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We examined renal sodium handling in rats with Hymann nephritis (HEN), an immunologically mediated model of nephrotic syndrome. Rats were studied 9-14 days following i.p. injection of anti-Fx1A antiserum. We previously demonstrated that HEN had a blunted volume expansion natriuresis (2% body weight isotonic saline infused over 5 min), excreting sodium at only half the rate of normal controls (CTL) despite similar increase in plasma atrial natriuretic peptide (ANP) concentration. Urinary excretion of cGMP accumulation by isolate glomeruli and inner medullary collecting duct (IMCD) cells in response to increasing concentration of ANP, and RNP (also called urodilatin). Results (fmol/mg prot/10 min) are means +/- SEM: [table: see text]. Basal accumulation of cGMP was not different among the groups, HEN rats hd reduced cGMP accumulation in response to ANP, and RNP. In binding studies using 125I-ANP, no difference in either density or affinity was found between CTL and HEN rats. Thus, there is a renal resistance to ANP in rats with HEN, which can be extended to other agents acting through the cGMP pathway. This resistance is not due to impaired binding of ANP, but to impaired accumulation of cGMP in responsive tissues, reflecting perhaps increased cGMP catabolism by phosphodiesterase. Such an observation may account for the altered sodium handling in nephrotic rats.

Angiotensin II may act as an angiogenic and growth promoting factor on different cell types. To assess the role of angiotensin II on the compensatory renal response of the remnant kidney to unilateral nephrectomy (UNX), we measured renin, angiotensinogen, and angiotensin II type 1 receptor (AT1) mRNA levels as well as angiotensin II receptor density in 2 groups of 7 Sprague-Dawley rats 7 days after either shamp operation or UNX, Following UNX, the ratio of kidney weight to body weight (KW/BW) increased from 0.38 +/- 0.01 to 0.46 +/- 0.01% (p < 0.01). Neither renin (kidney) or angiotensiongen (kidney and liver) mRNA levels, determined by slot blot hybridization, changed after UNX. Angiotensin II receptor density was determined using an 125I-Sar1-Ile8 Ang II in situ receptor binding assay on fixed kidney sections. Binding specificity was verified using unlabeled Sar1-Ang II. Glomerular angiotensin II receptor density did not change significantly after UNX, nor did AT1 receptor mRNA. Thus, these data do not support a critical role for angiotensin II in the compensatory renal growth following uninephrectomy.

ANP infusion increased hematocrit and decreased plasma volume (PV) by inducing a shift of plasma fluid from the vascular towards the interstitial compartment. Rats with experimental diabetes mellitus resulting from streptozotocin (STZ) treatment exhibit renal resistance to infused ANP. To determine if resistance to the extrarenal actions of ANP also occurs in these conditions, changes in arterial pressure and hematocrit were measured during infusion of ANP (1 microgram/kg/min for 45 min) in anesthetized binephrectomized rats 2-3 weeks after induction of diabetes. Blood glucose was significantly elevated in diabetic when compared to control and insulin-treated diabetic rats. Arterial pressure decreased similarly in control, diabetic and insulin-treated diabetic rats (by 7.6 +/- 1.6, 9.6 +/- 1.9 and 8.2 +/- 2% respectively; all p < 0.0002). In control rats, hematocrit increased progressively to a maximal value of 9.5 +/- 0.9% corresponding to a decrease in PV of 16 +/- 1%. In contrast, the ANP-induced increase in hematocrit was markedly blunted in diabetic rats (1.6 +/- 0.8%; p < 0.0001 vs ANP infusion in control rats), corresponding to a decrease in PV of only 2.2 +/- 1%. In addition, reducing the hyperglycemia in diabetic rats by insulin therapy restored the increase in hematocrit to ANP (8.5 +/- 1.1%; p < 0.0001 and p = NS vs ANP infusion in diabetic and control rats respectively). PV, measured at the end of the infusion period, did not differ between control and insulin-treated diabetic rats infused with ANP (21.3 +/- 1.4 and 22.5 +/- 1.4 ml/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic peptide lowers arterial pressure and increases hematocrit through reduction in plasma volume caused by a transcapillary shift of plasma fluid and protein toward the interstitium. Cyclic GMP, the second messenger of atrial natriuretic peptide is catabolized by cGMP-phosphodiesterase; therefore we examined the consequences of inhibition of the phosphodiesterase on these responses using the specific cGMP inhibitor M&B 22.948. In anesthetized, bilaterally nephrectomized rats, a 45-min infusion of atrial natriuretic peptide (1 microgram/kg/min) reduced arterial pressure by 7.6 +/- 1.5% and increased hematocrit by 9 +/- 0.6% (both p < 0.01), leading to a calculated decrease in plasma volume of 14.4 +/- 0.9%. Infusion of M&B 22.948 (0.68 mg/kg/min) did not affect hematocrit and lowered arterial pressure by 8.1 +/- 0.5% (p < 0.01), an effect similar to that observed following administration of sodium nitroprusside (10 micrograms/kg/min). Simultaneous infusion of atrial natriuretic peptide and M&B 22.948 had additive arterial pressure lowering effects (-15.9 +/- 1.1%; p < 0.01 vs atrial natriuretic peptide or M&B 22.948 alone), while the increase in hematocrit of 9.4 +/- 0.7% was identical to that seen with atrial natriuretic peptide alone. Thus, M&B 22.948 amplified atrial natriuretic peptide effects on arterial pressure, but not on vascular permeability. These findings indicate differential regulation of atrial natriuretic peptide effects by inhibition of the cGMP-phosphodiesterase.

To test the possibility that endothelin affects extracellular fluid partition between plasma and interstitium, we compared the effects of endothelin and vehicule in euvolemic binephrectomized anesthetized rats by measuring changes in hematocrit and plasma protein concentration. Forty-five minutes infusion of endothelin (25 ng/kg/min) induced a progressive increase in blood pressure by 1.7 +/- 1.3, 6.8 +/- 1.5 and 12.1 +/- 2.1% at 15, 30 and 45 min respectively from a basal value of 99 +/- 5 mmHg. Hematocrit increased by 8.0 +/- 0.6% (p less than 0.001) after 45 min of infusion, while the vehicle had no significant effect (+ 1.7 +/- 0.7%). The same increase in hematocrit was observed in binephrectomized and splenectomized rats. The calculated loss of plasma volume during endothelin infusion was 13.1 +/- 0.9% as compared to 2.1 +/- 1.2% in rats receiving the vehicle. Plasma protein concentration increased by only 4.2 +/- 0.6% suggesting an extravasation of proteins. To document and localize an alteration in vascular leak of proteins induced by endothelin, albumin-bound Evans Blue (EB) extravasation was measured spectrophotometrically in different tissues after extraction by formamide. Endothelin increased vascular permeation of EB-albumin in skeletal and cardiac muscle, intestine and mesentery. No change was observed in brain, liver, spleen as compared to rats receiving the vehicle. In addition, endothelin infusion elicits a three fold increase of the plasma immunoreactive atrial natriuretic peptide (ir-ANP) concentration (from 196 +/- 50 to 722 +/- 203 pg/ml; p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)