Lack of angiotensin II-facilitated erythropoiesis causes anemia in angiotensin-converting enzyme-deficient mice.

While nephrologists often observe reduced hematocrit associated with inhibitors of angiotensin-converting enzyme (ACE), the basis for this effect is not well understood. We now report that two strains of ACE knockout mice have a normocytic anemia associated with elevated plasma erythropoietin levels. (51)Cr labeling of red cells showed that the knockout mice have a normal total blood volume but a reduced red cell mass. ACE knockout mice, which lack tissue ACE, are anemic despite having normal renal function. These mice have increased plasma levels of the peptide acetyl-SDKP, a possible stem cell suppressor. However, they also show low plasma levels of angiotensin II. Infusion of angiotensin II for 2 weeks increased hematocrit to near normal levels. These data suggest that angiotensin II facilitates erythropoiesis, a conclusion with implications for the management of chronically ill patients on inhibitors of the renin-angiotensin system.

Acute angiotensin-converting enzyme inhibition increases the plasma level of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline.

Angiotensin I-converting enzyme (ACE) has two homologous active NH2- and COOH-terminal domains and displays activity toward a broad range of substrates. The tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) has been shown to be hydrolyzed in vitro by ACE and to be a preferential substrate for its NH2-terminal active site. This peptide is a regulatory factor of hematopoiesis which reversibly stem cells and normal early progenitors into S-phase. We found that a single oral dose of 50 mg of the ACE inhibitor, captopril, when administered to eight healthy subjects in a double-blind, crossover, placebo-controlled study, massively increased the plasma level of Ac-SDKP. ACE inhibition by captopril induced a 90-99% inhibition of in vitro [3H]Ac-SDKP hydrolysis and a long-lasting 5.5-fold (range: 4-8.5-fold) increase in the plasma levels of Ac-SDKP. These results demonstrate that Ac-SDKP is the first natural peptide hydrolyzed by the NH2-terminal domain of ACE not only in vitro but also in vivo, confirming that both catalytic sites of ACE are physiologically active. Our data suggest that ACE may also be implicated in the process of hematopoietic stem cell regulation, by permanently degrading this natural circulating inhibitor of cell entry into S-phase.

Relationships between angiotensin I converting enzyme gene polymorphism, plasma levels, and diabetic retinal and renal complications.

Insulin-dependent diabetes mellitus (IDDM), cardiovascular morbidity, and vital prognosis are linked to diabetic nephropathy, which is probably determined by renal hemodynamic abnormalities and by a genetic predisposition. Angiotensin I converting enzyme (ACE) regulates systemic and renal circulations through angiotensin II formation and kinins metabolism. Plasma and cellular ACE levels are genetically determined; an insertion/deletion polymorphism of the ACE gene is strongly associated with ACE levels, subjects homozygote for insertion (genotype II) having the lowest plasma values. We studied the relationship between the ACE gene polymorphism or plasma levels and microcirculatory disorders of IDDM through two independent studies: one involved 57 subjects with or without diabetic retinopathy, and the other compared 62 IDDM subjects with diabetic nephropathy to 62 diabetic control subjects with the same characteristics (including retinopathy severity) but with normal kidney function. The ACE genotype distribution was not different in diabetic subjects with or without retinopathy and in a healthy population. Conversely, an imbalance of ACE genotype distribution, with a low proportion of II subjects, was observed in IDDM subjects with diabetic nephropathy compared with their control subjects (P = 0.006). Plasma ACE levels were mildly elevated in all diabetic groups, independently of retinopathy, but they were higher in subjects with nephropathy than in those without nephropathy (P = 0.0022). The II genotype of ACE gene is a marker for reduced risk for diabetic nephropathy.

Additive effects of losartan and enalapril on blood pressure and plasma active renin.

The combination of single oral doses of an angiotensin I-converting enzyme inhibitor (captopril) and a type 1 angiotensin II receptor antagonist (losartan) has additive effects on blood pressure fall and renin release in sodium-depleted normotensive subjects. We planned the present study to determine whether the magnitude of the hemodynamic and hormonal consequences of renin-angiotensin system blockade by such a combination is larger than that obtained by doubling the dose of the angiotensin-converting enzyme inhibitor given alone. In a single-dose, double-blind, randomized, three-way crossover study, 10 mg enalapril, 20 mg enalapril, and the combination of 50 mg losartan and 10 mg enalapril were administered orally to 12 sodium-depleted normotensive subjects. The area under the time curve from 0 to 24 hours (AUC0-24) of the mean blood pressure fall after losartan-enalapril combination intake (-220 +/- 91 mm Hg.h) was significantly greater than that of either 10 or 20 mg enalapril (-124 +/- 91 and -149 +/- 85 mm Hg.h, respectively, P < .05 vs both doses). The combination significantly increased by 2.3 +/- 1.2-fold the AUC0-24 of plasma active renin compared with either 10 or 20 mg enalapril given alone (P < .05) but had no additive effect on plasma aldosterone fall. The losartan-enalapril combination is more effective in decreasing blood pressure and increasing plasma active renin than doubling of the enalapril dose.

Inhibition of human plasma renin activity by pepstatin.

Pepstatin, a pentapeptide isolated from streptomyces, is a powerful inhibitor of several acid proteases. Its ability to inhibit the renin-angiotensinogen reaction was studied in vitro, in various human plasma. A 50% inhibition of plasma renin activity was obtained with 10(-6)M pepstatin at pH 5.7 and 10(-5)M at pH 7.4. The inhibition of plasma renin activity by pepstatin was studied in hypertensive patients with various plasma renin levels. The inhibitory effect could be demonstrated in patients with low, normal and high renin activity at both pH's. The type of inhibition and the inhibitory constant were investigated by Dixon plot and Lineweaver-Burk plot in three separate experiments. On both representations, a competitive type of inhibition was found with an inhibitory constant of about 1.2 x 10(-6)M.

Hyporeninemic hypoaldosteronism in infancy: a familial disease.

Hyporeninemic hypoaldosteronism was found in two male siblings with urinary salt wasting and low plasma sodium levels. The eldest, aged 1 yr, had growth retardation, with hyponatremia and normal plasma potassium levels. The second, aged 2 months, had low plasma sodium and high plasma potassium levels. Both were severely and repeatedly hypoaldosteronemic. Primary adrenal deficiency was excluded by ACTH testing, which showed a good aldosterone rise and normal responses of other steroids. Both children had low PRA compared to that in age-matched normal subjects. The eldest sibling also had decreased total renin, low inactive to total renin ratio, and a subnormal level of angiotensinogen. The father had low plasma angiotensinogen levels. Congenital deficiency of renin activity and/or angiotensinogen production is suggested as the primary abnormality.

Renin release regulation during acute renin inhibition in normal volunteers.

Blockade of the renin-angiotensin system by an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II (Ang II) antagonist is accompanied by a reactive rise in renin release. This rise is generally attributed to interruption of the short feedback loop between Ang II and renin release. Similarly, after the administration of a renin inhibitor, the plasma concentrations of active and total renin are increased and plasma renin activity is suppressed. The aim of the present study was to investigate if a fall in the plasma Ang II level is the unique determinant of the rise in the active renin (AR) level that follows renin inhibition. Six normal male volunteers participated in three successive 240-minute experiments at weekly intervals according to a single-blind randomized Latin square design. For experiment 1, Ang II was infused at 2 ng/kg/min from 0 to 60 minutes and at 4 ng/kg/min from 60 to 120 minutes. For experiment 2, 0.3 mg/kg of the new potent renin inhibitor Ro 42-5892 was injected at 30 minutes followed by infusion at 0.1 mg/kg/hr from 30 to 240 minutes. For experiment 3, Ang II and Ro 42-5892 were administered simultaneously at the same doses as described above. The mean +/- SEM Ang II concentration increased from 10.2 +/- 1.6 to 33.7 +/- 11.2 pg/ml after infusion of exogenous peptide. It decreased from 9.5 +/- 0.9 to 1.4 +/- 0.3 pg/ml after the injection of Ro 42-5892 and increased from 15.6 +/- 2.9 to 37.1 +/- 11.8 pg/ml after the simultaneous infusion of both compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Coexpression of renin, angiotensinogen, and their messenger ribonucleic acids in adrenal tissues.

The presence of the two components of the renin-angiotensin system (RAS) has been systematically investigated in human normal and pathological adrenal tissues with two aims: 1) the detection of renin and especially angiotensinogen, which has not been reported before; and 2) to study possible differences in the coexpression of renin and angiotensinogen in tissue of cortical and medullary origin. The relative levels of renin and angiotensinogen mRNAs were determined by Northern blot analysis in normal (n = 5) and pathological adrenal tissues of cortical (n = 23) and medullary (n = 10) origin. Renin, prorenin, and angiotensinogen levels were also measured. Renin concentrations in normal and pathological adrenals were around 30-fold higher than those in the plasma of normal subjects, except for a Cushing's adenoma, which contains an extremely high renin content. Renin accounted for 56% of the total renin in normal adrenals and up to 87% in neoplastic tissues. This high proportion of renin indicates a likely conversion of prorenin to renin within these tissues. Renin mRNA was detected in each group of adrenal tissues. There was a significant correlation between the concentration of renin and its mRNA (r = 0.75; P less than 0.05). Angiotensinogen and its mRNA were detected in all normal and pathological adrenals. Compared to normal adrenal tissues, the relative amount of angiotensinogen mRNA was significantly higher in pheochromocytomas. However, the increased mRNA level in these tissues was not accompanied by a parallel increase in tissue angiotensinogen levels. Since the translational efficiency of angiotensinogen was verified by in vitro cell-free translation, the low level of angiotensinogen compared to the relatively high amount of its mRNA suggests a lack of storage of this protein in adrenal cells, as in liver cells. This study demonstrates that renin and angiotensinogen are coexpressed in normal and pathological tissues. Tissues of different cellular origin (zona glomerulosa, fasciculata, and medullary tissue), were able to express, store, and process renin and synthesize angiotensinogen. There was no obvious relationship between the expression of these proteins and the pathophysiology of the adrenal gland.

Influence of the M235T polymorphism of human angiotensinogen (AGT) on plasma AGT and renin concentrations after ethinylestradiol administration.

The T235 allele of the angiotensinogen (AGT) gene is associated with plasma AGT concentration and pregnancy-induced hypertension. The aim of this study was to compare changes in the circulating renin-angiotensin system after short-term (2 days) and repeated (7 days) administration of 50 microg ethinylestradiol (EE) in homozygous normotensive men (TT and MM). After repeated EE administration, renin stimulation was induced by a single oral dose of 40 mg furosemide, followed by 50 mg captopril, 12 h later. The short-term administration of EE did not induce a significant differential genotype-dependent increase in AGT concentration. In the 7-day study, TT subjects had higher peak plasma AGT concentrations than MM subjects. The more pronounced AGT increase in TT subjects resulted in similar plasma renin activity at a lower plasma active renin concentration, with a higher plasma renin activity/active renin ratio. The difference between genotypes in renin secretion resulted in readjustment of angiotensins production. In conclusion, the T235 allele of the AGT gene is associated with greater stimulation of AGT secretion in plasma after EE administration. In the short-term, complete readjustment of the circulating renin-angiotensin system occurs, through a decrease in renin release, which blunts the effects of the increase in AGT concentration.

Direct radioimmunoassay of human renin: comparison with renin activity in plasma and amniotic fluid.

Human plasma and amniotic liquid were activated by dialysis at pH 3.3. Then, renin before and after acidification was determined by two methods: enzymatic activity measurement, and direct radioimmunoassay. The identity between nonactivated and activated renin in plasma and amniotic fluid on the one hand, and pure renin on the other, was demonstrated by the dilution curves in radioimmunoassay. After acidification, mean plasma renin activity in 17 patients with high renin activity rose from 26.8 +/- 11.7 pmoles A I ml-1 h-1 to 67.9 +/- 29.3 pmoles A I ml-1 h-1, whereas the mean renin concentration tested by direct radioimmunoassay remained constant at 13.8 +/- 10.5 and 14.8 +/- 11.2 fmol/ml before and after acidification respectively. In amniotic fluid, renin activity increased from 9.7 to 227 pmoles angiotensin I/ml/h, but the renin concentration did not change. Direct radioimmunoassay of renin may therefore be considered as measuring total renin, regardless of its enzymatic activity. In 12 hypertensive patients undergoing bilateral renal-vein catheterization, the direct measurement of renin was very significantly correlated to the non-activated (r = 0.883) and activated renin values (r = 0.963).

Biological effects of estradiol-17 beta in postmenopausal women: oral versus percutaneous administration.

To determine whether the route of administration or the type of estrogen used in estrogen replacement therapy (ERT) is more important in avoiding effects on hepatic function, 24 postmenopausal women were studied before and at the end of 2 months of oral or percutaneous administration of the same estrogen, estradiol-17 beta (E2). The treatments studied were oral micronized E2, 2 mg/day (9 women); oral E2 valerate, 2 mg/day (5 women), and percutaneous E2, 3 mg/day (10 women). Specific plasma biological and biochemical markers of estrogenic action were evaluated, namely, E2, estrone (E1), LH, FSH, sex steroid binding protein (SBP), renin substrate, antithrombin activity, and lipoproteins (high density lipoprotein cholesterol, low density lipoprotein cholesterol, very low density lipoprotein triglycerides). Both oral and percutaneous administration of E2 increased plasma E2 levels up to midfollicular values and decreased LH and FSH levels into the same range. Oral administration of E2 led to substantial increases in plasma E1, SBP, renin substrate, and VLDL levels, whereas AT decreased significantly. Percutaneous administration of E2 led to a physiological plasma E1/E2 ratio and did not induce any change in hepatic proteins. These data suggest that the route of administration of E2 determines the biochemical response to ERT in postmenopausal women. SBP is the most sensitive marker of the liver action of estrogen, and triglycerides also are simple and useful markers for this effect. Percutaneous E2 therapy is an effective method of ERT, and has no measurable effects on hepatic markers of estrogen action.

Selective recognition of M235T angiotensinogen variants and their determination in human plasma by monoclonal antibody-based immunoanalysis.

The common M235T mutation of human angiotensinogen has been shown to be associated with a 10-20% increase in plasma angiotensinOgen level and increased frequency of essential and pregnancy-induced hypertension. The detection of such a common factor in the plasma of individuals at risk could be a useful tool for modern molecular-based medicine. The recognition of M235T variants was investigated using four monoclonal antibodies (mAbs) directed against human angiotensinogen; two immunometric assays were developed. The first assay (using mAbS 7B2 and 4G3) allowed the direct determination of angiotensinogen concentrations and did not show a significant difference with the enzymatic measurement of angiotensinogen. The second assay (using mAbs 1H8 and 1C11) showed a fine distinction between the T235 mutant and M235 wild-type forms of angiotensinogen, with a greater affinity for the latter, as confirmed by biosensor BIAcore experiments. This assay was extremely sensitive in measuring the proportions of the M235 and T235 forms present in the test samples, the first time such a distinction has been achieved in the serpin family. The simple immunoanalysis of the plasma allowed the direct determination of the M235T genotype of the individual tested. Furthermore, it was shown that the T174M mutation, described as being in complete linkage disequilibrium with the M235T mutation, had no influence on these results. Moreover, this assay suggested the presence of the M235 and T235 angiotensinogens in approximately equal amounts in heterozygous plasmas. In conclusion, the immunometric assay described in this study should provide original tools for investigating the relationship between M235T genotype, plasma angiotensinogen levels, and regulation of blood pressure.

Effect of the circulating renin-angiotensin system on prolactin release in humans.

We recently reported that renin, angiotensinogen, and angiotensin-converting enzyme were present in normal human pituitary lactotroph cells and PRL-secreting adenomas. Angiotensin-II and -III have also been shown to modulate PRL release in vitro. The present study was designed to determine whether angiotensin modulates PRL secretion in vivo. In 36 hypertensive patients with widely varying renin levels, active renin and basal PRL levels did not correlate. In 10 normal volunteers, both a sustained infusion of angiotensin-II and a graded infusion of angiotensin-III induced a 2- to 3-fold increase in aldosterone levels, but had no effect on PRL secretion. Administration of the angiotensin-converting enzyme inhibitor captopril had no effect on PRL circadian rhythm in 10 normal subjects or on PRL concentrations in 11 patients with PRL-secreting adenomas. Cross-over administration of placebo and captopril did not affect the peak PRL level measured after TRH treatment in 10 hypertensive men (placebo, 43.1 +/- 5.4; captopril, 40.0 +/- 6.2 micrograms/L; P = NS) or the rise in PRL induced by doperidone in 6 normal women (placebo, 129.5 +/- 16.2; captopril, 150.0 +/- 35.7 micrograms/L; P = NS). Further, administration of enalapril for 30 days to 6 hypertensive patients did not alter basal PRL concentrations or the peak concentrations induced by TRH. These data indicate that in humans the circulating renin-angiotensin system does not interact with diurnal PRL release or with the response to TRH or domperidone.

Pharmacodynamic effects of dual neutral endopeptidase-angiotensin-converting enzyme inhibition versus angiotensin-converting enzyme inhibition in humans.

BACKGROUND: There is currently no clear evidence that dual neutral endopeptidase-angiotensin-converting enzyme inhibitors have effects on angiotensin-converting enzyme, renin, or blood pressure that are different from specific angiotensin-converting enzyme inhibitors in humans. METHODS AND RESULTS: In a double-blind, placebo-controlled crossover study, single oral doses of the dual neutral endopeptidase-angiotensin-converting enzyme inhibitor, 10 mg BMS-186716 and the angiotensin-converting enzyme inhibitor fosinopril (20 mg) were administered to 9 normotensive subjects with induced mild sodium depletion. Values for area under the time curve from 0 to 24 hours [AUC(0-24)] for the plasma angiotensin II/angiotensin I ratio and for angiotensin II were similar for 10 mg BMS-186716 and 20 mg fosinopril. Plasma atrial natriuretic peptide decreased significantly after 20 mg fosinopril (9+/-3 pg/mL; P < .05 versus 10 mg BMS-186716 and placebo) compared with 10 mg BMS-186716 (16+/-5 pg/mL) and placebo (16+/-5 pg/mL). BMS-186716, 10 mg, significantly increased urinary atrial natriuretic peptide from baseline by 2+/-1.3-fold (P < .05 versus placebo and 20 mg fosinopril). AUC(0-24) of plasma active renin did not differ significantly between 10 mg BMS-186716 (3898+/-333 pg x h x mL(-1)) and 20 mg fosinopril (4383+/-302 pg x h x mL(-1); difference not significant). Both drugs decreased blood pressure, but the AUC(0-24) of the changes in mean blood pressure differed significantly from placebo (79+/-84 mm Hg x h) only for 20 mg fosinopril (181+/-6 mm Hg x h; P < .05) but not for 10 mg BMS-186716 (118+/-7 mmHg x h). CONCLUSIONS: In this model, single oral doses of 10 mg BMS-186716 and 20 mg fosinopril induced similar 24-hour in vivo angiotensin-converting enzyme inhibition. BMS-186716, 10 mg, increased urinary atrial natriuretic peptide and blunted the expected decrease in plasma atrial natriuretic peptide caused by angiotensin-converting enzyme inhibition. BMS-186716, 10 mg, did not inhibit plasma active renin rise compared with 20 mg fosinopril. A single oral dose of 10 mg BMS-186716 had a shorter blood pressure-lowering effect than 20 mg fosinopril.

Blood pressure effects of acute intravenous renin or oral angiotensin converting enzyme inhibition in essential hypertension.

OBJECTIVE: To assess the participation of the renin-angiotensin system in the blood pressure regulation of essential hypertensive patients through acute specific renin inhibition. DESIGN AND METHODS: Fifty-three consecutive untreated hypertensive patients (mean +/- SD age 55 +/- 10 years, 42 male) were investigated on their usual sodium diet in a 3-h protocol. The first 11 patients did not receive any drug, the following 20 patients ingested a single oral dose of captopril (1 mg/kg) and the last 22 patients received a renin inhibitor infusion (remikiren; 1 mg/kg over 60 min). RESULTS: The maximum diastolic blood pressure fall was comparable in the two treated groups. Diastolic blood pressure changes analysed as area under the curve were similar for both drugs (overall F1,40 = 1.26, P = 0.27). Even though the baseline renin levels were within the narrow range 5-80 pg/ml, the diastolic blood pressure fall analysed as area under the curve from time 32 min to time 60 min was significantly correlated with the baseline active renin level in both groups (remikiren r = 0.44, P < 0.05; captopril r = 0.47, P < 0.05). The plasma active renin levels were significantly increased at 30, 90 and 120 min in both groups, and the maximum active renin levels were significantly correlated with the baseline active renin level (remikiren r = 0.62, P < 0.01; captopril r = 0.66, P < 0.01). The plasma prorenin levels did not change. CONCLUSIONS: This study suggests that acute renin inhibition and acute angiotensin converting enzyme inhibition similarly decrease the blood pressure and increase the plasma active renin levels. Acute blockade of the renin-angiotensin system at its initial step by a renin inhibitor can therefore be used to investigate the renin dependence of the blood pressure in essential hypertension.

Pharmacokinetic-pharmacodynamic interactions of candesartan cilexetil and losartan.

BACKGROUND: The variability of the blood pressure response to blockade of the angiotensin II type 1 receptor is influenced by renin status and pharmacokinetics and pharmacokinetic-pharmacodynamic interactions. OBJECTIVE: To compare the pharmacokinetic-pharmacodynamic interactions of two doses of an ester prodrug of a noncompetitive angiotensin II type 1 receptor antagonist, candesartan cilexetil, at 8 and 16 mg, with those of the reference angiotenisn II type 1 receptor blocker, losartan, at the standard dose (50 mg), in a human model that controls renin status. DESIGN AND METHODS: In a double-blind placebo-controlled crossover study, we compared the effects on renin and mean blood pressure over 24 h of single oral doses of candesartan cilexetil at 8 and 16 mg and losartan at 50 mg in 16 sodium-depleted normotensive subjects. RESULTS: The area under the curve (0-24 h) for plasma active renin did not differ significantly between 8 mg candesartan cilexetil and 50 mg losartan, but was significantly higher for 16 than for 8 mg candesartan cilexetil or for 50 mg losartan. The area under the curve (0-24 h) for the fall in mean blood pressure with 16 mg candesartan cilexetil (-197 +/- 96 mmHg/h) was significantly greater than that for placebo (-112 +/- 81 mmHg/h; P< 0.05) but the difference was not statistically significant compared with either 8 mg candesartan cilexetil (-158 +/- 95 mmHg/h) or 50 mg losartan (-144 +/- 66 mmHg/h). The area under the curve (0-24 h) for the fall in mean blood pressure did not significantly differ between 8 mg candesartan cilexetil, 50 mg losartan and placebo. The area under the curve (0-24 h) for plasma active renin was significantly correlated to that for plasma levels of the active metabolite of losartan, EXP 3174 (r = 0.65, n = 16, P< 0.01). No such correlation was detected for each single dose of candesartan cilexetil but a dose-response relationship was present when both doses were combined. CONCLUSIONS: The pharmacodynamic effects of a single oral dose of 16 mg candesartan cilexetil are greater than those of 50 mg losartan and 8 mg candesartan cilexetil. The variability in the pharmacokinetic-pharmacodynamic interaction is less pronounced for candesartan than for EXP 3174, which could result in reduced variability of the blood pressure effects in patients.

Crossover design for the dose determination of an angiotensin converting enzyme inhibitor in hypertension.

In order to determine the dose regimen of new antihypertensive compounds, between-patient trials are usually performed. However, the combined use of a crossover design and a precise methodology to measure blood pressure (BP) and biological effects can provide relevant data with a minimal number of patients, if there is no carryover effect which invalidates the experiment. Such goals were successfully achieved with just 25 hypertensive patients who were randomly allocated in double-blind fashion every 2 weeks to a new angiotensin converting enzyme (ACE) inhibitor, benazepril [10 mg once a day (o.d.), 20 mg o.d., 10 mg twice a day (b.i.d.) and 20 mg b.i.d.], or a placebo. The mean BP fall [systolic (SBP)/diastolic (DBP), measured in mmHg] just before drug intake was significantly greater with benazepril: -14/-9 (10 mg o.d.); -15/-8.5 (20 mg o.d.); -22.5/-14 (10 mg b.i.d.), and -21/-13 (20 mg b.i.d.) in comparison with placebo (-3/-3). Mean active plasma renin (measured in pg/ml), assessed by an immunoradiometric assay based on two monoclonal antibodies, increased significantly in a dose-dependent manner, by +0.7 (placebo), +15.0 (10 mg o.d.), +23.4 (20 mg o.d.), +44.4 (10 mg b.i.d.) and +78.8 (20 mg b.i.d.), whereas plasma ACE decreased (by 67 and 78% after 10 and 20 mg o.d., respectively, and by 91-92% after 10 and 20 mg b.i.d.). In the clinical development of an antihypertensive drug, the earlier use of such within-patient studies, with the random insertion of one placebo period between the active periods, should help in the dose-response curve search.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporine-induced stimulation of the renin-angiotensin system after liver and heart transplantation.

To analyze the status of the renin-angiotensin system in hypertensive transplant recipients on cyclosporine, we prospectively explored 21 cardiac (CTR: 52 +/- 8.2 yr) and 12 liver (LTR: 45 +/- 10 yr) transplant recipients on a normal salt diet with 19 normotensive controls in the same age range. Systolic and diastolic blood pressure was measured in the supine and standing positions. Renal function was assessed by serum creatinine values, and 24-hr urinary sodium and potassium excretion were recorded. Plasma renin activity (PRA), active renin, total renin, angiotensinogen, aldosterone, and cortisol plasma levels were simultaneously determined. Results were expressed as mean +/- SD, and between-group differences were compared using variance analysis. Supine blood pressure (+/- SD) was 158 +/- 15/103 +/- 8.4 in CTR and 155 +/- 21.4/102 +/- 11.7 mmHg in LTR. Serum creatinine was higher in CTR (159 +/- 52 mumol/L) than in LTR (117 +/- 24.7, P < 0.05) and values in both groups were above controls (83 +/- 14.1, P < 0.05). Urinary sodium excretion tended to be lower in transplant recipients (59 +/- 42 mmol/L) for CTR and 44 +/- 36.7 in LTR than in healthy controls (117 +/- 24.7 mmol/L). Supine and upright PRA values tended to be higher in hypertensive transplant recipients than in healthy volunteers, although not significantly. Supine active renin was significantly higher in CTR (47 +/- 42 pg/ml) and in LTR (44 +/- 29.8 pg/ml) than in normal subjects (17 +/- 4.8 pg/ml, P < 0.05). Total renin levels in CTR (supine: 716 +/- 357 pg/ml) and in LTR (supine: 647 +/- 365 pg/ml) were 3- to 4-fold higher than in controls (supine: 207 +/- 69 pg/ml) (P < 0.05), as were inactive renin levels (P < 0.01). Active renin was effectively correlated with PRA (P < 0.001) and with total renin (P < 0.001) in the supine and in the upright position. Plasma aldosterone was almost within the normal range in CTR and in LTR, and it did not correlate with PRA values. Plasma angiotensinogen levels were normal in LTR (1032 +/- 226 ng/ml) but were significantly lower in CTR (938 +/- 216 ng/ml, P < 0.05). Cortisol plasma levels were lower in both CTR (7 +/- 4.4 micrograms/L) and LTR (6 +/- 1.9 micrograms/L) than in healthy controls (11 +/- 4 micrograms/L, P < 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

Genetic determination of plasma aldosterone levels in essential hypertension.

The renin-angiotensin-aldosterone system plays an important role in large artery structure and blood pressure homeostasis. Among the genes coding for different components of this system, the aldosterone synthase (CYP11B2) gene could play an important role, but has been less investigated. We examined the role of two variations of the aldosterone synthase gene (CYP11B2), one located in the promoter of the gene, T-344C, the other in the 7th exon, the T4986C (Val/Ala), on plasma levels of renin and aldosterone, blood pressure, and arterial stiffness in subjects with essential hypertension. Subjects of European origin (n = 216) were examined during a 1-day hospitalization. Treatment, if any, was interrupted for at least 21 days before. Arterial stiffness was evaluated by measuring pulse wave velocity. Renin and aldosterone levels were evaluated by using a radioimmunoassay. The two polymorphisms were in complete linkage disequilibrium, as suggested by the presence of only three haplotypes in this population (T-344T4986, T-344C4986, and C-344T4986). The mean age and blood pressure values were similar in the different genotypes. Presence of the -344C allele was associated with elevated levels of plasma aldosterone: 90 +/- 8 pg/mL for TT (n = 67), 110 +/- 6 pg/mL for TC (n = 107), and 129 +/- 10 pg/mL for CC (n = 42) (test of codominant effect, P < .002 after adjustment for age and 24-h Na+ urine excretion). Pulse wave velocity was also increased in the -344C allele carriers: 11.3 +/- 0.4 m/sec, 12.7 +/- 0.3 m/sec, 12.0 +/- 0.5 m/sec in the TT, TC, and CC genotypes, respectively. No association was found between the T4986C polymorphism and the studied variables. In patients with essential hypertension, a variant on the promoter region of the aldosterone synthase gene is associated with significant differences in plasma aldosterone levels and arterial stiffness. These differences are not associated with variations in blood pressure levels.

Plasma angiotensins, renin, and blood pressure during acute renin inhibition by CGP 38 560A in hypertensive patients.

The new renin inhibitor CGP 38560A has been shown to block angiotensin (ANG) production in healthy volunteers. In order to determine its potential antihypertensive effect, the compound was administered in a 30-min infusion, in 12 hypertensive patients (mean blood pressure (BP): 112.8 +/- 3.5 mm Hg). These patients were selected for their sensitivity to captopril: a single oral dose of 50 mg captopril lowered their mean BP by 8.8 +/- 2.2 mm Hg after 30 min and by 15.3 +/- 1.5 mm Hg after 90 min. At the end of the renin inhibitor infusion, mean blood pressure decreased by 5.7 +/- 2.2 mm Hg in the six patients infused with the dose of 0.125 mg/kg and by 6.0 +/- 1.8 mm Hg in the six patients infused with 0.250 mg/kg. The fall in blood pressure was correlated to the initial plasma renin activity (PRA) (r = 0.61, P less than .05). A dose-dependent effect was observed on plasma ANG I which fell by 74% with 0.125 mg/kg and by 94% with 0.250 mg/kg. Identical falls were found for plasma ANG II (72% and 94%, respectively) and ANG I and ANG II were well correlated (r = 0.91, P less than .001). The fall in BP was correlated to the fall in plasma ANG I (r = 0.77, P less than .01). The time-course of the BP changes was parallel to the changes in plasma angiotensins, as were the slightly delayed rise and fall in active renin measured by a direct immunoradiometric assay. When measured by the conventional ANG I radioimmunoassay, PRA values indicated a long-lasting inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)