Two groups of adult male Munich-Wistar rats and a third group of nondiabetic age-matched and weight-matched normal control rats underwent micropuncture study 1 mo, and morphologic studies 14 mo, after induction of streptozotocin diabetes or sham treatment. All animals were fed standard rat chow. Diabetic rats received daily ultralente insulin to maintain stable moderate hyperglycemia (-350 mg/dl). In addition, one group of diabetic rats was treated with the angiotensin I converting enzyme inhibitor, enalapril, 15 mg/liter of drinking water. Average kidney weight, whole kidney and single-nephron glomerular filtration rate, and glomerular plasma flow rate were elevated to similar values in both groups of diabetic rats, relative to normal control rats. Non-enalapril-treated diabetic rats exhibited significant elevations in mean glomerular capillary hydraulic pressure and transcapillary hydraulic pressure gradient, compared with the other groups studied, and only this group eventually developed marked and progressive albuminuria. Likewise, histological examination of the kidneys at 14 mo disclosed a high incidence of glomerular structural abnormalities only in non-enalapril-treated diabetic rats. These findings indicate that prevention of glomerular capillary hypertension in rats with diabetes mellitus effectively protects against the subsequekit development of glomerular structural injury and proteinuria. This protection is afforded despite pronounced hyperglycemia and elevated levels of glucosylated hemoglobin, further supporting our view that hemodynamic rather than metabolic factors predominate in the pathogenesis of diabetic glomerulopathy.

To characterize the hemodynamic events responsible for alterations in renal function during administration of atrial natriuretic peptide, we studied the systemic, renal, and glomerular circulatory effects of intravenous rANP[126-149], administered as a 4 micrograms/kg prime and 0.5 microgram/kg per minute continuous infusion in anesthetized, euvolemic rats. With this protocol, a small decline in mean systemic arterial blood pressure occurred in the context of markedly enhanced urinary sodium excretion, hemoconcentration, and reduced left ventricular end-diastolic pressure and +dP/dt. However, despite a significant decrement in renal vascular resistance, total peripheral resistance remained constant, thereby denoting a preferential renal vasodilatory effect of this peptide in vivo. Whole kidney and single nephron GFR increased by approximately 20%, while effective renal and glomerular plasma flow rates remained stable, resulting in a substantial rise in filtration fraction. Of all the parameters potentially capable of augmenting single nephron GFR, only glomerular capillary hydraulic pressure increased significantly and therefore accounted entirely for the hyperfiltration observed during ANP infusion. This rise in glomerular capillary pressure, in turn, resulted from afferent arteriolar vasodilatation and concurrent efferent arteriolar vasoconstriction, findings that proved independent of both endogenous angiotensin II activity and ANP-induced reductions in renal perfusion pressure. These renal hemodynamic effects are unique when compared with actions of previously studied renal vasodilatory agents.

2 The mechanism(s) underlying such actions remain incompletely elucidated, but several factors are believed to be important, including the rise in glomerular filtration rate (GFR), an increase in medullary blood flow, and direct inhibition of renal epithelial ion transport. 23 An additional possible mode of action is the ability of ANP to act as a potent renal vasodilator, 4 ' 6 which may serve to alter peritubular capillary physical factors and thereby promote natriuresis and diuresis. Earley and coworkers 7 implicated peritubular Starling forces as important determinants of the control of sodium and water excretion, based on studies in which infusions of vasodilators, such as acetylcholine or bradykinin, led to increments in sodium and water excretion. This natriuresis and diuresis was reversed by the concurrent infusion of hyperoncotic albumin and was restored by subsequent elevation of systemic arterial pressure, and Received April 24, 1986: accepted August 18, 1986 presumably peritubular capillary hydraulic pressure, by infusion of angiotensin II (All). 8The present studies employed similar maneuvers in an attempt to modify possible peritubular capillary actions of ANP. In the first set of experiments, we examined the effect of increasing renal perfusion pressure with All on the renal response to ANP infusion, while in the second set of experiments ANP was administered in the setting of elevated postglomerular capillary oncotic pressure. Materials and MethodsStudies were performed on 34 male Munich-Wistar rats weighing 233-321 g. They were allowed free access to standard rat chow (Wayne Rodent Blox #8604; Continental Grain Co., Chicago, II.) and tap water. Clearance experiments were carried out as follows:Rats were anesthetized with Inactin (100 mg/kg, i.p.; Byk Gulden, Konstanz, F.R.G.) and placed on a temperature-regulated table. Following tracheostomy, the left femoral artery was catheterized with PE-50 polyethylene tubing, and a baseline collection of 140 /xl of arterial blood was obtained. This arterial catheter was used for subsequent periodic blood sampling and estimation of mean arterial pressure (AP). SF was monitored with an electronic transducer (Model P23Db, Statham Instruments Division, Gould Inc., Oxnard, Calif.) connected to a direct-writing recorder (Model 7702B Hewlett-Packard Co., Palo Alto, Calif.). The left femoral vein was cannulated with PE-50 tubing, and an infusion of 7% inulin and 0.8% paraaminohippurate (PAH) in 0.9% NaCl was started at a rate of 1.2 ml/hr. PE-50 catheters were also inserted into the right and left jugular veins, and right femoral vein, as needed for infusions of plasma and solutions.by guest on

Atrial peptides (ANP) have been shown to preferentially increase blood flow to juxtamedullary nephrons and to augment vasa recta blood flow. To determine the effect of this alteration in intrarenal blood flow distribution on pressure relationships in inner medullary structures and their significance as a determinant of ANP-induced natriuresis, we measured hydraulic pressures in vascular and tubule elements of the renal papilla exposed in Munich-Wistar rats in vivo during an euvolemic baseline period and again during an experimental period. Rats in Group 1 received intravenous infusion of rANP administered as a 4 micrograms/kg prime and 0.5 microgram/kg/min continuous infusion, and were maintained euvolemic by plasma replacement. Infusion of ANP resulted in significant natriuresis, diuresis and increase in inulin clearance. Within 90 seconds of initiation of this systemic infusion, vasa recta hydraulic pressures were markedly increased and exceeded the small pressure increment occurring in loops of Henle and collecting ducts. Infusion of furosemide in Group 2 rats at a dosage which reproduced the increase in urine flow in Group 1 was associated with small and equivalent increases in both vascular and tubule elements, indicating that the differential pressure response observed in Group 1 was not due to increased tubule fluid flow rates, but was rather a specific ANP-induced vascular effect. Group 3 rats received an infusion of ANP in a setting where its whole kidney hemodynamic effects were prevented. This resulted in a marked blunting of natriuresis and diuresis, and obliteration of the pressure differential between vasa recta and tubules observed in Group 1.(ABSTRACT TRUNCATED AT 250 WORDS)