Increase In Renal Plasma Flow Research Articles

High altitude-induced albuminuria in normal man is enhanced by infusion of low-dose dopamine.

Renal function and the urinary excretion rate of albumin (Ualb) at rest and during infusion of dopamine (3 micrograms kg-1 min-1) were investigated in eight normal volunteers at sea level and 48 h after a rapid, passive ascent to an altitude of 4350 m. Oxygen saturation decreased to 81% (77-85) (median with quartiles in parentheses) at high altitude. High altitude hypoxia increased Ualb from 3.2 micrograms min-1 (2.7-3.5) to 5.0 micrograms min-1 (3.3-6.6) (p < 0.05); increased mean arterial blood pressure from 80 mmHg (73-95) to 102 mmHg (96 108) (p < 0.01); decreased the effective renal plasma flow (ERPF) from 465 ml min-1 (412-503) to 410 ml min-1 (385-451) (p < 0.05), and increased the filtration fraction from 24% (22-27) to 28% (26-29) (p < 0.01). Glomerular filtration rate (GFR), and the renal clearances of lithium (CLi) and sodium (CNa) remained unchanged at high altitude. Dopamine increased ERPF, GFR, CLi, CNa, and decreased the filtration fraction in both environments. Infusion of dopamine further increased Ualb to 10.5 micrograms min-1 (5.5-64.8) (p < 0.05) at high altitude, but had no effect on Ualb at sea level. In conclusion, high altitude hypoxia per se increases the urinary excretion rate of albumin, which is further increased by the renal vasodilating drug dopamine. This effect of dopamine at high altitude may result from combined effects of the increase in renal plasma flow and a hypoxia-induced increase in the glomerular capillary permeability to albumin.

Hemodynamic Effects of Renin Inhibitors

Renin inhibitors may offer an exciting new therapeutic means of blocking the action of the renin-angiotensin-aldosterone system. These compounds interfere with the first, rate-limiting step in the synthesis of angiotensin II by binding directly to the highly specific enzyme, renin. This approach may represent a more focused alternative to angiotensin-converting enzyme inhibitor therapy with an improved side-effect profile. Renin inhibitors given parenterally safely lower blood pressure in patients with essential heart failure. Under conditions of salt limitation, normal subjects show increases in renal plasma flow during infusion of renin inhibitors. The systemic and renal hemodynamic responses to renin inhibition are accompanied by suppression of plasma renin activity, plasma angiotensin II and plasma aldosterone levels. Recent scientific advances in discovering how to address the limitations of the low oral bioavailability of peptide-based compounds have made it possible to invent orally active renin inhibitors. Orally active renin inhibitors are presently being evaluated in clinical trials. The availability of intravenous and oral delivery of renin inhibitors broadens the potential of these agents to treat a wide variety of acute and chronic cardiorenal disorders.

Renal vascular responses to renin inhibition with zankiren in men*

Renin inhibition represents an alternative to angiotensin-converting enzyme (ACE) inhibition for pharmacologic interruption of the renin-angiotensin system. In addition to inhibiting the formation of angiotensin II, ACE inhibitors also inhibit the degradation of kinin and result in accumulation of powerful renal vasodilator prostaglandins and bradykinin. We were therefore surprised by the large renal vasodilator response achieved with the renin inhibitor enalkiren, because substrate-specific renin inhibitors reduce the formation of angiotensin II without affecting other vasodilator mechanisms. To determine whether previous findings were reflective of the renin inhibitor class, we studied 12 healthy men on a sodium-restricted diet, each of whom received two or three escalating oral doses of zankiren, a new agent. Plasma renin activity decreased with the smallest dose (5 mg), and this effect was sustained. The increase in renal plasma flow was clearly related to dose (r = 0.86, F = 9.67), reaching a maximum of 134 +/- 26 ml/min/1.73 m2 at 250 mg, the highest dose. Renin inhibition exerts a remarkable renal vasodilator action, perhaps reflecting the lipophilicity of the agents developed to date, an action that may have clinical implications for the prevention of renal injury in patients at risk.

Hyperuricemia in patients with hyperthyroidism due to graves' disease

The effects of hyperthyroidism on uric acid metabolism were investigated. First, the serum uric acid level was measured in 92 patients with hyperthyroidism due to Graves' disease, eight patients with subacute thyroiditis, six patients with hypothyroidism, and 70 sex- and age-matched controls. Second, the correlation between serum thyroxine (T4) and serum uric acid was obtained in hyperthyroid Graves' disease patients before and during antithyroid drug therapy. Finally, uric acid clearance (CUA) was determined in untreated patients with hyperthyroidism due to Graves' disease. Serum uric acid was significantly elevated in patients with hyperthyroidism, and the elevation correlated well with serum T4 before treatment as a group and during treatment in each patient. A significant elevation of serum uric acid was not present in patients with a transient mild thyrotoxicosis due to subacute thyroiditis. Serum uric acid was significantly decreased in patients with hypothyroidism. Renal excretion of uric acid clearly increased in hyperthyroid patients, and CUA also increased. The increase in CUA corresponded to the increase in renal plasma flow (RPF), which was measured by p-aminohippuric acid clearance. The fractional excretion of uric acid as determined by CUA/glomerular filtration rate (GFR) was similar and within the normal range in hyperthyroid patients and normal controls. A significant inverse correlation between CUA and serum uric acid concentration was present in hyperthyroid patients as in normal controls, indicating that the renal handling of uric acid in the tubule affected uric acid excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

AN IMPROVED GLOMERULAR FILTRATION RATE IN CARDIAC TRANSPLANT RECIPIENTS WITH ONCE-A-DAY CYCLOSPORINE DOSING1,2

We tested the hypothesis that there would be a difference in the unwanted side effects of cyclosporine (CsA) when heart transplant patients received CsA once a day versus half the dose twice a day. Eight stable cardiac transplant patients (>6 months posttransplant) were administered their dose of CsA either as a once-a-day dose or half the dose b.i.d. for 21 days in a random fashion. After 21 days the patients were crossed over to the other regimen. Patients underwent inulin and PAH clearances at CsA trough on each arm of the study. Each patient collected several 24-hr urines for determination of creatinine clearance, and had ambulatory blood pressure monitoring done during each arm of the study. Serum chemistries and lipid profiles were performed at the end of each arm of the study. The CsA dose was 1.9-7.2 mg/kg/day. All patients were hypertensive and on calcium channel antagonists. Once-a-day CsA dosing resulted in a 29% decrease in trough CsA levels. A significant increase in glomerular filtration rate, as estimated by the clearance of inulin, (65.16±24.4 q. day vs. 54.62±19.0 b.i.d. (ml/min)P<.02) and a significant increase in renal plasma flow, as estimated by the clearance of PAH, occurred with once-a-day dosing when compared with b.i.d. dosing (P=.02). Creatinine clearances were not different between the 2 arms of the study and significantly overestimated glomerular filtration rates (P=.01). CsA dosing b.i.d. resulted in significantly higher nocturnal blood pressures (91.2±8.3 b.i.d. vs. 86.4±8.1 q. day, mmHg,P=.015) when compared with once-a-day dosing. A significant increase in LDL cholesterol and a significant decrease in HDL cholesterol were noted during the b.i.d. dosing arm when compared with q. day CsA dosing. We conclude that in stable heart transplant patients once-a-day CsA dosing results in better GFR and renal plasma flow, a lower nocturnal blood pressure, and an improved lipid profile when compared with dosing CsA twice a day.

AN IMPROVED GLOMERULAR FILTRATION RATE IN CARDIAC TRANSPLANT RECIPIENTS WITH ONCE-A-DAY CYCLOSPORINE DOSING1,2

We tested the hypothesis that there would be a difference in the unwanted side effects of cyclosporine (CsA) when heart transplant patients received CsA once a day versus half the dose twice a day. Eight stable cardiac transplant patients (> 6 months posttransplant) were administered their dose of CsA either as a once-a-day dose or half the dose b.i.d. for 21 days in a random fashion. After 21 days the patients were crossed over to the other regimen. Patients underwent inulin and PAH clearances at CsA trough on each arm of the study. Each patient collected several 24-hr urines for determination of creatinine clearance, and had ambulatory blood pressure monitoring done during each arm of the study. Serum chemistries and lipid profiles were performed at the end of each arm of the study. The CsA dose was 1.9-7.2 mg/kg/day. All patients were hypertensive and on calcium channel antagonists. Once-a-day CsA dosing resulted in a 29% decrease in trough CsA levels. A significant increase in glomerular filtration rate, as estimated by the clearance of inulin, (65.16 +/- 24.4 q. day vs. 54.62 +/- 19.0 b.i.d. (ml/min) P < .02) and a significant increase in renal plasma flow, as estimated by the clearance of PAH, occurred with once-a-day dosing when compared with b.i.d. dosing (P = .02). Creatinine clearances were not different between the 2 arms of the study and significantly overestimated glomerular filtration rates (P = .01). CsA dosing b.i.d. resulted in significantly higher nocturnal blood pressures (91.2 +/- 8.3 b.i.d. vs. 86.4 +/- 8.1 q. day, mmHg, P = .015) when compared with once-a-day dosing. A significant increase in LDL cholesterol and a significant decrease in HDL cholesterol were noted during the b.i.d. dosing arm when compared with q. day CsA dosing. We conclude that in stable heart transplant patients once-a-day CsA dosing results in better GFR and renal plasma flow, a lower nocturnal blood pressure, and an improved lipid profile when compared with dosing CsA twice a day.

Calcitonin gene-related peptide reduces renal vascular resistance and modulates ET-1-induced vasoconstriction.

Calcitonin gene-related peptide (CGRP) is a novel polypeptide that exerts important effect on the cardiovascular system through its vasorelaxant properties. We studied in vivo in normal rats the effect of acute administration of CGRP on whole kidney function and showed that the intravenous infusion of the peptide resulted in a fall of blood pressure associated with a marked increase in renal plasma flow (RPF) as well as glomerular filtration rate (GFR). These changes were reversible with discontinuation of CGRP infusion. To evaluate whether the renal hemodynamic responses to the peptide were mediated by endogenous vasodilatory prostaglandins of endothelial origin, animals were preexposed to indomethacin, a cyclooxygenase enzyme inhibitor. Inhibition of prostaglandins synthesis with indomethacin failed, however, to prevent the increase in RPF and GFR observed during CGRP infusion. By contrast, NG-nitro-L-arginine methyl ester (L-NAME), which inhibits the synthesis of nitric oxide, a newly discovered endothelium-derived relaxing factor, completely abolished the renal hemodynamic changes induced by CGRP. Moreover, L-arginine infusion in L-NAME-treated rats restored the renal response to CGRP. We have also shown that systemic infusion of CGRP progressively normalized RPF and GFR that were reduced in response to a bolus intravenous injection of the vasoconstrictor endothelin-1. This indicates that CGRP regulates renal hemodynamics and modulates the deleterious effects of vasoconstrictive substances on the kidney.

Role of nitric oxide in the renal hemodynamic response to a meat meal

Ingestion of a high-protein meat meal results in significant increases in renal plasma flow (RPF) and glomerular filtration rate (GFR). The mechanism involved in this hemodynamic response to the meat meal has not yet been fully elucidated. The present study was designed to test the hypothesis that nitric oxide (NO) is involved in the renal hyperemic responses to a meat meal. To test this hypothesis, renal hemodynamic response to a meat meal (10 g/kg) was determined in conscious, chronically instrumented dogs with (n = 9) and without (n = 7) an intrarenal NO synthesis inhibition with NG-nitro-L-arginine methyl ester (L-NAME, 3 micrograms.kg-1.min-1 intrarenally). Under control conditions, the meat meal resulted in significant renal hyperemia. Three hours after ingestion of the meat meal, GFR (43 +/- 3 to 59 +/- 6 ml/min) and RPF (128 +/- 10 to 160 +/- 17 ml/min) progressively increased by approximately 40 and 25%, respectively. In contrast, pretreatment with intrarenal infusion of L-NAME abolished the GFR (48 +/- 6 to 52 +/- 6 ml/min) and RPF (129 +/- 20 to 121 +/- 17 ml/min) increases induced by the meat meal. Pretreatment with L-arginine (0.5 mg.kg-1.min-1) plus L-NAME (3 micrograms.kg-1.min-1) did not modify the meat meal-induced changes in GFR (41 +/- 4 to 66 +/- 6 ml/min) and RPF (127 +/- 9 to 182 +/- 14 ml/min). In summary, a meat meal in dogs results in marked increases in RPF and GFR. Intrarenal NO synthesis inhibition abolished the RPF and GFR responses to the meat meal.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of the serine protease inhibitor, aprotinin, on systemic haemodynamics and renal function in patients with hepatic cirrhosis and ascites.

1. Previous studies have documented activation of protease enzymes, such as the plasma kallikrein-kinin system, in hepatic cirrhosis. Increased plasma kinin generation could contribute to pathological systemic vasodilatation in cirrhosis, and reduced systemic vascular resistance has been suggested as a trigger to renal sodium retention in this disease. We investigated the effect of aprotinin, a protease inhibitor which binds to plasma kallikrein, on systemic haemodynamics and renal function in patients with hepatic cirrhosis and ascites. 2. Aprotinin was infused intravenously in high dosage (2 x 10(6) kallikrein inhibitory units loading, 1 x 10(6) kallikrein inhibitory units/h). 3. Of 13 patients, 10 had a low systemic vascular resistance (< 1200 dyn s cm-5) at baseline. In this group, eight showed an increase in systemic vascular resistance during aprotinin infusion. Overall, the increase in systemic vascular resistance was significant, and there was a small but significant increase in mean arterial pressure. In all patients, there were increases in renal plasma flow, glomerular filtration rate, and absolute and fractional urinary sodium excretion during aprotinin infusion. 4. Plasma renin activity, plasma angiotensin II and plasma aldosterone fell significantly during aprotinin infusion. Plasma prekallikrein, plasma noradrenaline and plasma atrial natriuretic peptide did not change. Plasma aprotinin concentration was 209 +/- 11 kallikrein inhibitory units/ml at the end of the infusion. 5. Before and during the infusion, there was a significant negative correlation between systematic vascular resistance and plasma renin activity. There was a positive correlation between the change in systemic vascular resistance and the change in renal plasma flow during aprotinin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of prostaglandin E1 on renal hemodynamics.

The glomerular filtration rate (GFR), renal plasma flow (RPF), renal blood flow (RBF), filtration fraction (FF), and the ratio of mean arterial pressure (MAP) to RBF (MAP/RBF), reflecting renal vascular resistance (RVR) were determined to investigate the effects of intravenously administered prostaglandin E1 (PGE1) on renal hemodynamics in humans. PGE1 produced no significant changes in GFR, but did cause significant increases in RPF and RBF and significant decreases in FF and MAP/RBF. The relationships between MAP and GFR, MAP and RBF, and MAP and MAP/RBF were investigated. PGE1 suppressed the increase of MAP/RBF along with the increase of MAP, increased the RBF along with the increase of MAP, and kept the GFR constant, regardless of MAP. Also, the effects of PGE1 on renal pericapillary vessels were simulated. According to this simulation, PGE1 had a vasodilator action on both preglomerular and postglomerular capillaries.

2 Glomerular filtration and volume regulation in gravid animal models

The gestational increase in glomerular filtration rate that occurs in the normal rat is exclusively the result of an increase in renal plasma flow and there is no sustained increase in glomerular capillary blood pressure during a normal pregnancy. The factor or factors that initiate the gestational renal vasodilatation (and plasma volume expansion) are maternal, not fetoplacental in origin. The precise nature of the initiating factors has not yet been defined, although it is unlikely that the gestational plasma volume expansion can be the sole cause of the increased glomerular filtration rate seen in pregnancy. A number of vasoactive hormones are activated in pregnancy but as yet no clear candidate has emerged as 'the renal vasodilator'. Preliminary evidence suggests that nitric oxide may play an important role in gestational vasodilatation. The normal kidney in pregnancy exhibits substantial renal reserve to amino acid infusion and unimpaired autoregulatory ability despite being already vasodilated by the gestational stimulus. There are marked and sometimes contradictory changes in the various volume sensing and control systems in pregnancy. In general, the sensors perceiving and controlling intravascular volume are reset during a normal pregnancy to enable to mother to accommodate the increased plasma volume without provoking a natriuretic response. Whether the expanded plasma volume of pregnancy is perceived as normal or underfilled is not clear at this time and may vary according to the volume regulatory system. Repetitive pregnancies do not have any cumulative, long-term deleterious effects on renal function, when the underlying function is normal, when it has been compromised by removal of renal mass or during chronic systemic hypertension in the spontaneously hypertensive rat. In the short term, pregnancy does not worsen kidney function when underlying glomerular damage is due to immune stimuli, ablation of renal mass or gentamicin, or in the spontaneously hypertensive rat. Therefore, the chronic renal vasodilatation of pregnancy does not appear to be a damaging entity, unlike other states of low preglomerular arteriolar resistance, studied in the male rat. When pregnancy is superimposed on Adriamycin nephrosis or chronic blockade of nitric oxide, hypertension occurs and renal function declines. In both situations endothelial damage/dysfunction occurs, as is also seen in pre-eclampsia. Further study of the effects of pregnancy in animal models of endothelial dysfunction will prove rewarding.

Insulin causes renal vasodilatation independently of renal prostaglandins in healthy humans

The effect of physiological hyperinsulinaemia on renal haemodynamics and renal sodium handling was studied in nine healthy males on two separate study occasions with and without indomethacin pretreatment, using the euglycaemic insulin clamp technique. Renal haemodynamics and segmental tubular sodium handling were evaluated by determining the inulin, PAH, sodium and lithium clearances. Changes in urinary dopamine excretion were also studied. Insulin infusion caused similar increases in renal plasma flow with as well as without indomethacin pretreatment, but no change in glomerular filtration rate in both experimental settings. Following indomethacin pretreatment, the basal sodium clearance decreased from 1.6 +/- 0.2 to 0.8 +/- 0.2 ml/min and the basal urinary dopamine excretion decreased from 107 +/- 8 to 86 +/- 6 nmol/h. In conclusion, the present study demonstrates a direct renal vasodilatory effect of insulin in healthy subjects that does not seem to be dependent on renal prostaglandins. Moreover, under the present experimental circumstances indomethacin reduced the basal urinary dopamine output, which could reflect a reduction in the filtered load of sodium following indomethacin pretreatment.

Insulin-like growth factor I produces renal hyperfiltration by a kinin-mediated mechanism.

Insulin-like growth factor-I (IGF-I) infusion into rats and humans reduces renal vascular resistance and raises glomerular filtration rate (GFR) and renal plasma flow (RPF). To investigate whether kinins mediate the renal vasodilatory effects of IGF-I, we infused rats with IGF-I alone or in the presence of a B2 kinin receptor antagonist. Left kidney GFR, RPF, and kinin excretion were measured during infusion of vehicle and subsequently during 60-min infusion of IGF-I or IGF-I plus kinin antagonist. IGF-I was given as a bolus (150 micrograms/kg body wt), followed by infusion at a rate of 8.3 micrograms.kg-1 x min-1 for 60 min. The kinin antagonist was infused at a dose of 1 microgram.kg-1 x min-1 for 60 min before the start of IGF-I infusion. GFR and RPF increased significantly after IGF-I infusion was begun, from baseline levels of 1.70 +/- 0.12 and 6.21 +/- 0.34 to 2.12 +/- 0.11 and 7.91 +/- 0.29 ml/min, respectively, at 20 min (P < 0.001). This effect was maintained throughout 60 min of infusion. The increase in GFR and RPF was associated with a marked rise in urinary kinin excretion, from a baseline of 8.51 +/- 6.7 to 24.7 +/- 6.7 pg/min at 20 min and 40.3 +/- 10.4 pg/min at 40 min (P < 0.001). Pretreatment with the kinin receptor antagonist blocked the rise in GFR and RPF in response to IGF-I. These data suggest that the renal vasodilatory effect of IGF-I is mediated by kinins.

Renal Responses to Acute Angiotensin II Inhibition and Administered Angiotensin II in the Aging, Conscious, Chronically Catheterized Rat

Studies of conscious, chronically catheterized, young (3 to 5 months of age) and old (19 to 22 months of age) male Sprague Dawley rats in the baseline state showed that glomerular filtration rate (factored for body weight) was lower and urine flow higher in old compared with young rats. Acute blockade of endogenous angiotensin II (All) with either converting enzyme inhibitor (CEI) or Losartan (Dupont Merck, Wilmington, DE) caused small variable decreases in blood pressure in both age groups and produced a significant renal vasodilation with increases in renal plasma flow in the older rats. In separate studies using low-dose All infusion (5 ng/kg body weight/min), an increase in filtration fraction was the only effect seen in both young and old rats with an intact renin/All system; no effect was seen with CEI. During high-dose All (20 ng/kg body weight/min), significant and similar increases were seen in blood pressure and renal vascular resistance in old and young rats, and the patterns of blood pressure and renal hemodynamic responses were similar with and without acute CEI. A natriuretic and diuretic response to high-dose All was seen in young rats with intact endogenous renin/All, whereas old rats were completely refractory to this action of All. Against a background of acute CEI, no natriuretic/diuretic response to high-dose All was seen in either age group. Thus, in the baseline state, renal hemodynamics in the old kidney are controlled by endogenous All since eEl and Losartan produce renal vasodilation in old but not young rats. Renal hemodynamic responses to administered All are generally similar in both age groups, irrespective of the presence or absence of CEI, suggesting an unaltered renal vascular sensitivity to All in aging. The inability of the old kidney to generate a natriuretic or diuretic response to All with an intact endogenous renin/All system may reflect a more generalized defect in the natriuretic capacity or may be due to enhanced All-dependent proximal tubular reabsorption in the old kidney. The mechanism by which acute CEI prevents the All-induced diuresis/natriuresis in young rats is unknown.

Pregnancy restores the renal vasodilator response to glycine in Dahl salt-sensitive rats.

To determine if pregnancy alters the impaired renal vasodilator responses in hypertensive Dahl salt-sensitive (Dahl S) rats, we measured glomerular filtration rate and effective renal plasma flow and calculated renal vascular resistance before, during, and after renal vasodilation with glycine (0.17 mmol/kg per minute IV). Conscious, midterm (day 11 to 14) pregnant and age-matched virgin Dahl S and Dahl salt-resistant (Dahl R) rats were fed an 8% NaCl diet for 4 weeks (n = 6 per group). Mean arterial pressure was elevated (P < .05) in Dahl S compared with Dahl R rats, with no significant difference between pregnant and virgin animals in either group. Pregnancy resulted in significant increases in plasma volume, baseline glomerular filtration rate, and renal plasma flow and a significant decrease in renal vascular resistance. The glycine-induced increase in filtration rate in virgin Dahl S rats (27 +/- 4%) was less (P < or = .01) than pregnant Dahl S (60 +/- 4%) and either group of Dahl R (virgin, 43 +/- 3%; pregnant, 45 +/- 5%) rats. Similarly, the 21 +/- 4% increase in renal plasma flow in virgin Dahl S rats was less (P < or = .01) than the pregnant Dahl S (45 +/- 4%) and either pregnant (45 +/- 5%) or virgin (45 +/- 5%) Dahl R rats. Glycine decreased renal vascular resistance only 12 +/- 2% in the virgin Dahl S compared with 31 +/- 3% in the pregnant Dahl S rats and 30 +/- 4% and 28 +/- 3% in pregnant and virgin Dahl R rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of muscarinic receptors in renal response to acetylcholine.

Renal arterial infusion of acetylcholine (ACh) (40 micrograms/min) in control dogs produced an ipsilateral increase in renal plasma flow (RPF) and in sodium excretion (UNaV) without a change in glomerular filtration rate (GFR). The increase in RPF and UNaV was maintained during the infusion of ACh. In indomethacin (Indo)-treated dogs (5 mg/kg) ACh produced a transient rise in RPF and UNaV, followed by a progressive decline in RPF and UNaV. The profound renal vasoconstriction was accompanied by a decline in GFR. To determine the role of the muscarinic receptor in the renal vasodilation and in vasoconstriction produced by ACh in Indo-treated dogs, atropine at 6, 60, and 600 micrograms/min was infused into the renal artery before and during the infusion of ACh. In Indo-treated dogs, all dosages of atropine prevented renal vasoconstriction by ACh. Renal arterial infusion of atropine at 600 micrograms/min completely inhibited the renal vasodilation produced by ACh. Atropine infused at 60 micrograms/min partially inhibited, whereas 6 micrograms/min atropine failed to inhibit, the renal vasodilation produced by ACh. Our data suggest that the renal vasodilator and vasoconstrictor effects of ACh in Indo-treated dogs are mediated by two separate types of muscarinic receptors.

Acute effect of physiological concentrations of vasopressin on rat renal function.

1. The antidiuretic, pressor and electrolyte transport effects of arginine vasopressin (AVP) were simultaneously evaluated in the anaesthetized water diuretic rat. Increasing concentrations of AVP (7.5, 75 and 750 ng/kg bolus and per h), were used to produce plasma levels which approximate the physiological range (408 +/- 2.4, 35.7 +/- 12.5, 85.2 +/- 16.1 pg/mL respectively). 2. Administration of a minimally effective antidiuretic dose (7.5 ng) increased mean urine osmolality (from 101 +/- 7 to 312 +/- 89 mosmol/kg) without altering mean arterial pressure (MAP), renal plasma flow (RPF) or glomerular filtration rate (GFR). A maximal antidiuretic dose of AVP (75 ng) increased mean urine osmolality to 2002 +/- 109 mosmol/kg and was associated with significant mean increases in MAP (9 mmHg), RPF and GFR (25%) by 30-60 min. A further ten-fold increase in AVP (750 ng) produced a greater increase in MAP (116 +/- 6 to 134 +/- 7 mmHg; P < 0.01) as well as increasing RPF and GFR by 35.5 and 38.9% respectively. 3. Increasing concentrations of AVP also progressively increased the fractional excretion of sodium, potassium and phosphate. However, fractional calcium and magnesium excretion was significantly decreased with maximal and supramaximal concentrations. 4. These studies support evidence that AVP is a pressor hormone in physiological concentrations in baroreceptor intact animals. Its role in renal electrolyte transport is unclear. Measured increases in RPF and GFR with the maximal and supramaximal AVP concentrations appear to be correlated with the increase in MAP.

Effect of calcium antagonist, manidipine hydrochloride, on renal hemodynamics and tubuloglomerular feedback in spontaneously hypertensive rats

The effects of a calcium antagonist, manidipine, on renal hemodynamics and the tubuloglomerular feedback (TGF) mechanism were examined in 7- to 8-week-old spontaneously hypertensive rats (SHRs) and age-matched normotensive Wistar-Kyoto rats (WKYs). Manidipine, 10 μg/kg intravenously, reduced blood pressure only in SHRs. A greater increase in renal plasma flow occurred in SHRs, but effects on GFR were observed in both SHR and WKY rats. Filtration fraction decreased only in SHRs. The TGF response curve in SHRs was shifted to the left compared with that in WKY rats, indicating a more active TGF in hypertensive rats. Manidipine infusion produced a right and upward shift of the feedback curve in SHRs and only an upward shift in WKY rats. We conclude that manidipine corrects hyperactivity of the TGF mechanism in SHRs.

Effects of low-dose captopril on renal hemodynamics and function in patients with cirrhosis of the liver

Background: In cirrhotic patients with ascites, captopril has deleterious effects on renal function, which have been referred to as captopril-induced arterial hypotension. The effects of this drug on renal function in cirrhosis were evaluated using low-dose captopril, thereby avoiding any change in arterial pressure. Methods: In a randomized, double-blind, placebo controlled, crossover trial, the effects of 12.5 mg captopril on renal plasma flow, glomerular filtration rate (measured by radioisotopic techniques), and sodium excretion in healthy controls and cirrhotic patients with and without ascites were determined. Results: In healthy subjects, captopril only induced a significant, 18% increase in renal plasma flow. In contrast, glomerular filtration rate significantly decreased in patients with (from 108 ± 7 to 78 ± 9 mL/min) and without ascites (from 102 ± 4 to 88 ± 3 mL/min), whereas renal plasma flow did not change. Urinary sodium excretion also significantly decreased in ascitic patients (from 43.8 ± 4.4 to 30.6 ± 3.8 μmol/min). Conclusions: These data suggest that angiotensin II contributes to maintain renal hemodynamics in cirrhosis with and without ascites.

The dopamine DA-1 receptor agonist fenoldopam enhances amino-acid-induced hyperemia in dogs.

The effect of the dopamine DA-1 receptor agonist fenoldopam on amino-acid-induced glomerular hyperemia and hyperfiltration was evaluated in conscious chronically instrumented dogs. Infusion of either amino acids (L-alanine, 4.1 mg/kg.min; L-proline, 3.2 mg/kg.min; L-serine, 2.9 mg/kg.min) or fenoldopam (0.05 micrograms/kg.min) alone resulted in significant (p < 0.05) increases in renal plasma flow of 85 +/- 41 and 53 +/- 24%, respectively. In dogs infused with both amino acids and fenoldopam, there was a dramatic (143 +/- 27%) increase in renal plasma flow (p < 0.01). This response was significantly greater than either treatment alone. The glomerular filtration rate did not change significantly when fenoldopam was infused; however, it increased to a similar degree when dogs were infused with either amino acids or a combination of fenoldopam and amino acids. The data suggest that fenoldopam either acts synergistically with amino acids to increase renal blood flow or perhaps magnifies the renal functional reserve.