Pharmacodynamics of atrial natriuretic peptide in isolated perfused Dahl rat kidneys.

Atrial natriuretic peptide (ANP) has been implicated in the development of hypertension in Dahl R and S rats. To test the responses of DR and DS kidneys in the absence of the influence of neural and humoral mechanisms, we investigated the pharmacokinetics and pharmacodynamics of ANP in isolated perfused DR and DS kidneys, obtained from rats given a high or low sodium diet, after a bolus injection of ANP (1 microgram) or after a bolus injection plus infusion of ANP to maintain the perfusate concentration at 1000 pg/ml. The elimination rate constant was not different between the groups (DR, 0.044 min-1 vs. DS, 0.050 min-1). Clearance of ANP was 4 times greater than the glomerular filtration rate, indicating that a receptor-mediated peritubular clearance is probably the primary route of elimination. DS kidneys excreted 50% less sodium than DR kidneys. However, ANP caused a 5-fold increase in fractional sodium excretion in both DR and DS. ANP also increased sodium excretion, creatinine clearance, and urine flow. No alteration in ANP kinetics occurred to account for the reportedly increased circulating concentrations of ANP seen in DS rats. We conclude that isolated DR and DS kidneys respond differently to ANP after bolus ANP administration to concentrations of 10,000 pg/ml. This difference in response is due to the sodium excretory defect inherent in the DS kidney and not to an alteration in the DS kidney's ANP responsiveness.

Progesterone antagonist RU 486 has bone-sparing effects in ovariectomized rats.

We demonstrated previously that progesterone prevents ovariectomy-induced bone loss. RU 486 is a synthetic steroid with antiprogesterone activities in reproductive tissue. We used 12-week-old rats to evaluate effects of RU 486 in sham-operated rats and to compare medroxyprogesterone (MPA), RU 486, and medroxyprogesterone plus RU 486 combined treatment in ovariectomized rats. Ovariectomized rats were treated with MPA (60 mg/kg intramuscularly), RU 486 (10 mg/kg/day subcutaneously every 4 days), both, or vehicle. Sham-operated rats were treated with similar doses of RU 486 or vehicle. After 4 weeks of treatment the rats were sacrificed and bone histomorphometry was performed on proximal tibial metaphysis. Trabecular bone volume was lower (33.9 +/- 1.5% vs. 46.3 +/- 1.4%) and bone turnover was higher in ovariectomized than in sham-operated rats. The fraction of trabecular bone in OVX rats treated with MPA, RU 486, or both were 41.6 +/- 2.5%, 44.8 +/- 2.8%, and 38.4 +/- 1.4%, respectively. Medroxyprogesterone treatment tended to preserve bone mass by inhibiting the increased resorption indices while maintaining higher formation rates seen in ovariectomized rats. The effects of RU 486 were similar to those of medroxyprogesterone, suggesting an agonist-like effect. Medroxyprogesterone effects were attenuated when it was combined with RU 486, suggesting that RU 486 acted as a partial antagonist in the presence of exogenous progesterone. Bone parameters were less affected in sham-operated RU 486-treated rats, and there was no significant change in bone volume (43.2 +/- 1.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of endurance exercise on bone histomorphometric parameters in intact and ovariectomized rats.

Physical activity is important for maintenance of bone mass. The effects of exercise on bone histomorphometry were studied in 9-month-old intact (INT) and ovariectomized (OVX) rats. The rats were either kept sedentary (SED) or were exercised (EX) on a treadmill at 21 m/min for 1 h/day 5 days/week for 3 months. Bone resorption as well as formation parameters were significantly higher in OVX-SED than in INT-SED rats, indicating increased bone turnover in OVX rats. In OVX rats, lower osteoclast perimeter and number, lower labeled perimeter but higher mineral apposition rate (MAR) and bone formation rate (BFR) were associated with higher trabecular bone in OVX-EX compared with OVX-SED rats. In intact rats, trabecular bone mass and osteoclast number and perimeter were not affected by exercise. Labeled perimeter was slightly lower while MAR was higher and BFR was insignificantly higher in INT-EX than in INT-SED rats. Thus, exercise resulted in fewer resorption-formation sites, as indicated by lower labeled perimeter, but higher activity of individual osteoblasts, as indicated by higher MAR, both in estrogen-depleted and estrogen-replete states.

Erythropoietin-induced antinatriuresis mediated by angiotensin II in perfused kidneys.

Erythropoietin (EPO)-induced hypertension is a common complication of EPO usage. The hypothesis that erythropoietin is antinatriuretic and that the sodium retention is mediated by intrarenal angiotensin II production was tested. Experiments were performed in Wistar rat kidneys perfused for 60 min in an isolated system. A dose-response curve was performed for EPO at 0, 10, 100, 1,000, and 10,000 mU/mL. EPO administration resulted in a dose-dependent decrease in sodium excretion to a maximum of 50% at the 1,000 mU/mL dose. In a second experiment, kidneys from five groups were perfused: controls, EPO (100 mU/mL), captopril (50 ng/mL), captopril (50 ng/mL) plus EPO (100 mU/mL), and the angiotensin receptor antagonist losartan (1 nM) plus EPO (100 mU/mL). The administration of EPO resulted in an immediate decrease in average sodium excretion (30%) with no change in GFR or other renal function parameters. Pretreatment with captopril or losartan blocked the effect of EPO. Captopril alone had no effect on renal function. A final experiment demonstrated the ability of losartan (10 nM) to block the pressor effects of angiotensin II (0.01, 0.1, and 1 nM). It was concluded that EPO acts within the kidney to cause the production of angiotensin II, which mediates the increased reabsorption of sodium.