Abstract 386: Compound 21 Induces Natriuresis via Renal AT2 Receptor Activation in Male and Female Rats

Endogenous renal des-aspartyl 1 -angiotensin II (angiotensin III) activates renal proximal tubule AT 2 receptors (AT 2 Rs) and induces natriuresis via a nitric oxide-cyclic GMP signaling pathway. The present study explores the ability of highly selective non-peptide AT 2 R agonist Compound 21 (C21) to induce natriuresis. Sprague-Dawley rats (12 weeks old; male N=22; female N=18) were studied in the presence and absence of concurrent 24-h AT 1 R blockade with candesartan (CAND;0.01 mg/kg/min). Rats were anesthetized with Inactin 100 mg/kg i.p., uninephrectomized and instrumented for delivery of 3 cumulative 30-min i.v. infusions of C21 (100, 200, and 300 ng/kg/min) following a 30-min control infusion of vehicle. Mean arterial pressure (MAP) was measured for all periods and urine Na + excretion rate (U Na V) was calculated for the control and final C21 collection periods. To determine whether the systemically induced natriuresis is mediated by renal AT 2 Rs, PD-123319 (PD), a specific AT 2 R antagonist, was infused directly into the renal cortical interstitium(20 μg/kg/min and 10 μg/kg/min for females and males, respectively) during the i.v. C21 infusions. In female rats, C21 increased U Na V from 1.5 ± 0.20 to 7.48 ± 0.95 μmol/min (P<0.0001). This response was abrogated by concurrent intrarenal PD infusion [control 0.74 ± 0.19 vs. C21 2.02 ± 0.50 μmol/min (P<0.001from C21 alone). Systemic CAND administration augmented the natriuretic response to C21 [control 1.29 ± 0.25 vs. C21 10.68 ± 0.70 μmol/min (P<0.05 from C21 alone)]. In male rats, C21 increased U Na V from 0.46 ±0.08 to 6.21 ± 1.33 μmol/min (P<0.01). This response was blocked by concurrent intrarenal PD infusion [control 0.39 ± 0.11 vs. C21 1.69 ± 0.53 μmol/min (P<0.05 from C21 alone). Systemic CAND did not significantly alter the natriuretic response to C21 alone [control 0.49 ± 0.15 vs. C21 7.67 ± 0.72 μmol/min (P = NS from C21 alone). In female rats, CAND augmented the natriuretic response to C21 over that of male rats (P<0.01). Systemic arterial pressures were decreased by CAND in both male and female rats but were unchanged by C21 alone or together with intrarenal PD. C21 induces natriuresis via renal AT 2 R activation in both male and female rats. These data suggest the potential for AT 2 R agonist therapy in hypertension.

Nephrogenic Rest in a Crl:CD (SD)IGS BR Rat

A nephrogenic rest was found in the kidney of an 11-week-old male Crl:CD (SD)IGS BR rat. Histologically, the rest was within the renal cortical interstitium and consisted of glomeruloid structures (primitive glomeruli) and inconsistently distinct basophilic tubules lined by a single layer of cuboidal to columnar cells and variably bordered by blastemal cells. Nephrogenic rests have not been reported previously in this rat strain.

Renal cortical interstitium and fluid absorption by peritubular capillaries

Every minute, the cortical peritubular capillaries in a 1-g rat kidney take up more than 0.5 ml tubular reabsorbate. Studies of renal lymph and measurements of pressure in capillaries (Pc) and interstitium (Pi) indicate that normally the protein colloid osmotic pressure of peritubular capillary plasma (COPp) provides the necessary absorptive force, keeping Pi at 2-4 mmHg, i.e., 8-10 mmHg lower than Pc. At reduced COPp, continued delivery of fluid from the tubules automatically raises Pi to maintain capillary fluid uptake. The transient Pi response to sudden exposure of the kidney to subatmospheric pressure shows that such adjustment of forces may take place in only 5 s. Most remarkable, adjustment of forces may take place in only 5 s. Most remarkable, reabsorption continues during protein-free perfusion of the isolated rat kidney, apparently effected by a Pi exceeding Pc. A relative retardation of interstitial uptake of ferritin from plasma in this case suggests fluid reabsorption through both small and large pores in the capillary wall. Collapse of the capillaries is presumably prevented by tight tethering to the capillary wall, giving the narrow interstitium a very low compliance.