Administration Of Converting Enzyme Inhibitor Research Articles

Dyskalemia: a management problem for students.

Although dyskalemia is common, its management can be problematic for students and general practitioners, especially when it occurs in patients with heart and renal failure. The basic academic knowledge of general medicine students, who have often not yet encountered clinical situations of dyskalemia, remains unclear in this regard. The purpose of this study was to evaluate the knowledge and reflexive practices of general medicine students in regard to dyskalemia. A cross-sectional survey, based on a self-questionnaire, of all of the students enrolled in general medicine studies at the Faculty of Medicine at the University of Nancy (France) at the end of their degree. The students were asked questions pertaining to specific clinical situations. The answers were compared to the information provided in the medical curriculum as well as to the relevant European guidelines. We collected 290 of the questionnaires (participation rate: 81.2%). The hyper- and hypokalemia thresholds considered pathological (3.5-5.0mmol/L) were known by 78% and 67% of the students, respectively. The perception of danger in case of severe hypokalemia was underestimated by 62.7% of them. In most cases, the proposed management of hyperkalemia in heart and renal failure did not comply with the relevant guidelines. The students tended to favor permanent discontinuation of the administration of converting enzyme inhibitors (ACE) and/or mineralocorticoid receptor antagonists (MRA) without considering the need for their reintroduction (51.6%). Sodium polystyrene sulfate was frequently seen as an appropriate first-line treatment for hyperkalemia (45%). The knowledge and competence of general medicine students appear to be lacking for hyperkalemia in heart and renal failure, and they are long way from full compliance with the relevant European guidelines. Exposure to complex clinical situations as part of the medical curriculum, therefore, seems essential to improve the way dyskalemia is managed in France.

Clinical observation on the effects of valsartan combined with fosinopril in patients with IgA.nephropathy

Objective To observe the effect and safety of valsartan combined with fosinopril on patients with IgA nephropathy.Methods 91 patients were assigned to three groups:conventional therapy group ( n=28),fosinopril group (n=31),and combined therapy group ( n = 32).Six months were as one therapeutic course.Urine protein,blood pressure and serum creatinine were detected during trial period.Results After six months of therapy,the level of 24hours proteinuria of all groups were decreased,especially in combined group (P＜0.05).The total effective rate was 84.38 % in combined therapy group,61.29% in fosinopril group,and 35.71% in conventional therapy group,Conclusion It is safe and effective to treat lgA nephropathy with angiotensin receptor antagonist combined with angiotensin converting enzyme inhibitor.It is superior to simple angiotensin converting enzyme inhibitor administration or conventional therapy. Key words: Fosinopril; Valsartan ; IgA nephropathy

Protection against ischemia: a physiological function of the renin-angiotensin system

The renin-angiotensin system (RAS) is involved in a complex mechanism that serves to preserve the blood supply to organs so that they can maintain cellular function. Angiotensin II exerts this effect, independently of the blood pressure generated, through two time-related events: a fast opening of the reserve collateral circulation and a much slower response of new vessel formation or angiogenesis. This effect is observed in rats with ligation of the abdominal aorta and in gerbils with abrupt or progressive unilateral carotid artery ligation. Inhibition of the angiotensin-converting enzyme (ACE) or the angiotensin II receptor represses this effect, and it appears that it is mediated through a non-AT 1 receptor site of angiotensin II. Many tumors, both benign and malignant, express renin and angiotensin. It seems that the stimulating action of angiotensin II on angiogenesis could also be involved in preserving the blood supply to tumor cells. Administration of converting enzyme inhibitors increases survival and decreases tumor size in tumor-bearing rats. These observations support the hypothesis that the RAS, directly or indirectly, is involved in situations in which the restoration of blood supply is critical for the viability of cells and that it is present not only in normal but also in pathological conditions such as tumors. In view of the ubiquitous presence of renins and angiotensins, it is also likely to be involved in other conditions, such as inflammation, arthritis, diabetic retinopathy, and retrolental fibroplasia, among others in which angiogenesis is prominent. In addition, angiotensin II could be involved, through the counterbalance of the AT 1 and AT 2 receptors, in the rarefaction of blood vessels as an etiologic component of essential hypertension.

Converting enzyme inhibitors cause pressure-independent resetting of baroreflex control of sympathetic outflow.

The current study was performed to determine whether baroreflex resetting after acute administration of converting enzyme inhibitors (CEIs) was dependent on the concomitant decrease in mean arterial pressure (MAP). Reflex changes in lumbar sympathetic nerve activity (LSNA) due to increases and decreases in MAP [i.v. phenylephrine (PE) and nitroprusside infusions] were determined in normotensive and renal hypertensive (1-kidney, 1-clip) anesthetized WKY rats 1) before (control), 2) 15 min after intravenous captopril (2 mg/kg) or enalaprilat (300 micrograms), and 3) 15 min after MAP was returned to pre-CEI levels with intravenous PE. CEIs decreased MAP and caused a leftward shift of the MAP-LSNA curve toward a lower operating pressure range in all hypertensive and in one group of normotensive rats. The baroreflex curve remained shifted to the left even after MAP was restored to pre-CEI levels by infusion of PE. Thus CEIs cause a pressure-independent resetting of baroreflex control of sympathetic outflow within 15 min. This effect of CEIs is most likely due to elimination of a central nervous system effect of circulating angiotensin II and could contribute to the antihypertensive actions of this class of compounds.

Angiotensin-(1-7) Dilates Canine Coronary Arteries Through Kinins and Nitric Oxide

Angiotensin-(1-7) [Ang-(1-7)] was recently recognized to have novel biological functions that are distinct from those of Ang II. In these studies, we determined the vasoactive effects of Ang-(1-7) together with the endothelium-dependent mediator(s) of these responses in canine coronary arteries. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers perfused with 95% O2/5% CO2 at 37 degrees C. Ang-(1-7) caused significant concentration-dependent vascular relaxation (2.73 +/- 0.58 micromol/L, EC50) of rings precontracted with the thromboxane A2 analogue U46,619. Pretreatment with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (1 mol/L) abolished the vasodilator response to Ang-(1-7), whereas treatment with the cyclooxygenase inhibitor indomethacin (10 micromol/L) was without effect. The vasodilator response produced by Ang-(1-7) was blocked by 75% with the bradykinin B2 receptor antagonist Hoe 140 (1 micromol/L) or by 80% with the nonselective Ang II antagonist [Sar1,Thr8]-Ang II (1 micromol/L). In contrast, the selective AT1 or AT2 Ang II antagonists CV 11974 (1 micromol/L), and PD 123319 (1 micromol/L), respectively, were ineffective in inhibiting the Ang-(1-7)-elicited vasodilation. Furthermore, pretreatment of the coronary rings with 2 micromol/L Ang-(1-7) markedly potentiated the bradykinin response. These results suggest that Ang-(1-7) elicits coronary vasodilation that is specifically mediated by the endothelium-dependent release of nitric oxide. These responses involve a B2 bradykinin receptor and a non-AT1, non-AT2, angiotensin receptor. These data suggest that increases in circulating levels of Ang-(1-7) accompanying long-term administration of converting enzyme inhibitors or Ang II receptor blockers may contribute to the cardioprotective actions of these drugs.

Skeletal muscle kallikrein. Potential role in metabolic regulation.

Skeletal muscle glucose metabolism appears to be regulated by locally derived factors as well as by systemically circulating hormones. Local factors may be particularly important during exercise, when substrate demand can increase rapidly. Numerous studies in perfused limbs suggest that the kallikrein-kinin system may participate in the regulation of substrate delivery and utilization by skeletal muscle. Evidence also suggests that kinins mediate the increase in insulin sensitivity after administration of converting enzyme inhibitors. Tissue kallikrein has been isolated and purified from rat skeletal muscles, and its level is highest in muscle with high oxidative activity. In other tissues, kallikrein synthesis is under the influence of insulin. It has not been possible to demonstrate effects of kallikrein or kinins on glucose metabolism in isolated skeletal muscle or cardiocytes. Therefore modulation of glucose metabolism by kallikrein or kinins may only be observed in intact perfused tissues or organs.

Effect of desalivation on water and sodium chloride intake in rats

Desalivate rats consumed significantly less water than sham-operated rats in response to acute challenges with a variety of dipsogens, including polyethelene glycol (PEG), isoproterenol, serotonin, and an angiotensin I converting enzyme inhibitor (CEI). Nonsignificant reductions were recorded after treatments with either angiotensin II or hypertonic NaCl. Meal-related hyperdipsia, and resultant possible hyperhydration, of desalivate rats does not account fully for these reductions in experimental thirsts. The mean 24-h intake of three concentrations of NaCl, in choice with water, showed no difference in the preferences for NaCl of desalivate and sham-operated animals. During chronic administration of CEIs, both desalivate and sham-operated rats showed comparable induction of NaCl appetite.

Effect of nonpeptide angiotensin receptor antagonists on water intake and salt appetite in rats

Nonpeptide angiotensin AT-1 and AT-2 receptor antagonists were administered cerebroventricularly to rats and their effects on various types of angiotensin II (AII)-stimulated water and NaCl intakes examined. The AT-1 receptor blocker, losartan potassium (DUP 753), inhibited water intake evoked by central administration of AII, with the 50% inhibitory dose being less than 0.1 μg. The functional inhibition by higher doses lasted at least 1 h. The AT-2 receptor antagonist PD 123319 also inhibited AII-induced water intake, but at doses about tenfold higher than losartan. Central, but not peripheral, administration of losartan partially inhibited NaCl intake induced by either sodium depletion, treatment with angiotensin converting enzyme inhibitors (CEIs), or adrenalectomy. PD 123319 partially inhibited NaCl intake induced by both sodium depletion and administration of CEI, but not after adrenalectomy. Another AT-2 receptor antagonist, CGP 42112A, likewise inhibited NaCl intake after sodium deprivation. These data suggest that both AT-1 and AT-2 receptor subtypes in the brain are involved in angiotensin-related water and NaCl intakes.

Dysregulation of Aldosterone Secretion and Its Relationship to the Pathogenesis of Essential Hypertension

The level of sodium intake has a reciprocal influence on the vascular and adrenal responses to angiotensin II, with sodium restriction enhancing the adrenal responses and reducing vascular, and particularly renal vascular, responses. In two subgroups of the essential hypertensive population, this relationship is abnormal. Both subgroups have sodium-sensitive hypertension. One is a subset of the low renin essential hypertensive subgroup and its abnormality is an enhanced aldosterone response to angiotensin II with sodium loading, ie, a failure to down-regulate the aldosterone response. The other subgroup, termed nonmodulators, is a subset of the normal-high renin essential hypertensive subgroup. In these patients, sodium intake modifies either adrenal or vascular responses, including renal vascular responses, to angiotensin II--resulting in a reduced aldosterone response to angiotensin II with sodium restriction. Of clinical importance, the nonmodulator's abnormality is corrected by the administration of converting enzyme inhibitors--this class of drugs therefore being a specific form of therapy in these patients.

Remodeling of Heart and Arteries by Chronic Converting Enzyme Inhibition in Spontaneously Hypertensive Rats

Hemodynamic and structural changes of the heart and large arterial vessels were studied in normotensive and spontaneously hypertensive rats following 12 weeks administration of converting enzyme inhibitor (perindopril, 2 mg/kg daily by gavage). In both strains, a significant blood pressure reduction was observed. In normotensive rats, the hemodynamic changes involved significant increase in systemic arterial compliance whereas slight changes in left ventricular weight and aortic medial thickness were observed. In hypertensive rats, the increase in compliance was relatively small, whereas there was a major reduction in medial thickness. Furthermore, the reduction of the media thickness was much more pronounced than that of the left ventricular hypertrophy. The present results suggest that the cardiac and arterial changes observed following long term converting enzyme inhibition do not strictly parallel the blood pressure changes in hypertensive rats. Dissociation between cardiac and arterial changes may be observed.

The Effect of Angiotensin-Converting Enzyme Inhibition on Prolactin Responses in Normal and Hyperprolactinemic Subjects*

Recent observations implicate angiotensin-II (AII) as a possible PRL-releasing factor. These observations prompted us to investigate the role of the renin-angiotensin system in PRL release in man. Nine normal volunteers ingesting a 20-40 mmol/day sodium, 70 mmol/day potassium diet and eight normal volunteers ingesting a 120 mmol/day sodium, 70 mmol/day potassium diet were infused with metoclopramide (2.5 mg over 1 min) and later with TRH (500 micrograms), two agents known to cause PRL release. The infusions were repeated after 36 h of oral administration of converting enzyme inhibitor [CEI; captopril (50 mg, orally, four times daily) or enalapril (5 mg, orally, twice daily)]. On a separate occasion, AII was infused at 10 ng/kg.h for 1 h into normal volunteers on normal salt diet. CEI administration lowered mean arterial pressure by 6-7 mm Hg and stimulated the release of active renin. The PRL responses on low and normal salt diet as well as before and after CEI were not statistically different. There was also no difference in the PRL responses of patients placed on captopril vs. those on enalapril. AII increased blood pressure by 11-25 mm Hg, but did not increase PRL significantly above basal concentrations during the control dextrose infusion. Five hyperprolactinemic volunteers were also given CEI for up to 4 weeks. They demonstrated no significant change in serum PRL levels. We conclude that AII in the pituitary does not significantly alter either basal PRL levels or metoclopramide- and TRH-induced PRL responses in normal subjects on low and high salt diets. In addition, CEI is not a useful therapy in patients with pathological hyperprolactinemia. These findings, however, do not exclude a role for AII in physiological regulation, since CEI does not cross the blood-brain barrier and would not be expected to alter hypothalamic AII.

Mechanisms underlying transition from acute glomerular injury to late glomerular sclerosis in a rat model of nephrotic syndrome.

Functional and morphologic measurements were performed in Munich-Wistar rats after a single central venous injection of puromycin aminonucleoside (PA) or saline vehicle (sham). During phase I, PA rats exhibited overt nephrotic syndrome and impaired glomerular filtration, primarily due to a reduction in the glomerular capillary ultrafiltration coefficient. The morphologic counterpart of the latter consisted of effacement of glomerular epithelial cell foot processes and decrease in the number of filtration slit diaphragms. Administration of the angiotensin I converting enzyme inhibitor (CEI) enalapril to PA rats did not ameliorate glomerular dysfunction. During phase II, PA rats exhibited spontaneous resolution of proteinuria, impaired function, and morphologic abnormalities. However, PA rats now demonstrated marked glomerular capillary hypertension and continued, albeit lesser, reductions in the ultrafiltration coefficient. Concurrent CEI administration modestly lowered systemic arterial pressure, and normalized the glomerular capillary hydraulic pressure and ultrafiltration coefficient. Additional rats were studied during phase III, 70 wk after injection. In PA rats, prior glomerular hypertension was associated with development of recurrent proteinuria and extensive glomerular sclerosis, whereas concurrent CEI administration limited these parameters to values comparable to those in sham rats. Glomerular hypertension thus may explain the development of glomerular sclerosis and renal failure long after an episode of acute glomerular injury.

Mechanism of antihypertensive effect of potassium depletion in renovascular hypertension.

K depletion (KD) prevents the development of hypertension in two-kidney, one-clip renovascular, hypertension [mean arterial pressure: 110 +/- 5 (KD) vs. 142 +/- 3 mmHg in potassium replete (KR); P less than 0.001]. The protective effect of KD is associated with a 60% decrease in angiotensin II (ANG II) pressor responsiveness and a 40% decrease in ANG II binding to mesenteric artery particles from rats with renovascular hypertension (receptor number 117 +/- 16 in KD vs. 165 +/- 14 fmol/mg protein in KR, P less than 0.05). To determine whether decreases in binding could account for decreases in ANG II pressor responsivity, we measured ANG II binding after bilateral nephrectomy or sustained administration of converting-enzyme inhibitor. Both maneuvers resulted in increases in binding, such that total binding and receptor number were greater than in comparably treated KR rats; e.g., after nephrectomy, receptor number was 215 +/- 26 in KD vs. 98 +/- 12 fmol/mg protein in KR, (P less than 0.01). Despite increased binding, the pressor response to ANG II in KD rats, which were nephrectomized or treated with converting-enzyme inhibitor, was still reduced by 50% compared with comparably treated KR rats. To determine whether the decreased ANG II pressor responsivity of KD was caused by cellular K depletion or to increases in ANG H induced by KD, we administered K to KD, ANG II-deficient rats. ANG II pressor responsivity increased, and total binding and receptor number decreased (KD, ANG II- deficient 246 +/ 22 fmol/mg protein; KD, ANG II-deficient + K 91 +/ 16 fmol/mg protein; P less than 0.005) with K.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of angiotensin II in experimental membranous nephropathy.

Glomerular hemodynamics measurements in rats with experimental membranous nephropathy [passive Heymann nephritis (PHN)] have demonstrated that the appearance of proteinuria 5 days after administration of anti-Fx1A antibody is temporally related to changes in the glomerular ultrafiltration coefficient (LpA). Previous studies in other models of glomerular injury have suggested a significant role for angiotensin II (ANG II) in the glomerular hemodynamic abnormalities. To evaluate the possible role of ANG II in the LpA decrease, converting enzyme inhibitor (CEI) was administered acutely or chronically (5 days before and after induction of PHN) to rats with PHN. Acute ANG II blockade produced a fall in mean arterial pressure (MAP), single-nephron glomerular filtration rate (SNGFR), absolute proximal reabsorption (APR), single-nephron plasma flow, single-nephron blood flow, and glomerular capillary hydrostatic pressure (PG); however, no changes in LpA were detected. Chronic administration of CEI (MK421, 5 mg.kg-1.day-1) in the drinking water was associated with a fall in MAP; however, both SNGFR and APR increased. PG and the transcapillary hydrostatic pressure gradient were unchanged, and LpA remained depressed. These results suggest that reduction of LpA in rats with PHN is ANG II independent and that other mechanisms are required to explain these changes in glomerular hemodynamics.

Converting enzyme inhibition and the common carotid circulation in older patients with sustained essential hypertension.

Arterial diameter, blood flow and vascular resistance of the common carotid artery were studied using a pulsed Doppler system in patients with uncomplicated sustained essential hypertension and compared with age-matched normal subjects. In hypertensive patients below the age of 45 years, arterial diameter and blood flow remained within the normal range, while vascular resistance was increased. In hypertensive patients over 45 years of age, arterial diameter was also normal, but blood flow was reduced and vascular resistance markedly increased. Thus, both small and large arteries were altered in the common carotid circulation of patients with sustained essential hypertension. Acute oral administration of converting enzyme inhibitor produced dilatation of both small (vascular resistance) and large (arterial diameter) arteries in the carotid circulation. In addition, in older patients, blood flow significantly increased and vascular resistance markedly decreased both in acute and long-term situations. Thus converting enzyme inhibition was able to reverse the abnormalities of the common carotid circulation of older subjects with sustained essential hypertension.

Effect of a kinin antagonist on the acute antihypertensive activity of enalaprilat in severe hypertension.

The purpose of this study was to assess the role of kinins in the acute antihypertensive effect of the converting enzyme inhibitor (CEI) enalaprilat in rats with severe hypertension induced by aortic ligation between both renal arteries. For this study, we used a bradykinin analogue, D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-DPhe-Thi-Arg-TFA, with in vivo antagonistic properties. Hypertensive rats were infused intra-aortically for 15 minutes with either saline (30 microliters/min) or the kinin antagonist (40 micrograms/kg/min). Five minutes after the infusion was begun, a bolus injection of enalaprilat (60 micrograms/kg) was given. The blood pressure of the saline-infused animals decreased 48 +/- 6 mm Hg (from 180 +/- 7 to 132 +/- 7 mm Hg), while that of the rats treated with the antagonist decreased only 21 +/- 4 mm Hg (from 175 +/- 3 to 154 +/- 3 mm Hg). The difference between both decrements was significant (p less than 0.01). In another group of hypertensive animals (n = 9), we measured kinin concentration in plasma from arterial blood before and after administration of CEI (41 +/- 10 vs 68 +/- 20 pg/ml, respectively; NS). These results are consistent with the hypothesis that kinins play a role in the acute antihypertensive effect of CEIs in rats with severe hypertension. However, since arterial blood kinin concentrations were not increased significantly after CEI administration, the effect of the CEI may be due to an increase in tissue kinins, which could act as autacoids regulating vascular resistance.

Tissue renin-angiotensin systems: focus on the heart.

Recent findings support the existence of independently functioning, local renin-angiotensin systems in a number of tissues. The clinical importance that inhibitors of the renin-angiotensin system have gained in the treatment of hypertension and cardiac failure, as well as molecular biology data, suggest that a functional, tissue renin-angiotensin system is present in the heart. Using several experimental approaches we present evidence to support the existence and the possible physiopathological relevance of such a cardiac renin-angiotensin system. Tissue angiotensins were documented and quantified in different regions of the heart by high performance liquid chromatography combined with specific radio-immunoassay. Reduction of cardiac angiotensin after administration of converting enzyme inhibitors in nephrectomized animals indicates that these peptides are generated locally. Effects of converting enzyme inhibitors on angiotensin II-dependent facilitation of cardiac sympathetic tone further support this concept and emphasize the potential physiological role of a cardiac renin-angiotensin system. Further, direct evidence for local generation of angiotensin II in the myocardium is provided by assessment of the intracardiac conversion of angiotensin I to angiotensin II and by measurement of the activity of angiotensin converting enzyme in the heart.

Role of the Kallikrein-Kinin System in Two-Kidneyed and One-Clipped Hypertensive Rats

The influence of aprotinin as a kallidinogenase inactivator on the antihypertensive effect of angiotensin I converting enzyme inhibitor (CEI) was studied in two-kidneyed and one-clipped hypertensive rats. Sixteen two-kidneyed and one-clipped hypertensive rats and sham-operated normotensive rats were prepared for this experiment. They were divided into two groups: those with the aprotinin infusion and those without. The effects of the oral administration of CEI were compared as regards mean arterial pressure (MAP) and urinary kallikrein activity (UKA). In 8 hypertensive rats under glucose infusion, MAP fell from 184.4 +/- 4.5 to 106.3 +/- 5.2 mm Hg, and UKA changed from 1.37 +/- 0.18 nkat/12 h to 0.61 +/- 0.11 nkat/12 h after the administration of CEI. In the remaining hypertensive rats under aprotinin infusion, MAP decreased from 175.0 +/- 3.0 to 140.6 +/- 5.1 mm Hg, and UKA slightly changed from 0.72 +/- 0.25 nkat/12 h to 0.59 +/- 0.12 nkat/12 h. Thus, the decrease of MAP after the administration of CEI was suppressed by the aprotinin infusion, and this significant difference was supported by the decrease of UKA. As for 16 normotensive rats, CEI did not alter MAP, nor did aprotinin have any effect on it. However, UKA tended to decrease after the administration of CEI. These results suggest that both the kallikrein-kinin system and the renin-angiotensin system play an important role in the maintenance of high blood pressure in two-kidneyed and one-clipped chronically hypertensive rats.

Antihypertensive action of angiotensin-I converting enzyme inhibitors in the kidney.

In order to elucidate the antihypertensive action of angiotensin-I converting enzyme inhibitors (CEIs) in the kidney, intrarenal (IR) administration of CEIs was performed in norepinephrine (NE) or angiotensin-II (AII) induced acute hypertension in conscious unrestrained rabbits. IR administration of the two kinds of CEIs, captopril (5 mg/kg) and MK-422 (1 mg/kg), dose which caused no significant effect when injected intravenously, elicited a prompt and marked depressor action in NE but not in AII induced hypertension. In addition, IR infusion of the angiotensin-II analogue, saralasin (2 and 10 micrograms/kg/min) showed no depressor effect in NE induced acute hypertension. These results indicate that the kidney plays an important role in the depressor action of CEIs in NE but not in AII induced hypertension and this effect may not be related to the IR renin-angiotensin system.

Superficial and juxtamedullary nephron function during converting enzyme inhibition.

The influence of the renin-angiotensin system on whole-kidney and regional single-nephron function was studied in anesthetized Munich-Wistar rats by use of a converting enzyme inhibitor (CEI), captopril (3 mg . h-1 . kg-1 body wt-1). Single-nephron glomerular filtration rate (SNGFR) was measured in superficial (S) and juxtamedullary (JM) nephrons by a micropuncture technique that blocked tubuloglomerular feedback (TGF) activity. Hydrostatic free-flow pressure (FFP) measurements were conducted in S proximal tubules, in JM loops of Henle, and in papillary vasa recta. Glomerular filtration rate (GFR) and urinary electrolyte excretion were measured in the contralateral kidney. In the control situation SNGFR of S nephrons was 35.4 +/- 2.24 nl . min-1 . g kidney wt-1 and of JM nephrons was 75.0 +/- 9.41 nl . min-1 . g-1 kidney wt-1. Thus it was more than twice as high in JM as in S nephrons when the TGF activity was blocked. In this situation administration of CEI had no additional effect on either S or JM nephrons. However, administration of CEI resulted in a significant increase in whole-kidney GFR by 25% (P less than 0.05) and in urine flow rate by 60% (P less than 0.001) under free-flow conditions. Further, intratubular FFP increased significantly in JM nephrons by an average of 2.9 +/- 0.52 mmHg (P less than 0.001), indicating an increase in tubular urine flow in JM nephrons, whereas S nephrons were unaffected. These results suggest an active preglomerular vasoconstriction in JM nephrons under normal free-flow conditions. This seems to be mediated by TGF and modulated by angiotensin II.