Early evolution of bladder emptying after myelomeningocele closure.

OBJECTIVES: To analyze bladder emptying in newborns with spina bifida after closure of the myelomeningocele defect. Manipulation of the spinal cord and nerve roots results in temporary changes in bladder function in many settings. METHODS: We reviewed 62 consecutive newborn patients who underwent closure of a myelomeningocele defect at our institution from January 1990 to December 1997. We examined the catheterized urine volumes obtained before and after closure, radiographic and urodynamic studies, and the subsequent need for intermittent catheterization. Poor bladder emptying was defined as most catheterized urine volumes greater than 10 mL (20% of expected bladder capacity). Adequate follow-up was available for 54 patients for a period of 4 to 96 months (mean 42). One patient with posterior urethral valves was excluded from the study, leaving 53 for evaluation. RESULTS: Of the 53 patients, 4 with high outflow resistance and dyssynergy never emptied the bladder adequately before or after closure. Of the remaining 49 patients, 6 (12%) emptied well immediately after the myelomeningocele repair. In the other 43 (88%), the bladder did not empty as well after closure. The mean volume obtained with catheterization after closure was 20 mL, significantly higher (P <0.001) than the mean volume obtained before repair (6.5 mL) or after resumption of better spontaneous emptying (4 mL). Intermittent catheterization done for poor emptying was required for an average duration of 11 days (range 2 to 42). Of the 43 patients with poor emptying immediately after closure, 32 (74%) required catheterization for 2 weeks or less; the remaining 11 (26%) required catheterization for 2 to 6 weeks. Despite the relatively early resumption of good emptying, numerous patients (19 of 49) required additional intervention (clean intermittent catheterization or vesicostomy) before attempts to toilet train. CONCLUSIONS: A clinical pattern similar to spinal shock does occur in most newborns after closure of a myelomeningocele defect. Resumption of near-complete emptying usually occurs less than 2 weeks after repair but may require up to 6 weeks.

The angiotensin type II receptor tonically inhibits angiotensin- converting enzyme in AT2 null mutant mice.

BACKGROUND: Pharmacologic inhibition of the angiotensin-converting enzyme (ACE) limits angiotensin II (Ang II)-induced vasoconstriction and cellular proliferation. There is emerging evidence that some of the beneficial effects of ACE inhibitors may be endogenously available through the angiotensin receptor type 2 (AT2). METHODS: To evaluate whether AT2 modulates ACE activity, we used an high-performance liquid chromatography (HPLC)-based enzymatic assay in tissues from AT2 knockout mice (Agtr2-/y) and cultured cells. These studies were complimented by physiologic studies of pharmacologic inhibition of AT2. RESULTS: Circulating (C) and tissue ACE activities in heart (H), lung (L), and kidney (K) were doubled in Agtr2-/y mice compared with wild-type mice [162.9 +/- 17.6 mU/mL (C), 97.7 +/- 20.7 (H), 6282.1 +/- 508.3 (L), and 2295.0 +/- 87.0 (K) mU/g tissue for Agtr2-/y vs. 65.3 +/- 35.4 mU/mL (C), 44.5 +/- 8.7 (H), 3392.4 +/- 495.2 (L), and 1146.1 +/- 217.3 (K) mU/g tissue for wild-type mice, P < or = 0.05, 0.025, 0.002, and 0.0001, respectively]. Acute pharmacologic inhibition of AT2 [PD123319 (PD), 50 microg/kg/min, i. v.] significantly increased ACE activity in kidneys of wild-type mice (1591.2 +/- 104.4 vs. 1233.6 +/- 88.0 mU/g tissue in saline-infused mice, P < 0.05; P < 0.01 vs. uninfused, wild-type mice). Moreover, ACE activity increased in A10 cells exposed to PD (10-6 mol/L) together with Ang II (10-7 mol/L), but not with an AT1 antagonist (losartan, 10-6 mol/L). This heightened ACE activity appears functionally relevant because infusion of angiotensin I caused more prompt hypertension in Agtr2-/y mice than in wild-type littermates. Likewise, infusion of bradykinin, also a substrate for ACE, caused significantly less hypotension in Agtr2-/y mice than controls. CONCLUSIONS: These studies indicate that AT2 functions to decrease ACE activity tonically, which may, in part, underlie AT2's increasingly recognized attenuation of AT1-mediated actions.

Renal angiotensin converting enzyme promotes renal damage during ureteral obstruction.

PURPOSE: We and others have shown that angiotensin II has a pivotal role in renal damage in various renal injuries. Although most angiotensin II actions are associated with the angiotensin type 1 receptor, there is increasing evidence that the angiotensin type 2 receptor also transduces some important effects of angiotensin II. In this regard we recently observed that mice with genetically engineered disruption of the angiotensin type 2 receptor, termed Agtr2 mutants, are more susceptible to structural renal damage after ureteral obstruction. Recent evidence suggests that a genetically determined increase in angiotensin converting enzyme activity in humans promotes end organ damage. Therefore, we determined whether renal damage in Agtr2 mutants is associated with heightened angiotensin converting enzyme activity. MATERIALS AND METHODS: We studied 28 wild type and 19 Agtr2 mutant mice with unilateral ureteral obstruction. Seven days after obstruction was created serum samples were obtained to evaluate angiotensin converting enzyme activity. The obstructed and contralateral kidneys were harvested for histological analysis and determination of renal angiotensin converting enzyme activity by high pressure liquid chromatography. RESULTS: Renal angiotensin converting enzyme was uniformly higher than serum angiotensin converting enzyme in normal wild type and Agtr2 mutant mice. However, even at baseline Agtr2 mutant mice had strikingly higher renal angiotensin converting enzyme activity than normal wild type mice (mean plus or minus standard error 1,492+/-83 versus 450+/-60 milliunits per gm. tissue weight, p <0.0005). Histological analysis revealed more extensive parenchymal damage in the obstructed kidneys of mutant mice than in identically treated controls. Notably while unilateral ureteral obstruction decreased renal angiotensin converting enzyme activity in each group, activity remained persistently higher in the Agtr2 mutants than in normal mice (mean 742+/-146 versus 310+/-43 milliunits per gm. tissue weight, p <0.005). CONCLUSIONS: We propose that elevated renal angiotensin converting enzyme activity contributes to more severe renal parenchymal damage in ureteral obstruction by promoting the availability of growth factors, such as angiotensin II, or depleting antiproliferation factors, such as bradykinin or nitric oxide. These findings complement previous observations that angiotensin converting enzyme inhibition preserves the renal parenchyma after injury, including obstruction.