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Biomedical subjects

M Barthelmebs

Publications and source records attributed to M Barthelmebs.

At least 19 recordsLinked to original sources
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

[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↗
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↗
PubMed1994

Plasma renin activity and changes in tissue angiotensin converting enzyme.

OBJECTIVES: Recent evidence suggests that tissue generation of angiotensins I and II depends on the level of the plasma components of the renin-angiotensin system and on tissue-specific processes. The present study was undertaken to clarify the possible relationship between plasma renin activity (PRA) and tissue angiotensin converting enzyme (ACE) activity in the heart, lung, kidney cortex and kidney medulla of Wistar-Kyoto rats. In the kidney cortex particular attention was focused on renal brush-border ACE. METHODS: Different experimental models known to have opposite effects on PRA were used: changes in salt intake, deoxycorticosterone acetate (DOCA) with or without salt supplements, and the Goldblatt two-kidney, one clip (2-K,1C) model. Two weeks after the start of the experiments the rats were killed, and PRA, and plasma and tissue ACE activity, were measured. RESULTS: At the end of the study the blood pressure in the treated rats was not significantly different from control. As expected, the PRA were highest in the 2-K,1C and depleted-salt groups and lowest in the DOCA, DOCA-salt and high-salt groups. ACE responses were different in different types of tissue, with no relationship between PRA and plasma or tissue ACE activity. For example, DOCA treatment led to increased ACE activity in the heart and the kidney only if the rats were maintained on a high salt intake. DOCA or salt alone failed to have this effect. In the 2-K,1C model the unclipped kidneys did not show any significant variation in ACE activity, but the clipped kidneys exhibited increased ACE activity compared with sham-operated rats. This increase, coupled with increased renal renin secretion, could play a role in the acceleration of local angiotensin II formation, and could thus initiate and sustain the development of hypertension in this model. CONCLUSION: The present results show that variations in ACE activity were organ-specific and were not linked either to hypertension or to changes in PRA.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

[Changing of renal endothelium-dependent vascular reactivity by cyclosporin A].

Clinical use of the immunosuppressant cyclosporine A (CSA) is hampered by its nephrotoxicity. The renal vascular resistance is increased, may be as a consequence of a deleterious effect of the drug on the vascular endothelial cell function. The renal effects of a subchronic treatment with CSA (50 mg/kg/d, sc, 18 days), or olive oil vehicule (1 ml/kg), were studied in normotensive male Wistar rats. Creatinine clearance was measured on 24 h urine collection before the right kidney of the animals was isolated and perfused in an open circuit at 6 ml/min with Tyrode's solution. Renal vasodilator responses to acetylcholine (ACH, 10(-10) to 10(-7) M) and sodium nitroprusside (NP, 3 x 10(-9) to 3 x 10(-6) M) were studied after reestablishment of a renal vascular tone by a continuous perfusion of noradrenaline (NA, 10(-7) M). ACH was more potent than NP to induce renal vasodilation (EC50 = 0.57 +/- 0.05 x 10(-9) M, n = 8, vs 3.42 +/- 0.29 x 10(-8) M, n = 5), but both drugs reversed the NA-induced vasoconstriction by near 90%. L-NAME (3 x 10(-5) M) had no effect on NP-induced renal relaxation but suppressed responses to low concentrations of ACH and decreased by half its Emax (47 +/- 17%).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1993

[Plasma renin activity and angiotensin converting enzyme of renal brush borders].

The present experiment was undertaken to examine the relationship between plasma renin activity and the concentration of angiotensin converting enzyme (ACE) in plasma and renal brush border of Wistar Kyoto rats. Different experimental models known to have opposite effects on plasma renin activity were used: changes in salt intake, the deoxycorticosterone acetate (DOCA) and DOCA-salt models and the two-kidneys one clip (2K1C) model. Two weeks after the start of these experimental series, the rats were killed. At this time, blood pressure did not differ from control group, even in the 2K1C and DOCA-salt groups. As expected, PRAs were highest in the 2K1C and depleted salt groups and lowest in the DOCA, DOCA-salt and high salt groups. No relationship between this wide variation in PRA and change of ACE activity in both plasma and renal brush border could be observed. In the plasma, ACE activity in sodium-depleted rats was slightly decreased whereas no change occurred in the other models. In the kidney, DOCA treatment led to increased ACE activity in the brush border only if the animals were maintained on a high salt intake. DOCA or NaCl alone failed to have this effect. In the 2K1C model, the clipped kidneys exhibited increased brush border ACE activity whereas the unclipped kidneys did not show any significant variation in ACE activity, when compared to sham operated rats. In summary, on one hand these findings show that variations in ACE activity were linked neither to hypertension nor to changes in PRA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

In vitro stability of the inhibition of serum converting enzyme by fosinopril.

With captopril, it has been shown that an erroneous measurement of serum angiotensin converting enzyme (ACE) can be induced by the dissociation of the inhibitor-ACE complex during long-term storage. We have studied the possible dissociation of the fosinopril-ACE complex during the storage of serum samples from healthy male volunteers given a single dose of fosinopril. Serum samples were collected from 5 volunteers, 5 min before, then 4 and 24 h after a unique oral dose of 10 mg fosinopril. ACE activity was measured by a colorimetric and a fluorimetric assay during the hour following the sampling (day 0) and after 21 or 61 days of storage at -20 or -196 degrees C. The degree of ACE inhibition measured in vitro in fresh serum samples differed according to the technique used. Fosinopril has a long-lasting effect with 80% inhibition 24 hours after drug administration. Storage at -20 and -196 degrees C induced a significant decrease in the degree of inhibition measured with the colorimetric method. With the fluorimetric method, a decrease in ACE inhibition was only observed after storage at -20 degrees C but not at -196 degrees C.

Administration, Oral↗
PubMed1991

The effects of muzolimine and urine from muzolimine-treated rats on Na+K+Cl- cotransport in Madin-Darby canine kidney cells.

Muzolimine is a loop diuretic with an original chemical structure devoid of the acidic or sulfonamide group known to be necessary for an interaction with Na+K+Cl- cotransport. We studied the effects of urine from muzolimine-treated rats on the Na+K+Cl- cotransport-dependent 86Rb influx in MDCK cells. Na+K+Cl- cotransport was inhibited by urine obtained 15 min (42% inhibition) and 60 min (49% inhibition) after muzolimine injection (50 mumol/kg i.v.). Muzolimine itself was not detectable in the urine. Probenecid (100 mumol/kg i.v.) suppressed both the diuretic effect of muzolimine and the inhibition of Na+K+Cl- cotransport by urine from muzolimine-treated rats. These results suggest that the diuretic effect of muzolimine is due to the metabolism of muzolimine into an active compound which inhibits Na+K+Cl- cotransport after its secretion into the tubular lumen via a proximal pathway. The direct effect of muzolimine on Na+K+Cl- cotransport in MDCK cells was also tested: surprisingly, the inhibition of 86Rb influx was significant in the presence of muzolimine (IC50 = 1.44 microM). We show that this effect was due to the metabolism of muzolimine by these cells into an active compound.

Animals↗
PubMed1991

[3H]ramiprilat binding to the angiotensin-converting enzyme in rat renal brush-border membranes: the effect of chloride.

The [3H]ramiprilat binding to the angiotensin-converting enzyme (ACE) in rat renal brush-border membranes was studied. At pH 7.9, and in the presence of 50 mM NaCl, specific binding of [3H]ramiprilat was saturable with a dissociation constant KD = 5.05 nM and maximum number of binding sites of 1.52 pmol/mg prot. [3H]Ramiprilat binding was completely inhibited by specific inhibitors of ACE: ramiprilat, ramipril, enalaprilat, enalapril and captopril. [3H]Ramiprilat binding was Zn2(+)- and Cl(-)-dependent. In the presence of EGTA, which chelates Zn2+ ions, ramiprilat binding was inhibited, but the addition of Zn2+ restored the initial binding. Binding was maximum in the presence of 10 mM NaCl while higher NaCl concentrations decreased the binding, corresponding to a decrease in affinity. The association and dissociation kinetics were also NaCl-dependent. In the absence of NaCl, association and dissociation kinetics were rapid and monophasic. Two-step dissociation kinetics appeared in the presence of 10, 50 and 300 mM NaCl and dissociation time increased with the NaCl concentration. These results confirmed the role of Cl- in the isomerisation and the stability of the membrane-associated ACE-inhibitor complex.

Alkaline Phosphatase↗
PubMed1991

Effects of dopamine prodrugs and fenoldopam on glomerular hyperfiltration in streptozotocin-induced diabetes in rats.

The effects of dopamine (DA) prodrugs (L-dopa and gludopa) and of a D1-selective agonist (fenoldopam) on glomerular hyperfiltration were studied in the early stage of diabetes in rats. Wistar rats received one injection of streptozotocin (STZ) and were treated 1 week later with L-dopa (2 x 10 mg/kg/day, s.c.), gludopa (2 x 3 or 2 x 10 mg/kg/day, s.c.), or fenoldopam (2 x 0.3 or 2 x 1 mg/kg/day, s.c.). Their renal functions were compared with those of untreated diabetic and nondiabetic control rats. STZ injection led to hyperglycemia that was kept moderate (20-25 mmol/L) by daily insulin therapy (2-4 U of NPH insulin). Within 2 weeks, glomerular hyperfiltration (polyfructosan clearance) developed in diabetic rats (30% increase vs. nondiabetic control). A rise in renal plasma flow (PAH clearance) was sometimes observed. One week of treatment with either L-dopa, gludopa, or fenoldopam normalized the glomerular filtration rate and decreased filtration fraction. These corrections occurred despite similar metabolic disturbance and kidney hypertrophy. Gludopa was less well tolerated by diabetic rats than L-dopa. Results with L-dopa showed that the normalization of glomerular hyperfiltration was linked to DA synthesis and stimulation of D1 receptors, since it was reversed by carbidopa, a dopa decarboxylase inhibitor, and by SCH 23390, a D1-selective antagonist. These data show that DA prodrugs and a D1 agonist can suppress diabetic glomerular hyperfiltration in the very early course of the disease in rats.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

In vitro tissue potencies of converting enzyme inhibitors. Prodrug activation by kidney esterase.

The inhibition of angiotensin converting enzyme by ramipril, ramiprilat, enalapril, enalaprilat, and captopril was studied in the plasma and various tissues (lung, heart, renal cortex, renal medulla) of normotensive rats and spontaneously hypertensive rats. Displacement curves for [3H]ramiprilat were established on each tissue with the converting enzyme inhibitors, and their potencies were expressed as the concentration that inhibited 50% of the specific [3H]ramiprilat binding. In the plasma, lung, and heart, the order of activities was: ramiprilat greater than enalaprilat greater than captopril greater than ramipril greater than enalapril. This order was different in the kidney (cortex and medulla): ramiprilat greater than enalaprilat greater than ramipril greater than captopril greater than enalapril. For ramiprilat, enalaprilat, and captopril, there were no differences in their respective potencies between tissues or between rat strains. However, the two prodrugs ramipril and enalapril were 10-30 times more active in the kidney than in the other tissues in both groups of rats. This was due to the deesterification of the prodrugs: in the presence of an esterase inhibitor (diethyl nitrophenyl phosphate, 10 microM), the potencies of ramipril in the kidney were not different from that obtained in the lung, which was not affected by the presence of the esterase inhibitor. These results suggest that the variations in the tissue activities of an angiotensin converting enzyme inhibitor are probably not due to differences in tissue affinities of the angiotensin converting enzyme inhibitor but depend on the concentration of this angiotensin converting enzyme inhibitor in each tissue.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

[Changing factors of the activity of angiotensin converting enzyme of renal brush border in rats].

In the kidney, angiotensin I-converting enzyme (ACE) is present in the vascular endothelial cells and in the brush border of epithelial cells of the proximal tubule. In spite of this well-known distribution of ACE, little is known of its regulation. In order to elucidate the possible mechanisms of control for brush border ACE, the effects of dexamethasone (DM), (40 micrograms s.c. per day, for 7 days) and triiodothyronine (T3) 0.5 mg/kg s.c. per day, for 10 days) were investigated in male Wistar rats. Plasma and brush border ACE activities were measured by fluorimetry in the presence of an artificial substrate Cbz-Phe-His-Leu and brush border ACE was characterized with a binding assay using 3H-ramiprilat, a specific radiolabelled ACE inhibitor. DM elicited a significant decrease in plasma ACE activity (from 0.46 +/- 0.03 to 0.28 +/- 0.02 nmol His-Leu/min/mg protein) but did not alter enzyme activity in the brush border: 47.12 +/- 5.12 nmol His-Leu/min/mg protein (control, n = 6) and 47.78 +/- 5.63 (DM, n = 6). Administering T3 produced a marked increase in the brush border ACE activity (from 42.87 +/- 4.9 to 81.41 +/- 11.7 nmol His-Leu/min/mg protein). Similarly, the maximum number of 3H-ramiprilat-binding sites increased in the brush border, indicating a good correlation between ACE activity and the quantity of 3H-ramiprilat bound. Thus, the variation in tissue ACE activity corresponded to a change in the enzyme concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

[Do renal vascular D2 receptors exist?].

Two dopamine receptors are present on the renal vasculature: post-synaptic D1-receptors and neuronal D2-receptors. The existence of postsynaptic vascular D2-receptors is now under discussion. The aim of this study was to characterize in vitro the renal vascular response to bromocriptine, a D2 preferential agonist. Bromocriptine (10(-7) to 3.10(-5) M) induced a concentration dependent relaxation (EC50 = 1.4 +/- 0.1 x 10(-6) M, m +/- SEM, n = 5) on the isolated perfused rat kidney whose vascular tone had been previously increased by 25% with prostaglandin F2 alpha and adrenoceptors blocked (phenoxybenzamine 10(-5) M, sotalol 10(-5) M). Response to bromocriptine was comparable to that induced by dopamine on terms of EC50 and Emax (87 +/- 3% reversion of the increase in renal vascular resistance induced by prostaglandin F2 alpha). Nevertheless, unlike response to dopamine, bromocriptine-induced relaxation was not antagonized by the selective D1-receptor antagonist, SCH 23390 (3 x 10(-9) M) but was inhibited by selective D2-receptor antagonists, domperidone (10(-8) M) and DO 710 (3 x 10(-8) M). To account for renal vasodilatation, an interaction of bromocriptine with 5-HT receptors was excluded. Indeed, neither 8-OHDPAT, 5-methoxytryptamine nor 5-HT were able to induce any renal vasodilatation on the isolated perfused rat kidney and domperidone is devoid of antagonist activity on 5-HT receptors. The present results suggest that bromocriptine-induced vasodilatation on the rat renal vascular bed was linked to an interaction with vascular postsynaptic D2-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Metabolism and vascular effects of gamma-L-glutamyl-L-dopa on the isolated rat kidney.

Gamma-L-glutamyl-L-dopa (or gludopa), a dopamine (DA) prodrug, is selectively metabolized in vivo by the kidney through the sequential action of two renal enzymes, gamma-glutamyl transpeptidase (gamma-GT) and aromatic L-amino acid decarboxylase (AADC). This study was designed to analyze, in vitro, the factors regulating gludopa metabolism and its renal vascular effects. Rat kidneys were perfused in closed circuit with a cell-free perfusion buffer containing 6% bovine serum albumin (BSA). Adding gludopa (final concentration 10(-5) M in the perfusate) led to the release of DA both into urine and perfusate (0.53 +/- 0.21 and 1.38 +/- 0.28 nmol/min/g kidney wt, respectively, during the first 5 min after substrate addition, N = 5, mean +/- SEM). Total DA release (urine plus perfusate) was 73.7 +/- 15.8 nmol/g kidney wt within 30 minutes of recirculation. In non-filtering kidneys, total DA release in the recirculating medium was lower (12.5 +/- 1.4 nmol/g kidney wt, P less than 0.01). Glomerular filtration and access to the gamma-GT on the brush border membrane of proximal tubular cells are therefore required for the maximal conversion rate of gludopa. On filtering kidneys, L-dopa was also converted to DA, but at a higher rate than gludopa (total DA formed within 30 min of recirculation = 131.2 +/- 31.9 nmol/g kidney wt) and this rate was not reduced in non-filtering kidneys (224.2 +/- 41.7 nmol/g kidney wt DA formed within 30 min). Metabolic conversion of L-dopa by AADC is thus preserved in the case of an approach via the basolateral side of the proximal tubular cells. The renal vascular effects of gludopa were studied after vascular tone had been restored by continuous perfusion of PGF2 alpha and after the inhibition of alpha- and beta-adrenoceptors. Gludopa (3.10(-6) to 4.10(-5) M) elicited concentration-dependent renal vasodilatation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗