Biomedical subjects

M Grima

Publications and source records attributed to M Grima.

At least 19 recordsLinked to original sources

PubMed2000

Vascular catabolism of bradykinin in the isolated perfused rat kidney.

Kinins in the circulation are rapidly metabolized by several different peptidases. The purpose of this study was to evaluate the contribution of membrane-bound peptidases to kinin metabolism in the renal circulation. Experiments were performed in vitro, in isolated rat kidneys perfused at a constant flow rate (8 ml/min) with Tyrode's solution. The effects of peptidase inhibitors were evaluated on the functional vasodilator response caused by bradykinin (30 nM) or [Tyr(Me)(8)]bradykinin (10 nM) via activation of bradykinin B2 receptors in kidneys precontracted with prostaglandin F2alpha. Angiotensin converting enzyme inhibitors, enalaprilat (3 microM), ramiprilat (1 microM) or lisinopril (1 microM), increased the bradykinin-induced renal vasodilation by 40% or more. Inhibitors of neutral endopeptidase (thiorphan or phosphoramidon, 10 microM), basic carboxypeptidase (DL-2-mercaptomethyl-3-guanidino-ethylthiopropanoic acid or MGTPA, 10 microM) and aminopeptidase P (apstatin, 20 microM) however did not enhance the renal vasodilator response elicited by kinins, whatever tested alone or in the presence of lisinopril. These findings indicate that angiotensin converting enzyme is the major peptidase whose inhibition potentiates the renal bradykinin B2 receptor mediated vasodilator response of kinins. The relative contribution in this potentiation of inhibition of kinin inactivation and of cross-talk of angiotensin converting enzyme with bradykinin B2 receptor remains however to be clarified.

Aminopeptidases↗

PubMed2000

Vasopressin does not effect hypertension caused by long-term nitric oxide inhibition.

Nitric oxide attenuates both vasopressin-induced vasoconstriction and vasopressin release. We tested whether hypertension and renal dysfunction elicited by chronic inhibition of nitric oxide (NO) synthesis using N(G)-nitro-L-arginine (L-NNA) could be mediated in part by vasopressin V(1A) receptors. Male rats were treated orally for 6 weeks with L-NNA (15 mg/kg per day), a nonpeptide V(1A) receptor antagonist (2S)-1-[(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3, 4-dimethoxybenzene-sulfonyl)-3-hydroxy-2, 3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide (SR 49059, 30 mg/kg per day), or a combination of SR 49059 and L-NNA (same doses), or they received no treatment. Both drugs were added to the food. Measurements were performed in conscious rats (urine collection in metabolic cages, tail-cuff arterial pressure) and at the end of the study in anesthetized rats (clearance measurements). L-NNA produced sustained hypertension, decreased glomerular filtration rate, and increased renal vascular resistance, plasma renin activity, and urinary albumin excretion. SR 49059 had no effect per se on these parameters and also did not attenuate the hypertension and renal dysfunction induced by L-NNA. Surprisingly, SR 49059 potentiated L-NNA-induced hypertension at the end of the 6-week treatment. However, the blood pressure response and the renal and mesenteric vasoconstriction elicited by exogenous vasopressin were attenuated in rats treated with SR 49059. L-NNA did not change plasma vasopressin concentration or 24-hour urinary vasopressin excretion. Our findings suggest that activation of vasopressin V(1A) receptors does not contribute to the hypertension and renal dysfunction induced by chronic NO synthesis inhibition. They also document unchanged plasma vasopressin concentration in NO-deficient hypertension.

Albuminuria↗

PubMed1999

Cardiovascular and renal effects of central administration of a mineralocorticoid receptor antagonist in conscious female rats.

In a previous study we showed that in normotensive male rats brain mineralocorticoid receptor blockade induced a long lasting decrease in blood pressure associated with increased urinary excretion of water and electrolytes. Here, we report the effect of intracerebroventricular injection of a mineralocorticoid receptor antagonist (RU28318; 3,3-oxo-7 propyl-17-hydroxy-androstan-4-en-17yl-propionic acid lactone) on cardiovascular and renal function in female rats. Compared with male rats, females are less sensitive to brain mineralocorticoid receptor blockade. Administration of RU28318 (10 ng, 100 ng) caused a significant decrease in systolic blood pressure (10-12.5%) only at 8 h after injection. An increased urinary excretion of water (about 160%) and electrolytes (about 175%) during the first 8 h after the injection was observed in the 100 ng RU28318 treated group. Heart rate, food intake and water consumption were not affected at either dose. In conclusion, in conscious female rats, brain mineralocorticoid receptors participate in blood pressure and renal function control.

Animals↗

PubMed1999

Brain mineralocorticoid receptor control of blood pressure and kidney function in normotensive rats.

Brain mineralocorticoid receptors appear to contribute to mineralocorticoid hypertension and may be involved in blood pressure control in normotensive rats. We examined the effect of blockade of central mineralocorticoid receptors with the use of a selective antagonist (RU28318) on cardiovascular and renal function in conscious normotensive rats. The contribution of renal innervation was evaluated in rats with bilaterally denervated kidneys. Young adult, male Wistar rats were trained for systolic blood pressure measurement by a tail sphygmographic method and accustomed to metabolic cages for collection of urine. One week before experimentation, an intracerebroventricular cannula was implanted. Systolic blood pressure was diminished 30 minutes after an intracerebroventricular dose of 10 ng of RU28318. The effect was maximal at 8 hours and was still present after 24 hours. Blood pressure returned to the basal level by 48 hours. During the period 0 to 8 hours after intracerebroventricular injection, rats treated with the antagonist showed an increase in diuresis and urinary electrolyte excretion. No significant effect on plasma renin activity, measured 8 and 30 hours after administration of RU28318, was observed. In denervated rats, the decrease in systolic blood pressure after administration of RU28318 was reduced. The difference was statistically significant compared with controls at 2 hours but not at 8 hours, and blood pressure returned to the basal value by 24 hours. The increases in diuresis and urinary electrolyte excretion induced by RU28318 were abolished in denervated rats. These results show that brain mineralocorticoid receptors are involved in blood pressure regulation and kidney function homeostasis in conscious normotensive rats. The renal nerves appear to participate in the brain mineralocorticoid receptor control of blood pressure.

Animals↗

PubMed1998

Plasma active renin, angiotensin I, and angiotensin II during pregnancy and in preeclampsia.

OBJECTIVE: To evaluate the activity of the renin-angiotensin-aldosterone system in the circulation during the three trimesters of normal pregnancy and in women with preeclampsia. METHODS: Normal pregnant volunteers (n = 7) were studied throughout pregnancy, and women with preeclampsia (n = 8) were studied in the third trimester. Plasma active renin and aldosterone were measured by radioimmunoassay. Angiotensin I and angiotensin II were determined by radioimmunoassay after separation of the peptides by high-performance liquid chromatography. RESULTS: Active renin concentration increased in the first trimester of normal pregnancy, whereas angiotensin I, angiotensin II, and aldosterone remained at a level comparable to the postpartum values. Highest activity of the renin-angiotensin-aldosterone system was observed during the third trimester with increased levels of angiotensin I, angiotensin II, and aldosterone. In contrast, in patients with preeclampsia, despite a slight increase of active renin levels, the other parameters of the renin-angiotensin-aldosterone system were low compared with the third trimester of normal pregnancy and were comparable to postpartum data. CONCLUSION: Our results suggest that during the first trimester of normal pregnancy, active renin concentration in the plasma is increased and that renin is not the factor that limits angiotensin II synthesis. These results also confirm decreased activity of the renin-angiotensin-aldosterone system in preeclampsia. This could contribute to the diminished hemodynamic control observed in pregnant women developing preeclampsia.

Adult↗

PubMed1998

[Effects of hydroxyl radicals on purified angiotensin I converting enzyme].

Somatic angiotensin-converting enzyme (ACE) is a protein which contains two similar domains (N and C), each possessing a functional active site. The relationship between ACE, its natural substrates and oxygen free radicals is starting to be explored. On one hand, superoxide anions production is induced by angiotensin II and on the other hand, activated polynuclear neutrophils, through free radicals generation, alter endothelial ACE activity. In this study, we examined the impact of hydroxyl radicals (.OH) on purified ACE. .OH were produced using a generator: 2,2'-azo-bis 2-amidinopropane (GRH) provided by Lara-Spiral (Fr). GRH (3 mM), in a time-dependent fashion, inhibited ACE activity. When ACE was co-incubated for 4 h with GRH, its activity decreased by 70%. Addition of dimethylthiourea (DMTU: 0.03 to 1 mM) or mannitol + methionine (20/10 mM), two sets of .OH scavengers, produced a dose-dependent protection on ACE activity. To examine whether oxidation of thiol groups in the ACE molecule could be involved in the action of GRH, the effects of thiol reducing agents: mercaptoethanol and dithiotreitol (DTT) were investigated. These compounds produced a dose-dependent and significant protection; with 100% protection at 0.2 and 0.3 mM for mercaptoethanol and at 0.1 mM for DTT. The hydrolysis of two natural and domain-specific substrates were also explored. The hydrolysis of angiotensin I preferentially cleaved by the C domain was significantly (p < 0.01) inhibited by 57, 58 and 69% in contact with 0.3, 1 and 3 mM GRH [in nmol angio II formed/min/nmol of ACE, n = 4; 35.9 +/- 0.6 (control), 15.5 +/- 2.8 (GRH : 0.3 mM), 15.1 +/- 0.5 (1), 10.9 +/- 0.6 (3)]. The hydrolysis of the hemoregulatory peptide (hp), preferential substrate for the N domain was not affected by GRH at 0.3 mM and inhibited by 28% (not significant) by 1 mM GRH [in nmol ph hydrolized/min/nmol ACE, n = 4; 12.6 +/- 1.9 (control), 14.9 (GRH : 0.3 mM), 8.3 +/- 4.0 (1). These results demonstrated that .OH affect ACE activity and could suggest a privileged impact of GRH on the C domain. The precise sites of action of .OH remain unknown. The Cys residues near the active centers, by forming disulphide bridges during the oxidation could be of critical importance. Further studies will be needed to determine whether oxidative stress again ACE can be involved in the genesis of inflammatory vascular pathologies.

Enzyme Activation↗

PubMed1998

[Modulation by nitric oxide of vasopressin induced renal vasoconstriction varies with perfusate viscosity in the isolated rat kidney].

Previously we reported that AVP is a potent vasoconstrictor in the TYRODE's perfused rat kidney. In vivo however AVP elicited only minor effects on renal blood flow. We hypothetized that differences in shear stress, particularly related to differences in viscosity could be involved. In this study, we investigate the role of perfusate viscosity in the modulation of AVP-induced renal vasoconstriction by NO. Experiments were performed in kidneys isolated from male Sprague-Dawley rats (220 g). Kidneys were perfused at a constant flow of 8 mL/min, in a recirculating system, with TYRODE's solutions supplemented with 6% bovin serum albumin (BSA) or 4.7% Ficoll 400 (Ficoll). The viscosities relative to water were respectively of 1.33 (BSA), 2.32 (Ficoll) and 1.03 (TYRODE). Concentration-response curves to AVP were constructed in the absence or presence of 100 microM N omega-nitro-L-arginine (L-NA), an inhibitor of NO synthase, and compared to those obtained in kidneys perfused with TYRODE's solution. AVP elicited a concentration-dependent renal vasoconstriction, with a progressive shift of the curves to the right and a small decrease in the maximum response when the kidneys were perfused with perfusates of increasing viscosities: logEC50 = -9.9 +/- 0.1 (TYRODE, n = 14), -9.7 +/- 0.1 (BSA, n = 5), -9.0 +/- 0.1 (Ficoll, n = 5) (m +/- e.s.m. Anova, p < 0.001); Emax = 34 +/- 1, 31 +/- 2 and 26 +/- 3 mmHg/mL/min (Anova, p < 0.001). L-NA abolished the differences between kidneys perfused with solutions of different viscosities in logEC50 for vasopressin (10.3 +/- 0.1, 10.4 +/- 0.1 and 10.5 +/- 0.1, n = 5-11, Anova, NS) but did not affect Emax values. In conclusion, present results show that 1) AVP-induced renal vasoconstriction is modulated according to the viscosity of perfusate and 2) NO is involved in this effect. Viscosity, a major determinant of shear stress, should be considered in hemodynamic studies performed on isolated kidneys.

Animals↗

PubMed1998

[Diuretic resistance: mechanisms and therapeutic possibilities].

The diuretics, with the exception of spironolactone, act on the luminal (or apical) surface of the tubular cells of different segments of the nephron. In order to act, they must be secreted into the tubular lumen. This transfer of the drug to its site of action may be blocked by decreased renal blood flow, the saturation of the systems of tubular transport or fixation to the albumin present in the primary urine. All these pharmacokinetic abnormalities (observed in renal failure or the nephrotic syndrome) lead to diuretic resistance. Increasing the dosage, the repetition, intravenous administration, even as an infusion, are possible solutions. Resistance may be observed in the absence of pharmacokinetic abnormalities: in these cases, there is an abnormal response of the tubular cells to otherwise effective diuretic concentrations, or the activation of homeostatic mechanisms leading to sodium retention and preventing negativisation of the salt and water balance. These situations are often associated in cardiac failure or cirrhosis with oedema. Increasing the dosage is not a logical solution, but increasing the frequency of administration may be helpful. The importance of secondary hyperaldosteronism in cirrhotic oedema makes spironolactone the treatment of choice. In all cases, the addition of two mechanisms of inhibition of tubular reabsorption of sodium at different sites in the nephron often results in an effective diuresis: usually, this implies the addition of a thiazide (e.g. hydrochlorothiazide) to an initial prescription of a loop diuretic.

Diuretics↗

PubMed1997

[Renal vascular responses of bradykinin in the isolated rat kidney].

Kinins, by an autocrine or paracrine hormonal action, are potent modulators of regional vasomotricity. Their effects on the renal circulation are not well defined. The aim of this study was to analyse the renal vascular response induced by bradykinin, to precise the type(s) of receptor involved and to evaluate the contribution of various peptidases in the local catabolism of the kinin. Experiments were performed on the isolated rat kidney, perfused in an open circuit, at a constant flow of 8 mL/min, with a Tyrode's solution. Vasodilator responses were evaluated after renal vascular tone had been restored by a continuous perfusion with prostaglandin F2 alpha. Infusion of bradykinin (0.1-30 nM) induced a concentration-dependent renal vasorelaxation. A maximal response of 39.5 +/- 2.8% (n = 32) reversion of the tone induced by prostaglandin F2 alpha (about 50% of the maximal response induced by acetylcholine on the same kidneys) was obtained at 30 nM. Bradykinin-induced vasodilatation was completely inhibited by HOE 140 (10 nM), a selective bradykinin B2 receptor antagonist. At a supramaximal concentration of 300 nM, bradykinin-induced vasorelaxation was modulated by a concomitant vasoconstriction. A concentration-dependent vasoconstriction was also obtained with desArg9 bradykinin (1-8 microM), a selective agonist of the bradykinin B1 receptor. The inhibition of neutral endopeptidase by phosphoramidon (10 microM) or the inhibition of carboxypeptidase M by MGTPA (10 microM) did not modify the bradykinin-induced renal vasorelaxation. On the other hand, the inhibition of angiotensin I converting enzyme by lisinopril (1 microM) potentiated by about 32% the vasorelaxant response induced by 30 nM bradykinin (52.3 +/- 11.8% relaxation, n = 5, p < 0.05). Present results demonstrate that 1) bradykinin primarily evokes B2 receptor-linked renal vasodilatation, 2) bradykinin B1 receptors appear also to be present on the rat renal vasculature and 3) angiotensin 1 converting enzyme contributes to the local vascular catabolism of the kinin.

Adrenergic beta-Antagonists↗

PubMed1997

[Renal tissue angiotensins during converting enzyme inhibition of angiotensin I in spontaneously hypertensive rat].

To compare the effects of an angiotensin-converting enzyme inhibitor on circulating and tissue renin-angiotensin system, we measured different renin-angiotensin system parameters during the first day of treatment (Day 1) as well as after two weeks of treatment (Day 14). Ramipril was given orally once daily to adult male spontaneously hypertensive rats. Renin activity, angiotensin-converting enzyme activity and levels of angiotensin I and angiotensin II in the plasma, renal cortex and renal medullar were assessed at Day 1 and Day 14 of the treatment. In the plasma, both renin activity and angiotensin I increased 10 to 15 fold one to four hours after acute as well as at Day 14 of ramipril treatment and then returned to basal values within 24 hours. Plasma angiotensin II levels were not significantly decreased at Day 1 or Day 14. The decrease in the angiotensin II/angiotensin I ratio suggested a sustained inhibition of plasma angiotensin-converting enzyme at Day 14. In the renal cortex and medulla, a clearly different pattern was observed: in ramipril treated rats, renin activity in the renal cortex and medulla did not change at Day 1 but at Day 14 we observed a slight and sustained increase in renin activity. Despite very high basal levels of renin activity, angiotensin I levels in the renal cortex were comparable to those in the plasma. The angiotensin I level increased only one-fold one hour after ramipril intake at Day 1 and Day 14. This suggests that angiotensinogen may have a limiting role in the synthesis of angiotensin I in the kidney. Angiotensin II levels were slightly higher in the renal cortex and medulla than in the plasma suggesting local synthesis of the peptide. In the kidney, angiotensin II levels decreased one and four hours after the acute or prolonged ramipril treatment and the angiotensin II/angiotensin I ratio was reduced at the same time. Our results show that the responses of the plasma and kidney components of the renin-angiotensin system to angiotensin-converting enzyme inhibition are different in the plasma and the kidney suggesting that the circulating and tissue renin-angiotensin system are at least in part independent.

Angiotensin I↗

PubMed1996

Vascular effects of [Arg8]vasopressin in the isolated perfused rat kidney.

The renal vascular effects of [Arg8]vasopressin (vasopressin) were investigated in the isolated perfused rat kidney. Vasopressin (0.01-3 nM) elicited a dose-dependent vasoconstriction in kidneys from Sprague Dawley rats, with a EC50 value of 0.206 +/- 0.044 nM. Inhibition of nitric oxide synthase by N omega-nitro-L-arginine (100 microM) shifted the vasopressin-induced vasoconstrictor response curve to the left. Inhibition of cyclooxygenase by indomethacin (10 or 30 microM) blunted the constriction induced by low concentrations of the peptide. Vasopressin, like angiotensin II but not noradrenaline, induced tachyphylaxis, SR 49059 ((2S)1-[(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzene- sulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2- carboxamide) (1-30 nM), a new potent and selective non-peptide vasopressin V1A receptor antagonist, shifted the concentration-response curve for vasopressin to the right without decreasing the maximum contraction. Antagonism became competitive with a pA2 value (+/- S.D.) of 9.72 +/- 0.20 during inhibition of nitric oxide release. [Mpa1,D-Arg8]Vasopressin (desmopressin; 0.1-100 nM), or vasopressin (0.01-1 nM) after blockade of the vasopressin V1A receptor by SR 49059, induced no vasopressin V2 receptor-related renal relaxation in kidneys with vascular tone previously restored by noradrenaline or prostaglandin F2 alpha. These findings indicate that in the isolated perfused rat kidney vasopressin is a potent renal vasoconstrictor. The constriction depends on activation of smooth muscle vasopressin V1A receptors and is modulated by endothelial nitric oxide but not by prostacyclin or vasopressin V2 receptor-related vasodilation.

Angiotensin II↗

PubMed1996

Interruption of prolonged ramipril treatment in hypertensive patients: effects on the renin-angiotensin system.

The increase in renin secretion and the induction of the converting enzyme (ACE) observed during treatment by ACE inhibitors (CEIs) could result in increased angiotensin II (ang II) synthesis when the treatment is stopped. The object of this study was to compare changes in the components of the renin-angiotensin system with changes in arterial pressure in hypertensives, following the cessation of long-term ramipril treatment. Twenty hypertensives, treated for at least three months with ramipril, in monotherapy for the last three weeks, were randomly allocated to two parallel groups and received for fifteen days, on a double-bind basis, either a placebo (withdrawal group W, n = 12) or ramipril at the previous doses (treated group T, n = 8). Blood pressure was measured using four different techniques. The active renin (AR), angiotensinogen, angiotensin I (ang I), angiotensin II (ang II) and aldosterone plasma concentrations were measured, as was plasma angiotensin I converting enzyme (ACE) activity in vitro (colorimetric and fluorimetric method) and in vivo (the ang II/ang I ratio). The biological effects of cessation of long-term ramipril treatment in hypertensives were a decline in AR and angiotensin I concentrations, an increase in ACE activity and no significant changes in angiotensinogen, angiotensin II and aldosterone levels. Fifteen days after withdrawal, the different parameters of the renin-angiotensin system appear to have returned to basal value. A slow rise in blood pressure was also observed but no rebound increase was noted during the 15 days neither in angiotensin II levels nor in blood pressure. Following the cessation of prolonged ramipril treatment, in vivo converting enzyme inhibition disappears slowly, probably on account of the slow tight binding inhibitor properties of ramiprilat, the active metabolite of this CEI. The gradual decline in AF, plasma levels, together with the prolonged ACE inhibition as measured in vivo by the ang II/ang I ratio, explains the absence of a rise in ang II synthesis.

Aldosterone↗

PubMed1995

Stereoselective renal effects of the loop diuretic ozolinone in the anesthetized dog.

The renal effects of i.v. injections of (+/-)-ozolinone, its enantiomers (-)-ozolinone and (+)-ozolinone and its prodrug (+/-)-etozoline, were compared with those of furosemide, in pentobarbital anesthetized dogs. Renal blood flow (electromagnetic flow-meter) and glomerular filtration rate (polyfructosan clearance) were assessed on the left denervated kidney together with renin secretion and urinary electrolyte excretion. (-)-Ozolinone (15.5 mg/kg i.v.) behaves as a stereoselective loop diuretic equipotent to 20 mg/kg of furosemide and 45 mg/kg of (+/-)-ozolinone; (+)-ozolinone induced only minor salidiuretic effects. Both ozolinone enantiomers markedly increased the renal blood flow and decreased the filtration fraction, suggesting that the vosodilating effect predominates on the efferent glomerular arterioles. (-)-Ozolinone also induced an acute rise in renin secretion. The inhibition of prostaglandin synthesis (indomethacin or meclofenamate) prevented renin hypersecretion in response to (-)-ozolinone and modified its salidiuretic effects but had no effect on the vascular response. The inhibition of the kallikrein-kinin system by aprotinin had no effect on the overall renal response to (-)-ozolinone. The inhibition of the renin-angiotensin system by captopril decreased blood pressure, prolonged the (-)-ozolinone-induced decrease in renal vascular resistance and increased renin secretion. Our results demonstrate that the loop diuretic, ozolinone, induces stereoselective and prostaglandin-dependent renin secretion, which is involved in the regulation of intra-renal hemodynamics.

Analysis of Variance↗

PubMed1995

Endothelium-dependent relaxation in the isolated rat kidney: impairment by cyclosporine A.

The therapeutical use of cyclosporine A (CsA) is hampered by the development of nephrotoxicity characterized by a marked increase in renal vascular resistance (RVR). We investigated vascular functions in kidneys of rats treated with CsA. The ex vivo vascular reactivity of kidneys from control rats and animals treated subacutely with CsA [50 mg/kg/day subcutaneously (s.c.) for 16-21 days] or an olive oil vehicle (1 ml/kg) was analyzed in male Wistar rats. The right kidney was isolated and perfused with Tyrode's or Krebs solution in an open circuit. The effects of acetylcholine (Ach), fenoldopam (FEN), and sodium nitroprusside (SNP) on norepinephrine (NE) preconstricted kidneys were studied. In control kidneys (untreated or vehicle-treated), Ach induced a relaxation (EC50 = 0.56 +/- 0.05 x 10(-9)M; Emax = 88.2 +/- 2.1% decrease in the vascular tone restored by NE) which was endothelium-dependent [near-complete abolition after treatment with a detergent, 3-[(3-cholamidopropyl)-dimethyl-ammonio]-1-propane-sulfonate (CHAPS) treatment] but only partially inhibited by indomethacin (EC50 = 1.71 +/- 0.39 x 10(-9)M, p < 0.05; Emax = 87.1 +/- 4.9%, NS) or indomethacin with NG-nitro-L-arginine methyl ester (L-NAME: EC50 = 1.04 +/- 0.38 x 10(-9)M, NS; Emax = 63.8 +/- 2.5%, p < 0.01). CsA treatment induced a marked decrease in creatinine clearance and natriuresis measured in vivo but had no effect on systolic blood pressure (SBP). In CsA-treated rats, Ach-induced renal relaxation was partially blunted (EC50 = 1.88 +/- 0.34 x 10(-9)M, p < 0.01; Emax = 82.8 +/- 4.6, NS), with both a defect in prostaglandin (PG) and nitric oxide (NO)-related responses. CsA treatment had no effect on endothelium-independent relaxations induced by FEN and SNP. These results show that subacute CsA treatment selectively impairs renal endothelium-dependent relaxation related to PGs and NO release.

Animals↗

PubMed1995

Ramipril-induced decrease in renal lithium excretion in the rat.

1. The interaction of ramipril, an inhibitor of angiotensin I converting enzyme, with renal lithium handling was analysed in conscious normotensive Wistar rats and compared with the known increase in renal tubular lithium reabsorption induced by the non-steroidal anti-inflammatory drug, indomethacin. 2. The rats were treated for five days with ramipril (1 mg kg-1 day-1 orally), indomethacin (2.5 mg kg-1 day-1 intramuscularly) or their solvents. Lithium chloride (16.7 mg kg-1 intraperitonealy) was given as a single dose on the fifth day and renal functions were measured. 3. Ramipril induced a decrease in renal lithium clearance which was correlated with the decrease in the quantity of filtered lithium and the increase in the tubular fractional reabsorption of the metal. Ramipril also reduced the systolic blood pressure of the rats by about 15 mmHg. 4. In the absence of any effect on creatinine clearance or systolic blood pressure, indomethacin increased renal fractional lithium reabsorption and led to an increase in plasma lithium levels, as previously reported by our group. 5. In conclusions, our results indicate that ramipril decreases renal lithium excretion in Wistar rats, when given orally at a dose of 1 mg kg-1 day-1 over five days.

Angiotensin I↗

PubMed1995

Absence of a losartan interaction with renal lithium excretion in the rat.

1. The interaction of losartan, a non-peptide specific AT1 receptor antagonist with the renal handling of lithium was analysed in conscious normotensive Wistar rats and compared with the known increase in renal tubular lithium reabsorption induced by the non-steroidal anti-inflammatory drug, indomethacin. 2. The rats were treated for five days with losartan (10 mg kg-1 day-1, orally), indomethacin (2.5 mg kg-1 day-1, intramuscularly) or their solvents. Lithium chloride (16.7 mg kg-1, i.p.) was given as a single dose on the fifth day; renal functions were then measured. 3. Indomethacin, in the absence of any effect on creatinine clearance, increased renal fractional lithium reabsorption and led to an increase in plasma lithium levels. 4. Losartan did not modify renal lithium handling and its plasma level. No change was observed in renal lithium clearance, the quantity of filtered lithium or the fractional reabsorption of the metal. As expected, losartan had no effect on systolic blood pressure in normotensive rats. 5. In conclusion, our results indicate that losartan, when given orally in the rat at a dose of 10 mg kg-1 day-1 over five days, does not modify renal lithium handling. They suggest that blockade of the angiotensin II receptors does not interfere with renal lithium reabsorption, which occurs mainly at a proximal tubular site.

Angiotensin I↗

PubMed1995

Pathophysiological role of dopamine in the kidney: effects in diabetes mellitus and after contralateral nephrectomy.

Both insulin-dependent diabetes mellitus (IDDM) and unilateral nephrectomy (UNX) are associated with an increase in the glomerular filtration rate. Glomerular hyperfiltration has been linked to intraglomerular hypertension in both conditions, although it has only been linked to the development of nephropathy in diabetes. In this study, we examined the possibility of preventing diabetic nephropathy through early dopamine (DA) prodrugs treatment and we also investigated the participation of endogenous DA in the acute functional adaptation of the remaining kidney after UNX. In an animal model of IDDM (steptozotocin-treated Wistar rats), the early increase in the glomerular filtration rate was prevented by treatment with DA prodrugs (L-dopa or gludopa), an effect which was mimicked by fenoldopam (a D1 agonist) and suppressed by carbidopa and SCH 23390 (a D1 antagonist). An increase in endorenal DA synthesis and the subsequent stimulation of vascular D1 receptors appears to prevent early glomerular hyperfiltration in diabetic rats. However, in a long-term study lasting more than one year, streptozotocin-diabetic Wistar rats (unlike to diabetic Munich Wistar rats) failed to develop overt nephropathy characterized by albuminuria and systemic hypertension. During long-term treatment of diabetic rats with L-dopa, the renal availability of DA was diminished. The acute adaptation of the remaining kidney to UNX took the form of an early transient pressor effect with a moderate increase in the glomerular filtration rate and renal blood flow, and a marked decrease in tubular sodium reabsorption. SCH 23390 suppressed the hemodynamic and tubular responses to UNX, suggesting that endogenous DA plays a key role.

Adaptation, Physiological↗

PubMed1995

[Ramipril and cardiac and renal angiotensin converting enzyme].

The role of the angiotensin converting enzyme (ACE) in the regulation of local synthesis of angiotensin II has not been clearly defined. The authors investigated the local factors which might orientate the effects of ACE inhibitors to particular organs in the Wistar rat. The in vivo study of the effects of low doses of ramipril on the myocardium showed that cardiac ACE was significantly inhibited by the non-antihypertensive dose of 0.01 mg/kg whereas the inhibition only occurred from doses higher than 0.1 mg/kg in the other tissues studied. In the kidney: the affinity of 3H-ramiprilate for the brush borders of the proximal tubular cells was increased by high concentrations of chloride ions as observed in the renal parenchyma, the presence of esterases makes local activation of ramipril (diester) into ramiprilate (active diacid) possible, prolonged treatment with ramipril leads to a lowering of the concentration of ACE in the brush border of the proximal tubular cells, verified after the elimination of the ACE inhibitor fixed on the tissue. These data indicate that the myocardium and the kidney could be privileged targets of the action of ramipril.

Angiotensin-Converting Enzyme Inhibitors↗