Biomedical subjects

M Barthelmebs

Publications and source records attributed to M Barthelmebs.

At least 37 records · Page 2Linked to original sources

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↗

PubMed1997

AT2-antagonist sensitive potentiation of angiotensin II-induced vasoconstrictions by blockade of nitric oxide synthesis in rat renal vasculature.

1. Although the actions of angiotensin II (Ang II) on renal haemodynamics appear to be mediated by activation of the AT1 receptor subtype, AT2 binding sites have also been evidenced in the adult kidney vasculature. As NO is known to mask part of the renal effects of vasoconstrictor drugs, we queried whether the Ang II-induced vasoconstrictions could occur via multiple receptor subtypes during inhibition of NO synthesis. We explored the effect of AT1 and AT2 receptor (AT-R) antagonists on Ang II-induced pressure increases during NO synthase or soluble guanylyl cyclase inhibition in rat isolated kidneys perfused in the presence of indomethacin at constant flow in a single-pass circuit. 2. In the absence of NO blockade, the AT1-R antagonist L-158809 (500 nM) antagonized the Ang II-induced vasoconstrictions, while the AT2-R antagonist PD-123319 (500 nM) had no effect. 3. Perfusing kidneys in the presence of either NO synthase inhibitors, L-NAME (100 microM) or L-NOARG (1 mM), or soluble guanylyl cyclase inhibitor, LY-83583 (10 microM), significantly increased both molar pD2 (from 9.40+/-0.25 to 10.36+/-0.11) and Emax values (from 24.9+/-3.1 to 79.9+/-4.9 mmHg) of the concentration-response curve for Ang II-induced vasoconstriction. 4. In the presence of L-NAME, 500 nM L158809 abolished the Ang II-induced vasoconstrictions whatever the concentration tested. On the other hand, 500 nM PD-123319 reversed the left shift of the concentration-response curve for Ang II (molar pD2 value 9.72+/-0.13) leaving Emax value unaffected (91.3+/-7.6 mmHg). 5. In the presence of L-NAME, the potentiated vasoconstriction induced by 0.1 nM and the augmented vasoconstriction induced by 10 nM Ang II were fully inhibited in a concentration-dependent manner by L-158809 (0.05-500 nM). By contrast, PD-123319 (0.5-500 nM) did not affect the 10 nM Ang II-induced vasoconstriction and concentration-dependently decreased the 0.1 nM Ang II-induced vasoconstriction plateauing at 65% inhibition above 5 nM antagonist. 6. Similar to PD-123319, during NO blockade the AT2-R antagonist CGP-42112A at 5 nM decreased by 50% the 0.1 nM Ang II-induced vasoconstriction and at 500 nM had no effect on 10 nM Ang II-induced vasoconstriction. 7. In conclusion, the renal Ang II-induced vasoconstriction, which is antagonized only by AT1-R antagonist in the presence of endogenous NO, becomes sensitive to both AT1- and AT2-R antagonists during NO synthesis inhibition. While AT1-R antagonist inhibited both L-NAME-potentiated and -augmented components of Ang II-induced vasoconstriction, AT2-R antagonists inhibited only the L-NAME-potentiated component.

Angiotensin II↗

PubMed1997

[Mechanisms of drug interactions with renal elimination of lithium].

Using indomethacin (2.5 mg/kg/day, i.m.) in rats, we confirmed the well-known interaction of NSAID's and the urinary elimination of lithium. This is due to an increase in the tubular reabsorption of lithium, probably associated with an increase in the reabsorption of sodium in the ascending limb of the loop of Henle, following inhibition of the synthesis of prostaglandins. With ramipril (1 mg/kg/day, p.o.), we confirmed an interaction with lithium pharmacokinetics in rats, also associated with an increase in the tubular reabsorption of sodium. In contrast, the angiotensin receptor antagonist losartan (10 mg/kg/day, p.o.) had no effect in this paradigm. Since the effects of ramipril were partially inhibited by an i.v. infusion of an antagonist of the bradykinin B2 receptor icatibant (0.1 mg/kg/day), we suggest that bradykinin contributes to the interaction between angiotensin converting enzyme inhibitors and renal excretion of lithium.

Animals↗

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↗

PubMed1995

[Relation between plasma renin level and antihypertensive response to nicardipine].

The antihypertensive efficacy of calcium antagonists could depend on the concentration of circulating renin. To investigate this hypothesis, 102 hypertensive men or women were included in this study. After an initial 2 week placebo period, the patients were administered slow-release nicardipine, 50 mg twice a day for twelve weeks. The blood pressures were measured with a mercury sphygmomanometer at inclusion (S2) and after 12 weeks of treatment (S14), in addition to home automeasure during the week before inclusion and the two weeks preceding the final visit. The plasma renin activity (RA) was measured at S2 and S14. Its value at inclusion was used to differentiate patients with low renin (< or = 11 ng/l) from those with normal (> 11 < or = 17 ng/l) or high renin activity (> 17 ng/l). The blood pressure measured by sphygmomanometer or automeasure was significantly lower at the end of the active treatment period (SBP: -8 mmHg; DBP: -9.5 mmHg; and SBP: -5.8 mmHg; DBP: -5.7 mmHg respectively); the reduction in blood pressure was significantly higher in the group with low RA than in the group with high RA. The reductions in SBP measured in the morning and evening and in DBP measured in the morning were significantly greater in the group with low RA than in the group with high RA. The reduction of SBP measured in the morning at midday, and in the evening was correlated to the basal value of RA. Mild side effects were observed in 20 patients leading to the interruption of treatment in 11 cases because of headache. The best antihypertensive response is observed in patients with low plasma RA. This could explain the good response to calcium antagonists usually observed in elderly hypertensives.

Blood Pressure↗

PubMed1994

Vascular effects of loop diuretics: an in vivo and in vitro study in the rat.

The vascular effects of loop diuretics were studied in two models designed to eliminate hemodynamic repercussions linked to sodium and water depletion: in vivo, in unilaterally nephrectomized rats with a contralateral uretero-venous shunt, and in vitro, in the isolated perfused rat kidney. In anesthetized rats, local vascular resistance was calculated from the simultaneous recording of blood pressure and renal, iliac and carotid blood flows (electromagnetic flowmeter, Skalar). Furosemide and piretanide (10 to 80 mg/kg i.v.) induced a comparable dose-dependent decrease in renal vascular resistance, which was not modified by reserpine and indomethacin pre-treatment. The iliac relaxing response was blunted by vasoconstriction, which disappeared after combined treatment with reserpine and indomethacin. The relaxation induced in the iliac and carotid vasculature persisted after bilateral nephrectomy. In vitro, the vasorelaxing effect of diuretics in isolated rat kidneys perfused in an open circuit was studied after vascular tone had been re-established by a continuous perfusion of PGF2 alpha. Furosemide, piretanide and ozolinone induced a concentration-dependent decrease in renal tone (EC50 = 0.47 x 10(-4) mol/l, 1.03 x 10(-4) mol/l and 2.07 x 10(-4) mol/l respectively) in Wistar rats. A similar response to piretanide was found in spontaneously hypertensive stroke-prone rats (EC50 = 0.32 x 10(-4) mol/l) and in their normotensive controls (EC50 = 0.74 x 10(-4) mol/l). Our results show that loop diuretics induce a direct relaxation in the renal, iliac and carotid vasculature. This vascular effect, which appears at relatively high concentrations of the drugs, is prostaglandin independent and persists after bilateral nephrectomy.

Animals↗

PubMed1994

Effects of dietary protein and uninephrectomy on renal angiotensin converting enzyme activity in the rat.

This study examines the effects of dietary protein and of uninephrectomy on angiotensin converting enzyme (ACE) in the normotensive rat, with particular regard to the kidney. Male Wistar Kyoto rats were fed isocaloric diets containing 5, 16 or 50% protein for three weeks. Other groups of rats were subjected to either left unilateral nephrectomy or sham operations, and the rats were killed eight days after surgery. ACE activity was measured in the kidney medulla, cortex, proximal tubule brush border membrane and in the plasma, heart and lung. Renal cortex and brush border ACE activity increased in parallel with protein intake, whereas plasma and lung ACE activity decreased; heart and kidney medulla ACE activity did not vary significantly. Uninephrectomy also led to a high increase in brush border ACE activity in the contralateral kidney, with no effect in the renal medulla or in the other tissues. The increase in ACE activity in the brush border membrane corresponded to a similar increase in the maximum number of binding sites of 3H-ramiprilat. This suggested that the increase in ACE activity corresponded to an increase in ACE concentration. The increase in renal tubular ACE activity could result in higher angiotensin II levels, and could consequently play a role in the modification of sodium reabsorption and cellular growth which occurs in the proximal tubule in these experimental models.

Alkaline Phosphatase↗

PubMed1994

Short-term effects of quinapril and nifedipine on early renal changes in streptozotocin-induced diabetes in rats.

The effects on renal function of quinapril, an angiotensin I converting enzyme (ACE) inhibitor, and of nifedipine, a dihydropyridine calcium antagonist, were studied in the early stages of diabetes in rats. Wistar rats received one injection of streptozotocin (STZ) to induce diabetes; the hyperglycaemia was then controlled with daily insulin therapy (2-3 units NPH insulin/rat). One week after STZ injection, rats were treated orally with quinapril (0.3 or 3 mg/kg/d) or nifedipine (30 mg/kg/day) for 1 week, after which renal functions were compared with those of untreated diabetic rats or non-diabetic control rats. At the end of these two weeks, diabetic rats had gained less weight and had developed renal hypertrophy and glomerular hyperfiltration (3.21 +/- 0.23 vs 2.36 +/- 0.09 ml/min for non-diabetic rats, mean +/- SEM, P < 0.01). Their urinary albumin excretion was higher, as was the urinary excretion of water, sodium, potassium, urea and glucose. One week treatment with quinapril or nifedipine had no significant effect on the increase in the glomerular filtration rate (respectively 2.97 +/- 0.18 and 2.99 +2- 0.15 ml/min). Quinapril and nifedipine differed with regard to their effects on urinary albumin excretion. Albuminuria was increased by nifedipine but not by quinapril (respectively 0.554 +/- 0.158 and 0.149 +/- 0.046 mg/day/100 g BW, P < 0.05). This difference between the effects of the dihydropyridine and the ACE inhibitor on albuminuria may be linked to different effects on the glomerular functions.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1994

Effects of triiodothyronine and dexamethasone on plasma and tissue angiotensin converting enzyme in the rat.

In order to identify tissue specific regulation of angiotensin converting enzyme (ACE), the effects of dexamethasone (0.04 mg sc per day for 7 days) and triiodothyronine (T3) (0.5 mg/kg sc per day for 10 days) on ACE activity were investigated in different tissues in male Wistar rats. ACE activity was measured by fluorimetry in the plasma, heart, lung and kidney. In the kidney, ACE activity was measured in the medulla, cortex and brush border of proximal tubular cells and 3H-ramiprilat binding was used to characterise the changes in brush border ACE activity. Dexamethasone elicited a significant increase in lung ACE activity and a significant decrease in plasma ACE activity, but did not alter enzyme activity in the other tissues studied. T3 produced a significant decrease in lung ACE activity and an increase in ACE activity in the plasma and heart. In the kidney, ACE activity was not modified in the medulla whereas in the cortex and brush border ACE activity was doubled. This increase in ACE activity corresponded to a similar increase in the maximum number of binding sites of 3H-ramiprilat, suggesting that the increase in activity corresponded to an increase in the ACE level. The increased heart and kidney ACE activity in response to T3 may contribute to the cardiovascular effects of thyroid hormones through increased local angiotensin II generation. These results show that under dexamethasone or T3, ACE activity can vary from one tissue to another, suggesting that the ACE regulatory mechanism acts differently in each tissue.

Animals↗