Potassium restores vasorelaxation of resistance arterioles in non-hypertensive DOCA/salt fed mice.

BACKGROUND: Potassium-enriched diets exert renal and cardiovascular protective effects, but the underlying mechanisms are largely unknown. METHODS: Using the dorsal skinfold chamber model for intravital microscopy, we examined endothelium-dependent vasorelaxation of precapillary resistance arterioles in response to acetylcholine or the NO donor SNAP in awake mice. Experiments were performed in uni-nephrectomized one renin gene (Ren-1c) C57BL/6 mice (control group) and in mice having received a continuous administration of deoxycorticosterone acetate and a dietary supplementation of 1% sodium chloride for 8 weeks (DOCA/salt group). An additional group of DOCA/salt treated animals received a dietary supplement of 0.4% KCl for 3 weeks prior to the experiments (DOCA/salt + potassium group). RESULTS: DOCA/salt treatment for 8 weeks resulted in hypokalemia, but blood pressure remained unchanged. In DOCA/salt mice, relaxation of resistance arterioles was blunted in response to acetylcholine, and to a lesser extent to SNAP, suggesting endothelial dysfunction. Endothelium-dependent vasorelaxation was restored by the potassium-enriched diet. CONCLUSION: This study is the first to demonstrate a protective effect of potassium on endothelium-dependent vasorelaxation in the absence of confounding anti-hypertensive effects, as observed in most animal models and the clinical situation. We propose that the known cardio- and nephro-protective effects of potassium might - at least in part - be mediated by the salutary effects on endothelium-dependent arteriolar relaxation.

[Primary hyperaldosteronism in cats]. / Primärer Hyperaldosteronismus bei Katzen.

Primary hyperaldosteronism is a clinical syndrome characterized by an elevated aldosterone secretion by the adrenals. The present case series describes 7 cats with primary hyperaldosteronism, which were presented between 2002 and 2011. Common clinical symptoms were weakness, anorexia, cervical ventroflexion and blindness. All cats showed hypokalemia. In 6 cats, blood pressure was determined: 5 cats showed hypertension, of which 4 animals exhibited retinal detachment and blindness. In the ultrasonographic examination, unilateral adrenomegaly was present in 6 cats whereas one animal showed normal adrenals. In 4 cats, the serum aldosterone concentration was above the reference range. Five cats underwent unilateral adrenalectomy, which was accomplished uneventfully and returned the electrolytes back to normal. Histopathological examination of the adrenals revealed 2 carcinomas and 4 adenomas; one cat with ultrasonographic normal adrenals exhibited bilateral nodular hyperplasia.

Effects of the peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone on renal and hormonal responses to salt in diabetic and hypertensive individuals.

AIMS/HYPOTHESIS: Glitazones are powerful insulin sensitisers prescribed for the treatment of type 2 diabetes. Their use is, however, associated with fluid retention and an increased risk of congestive heart failure. We previously demonstrated that pioglitazone increases proximal sodium reabsorption in healthy volunteers. This study examines the effects of pioglitazone on renal sodium handling in individuals prone to insulin resistance, i.e. those with diabetes and/or hypertension. METHODS: In this double-blind randomised placebo-controlled four-way crossover study, we examined the effects of pioglitazone (45 mg daily during 6 weeks) or placebo on renal, systemic and hormonal responses to changes in sodium intake in 16 individuals, eight with type 2 diabetes and eight with hypertension. RESULTS: Pioglitazone was associated with a rapid increase in body weight and an increase in diurnal proximal sodium reabsorption, without any change in renal haemodynamics or in the modulation of the renin-angiotensin aldosterone system to changes in salt intake. A compensatory increase in brain natriuretic peptide levels was observed. In spite of sodium retention, pioglitazone dissociated the blood-pressure response to salt and abolished salt sensitivity in salt-sensitive individuals. CONCLUSIONS/INTERPRETATION: Pioglitazone increases diurnal proximal sodium retention in diabetic and hypertensive individuals. These effects cause fluid retention and may contribute to the increased incidence of congestive heart failure with glitazones. TRIAL REGISTRATION: ClinicalTrial.gov NCT01090752 FUNDING: Hypertension Research Foundation Lausanne.

Renal and hormonal responses to direct renin inhibition with aliskiren in healthy humans.

BACKGROUND: Pharmacological interruption of the renin-angiotensin system focuses on optimization of blockade. As a measure of intrarenal renin activity, we have examined renal plasma flow (RPF) responses in a standardized protocol. Compared with responses with angiotensin-converting enzyme inhibition (rise in RPF approximately 95 mL x min(-1) x 1.73 m(-2)), greater renal vasodilation with angiotensin receptor blockers (approximately 145 mL x min(-1) x 1.73 m(-2)) suggested more effective blockade. We predicted that blockade with the direct oral renin inhibitor aliskiren would produce renal vascular responses exceeding those induced by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. METHODS AND RESULTS: Twenty healthy normotensive subjects were studied on a low-sodium (10 mmol/d) diet, receiving separate escalating doses of aliskiren. Six additional subjects received captopril 25 mg as a low-sodium comparison and also received aliskiren on a high-sodium (200 mmol/d) diet. RPF was measured by clearance of para-aminohippurate. Aliskiren induced a remarkable dose-related renal vasodilation in low-sodium balance. The RPF response was maximal at the 600-mg dose (197+/-27 mL x min(-1) x 1.73 m(-2)) and exceeded responses to captopril (92+/-20 mL x min(-1) x 1.73 m(-2); P<0.01). Furthermore, significant residual vasodilation was observed 48 hours after each dose (P<0.01). The RPF response on a high-sodium diet was also higher than expected (47+/-17 mL x min(-1) x 1.73 m(-2)). Plasma renin activity and angiotensin levels were reduced in a dose-related manner. As another functional index of the effect of aliskiren, we found significant natriuresis on both diets. CONCLUSIONS: Renal vasodilation in healthy people with the potent renin inhibitor aliskiren exceeded responses seen previously with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. The effects were longer lasting and were associated with significant natriuresis. These results indicate that aliskiren may provide more complete and thus more effective blockade of the renin-angiotensin system.

Dilated cardiomyopathy and impaired cardiac hypertrophic response to angiotensin II in mice lacking FGF-2.

FGF-2 has been implicated in the cardiac response to hypertrophic stimuli. Angiotensin II (Ang II) contributes to maintain elevated blood pressure in hypertensive individuals and exerts direct trophic effects on cardiac cells. However, the role of FGF-2 in Ang II-induced cardiac hypertrophy has not been established. Therefore, mice deficient in FGF-2 expression were studied using a model of Ang II-dependent hypertension and cardiac hypertrophy. Echocardiographic measurements show the presence of dilated cardiomyopathy in normotensive mice lacking FGF-2. Moreover, hypertensive mice without FGF-2 developed no compensatory cardiac hypertrophy. In wild-type mice, hypertrophy was associated with a stimulation of the c-Jun N-terminal kinase, the extracellular signal regulated kinase, and the p38 kinase pathways. In contrast, mitogen-activated protein kinase (MAPK) activation was markedly attenuated in FGF-2-deficient mice. In vitro, FGF-2 of fibroblast origin was demonstrated to be essential in the paracrine stimulation of MAPK activation in cardiomyocytes. Indeed, fibroblasts lacking FGF-2 expression have a defective capacity for releasing growth factors to induce hypertrophic responses in cardiomyocytes. Therefore, these results identify the cardiac fibroblast population as a primary integrator of hypertrophic stimuli in the heart, and suggest that FGF-2 is a crucial mediator of cardiac hypertrophy via autocrine/paracrine actions on cardiac cells.

Prejunctional angiotensin II receptors. Facilitation of norepinephrine release in the human forearm.

To determine if peripheral angiotensin II (Ang II) prejunctional receptors facilitating NE release exist in humans, we used [3H]NE kinetic methodology to measure forearm NE spillover during intrabrachial arterial Ang II infusions in eight normal male subjects. We used the following protocol to optimize conditions for demonstrating these receptors: (a) lower body negative pressure (-15 mmHg) to increase sympathetic nerve activity to skeletal muscle; and (b) intraarterial nitroprusside to maintain a high constant forearm blood flow (approximately 10 ml/min.100 ml) to maximize the proportion of neuronally released NE that spills over into the circulation. During lower body negative pressure, the following were infused intraarterially for three consecutive 20-min periods: saline, Ang II (4 ng/min), and Ang II (16 ng/min). During the Ang II infusions, forearm venous NE increased significantly from 173 to 189 and 224 pg/ml (P < 0.01), and forearm NE spillover increased from 384 to 439 and 560 ng/min.100 ml (P < 0.05 for high Ang II). Forearm NE clearance was unchanged. During low and high dose Ang II, the plasma venous Ang II concentrations were 25 and 97 pM, respectively. Since normal subjects increase plasma Ang II from 4 to 20-22 pM with exercise, standing, or diuretic administration, and patients with severe congestive heart failure can have a plasma Ang II of approximately 25 pM at rest, we suggest that Ang II might facilitate NE release in severe congestive heart failure, especially under conditions of stress.

[Blood pressure lowering tripeptides derived from milk protein]. / Blutdrucksenkende Tripeptide aus der Milch.

Fermentation of milk by the Lactobacillus helveticus LBK-16H or hydrolysis of casein by protease of Aspergillus oryzae generates the tripeptide casokinines Val-Pro-Pro and Ile-Pro-Pro. These peptides inhibit the kininase II (also known as Angiotensin Converting Enzyme, ACE). Daily intake of these peptides in sufficient amounts in milk, fruit vegetable drinks or pills slightly decreases the blood pressure in hypertensive patients. The currently available milk peptides decrease the blood pressure clearly less than the antihypertensive drugs. They can therefore merely be used for concomitant and safe lifestyle modification during prevention and therapy of hypertension.

[Prevalence of carotid artery stenosis in nonagenarians: Survey in a primary care hospital]. / Prévalence d'une sténose carotidienne chez le nonagénaire : résultats d'une enquête hospitalière.

AIM: Carotid artery stenosis increases with age and may cause brain ischemia if arterial hypotension occurs. We performed a monocentric pilot study to investigate its prevalence in the very elderly and to assess its potential influence on blood pressure (BP) goals during antihypertensive treatment. METHODS: All patients≥90 years of a primary care medical ward were prospectively included over 15 months. Ultrasound exams of the precerebral arteries were offered to all elderly patients for routine evaluation of their cardiovascular risk. Frequencies of stenosed common, internal and external carotid arteries (CCA, ICA, ECA) were analyzed together with clinical BP and antihypertensive therapy. Patients with circulatory shock and readmissions were excluded. RESULTS: Sixty-three patients aged 92±3 years (78% female) hospitalized for a median of 11 days were included. On admission, 76% were on antihypertensive drugs vs. 86% at discharge. Mean admission BP was 149/77 vs. 129/72mmHg at discharge; systolic BP<140mmHg 36% vs 64% (P<0.05). Mean intima-media thickness (ACC, right/left) was 8.7/9.4mm. Prevalence of plaque or stenosis<60% was: CCA 19.0%, ICA 19.0%, ECA 31.7%, bulb 74.6%; of stenosis≥60%: CCA 0%, ICA 7.9%, ECA 19.0%, ICA bilateral 1.6% (unilateral occlusion 3.1%, no bilateral). Coincidence of systolic BP<120mmHg and ACI stenosis≥60% had a probability of 1-2%. CONCLUSION: Concerning the risk of brain ischemia due to carotid artery stenosis, a BP goal<140mmHg should be safe for most nonagenarians. If individual BP goals are lower, searching for significant stenosis by ultrasound may be useful.

Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability.

BACKGROUND: Patients with an activated renin-angiotensin system (RAS) or genetic alterations of the RAS are at increased risk of myocardial infarction (MI). Administration of ACE inhibitors reduces the risk of MI, and acute coronary syndromes are associated with increased interleukin 6 (IL-6) serum levels. Accordingly, the present study evaluated the expression of angiotensin II (Ang II) in human coronary atherosclerotic plaques and its influence on IL-6 expression in patients with coronary artery disease. METHODS AND RESULTS: Immunohistochemical colocalization of Ang II, ACE, Ang II type 1 (AT(1)) receptor, and IL-6 was examined in coronary arteries from patients with ischemic or dilated cardiomyopathy undergoing heart transplantation (n=12), in atherectomy samples from patients with unstable angina (culprit lesion; n=8), and in ruptured coronary arteries from patients who died of MI (n=13). Synthesis and release of IL-6 was investigated in smooth muscle cells and macrophages after Ang II stimulation. Colocalization of ACE, Ang II, AT(1) receptor, and IL-6 with CD68-positive macrophages was observed at the shoulder region of coronary atherosclerotic plaques and in atherectomy tissue of patients with unstable angina. Ang II was identified in close proximity to the presumed rupture site of human coronary arteries in acute MI. Ang II induced synthesis and release of IL-6 shortly after stimulation in vitro in macrophages and rat smooth muscle cells. CONCLUSIONS: Ang II, AT(1) receptor, and ACE are expressed at strategic sites of human atherosclerotic coronary arteries, suggesting that Ang II is produced primarily by ACE within coronary plaques. The observation that Ang II induces IL-6 and their colocalization with the AT(1) receptor and ACE is consistent with the notion that the RAS may contribute to inflammatory processes within the vascular wall and to the development of acute coronary syndromes.

Recognition of peptide orientation: studies with angiotensin II in the guinea-pig.

Antipeptide sera of defined subspecificities were obtained when angiotensin II was unidirectionally conjugated to its carrier protein. Antisera with predominantly amino terminal specificity were produced when guinea-pigs were immunized with angiotensin II conjugated via its carboxy terminus to thyroglobulin. When angiotensin II was coupled via its amino terminus, carboxy terminal-specific antisera were obtained. The same conjugates failed to provide antisera with the corresponding specificities when rabbits were used instead of guinea-pigs. This work demonstrates that the peptide-protein coupling strategy may affect the specificity of the resulting antiserum.

[Autonomic angiotensinergic fibres in the human heart with an efferent sympathetic cophenotype]. / Le cophénotype sympathique efférent des fibres autonomes angiotensinergiques dans le cœur humain.

AIM: The autonomic innervation of the heart consists of sympathetic and parasympathetic nerve fibres, and fibres of the intrinsic ganglionated plexus with noradrenaline and acytylcholine as principal neurotransmitters. The fibres co-release neuropeptides to modulate intracardiac neurotransmission by specific presynaptic and postsynaptic receptors. The coexpression of angiotensin II in sympathetic fibres of the human heart and its role are not known so far. METHODS: Autopsy specimens of human hearts were studied (n=3; ventricles). Using immunocytological methods, cryostat sections were stained by a murine monoclonal antibody (4B3) directed against angiotensin II and co-stained by polyclonal antibodies against tyrosine hydroxylase, a catecholaminergic marker. Visualisation of the antibodies was by confocal light microscopy or laser scanning microscopy. RESULTS: Angiotensin II-positive autonomic fibres with and without a catecholaminergic cophenotype (hydroxylase-positive) were found in all parts of the human ventricles. In the epicardium, the fibres were grouped in larger bundles of up to 100 and more fibres. They followed the preformed anatomic septa and epicardial vessels towards the myocardium and endocardium where the bundles dissolved and the individual fibres spread between myocytes and within the endocardium. Generally, angiotensinergic fibres showed no synaptic enlargements or only a few if they were also catecholaminergic. The exclusively catechalominergic fibres were characterised by multiple beaded synapses. CONCLUSION: The autonomic innervation of the human heart contains angiotensinergic fibres with a sympathetic efferent phenotype and exclusively angiotensinergic fibers representing probably afferents. Angiotensinergic neurotransmission may modulate intracardiac sympathetic and parasympathetic activity and thereby influence cardiac and circulatory function.

Does renin determine the blood pressure response to calcium entry blockers?

Male Wistar rats with one-kidney, one clip renal hypertension were maintained on either a regular or a low salt diet for 3 weeks after clipping. At that time mean blood pressure in the unanesthetized rats was equally elevated in sodium-depleted (n = 17) and in sodium-replete rats (n = 19), but plasma renin activity was significantly higher in the former (p less than 0.05). Infusion of the calcium entry blocker verapamil at a rate of 0.05 mg/kg/minute decreased blood pressure within 60 minutes to a similar extent in rats kept on a salt-deficient diet and in rats fed a regular salt diet. In all rats taken as a group, there was a close, direct correlation (r = 0.87, p less than 0.001) between the magnitude of the blood pressure response to verapamil and the pretreatment blood pressure levels. Verapamil markedly accelerated heart rate and stimulated renin release in all rats. In additional groups of sodium-depleted (n = 8) and sodium-replete renal hypertensive rats (n = 7), nifedipine administration (4 micrograms/kg/min i.v.) within a 45-minute observation period caused a blood pressure fall (p less than 0.001) and heart rate acceleration (p less than 0.001) that were comparable in both groups. These findings suggest that in the rat with renal hypertension the short-term blood pressure response to the calcium antagonists verapamil and nifedipine is not influenced by the state of sodium balance and plasma renin activity. In this experimental model of hypertension, the magnitude of the blood pressure lowering effect of calcium entry blockers appears to be proportional to pretreatment blood pressure levels.

Two-kidney, one clip and one-kidney, one clip hypertension in mice.

The mouse remains the animal of choice in transgenic experiments, creating a need for methods of evaluating the physiology of genetically modified animals. We have established and characterized two murine models of renovascular hypertension known as the two-kidney, one clip and one-kidney, one clip models. The appropriate size of the clip lumen needed to induce high blood pressure was determined to be 0.12 mm. Clips with a lumen of 0.11 mm induced a high percentage of renal infarction, and clips with a 0.13-mm opening did not produce hypertension. Four weeks after clipping, two-kidney, one clip hypertensive mice exhibited blood pressure approximately 20 mm Hg higher than their sham-operated controls. After a similar period, this increase reached almost 35 mm Hg in the one-kidney, one clip model. Depending on the model, mice develop either renin-dependent or renin-independent hypertension. Both models are characterized by the development of cardiovascular hypertrophy.

Does pharmacological profiling of a new drug in normotensive volunteers provide a useful guideline to antihypertensive therapy?

Similar pressor mechanisms should be active in hypertensive and normotensive subjects since hypertension is a quantitative rather than qualitative disorder. Consequently, if an antihypertensive drug is designed to specifically block a well-defined mechanism involved in blood pressure regulation, it should be possible to evaluate its efficacy rather precisely in normotensive volunteers before even administering the compound to a hypertensive patient. That this is indeed the case is illustrated by the example of angiotensin-converting-enzyme inhibitors. The magnitude of blockade that can be obtained in humans, the minimal does needed for maximal efficacy, and the onset and duration of action of the agents have all been precisely determined in normotensive volunteers. Subsequent administration to hypertensive patients merely confirmed these findings. Moreover, if the antihypertensive effect of converting-enzyme inhibitors could not be predicted in an individual hypertensive patient, this is not related to some unknown action of the drug that cannot be assessed in normal volunteers but rather to our lack of understanding of the precise mixture of pathogenetic mechanisms prevailing in any particular patient. Only the safety evaluation and the search for side-effects still has to be carried out in nonspecific fashion, thus requiring long-term observations in large numbers of patients. If the tolerance of new converting-enzyme inhibitors were more predictable, the number of studies in hypertensive patients could be drastically reduced since the antihypertensive profile of any new converting-enzyme inhibitor can probably be precisely determined in normotensive volunteers.

Specific measurement of angiotensin metabolites and in vitro generated angiotensin II in plasma.

Combining high-performance liquid chromatography with radioimmunoassay enabled the precise measurement of different angiotensins and their metabolites in plasma. Peptides were extracted from 2 ml of plasma by reversible adsorption to phenylsilyl-silica, separated by isocratic high-performance liquid chromatography, and quantitated by radioimmunoassay using a sensitive but suitably cross-reacting angiotensin II antiserum. For the C-terminal angiotensin II metabolites (2-8)heptapeptide, (3-8)hexapeptide, and (4-8)pentapeptide, overall recoveries of 10 fmol peptide added to 1 ml of plasma were (mean +/- SD), 74 +/- 6, 68 +/- 8, and 67 +/- 11%, respectively. The detection limit for these peptides in plasma was 0.2 fmol/ml. Blanks were below the detection limits. In eight seated normal subjects treated for 4 days with enalapril, 20 mg p.o., q.d., angiotensin II metabolites tended to decrease during the 4 postdrug hours. However, their cumulated concentration in relation to octapeptide increased from 54 to 163% on Day 1 and from 62 to 103% on Day 4. After 4 hours of converting enzyme inhibition with enalapril there was still a close correlation between plasma renin activity and angiotensin-(1-8)octapeptide level (r = 0.83, p less than 0.05) and between blood angiotensin I and angiotensin-(1-8)octapeptide levels (r = 0.86, p less than 0.01). Adding angiotensin I in vitro raised the angiotensin-(1-8)octapeptide levels after incubation at 4 degrees C for 4 hours. Thus, immunoreactive "angiotensin II" does not disappear after converting enzyme inhibition largely because of the cumulated contribution of cross-reacting metabolites and partly because of in vitro generation of true angiotensin II.

Characterization of the angiotensin II receptor antagonist TCV-116 in healthy volunteers.

The purpose of this study was to assess the inhibitory effect of TCV-116, an orally active angiotensin II (Ang II) antagonist, on the pressor action of exogenous Ang II and to determine the compensatory rise in plasma renin activity and Ang II levels. Twenty-three male volunteers were treated for 8 days in a double-blind fashion with either placebo or TCV-116 (1, 2, or 4 mg PO daily) and challenged on the first, fourth, and eighth days with repeated bolus injections of Ang II. An additional 4 subjects received 8 mg PO daily in a single-blind fashion. The inhibitory effect on the systolic blood pressure response to Ang II was long lasting and clearly dose related. Six hours after 4 mg TCV-116, the systolic blood pressure response to a given dose of Ang II was reduced to 40 +/- 4% and 35 +/- 8% of baseline value on days 1 and 8, respectively. TCV-116 induced a dose-related increase in plasma renin activity and Ang II levels that was more pronounced on the eighth than on the first day of drug administration. Despite this compensatory mechanism, the relation between the time-integrated systolic blood pressure response to Ang II and the time-integrated CV-11974 levels, the active metabolite of TCV-116, was not different between days 1 and 8. In conclusion, TCV-116 appears to be a well-tolerated, orally active, potent, and long-lasting antagonist of Ang II in men.

True versus immunoreactive angiotensin II in human plasma.

To measure specifically angiotensin-(1-8)octapeptide, peptides were extracted from 2 ml of plasma by reversible adsorption to bonded-phase silica. The angiotensin-(1-8)octapeptide was then isolated by isocratic reversed-phase high-performance liquid chromatography and quantified by radioimmunoassay. The extraction recovery of 125I-angiotensin II added to 2 ml of plasma was 99 +/- 2% (mean +/- SD). The overall recovery of 5, 10, and 20 fmol unlabeled angiotensin II added to 1 ml of plasma was 80 +/- 10%. The coefficient of variation for within-assay precision was 0.06 and for between-assay precision 0.13. The detection limit was 0.4 fmol/ml. Buffer and plasma blanks were below the detection limit. Normal subjects on a free diet in supine position averaged 4.2 +/- 1.7 fmol/ml angiotensin-(1-8)octapeptide. Furosemide (40 mg p.o.) and standing increased these values to 22 +/- 7.6 fmol/ml. In four volunteers, immunoreactive "angiotensin II" (more or less angiotensin-like material) was measured serially before and after converting-enzyme inhibition (Hoe 498) with conventional Dowex extraction. At peak inhibition, plasma immunoreactive "angiotensin II" levels decreased by only 44%. In contrast, angiotensin-(1-8)-octapeptide isolated by high-performance liquid chromatography completely disappeared. In hypertensive patients receiving long-term treatment with enalapril, plasma levels of angiotensin-(1-8)octapeptide fell from 2.7 +/- 0.9 to 0.9 +/- 0.3 fmol/ml (mean +/- SEM) 2 hours after the morning dose, whereas levels of immunoreactive "angiotensin II" were not significantly changed. We found that this sensitive method specifically measured angiotensin-(1-8)octapeptide and demonstrated that true angiotensin II virtually disappears during converting-enzyme inhibition.

Individual responses to converting enzyme inhibitors and calcium antagonists.

This study was designed to assess whether the acute blood pressure response of an individual hypertensive patient to a calcium antagonist or an angiotensin converting enzyme (ACE) inhibitor is a good predictor of the long-term efficacy of these drug classes in this particular patient. The concept that good responses to ACE inhibitors and calcium antagonists may be mutually exclusive was also tested. Sixteen patients were included in a randomized crossover trial of enalapril, 20 mg daily, and diltiazem, 120 mg daily, for 6 weeks each. Blood pressure was measured by ambulatory blood pressure recording. During the washout phase, the acute effect of nifedipine, 10 mg p.o., and enalaprilat, 5 mg i.v., was evaluated. Nifedipine and enalaprilat reduced blood pressure equally well. The long-term blood pressure reduction induced by enalapril and diltiazem was similar. The acute blood pressure response to a given drug was not a good predictor of the result obtained with long-term therapy. No age dependency of the antihypertensive effect of either drug class was apparent. There was no evidence that a good response to one drug excluded a similarly good response to the other.

Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects.

This study was designed to evaluate in healthy volunteers the renal hemodynamic and tubular effects of the orally active angiotensin II receptor antagonist losartan (DuP 753 or MK 954). Losartan or a placebo was administered to 23 subjects maintained on a high-sodium (200 mmol/d) or a low-sodium (50 mmol/d) diet in a randomized, double-blind, crossover study. The two 6-day diet periods were separated by a 5-day washout period. On day 6, the subjects were water loaded, and blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 6 hours after a single 100-mg oral dose of losartan (n = 16) or placebo (n = 7). Losartan induced no significant changes in blood pressure, glomerular filtration rate, or renal blood flow in these water-loaded subjects, whatever the sodium diet. In subjects on a low-salt diet, losartan markedly increased urinary sodium excretion from 115 +/- 9 to 207 +/- 21 mumol/min (P < .05). The fractional excretion of endogenous lithium was unchanged, suggesting no effect of losartan on the early proximal tubule in our experimental conditions. Losartan also increased urine flow rate (from 10.5 +/- 0.4 to 13.1 +/- 0.6 mL/min, P < .05); urinary potassium excretion (from 117 +/- 6.9 to 155 +/- 11 mumol/min); and the excretion of chloride, magnesium, calcium, and phosphate. In subjects on a high-salt diet, similar effects of losartan were observed, but the changes induced by the angiotensin II antagonist did not reach statistical significance. In addition, losartan demonstrated significant uricosuric properties with both sodium diets.(ABSTRACT TRUNCATED AT 250 WORDS)