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RATS WITH STREPTOZOTOCIN DIABETES-MELLITUS ARE RESISTANT TO THE ACTION OF ATRIAL-NATRIURETIC-PEPTIDE TO INCREASE VASCULAR-PERMEABILITY
No full textANP 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 (I mug/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 < 0.002). 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 contol and insulin-treated diabetic rats infused with ANP (21.3 +/- 1.4 and 22.5 +/- 1.4 ml/kg). In contrast, PV was significantly higher in diabetes (32 +/- 1.1 ml/kg) as compared to both ANP or vehicle (25.2 +/- 1.1 ml/kg) infused control rats. This study demonstrate that a) the effect of ANP on hematocrit and volemia is blunted in STZ-induced diabetes while it's hypotensive action is preserved, and b) restoring the glucose levels to normal in diabetic rats by insulin treatment normalizes the hemoconcentrating effect to exogenous administered ANT. Such an effect may account for the plasma volume expansion observed in untreated diabetic rats
BLUNTED EFFECT OF ANP ON HEMATOCRIT AND PLASMA-VOLUME IN STREPTOZOTOCIN-INDUCED DIABETES-MELLITUS IN RATS
No full textAtrial natriuretic peptide (ANP) infusion increases hematocrit and decreases plasma volume by inducing a transfer of plasma fluid from the vascular to the interstitial compartment. Diabetes mellitus is associated with resistance to the renal actions of ANP. We explored the possibility that the extrarenal responses to ANP may also be altered in the diabetic state by measuring changes in arterial pressure and hematocrit during infusion of ANP (1 mu g.kg(-1).min(-1) for 45 min) into anesthetized, acutely nephrectomized rats 2-3 wk after induction of diabetes from intravenous streptozotocin (STZ) injection (60 mg/kg). Blood glucose was significantly elevated in diabetic rats when compared with control and insulin-treated diabetic rats. Arterial pressure during ANP infusion 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 < 0.002). In control rats, hematocrit increased progressively to a maximum value of 9.5 +/- 0.9% as a result of the infusion, corresponding to a decrease in plasma volume of 16.3 +/- 1.3%. 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). Reducing the hyperglycemia in diabetic rats by insulin therapy restored the increase in hematocrit in response to ANP (8.5 +/- 1.1%; P < 0.0001 vs. ANP infusion in diabetic rats and P = NS vs. control rats). ANP infusion increased plasma ANP levels to the same extent in the three groups, whereas plasma guanosine 3',5'-cyclic monophosphate (cGMP) was significantly less in diabetic as compared with control and insulin-treated diabetic rats. Acute reduction of hyperglycemia did not restore the ANP-induced increase in hematocrit (1.3 +/- 2.2%; P = NS vs. ANP infusion in diabetic rats). This study demonstrates that 1) the effect of ANP on hematocrit and fluid distribution is blunted in STZ-induced diabetes, while its hypotensive action is preserved, and 2) restoring the glucose levels to normal in diabetic rats by chronic but not by acute insulin treatment normalizes the hemoconcentrating effect of exogenously administered ANP. Such a defect is reflected in a blunted plasma cGMP concentration after ANP infusion in STZ-diabetic rats and may contribute to the altered body fluid physiology in this condition
ATRIAL-NATRIURETIC-PEPTIDE AND BLUNTED RENAL RESPONSES TO VOLUME EXPANSION IN RATS WITH HEYMANN NEPHRITIS
No full textRATS WITH HEYMANN NEPHRITIS ARE RESISTANT TO THE ACTIONS OF ATRIAL AND RENAL NATRIURETIC PEPTIDES TO INCREASE CGMP ACCUMULATION IN-VITRO
No full textWe examined renal sodium handling in rats with Heymann nephritis (HEN), an immunologically mediated model of nephrotic syndrome. Rats were studied 9-14 days following ip 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 was also reduced by half in HEN compared to CTL. We next compared cGMP accumulation by isolated 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 : [GRAPHICS] significantly less than CTL; p < 0.05. 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 I-125-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 perharps increased cGMP catabolism by phosphodiesterase. Such an observation may account for the altered sodium handling in nephrotic rats
THE RENIN-ANGIOTENSIN SYSTEM AND THE COMPENSATORY RENAL RESPONSE TO UNILATERAL NEPHRECTOMY
No full textAngiotensin II may act as an angiogenic anf 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 I 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 angiotensinogen (kidney and liver) mRNA levels, determined by slot blot hybridization, changed after UNX. Angiotensin II receptor density was determined using an I-125-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
RENIN-ANGIOTENSIN SYSTEM GENE-EXPRESSION DURING COMPENSATORY RENAL HYPERTROPHY IN THE RAT
No full textURODILATIN BINDS TO AND ACTIVATES RENAL RECEPTORS FOR ATRIAL-NATRIURETIC-PEPTIDE
No full textUrodilatin is a recently described member of the atrial natriuretic peptide family, thought possibly to be synthesized in the kidney. To determine if urodilatin binding sites are present in rat and human kidney, we evaluated the effect of urodilatin on iodine-125-labeled atrial natriuretic peptide (ANP) (100 pM) binding to tissue sections using an in situ autoradiographic technique. I-125-ANP binding occurred primarily in glomeruli and medullary structures of both rat and human kidney. Increasing concentrations of urodilatin yielded a monophasic displacement of I-125-ANP binding with an IC50 of 4.2 nM, a value nearly identical to that achieved with unlabeled ANP (7.2 nM). In additional experiments, rat glomeruli and inner medullary collecting duct cells were isolated and incubated in vitro with either ANP or urodilatin (10(-11) to 10(-6) M) and cyclic guanosine-3',5'-monophosphate accumulation measured by radioimmunoassay. Dose-response curves for the two peptides were superimposable in each tissue; at 10(-6) M, ANP generated 613+/-41 and urodilatin 603+/-55 fmol cyclic guanosine monophosphate per 10 minutes per milligram protein in inner medullary collecting duct cells (p = NS). Thus, urodilatin is as effective as ANP in displacing I-125-ANP binding to both rat and human renal tissue and in generating cyclic guanosine monophosphate in renal target cells in the rat, suggesting that its physiological effects may occur through the same receptors and signaling pathways that mediate the actions of ANP
Phosphodiesterase inhibitors correct resistance to natriuretic peptides in rats with Heymann nephritis
No full textExperimental nephrotic syndrome is characterized by abnormal sodium metabolism, reflected in a blunted natriuretic response both to volume expansion and to infused atrial natriuretic peptide (ANP), The studies presented here examined the relationships among plasma ANP concentration and urinary sodium (UNaV) and cyclic GMP excretion (UcGMPV) in vivo, and the responsiveness of isolated glomeruli and inner medullary collecting duct (IMCD) cells to ANP and urodilatin (renal natriuretic peptide; RNP) in vitro in rats with Heymann nephritis, an immunologically mediated model of nephrotic syndrome, Nine to 14 days after ip injection of anti-Fx1A antiserum, rats were proteinuric and had a blunted natriuretic response to intravenous infusion of isotonic saline (2% body weight, given over 5 min). Thirty min after the onset of the infusion, plasma ANP concentration was increased to the same extent in both normal and nephritic rats, compared with their respective hydropenic controls, Despite this increase, UcGMPV was significantly less in nephritic rats after the saline infusion, Accumulation of cGMP by isolated glomeruli and IMCD cells from nephritic rats after incubation with ANP and RNP was also significantly reduced, compared with normal rats. This difference was not related to differences in either density or affinity of renal ANP receptors, but was abolished when accumulation of cGMP was measured in the presence of 10(-3) M isobutylmethylxanthine or Zaprinast, two different inhibitors of cyclic nucleotide phosphodiesterases (PDE), Infusion of Zaprinast into one renal artery in nephritic rats normalized both the natriuretic response to volume expansion and the increase in UcGMPV from the infused, but not the contralateral, kidney. Furthermore, cGMP-PDE activity was increased in IMCD cell homogenates from nephritic compared with normal rats (388 +/- 32 versus 198 +/- 93 pmol/min per mg protein, P < 0.03). These results indicate that blunted volume expansion natriuresis accompanied by cellular resistance to ANP in vitro occurs in an immunologic model of renal injury, The resistance is not related to an alteration in ANP release or binding to its renal receptors, but is suppressed by PDE inhibitors and is associated with increased renal cGMP PDE activity, thus suggesting that enhanced cGMP-PDE activity may account for resistance to the natriuretic actions of ANP observed in vivo. This defect may represent the intrinsic sodium transport abnormality linked to sodium retention in nephrotic syndrome
Receptors for atrial natriuretic peptide are decreased in the kidney of rats with streptozotocin-induced diabetes mellitus
No full textAbstract
To determine whether decreased renal responsiveness to atrial natriuretic peptide (ANP) in diabetes is mediated by
alterations in the renal ANP receptor, ANP receptor density and affinity were measured 17-20 d after streptozotocin injection and compared with values in vehicle-treated controls
and streptozotocin-treated rats made euglycemic with insulin. Plasma ANP concentration was significantly greater in hyperglycemic diabetic rats than in control or euglycemic diabetic rats. Both in glomeruli and inner medulla, ANP
receptor dissociation constant did not differ among the three study groups, whereas the maximum binding capacity was decreased significantly in hyperglycemic diabetics in comparison with controls and euglycemic diabetics. Glomerular clearance receptors were also decreased significantly in hyperglycemic
diabetic rats in comparison with control and
euglycemic diabetic rats. To determine whether the decreased number of renal ANP receptors in diabetic rats was associated with a decreased biological response, we measured ANP-dependent cyclic GMP (cGMP) accumulation by isolated glomeruli and inner medullary collecting duct
cells in vitro. cGMP accumulation was significantly less in hyperglycemic diabetic rats than in controls or euglycemic
diabetic rats both in the presence or absence of the phosphodiesterase inhibitor zaprinast. cGMP phosphodiesterase activity in inner medullary collecting duct cells obtained from control and hyperglycemic diabetic rats did not differ. Thus,
the decreased number of biologically active ANP receptors in the kidneys of diabetic rats is accompanied by decreased biological responsiveness in vitro and provides a potential
explanation forthe reduction in renal sensitivity to ANP in this condition
The renin-angiotensin system and compensatory renal hypertrophy in the rat
No full textAngiotensin II (Ang II) may act as an angiogenic and growth promoting factor in different tissues. To assess the role of Ang II in compensatory renal growth following unilateral nephrectomy (UNX), we measured renin, angiotensinogen, and Ang II type 1 (AT(1)) receptor mRNA levels, as well as Ang II receptor density, in two groups of Sprague-Dawley rats 7 days after either sham operation or UNX. Half of each group received either no treatment or an angiotensin-converting enzyme inhibitor (100 mg/dL captopril in the drinking water, initiated at the time of the intervention). Following UNX, the ratio of kidney weight to body weight (KW/BW) in untreated animals was greater than in rats undergoing sham UNX (0.46 +/- 0.01 v 0.37 +/- 0.01%, P <.01). Neither renal renin, nor renal or hepatic angiotensinogen mRNA levels, determined by slot blot hybridization, changed significantly after UNX. Ang II receptor density in glomeruli, determined using an I-125-Sar(1)-IIe(8) Ang II in situ receptor binding assay on frozen kidney sections, did not change significantly after UNX, nor did renal AT(1) receptor mRNA. In captopril-treated rats, KW/BW was greater in UNX than in sham operated rats (0.44 +/- 0.01 v 0.37 +/- 0.01%, P <.01), similar to results in untreated animals. Renal and hepatic angiotensinogen mRNA levels were not affected by captopril treatment and did not change further in response to UNX. Captopril treatment increased renin mRNA in both sham operated and UNX rats as compared with untreated controls, but had no significant effect on Ang II receptor density and AT(1) receptor mRNA; and no change was observed in either variable as a consequence of UNX. Thus, compensatory renal hypertrophy following UNX occurred in the absence of measurable changes in components of the renin-angiotensin system, and despite functionally significant inhibition of this system by captopril. These data do not support a critical role for Ang II in compensatory renal hypertrophy. (C) 1997 American Journal of Hypertension, Ltd
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