.3 +/- 1.7 and 17.5 +/- 3.4 ml. per minute, respectively); however, Group 2 remained decreased during the period after release while group 3 increased to 23.4 +/- 3.4 ml. per minute (p < 0.01) at 11 hours after release of obstruction. In Group 2 the control plasma ANP level was 17.9 +/- 3.7 pg./ml. and was not altered by BUO, whereas ANP increased significantly after 48 hour BUO in Group 3, from 30.6 +/- 6.7 to 63.7 +/- 11.7 pg./ml. (p < 0.01). Before and after 48 hours of BUO, the pulmonary capillary wedge pressure was 5.0 +/- 2.0 mm. Hg and 7.0 +/- 1.0 mm. Hg (NS) in Group 2, while it increased from 7.18 +/- 1.5 mm. Hg to 11.6 +/- 1.9 mm. Hg (p < 0.01) in Group 3. We conclude that volume expansion during BUO enhances postobstructive diuresis and natriuresis and allows a greater recovery of GFR after release of the obstruction. This effect may be mediated through elevated plasma levels of ANP as measured in this study.

The renal hemodynamic response to endothelin in chronic cyclosporine-treated dogs.

Use of the immunosuppressive agent cyclosporine A (CyA) is limited by its associated nephrotoxicity, characterized by an increase in renal vascular resistance (RVR) and reductions in renal blood flow (RBF) and glomerular filtration rate (GFR). The vascular endothelium produces vasoactive substances including endothelium derived relaxation factor (EDRF) and endothelin (ET), which modulate vascular tone. Since CyA has been shown to damage the endothelium, we examined the renal hemodynamic response to intrarenal ET infusion (4 micrograms./kg./minute) in chronic cyclosporine-treated dogs. Prior to ET infusion, CyA-treated dogs had a lower RBF and a greater RVR than normal dogs. In normal dogs, after ET infusion RVR increased from 30.24 +/- 0.64 to 44.60 +/- 1.66 mmHg./ml./minute (p < 0.001), RBF decreased from 4.26 +/- 0.28 to 2.90 +/- 0.30 ml./min./g. (p < 0.001) and GFR decreased from 50.20 +/- 5.90 to 36.50 +/- 7.90 ml. per minute (p < 0.001). In contrast, there was no change in RBF, GFR and RVR after intrarenal ET infusion in CyA-treated dogs. Prior to ET infusion, arterial plasma ET concentration was 5.0 +/- 1.1 pg./ml. in CyA-treated dogs, similar to 7.5 +/- 1.4 pg./ml. in normal dogs, and was not significantly altered in either group after intrarenal ET infusion. We conclude that ET may not contribute to the increased RVR in chronic cyclosporine nephrotoxicity, and suggest a vascular toxicity of CyA, rendering renal vessels unresponsive to the vasoconstrictive effect of ET.

Atrial natriuretic peptide in patients with obstructive uropathy.

Renal response to release of bilateral ureteral obstruction resembles that to intravenous administration of atrial natriuretic peptide. In a prospective study we measured plasma atrial natriuretic peptide levels before and serially after relief of obstruction in 9 patients (mean age 65 +/- 2 years old) with bilateral ureteral obstruction and azotemia. Obstruction was documented by renal ultrasonography. Before relief of obstruction blood urea nitrogen and serum creatinine levels were 85 +/- 18 (mean +/- standard error) and 8.2 +/- 1.3 mg. per dl., respectively, accompanied by metabolic acidosis but not hyperkalemia. Mean plasma atrial natriuretic peptide (measured by radioimmunoassay) was 129 +/- 28, which was markedly elevated compared to 46 +/- 7 pg. per ml. in 7 age-matched control subjects (p less than 0.01). After relief of obstruction, prominent post-obstructive diuresis and natriuresis ensued; the plasma atrial natriuretic peptide level progressively decreased to that noted in the control group, accompanied by improvement in renal function, and diminishing diuresis and natriuresis. These findings were associated with a significant weight loss and an increase in plasma renin activity (from a mean of 1.57 +/- 0.68 to 5.27 +/- 1.82 ng. per ml. per hour, p less than 0.01). These results suggest that atrial natriuretic peptide release is augmented in patients with bilateral ureteral obstruction and azotemia, probably due to hypervolemia, and may contribute to post-obstructive diuresis and natriuresis.

Primary localized amyloidosis of ureter.

Primary localized amyloidosis of the ureter is very rare, and only 22 cases have been reported in the world literature. We report the twenty-third case along with a review of the relevant literature. Due to its radiologic resemblance to malignancy, many cases were treated by nephroureterectomy in the past. The case being reported here was successfully treated by local excision and ureteroneocystostomy.