Faculty Bibliography

PURPOSE: Atrial natriuretic peptide (ANP) contributes to post-obstructive diuresis in bilateral ureteral obstruction (BUO). In this study we examined the activity of neutral endopeptidase (NEP), an enzyme responsible for degradation of ANP, in the kidney in rats subjected to BUO for 24 hours. MATERIALS AND METHODS: Renal function was examined by the clearance method in sham operated rats and BUO rats after obstruction release. Renal responses to an intravenous bolus injection of ANP (5 microg/kg) were studied in sham operated and BUO rats with or without pretreatment with intravenous phosphoramidon (100 microg/kg per minute), a NEP inhibitor. RESULTS: In BUO rats natriuresis and diuresis occurred despite a marked decrease in the glomerular filtration rate (GFR). ANP administration increased GFR and induced marked natriuresis and diuresis in sham operated and BUO rats. Inhibition of ANP degradation by phosphoramidon induced natriuresis and diuresis, and accentuated these renal responses to ANP. CONCLUSIONS: Renal responses to ANP and renal NEP activity were preserved in 24-hour BUO. NEP inhibition to attenuate ANP degradation augmented responses to ANP in increasing GFR, natriuresis and diuresis. These findings provide the theoretical potential for facilitating the recovery of GFR after BUO release by inhibiting ANP degradation by pharmacological means.

PURPOSE: Unilateral ureteral obstruction (UUO) for 21 hours causes severe renal vasoconstriction. We examined the role of endothelin (ET)-A receptor in renal hemodynamic alterations induced by UUO. MATERIALS AND METHODS: Hemodynamic and clearance experiments were performed in 3 groups of anesthetized dogs. In group 1, 6 sham operated dogs received intrarenal infusion of the specific ET-A receptor antagonist BQ-610 (Peninsula Laboratories, Inc., Belmont, California), followed by infusion of the nitric oxide synthase substrate L-arginine. In the 7 group 2 dogs release of 21-hour UUO was followed by intrarenal infusion of BQ-610 and L-arginine. In the 5 group 3 dogs release of 21-hour UUO was followed by L-arginine infusion. RESULTS: UUO caused marked decreases in renal blood flow (RBF) and glomerular filtration rate (GFR) in groups 2 and 3 compared with group 1. In group 1 BQ-610 and L-arginine infusion did not alter RBF or GFR. In contrast, BQ-610 infusion in group 2 after UUO release led to a significant increase in RBF and GFR as well as additional increases after L-arginine infusion. After UUO release in group 3 L-arginine infusion alone did not change RBF or GFR. CONCLUSIONS: After UUO release blockade of the ET-A receptor ameliorates renal vasoconstriction. The addition of L-arginine, which is a substrate for nitric oxide synthase, superimposed on ET-A receptor blockade confers a further decrease in renal vascular resistance, suggesting that the ET and L-arginine-nitric oxide systems are involved in renal hemodynamic alterations caused by UUO.

PURPOSE: Human prostate contains alpha-1 adrenergic, cholinergic and nonadrenergic noncholinergic neuroreceptors. Using agonistic and antagonistic agents at these neuroreceptors we studied the resultant contractile responses in isolated human prostate. MATERIALS AND METHODS: Human prostate tissue was obtained at prostatectomy for benign prostatic hyperplasia in 37 adult male patients. Tissues were suspended in tissue bath chambers connected to force displacement transducers. Specimens were subjected to agonist induced contractions, the first always being norepinephrine (NE). Specimens were pretreated with antagonist (adrenergic, cholinergic, nonadrenergic noncholinergic or none if control), followed by contraction with a second agonist (NE or other). Contractile tensions were recorded on a polygraph and then statistically analyzed. RESULTS: The order of highest to lowest agonist induced tensile forces was NE, dopamine, acetylcholine, bethanechol, histamine and serotonin. Excitatory concentration EC(50) values were determined for each agonist tested. Significant differences were found between specific alpha-1 adrenergic receptor blockers (terazosin, prazosin and the experimental drug LY253352). In addition, many other agents antagonized the alpha-1 adrenergic receptor. Inhibitory concentration IC(50) values were obtained and the order of alpha-1 adrenergic antagonistic strengths from strongest to weakest was LY253352, prazosin, terazosin, ketanserin, SCH23390, diphenhydramine, DO710, dopamine, serotonin and histamine. CONCLUSIONS: Human prostate neuroreceptors were determined to be alpha-1 adrenergic, dopaminergic, muscarinic cholinergic, 2A serotonergic and H1 histaminergic. Dopamine, serotonin, histamine and their antagonists blocked the adrenergic response, indicating possible receptor-receptor interaction. Further study of the pharmacology of human prostate would likely identify new drugs for treating patients with bladder outlet obstruction due to benign prostatic hyperplasia

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.

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.

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.

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.