The effects of perindoprilat on renal hemodynamics and the elimination of water and electrolytes were studied acutely in the anesthetized dog. Two groups of animals were compared, one on normal sodium and water, the other on an acutely restricted sodium and water diet. In all cases, perindoprilat injected into renal artery (0.1 and 0.5 mg/kg) reduced blood pressure. In the animals on a low sodium diet, perindoprilat increased renal blood flow from 2.2 +/- 0.3 to 2.9 +/- 0.3 ml/min/g and decreased the filtration fraction; the decrease in renal vascular resistance predominated on the efferent arteriole of the glomerule (45% decrease), preferential site for the vasoconstrictor action of angiotensin II. In the animals on a normal sodium diet, renal blood flow was also increased from 4.1 +/- 0.6 to 5.1 +/- 0.6 ml/min/g but without the filtration fraction being affected. The renal vascular resistance was decreased at both pre- and post-glomerular levels (respectively, 50 and 25% decrease). After sodium and water restriction, but not in animals on a normal sodium diet, perindoprilat increased the fractional elimination of water and electrolytes. This salidiuresis might be accounted for by the hemodynamic effect of converting enzyme inhibitor and the decrease it elicits in filtration fraction, modifying sodium and water reabsorption in the proximal tubule.

Summary— Loop diuretics of the benzoic acid and aryloxyacetic acid families inhibit Na+K+Cl − cotransport. The ranking order of potencies measured in the thick ascending limb of Henle's loop and the ranking order of affinities for [ 3 H]piretanide receptors on renal plasma membranes are the same. Potencies and affinities correlate well (correlation coefficient r = 0.959 for the medulla and r = 0.951 for the cortex). Therefore, measurement of [ 1 H]piretanide binding is proposed to facilitate screening for loop diuretic action.

The renal vascular effects of dopaminomimetics and dopaminolytics were studied in the isolated perfused rat kidney after pretreatment with phenoxybenzamine (10(-5) M) and sotalol (10(-5) M) and after contraction of the vascular bed with prostaglandin F2 alpha. The DA1- and D1-selective antagonist, SCH 23390, antagonized competitively the relaxation induced by dopamine (pA2 = 9.7 +/- 0.08, m +/- S.D.). On the other hand, (+/-)-DO 710, a D2-preferential benzamide, only antagonized the renal vascular response to dopamine at a concentration 30 times higher than that active on D2 receptors. The ergot derivative, quinpirole, a selective agonist for DA2 and D2 receptors had no renal vascular dopaminomimetic activity, whereas (-)-EOE, a D2-selective ergoline, seemed to be a partial agonist, but 10 times less potent than dopamine. These results confirm the existence of DA1 receptors on the vascular bed of isolated rat kidney but rule out the presence of DA2 receptors. They also reinforce the analogy between DA1 and D1 dopamine receptors.

Angiotensin-converting enzyme (ACE) activity was measured in the plasma, the kidney, and other organs of 5-, 8-, and 11-week-old spontaneously hypertensive male rats (SHR) of the Okamoto-Aoki strain and compared with that of age-matched Wistar-Kyoto (WKY, bred by Iffa-Credo) or normotensive Wistar rats. ACE activity was measured spectrofluorometrically, using the artificial substrate N-CBZ-L-phe-L-his-L-leu. ACE activity was constantly lower in the plasma and renal cortex of SHR from 5 weeks on than in WKY rats. This difference in the renal cortex ACE activity persisted after 1 h of open circuit perfusion of the isolated kidney with Krebs-Henseleit medium. On the other hand, there lung, the brain occipital cortex, or the abdominal aorta of hypertensive or normotensive rats. The percentage inhibition of ACE activity provoked by 7 days of oral administration of ramipril (Hoe 498, 1 mg/kg/day) was analogous in the kidneys and lungs of WKY rats and SHR. Enalapril (MK 421, 30 mg/kg/day) was equipotent to ramipril in the kidney but had lower inhibitory effects on the pulmonary ACE activities of WKY rats and SHR.

On the isolated perfused rat kidney, angiotensin-converting-enzyme activity was evaluated by two approaches: one, biochemical, through the measurements of the enzymatic activity on renal homogenate, the other, pharmacological, through the vasoconstrictor response to angiotensin I. Renal tissue angiotensin-converting-enzyme activity was not modified by setting the kidney under perfusion with a modified Krebs-Henseleit solution but was inhibited after addition of captopril into the perfusion medium (10(-5) M, 100 p. 100 inhibition) or after pretreatment of the animals with ramipril (10 mg/kg/day over 3 weeks, per os, 60 p. 100 inhibition). On the isolated perfused rat kidney, angiotensin I and angiotensin II induced a concentration dependent renal vasoconstriction (EC50 = 1.05 +/- 0.18 X 10(-8) and 0.11 +/- 0.05 X 10(-8) M) which was competitively antagonized by saralasin, an angiotensin II receptor antagonist. Addition of angiotensin-converting-enzyme inhibitors to the perfusion medium (captopril or ramiprilat, 10(-5) M) or pretreatment of the animals with ramipril (50 mg/kg, i.p. the day before or 10 mg/kg/day over 3 weeks, per os) only shifted the angiotensin I concentration-response curve to the right by a factor 3 to 4. The residual vasoconstrictor effect of angiotensin I was abolished by 10(-5) M saralasin and remains linked to a local generation of angiotensin II. Our results suggest that, on the isolated perfused rat kidney, besides the angiotensin-converting-enzyme, an iso-enzyme may also be able to generate angiotensin II.

Postjunctional renal alpha-adrenoceptors were studied (1) in vivo, on the renal vasculature of the anaesthesized rat and compared with those in the femoral vasculature, and (2) in vitro, on the renal vascular bed of isolated perfused rat kidney. In vivo, renal and iliac blood flows were measured with an electromagnetic flow meter. The i.v. injection of (-)-phenylephrine (1-16 micrograms/kg) and B-HT 920 (0.6-600 micrograms/kg) induced an increase in both renal and iliac vascular resistance, inhibited respectively with prazosin (300 micrograms/kg) or yohimbine (300 micrograms/kg). In the kidney, maximum response to B-HT 920 was equivalent to 64% of that to (-)-phenylephrine; on the iliac vasculature, vasoconstrictor responses to both drugs were identical, but only corresponded to 50% of the maximum renal response to (-)-phenylephrine. This indicates the predominance of alpha 1- over alpha 2-adrenoceptors in the renal vascular bed. In vitro, on the isolated perfused rat kidney, vasoconstriction was induced by the preferential alpha 1-adrenoceptor agonists [(-)-phenylephrine, cirazoline and methoxamine] and the preferential alpha 2-adrenoceptor agonists (alpha-methylnoradrenaline, dopamine and clonidine) at concentrations at which they lose their selectivity for the alpha 2-adrenoceptors; all responses were antagonised by prazosin but not by yohimbine. B-HT 920, the selective alpha 2-adrenoceptor agonist, only induced renal vasoconstriction in vitro under concomitant infusion of rabbit plasma.

Since the first observation in 1978, it has been clearly established that the non-steroidal anti-inflammatory drugs (NSAIDs) interfere with the pharmacokinetics of lithium: by reducing urinary clearance of the metal, they can raise the plasma lithium level and thus lead to intoxication. Among the NSAIDs available in France, this interaction has been reported with phenylbutazone (Butazolidine, Carudol), diclofenac (Voltarène), indomethacin (Indocid) and its antalgic derivative clomethacin (Dupéran), ketoprofen (Profenid), mefenamic acid (Ponstyl), niflumic acid (Nifluril) and piroxicam (Feldène). This interaction does not occur with aspirin; this exception suggests that the inhibition of prostaglandins synthesis is not the mechanism responsible for the decrease in the urinary elimination of lithium linked with an increase in its tubular reabsorption. In practice, in view of the growing diffusion of NSAIDs, it is necessary to inform all patients under lithium treatment of the risk of interaction resulting from their use.

On the isolated perfused rat kidney, the angiotensin converting enzyme (ACE) activity was evaluated with two approaches: one, pharmacological, through the vasoconstrictor response to angiotensin I (ANG I), and the other, biochemical, through the measurements of the enzymatic activity on renal homogenate. ANG I and angiotensin II (ANG II) induced a concentration-dependent renal vasoconstriction (EC50 = 10.5 +/- 1.8 X 10(-9) and 1.1 +/- 0.5 X 10(-9) M, respectively). Both responses were competitively antagonized by an ANG II receptor antagonist, saralasin (pA2 = 8.65 +/- 0.63 and 8.94 +/- 0.28, respectively). The effects of ACE inhibitors were studied in vitro after addition of captopril and ramiprilat (10(-5) M) directly to the perfusion medium, and ex vivo, after pretreatment of the rats with ramipril (50 mg/kg, i.p. the day before or 10 mg/kg/day, per os, over 3 weeks). In spite of the high doses of ACE inhibitors used, the ANG I concentration-response curve was only shifted to the right by a factor of 4, although renal tissue ACE activity was completely inhibited. Saralasin (10(-5) M) totally abolished the ANG I-induced vasoconstriction elicited in the presence of ACE inhibitors, this response being therefore linked to a generation of ANG II from ANG I. Our results suggest that, on the isolated perfused rat kidney, ANG II may be formed from ANG I by a peptidyl dipeptidase different from the ACE.

s: Groupe Hypertension de la Société Français de Cardiologie, Journées de L'Hypertension Artérielle: Oral Papers: PDF Only

Dopamine remains the reference in the study of the mechanisms involved in the antihypertensive effects of dopaminomimetics. Its renal vasodilator effects are well characterized but relaxation of other vascular beds is less known. The iliac vascular response to dopamine was studied in the anesthetized rat (pentobarbital) and compared to the renal response. Simultaneous measurements of arterial pressure, iliac and renal blood flows (electromagnetic flowmeter probes, Skalar, Delft) allowed iliac and renal vascular resistance (IVR, RVR) to be calculated. Their variations were studied after intravenous injections of increasing doses of dopamine (1.5 to 200 micrograms/kg) in unpretreated animals and in animals receiving various pretreatments. Without pretreatment, dopamine induced a biphasic renal response, vasodilation partially masked by subsequent vasoconstriction for doses above 12.5 micrograms/kg of dopamine. Simultaneously, IVR was increased. After alpha-adrenolytic pretreatment (prazosin 2.5 mg/kg, i.v.), dopamine decreased the RVR while iliac vasoconstriction persisted. The association of yohimbine (5 mg/kg, i.v.) to prazosin completely abolished the vasoconstrictive effects: dopamine lowered then by about 30% both IVR and RVR. Dopamine-induced iliac and renal decrease in vascular resistance persisted in the presence of a beta-adrenoceptor antagonist [+/-)-sotalol 30 mg/kg, i.v.), after depletion of catecholamines from sympathetic terminals (reserpine 10 mg/kg, i.p. 20 h before the experiment) or inhibition of cyclo-oxygenase (indomethacin 2.5 mg/kg, i.p. 20 h and 1 h before dopamine). On the contrary, a specific antagonist of dopamine receptors, (+)-butaclamol (60 micrograms/kg/min, i.v.) stereoselectivity inhibited the dopamine-induced renal vasodilation but did not modify the iliac response.(ABSTRACT TRUNCATED AT 250 WORDS)

The renal vascular effects of benzazepine derivatives were studied on the isolated perfused rat kidney in the presence of phenoxybenzamine and sotalol after contraction of the vascular bed with prostaglandin F2 alpha. SK&F 82526 was a very potent dopaminomimetic drug (ED50 = 7.6 +/- 0.8 X 10(-9) M) on the renal vascular dopamine receptor. It displayed partial agonist activity (similar to SK&F 38393) and was devoid of alpha-adrenomimetic effects. SK&F 83742 was a potent dopaminolytic drug. It antagonized dopamine-induced relaxation of the renal vascular bed in a competitive way, with an apparent pA2 of 7.47 +/- 0.23.

Receptors which bind [3H]-piretanide were demonstrated on membranes prepared from renal medulla and cortex. They exhibit all the characteristics of a specific receptor such as high affinity, specificity, tissue selectivity, reversible binding kinetics and proportionality between affinity and diuretic effect. Medullary and cortical receptors are clearly distinct since they have different ion requirements.