The acute and 24-hour modifications to the atrial natriuretic factor in patients who have undergone mitral valvuloplasty. The hemodynamic and echocardiographic correlations

BACKGROUND: The recent introduction of percutaneous transvenous mitral valvuloplasty (PTMV) for the treatment of mitral stenosis (MS) has provided a unique human model for the study of short-term changes in ANF secretion before and after a reduction in left atrial pressure. This study was designed to investigate the effect of a short-term reduction in left atrial pressure and volume, as determined by echocardiographic study, on ANF and other neurohumoral factor plasma levels (renin and aldosterone). MATERIALS AND METHODS: 10 patients in III FC NYHA, with normal sinus rhythm and MS underwent PTMV. Hemodynamic parameters were measured immediately before and after (20-30 minutes) PTMV. Plasma levels of ANF, aldosterone and plasma renin activity (PRA) were obtained before (24 h) and after (2 h and 24 h) valvuloplasty; echocardiographic left atrial size before (24 h) and 24 h after PTMV. RESULTS: Immediately after PTMV mean left atrial (LA) pressure decreased from 22.3 +/- 6.8 mmHg to 10.0 +/- 2.4 mmHg (p < 0.01); mitral valve area (MVA) increased from 0.99 +/- 0.28 cm2 to 2.17 +/- 0.26 cm2 (p < 0.01). 24 hours after PTMV on echocardiography, LA systolic volume decreased from 59.5 +/- 16.9 cm3 to 42.3 +/- 8.3 cm3 (p < 0.01), LA diastolic volume from 82.6 +/- 15.8 cm3 to 66.5 +/- 12.6 cm3 (p < 0.01), and LA diameter from 48.1 +/- 7.5 mm to 39.2 +/- 4.4 mm (p < 0.01). ANF plasma levels before PTMV were 64.0 +/- 36.9 fmol/ml; 2 and 24 hours after PTMV they fell to 34.2 +/- 21.6 fmol/ml (p < 0.01) and to 20.3 +/- 21.0 fmol/ml (p < 0.01), respectively. PRA values were 15.7 +/- 13.2 ng/ml/h before PTMV; 2 and 24 hours after PTMV they increased to 17.5 +/- 23.2 ng/ml/h (NS) and to 22.3 +/- 16.8 ng/ml/h (p < 0.01). The aldosterone plasma levels were 43.2 +/- 27.9 ng/dl before PTMV and 47.3 +/- 35.8 ng/dl (NS) and 45.3 +/- 28.0 ng/dl (NS) 2 and 24 hours after PTMV. CONCLUSIONS: These results indicate that LA "de-stretching" due to the MVA increase and LA pressure decrease, leads to an abrupt reduction of ANF secretion. According to other studies, PRA increases immediately after PTMV, with a further increase 24 hours after PTMV.     

Effect of sodium restriction and angiotensin II infusion in Bartter's syndrome

Five patients with Bartter's syndrome were investigated. Sodium restriction (less than 10 mEq/day for at least 5 days) showed a renal sodium wastage in only two patients (I and II) in spite of increased aldosterone secretion rate (from 151-427 to 680-842 mug/day). The effect of angiotensin II (A II) 80ng/kg/min for 30-180 min, on plasma renin activity (PRA), plasma aldosterone, and urinary sodium excretion was compared with the effect of a previous infusion of 5% dextrose given at the same rate, 0.5 ml/min for 1 hr. A II infusion resulted in increased plasma aldosterone levels: from 236-330 pg/ml to 800-881 pg/ml in 30 min. This increase was also observed in patient II (from 139 to 600 pg/ml). PRA was decreased by A II infusion (from 1,142-2,462 to 121-1,625 ng/liter/min). In patient IV, this decrease in PRA was also observed when he was on a salt-restricted diet (from 1,934 to 370 ng/liter/min); but the minimal PRA was still higher (370 ng/liter/min) than with a normal diet (121 ng/liter/min). In no case could normal PRA level be obtained. A II infusion induced an increase in urinary sodium excretion only in the two patients with renal sodium wastage (from 80-90 to 265-230 muEq/min in 30 min). Urinary sodium excretion decreased in the other patients from (37.5-213 to 4.30-46 muEq/min) and fractional sodium excretion was reduced in patient V (from 0.56% to 0.45% at 30 min and to 0.29% at 120 min). No significant change with A II infusion was observed in patient IV when he was on a sodium-restricted diet (from 1 to 2.5 muEq/min in 30 min). Urinary potassium excretion was similar to sodium excretion. No change was observed in plasma potassium and sodium.     

Comparison of amlodipine and quinapril on ambulatory blood pressure and platelet function in hypertension

The effect of calcium channel blocker (CCB), amlodipine (5-10 mg/day) and angiotensin-converting enzyme (ACE) inhibitor, quinapril (10-40 mg/day) on ambulatory blood pressure (ABP), rheological and platelet function in hypertension were compared in this randomised double-blind placebo-controlled cross-over study. This study was preceded by 4 weeks placebo run-in period and the total duration of the study was 28 weeks. Casual and 24 h ABP, plasma renin activity (PRA) and plasma aldosterone (PA) concentration as well as metabolic and platelet function were determined before and at the end of each drug therapy. A total of 27 patients completed this study. Casual BP was significantly reduced after amlodipine or quinapril treatment, but there was no change in heart rate. Regarding the 24 h ABP, amlodipine produced a fall from 145 +/- 8/94 +/- 7 to 130 +/- 13/85 +/- 10 mm Hg (P < 0.001 for both SBP and DBP). Quinapril also caused a reduction from 144 +/- 10/94 +/- 7 to 134 +/- 12/88 +/- 8 mm Hg (P < 0.001 for both SBP and DBP). Neither amlodipine nor quinapril produce any significant change in heart rate. The level of 6-keto-prostaglandin Fl alpha (6-Keto-PGFl alpha) was increased from 36.8 +/- 4.4 to 45.1 +/- 2.5 pg/ml (P < 0.05) and no significant change of thromboxane B2(TXB2) was noted after amlodipine treatment. PRA was increased from 1.24 +/- 0.31 to 1.62 +/- 0.41 ng/ml/h (P < 0.05) after quinapril treatment. Other biochemical parameters were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Aldosterone precursors and hypertension with hypokalemia and adrenal module non caused by primary hyperaldosteronism

The purpose of the study was to evaluate the interest of aldosterone precursors assays in arterial hypertension with hypokaliemia and adrenal nodules non due to aldosterone. Seven hypertensive patients, 3 men and 4 women, aged 59.5 +/- 10.1 years were included in the study. After drug withdrawal, kaliemia was 3.1 +/- 0.3 mmol/l (2.7-3.6), active renin 2.9 +/- 1.4 ng/l, plasma aldosterone (aldo) 108 +/- 49.4 pg/ml, cortisol 13 +/- 3.1 micrograms/100 ml, and [S] 0.47 +/- 0.5 micrograms/100 ml. Adrenal CT scan showed an adenoma in 3 patients (30.5 +/- 5 mm) and an unilateral nodular hyperplasia in 4 patients. In all patients, the plasma levels (RIA, chomatographic step) of the following steroids in the mineralocorticoid (MC) pathway were determined: DOC, 18 OH-DOC, B, 18 OH-B and aldosterone. Two from 7 (28%) exerted aldosterone precursors excess, 1 with DOC-producing adenoma (DOC-PA) (table), and 1 with a partial 11 beta hydroxylase deficiency (DOC: 211 pg/ml; S: 1 mu/100 ml). Aldosterone/DOC + 18 OH-DOC ratio proposed as a malignancy index was decreased in the patient with DOC-PA (8.1). No dysfunction in the MC pathway was identified in the 5 other patients. [table: see text] The study suggests the relevance of aldosterone precursors assays in low renin hypertension non due to aldosterone and in incidentally discovered adrenal masses.     

Molecular analysis of the histone gene cluster of Psammechinus miliaris: III. Polarity and asymmetry of the histone-coding sequences

The Ca2+ antagonistic coronary vasodilator, Nifedipine, was sublingually administered by a dose of 30 mg to 19 patients with hypertension. Blood pressure of patients with with essential hypertension (n=14) decreased from 177 +/- 24 to 123 +/- 13 mmHg systolic and from 108 +/- 12 to 80 +/- 11 mmHg diastolic (mean +/- SD) (p less than 0.01). Plasma renin activity (PRA) increased significantly from 0.73 +/- 0.62 to 1.50 +/- 1.02 ng/ml/h (p less than 0.05). The same tendency was observed in malignant and renovascular hypertension. In primary aldosteronism (n = 2), blood pressure decreased but PRA did not increase. Hypotensive action and increased plasma renin activity by Ca2+ antagonist, Nifedipine, were clearly demonstrated in patients with hypertension.     

Effect of administered potassium on the renin-aldosterone axis in young blacks compared with whites

BACKGROUND: We had observed previously that the aldosterone excretion rate and plasma aldosterone concentration were lower for black children than they were for white children. We did not know whether this was secondary to a lower intake of potassium or to suppression of the renin-angiotensin system in blacks. OBJECTIVE: To test the hypothesis that the secretion of aldosterone in response to potassium would be different in blacks than in a control group of whites. DESIGN: Black and white subjects were selected on the basis of their having aldosterone excretion rates that were in the lowest quartile for the entire original cohort. Since the blacks typically had lower aldosterone excretion rates than did the whites, the black participants were represented primarily by those with average rates of aldosterone production among blacks, whereas the whites were represented by those with the lowest aldosterone production rates among whites. The protocol consisted of a placebo-controlled, randomized cross-over study design. METHODS: Twelve blacks and 12 whites, aged 14.1 +/- 1.6 (mean +/- SD) and 15.4 +/- 2.1 years, respectively, were allocated randomly to double-blind treatment either with placebo or with 40 mmol/day potassium chloride for 7 days and then the alternate treatment Measurements of the plasma renin activity (PRA), plasma aldosterone concentration, and urinary aldosterone excretion were performed in an inpatient research unit at the end of the treatment. The blood pressure was monitored for 24 h. RESULTS: Treatment with potassium increased the plasma aldosterone concentration (P = 0.0006) and the urinary excretion of aldosterone (P = 0.0002) significantly both for blacks and for whites. There was no significant racial difference in the response to potassium. The PRA was overall 1.605-fold lower in the blacks than it was in the whites (P = 0.0124). The lowest PRA levels, such as those in the blacks when they were supine, tended to be increased with the potassium treatment. The blood pressure did not change significantly with the potassium supplement for either racial group. CONCLUSIONS: After we had supplemented the intake of potassium, aldosterone production increased in the blacks and in the control group of whites to the same extent The potassium treatment appeared to increase lower PRA levels. A lower intake of potassium could at least partially account for the suppression of the renin-aldosterone system in blacks.     

T235 variant of the angiotensinogen gene and blood pressure in the Chilean population

BACKGROUND: The angiotensinogen gene has recently been linked to essential hypertension. A variant within this gene, encoding threonine rather than methionine at amino acid position 235, was associated with essential hypertension. However, results of new studies have not confirmed this association, suggesting that ethnic differences may explain the different results. OBJECTIVE: To evaluate whether the T235 variant is associated with a higher incidence of essential hypertension among Hispanics (a group that has scarcely been evaluated) and to determine whether T235 is associated with variations in the plasma renin activity or the serum aldosterone level. PATIENTS AND METHOD: We studied 64 patients with essential hypertension and 62 normotensives, matched for age and sex. We obtained samples for determinations of plasma renin activity, serum aldosterone level and genome DNA from all subjects. The genomic DNA was amplified using the polymerase chain reaction technique and digested by the restriction enzyme streptococcus faecalis (Sfa NI) which cuts M235 only, not T235. RESULTS: The patients with essential hypertension had a higher prevalence of the risk variant T235 (alleles 77/128 = 60.2%) than did the normotensive controls (alleles 65/124 = 52.4%), but the difference was not statistically significant (chi2=1.53, P=0.22). The plasma renin activity levels in hypertensives were not statistically different for homozygous T235, heterozygous and homozygous M235 (1.0 +/- 0.96, 2.0 +/- 2.25 and 1.55 +/- 1.49 ng/ml per h, respectively, P=0.5 1). However, when we considered those hypertensives with low plasma renin activity levels (< 1 ng/ml per h), we found a high prevalence (72.7%) of subjects homozygous for the T235 variant. We found no association between the T235 variant and the serum aldosterone levels in hypertensive and normotensive subjects. CONCLUSIONS: We demonstrated that there is a high prevalence of T235 variant in our Hispanic population. The slight difference between prevalences of T235 variant among hypertensive and normotensive subjects that we found was not statistically significant and did not permit us to establish an association between T235 variant and essential hypertension. We believe that only studying a larger cohort of subjects could show whether there is a quantitative effect of the T allele on plasma renin activity levels.     

Lack of effect of captopril on glomerular hyperfiltration in normoalbuminuric normotensive insulin-dependent diabetic patients

The aim of the present study was to evaluate the effects of captopril on the glomerular filtration rate (GFR) and urinary albumin excretion rate (UAER) of normoalbuminuric normotensive insulin-dependent diabetes mellitus (IDDM) patients with and without glomerular hyperfiltration. Eleven normoalbuminuric (UAER < 30 micrograms/min) patients (age: 34.3 +/- 4.6 years: diabetes duration: 9.5 +/- 6.4 years) participated in the study. Six patients were considered to be hyperfiltering (GFR > or = 134 ml/min/ 1.73m2). GFR (51Cr-EDTA single injection technique), extracellular volume (ECV; distribution volume of 51Cr-EDTA), UAER (RIA) and metabolic and biochemical parameters were measured at baseline, after 6 weeks on captopril (25 mg p.o. twice daily) and after 6 weeks off captopril. Plasma renin activity (PRA; RIA), plasma aldosterone (RIA) and blood volume (51Cr red cell labeled) were measured at baseline and after 6 weeks on captopril. The baseline clinical and laboratory characteristics of hyperfiltering and normofiltering IDDM patients were similar. GFR did not change during the study (144.1 +/- 28.8; 139.7 +/- 21.8; 132.8 +/- 29.9 ml/min/1.73 m2) either in patients with hyperfiltration (164.6 +/- 20.7; 153.8 +/- 18.3; 148.6 +/- 31.0 ml/min/1.73 m2; n = 6) or without hyperfiltration (119.6 +/- 11.1; 123.2 +/- 11.9; 113.8 +/- 14.4 ml/min/1.73 m2; n = 5). Also, ECV (22.2 +/- 3.6; 21.5 +/- 4.3; 21.5 +/- 3.5 L/1.73 m2), UAER (3.9 [0.4-22.1]; 4.0 [0.2-11.4]; 3.7 [2.0-26.2] micrograms/min), systolic (112 +/- 13; 105 +/- 10; 111 +/- 11 mmHg) and diastolic (76 +/- 12; 72 +/- 9; 73 +/- 12 mmHg) blood pressure did not change. No difference in blood volume (60.8 +/- 10.4; 62.3 +/- 8.4 ml/kg) or plasma aldosterone (10.4 +/- 4.9; 7.7 +/- 3.8 ng/dl) was observed between baseline values and values after captopril use. PRA increased (2.4 [0.4-22.1]; 12.9 [2.2-41.1]ng/ml/h) at the end of 6 weeks on captopril (P = 0.002). Fasting plasma glucose, glycated hemoglobin, fructosamine, plasma cholesterol and potassium, 24 h urinary urea and sodium were similar during the study. These results were unchanged when patients with and without hyperfiltration were analyzed as separate groups. From baseline to the end of 6 weeks on captopril there was no correlation between change in GFR and change in glycated hemoglobin (r = 0.02, P = 0.96), systolic (r = 0.23; P = 0.49) and diastolic (r = -0.32, P = 0.32) blood pressure, urinary urea (r = 0.21; P = 0.53) and UAER (r = -0.16; P = 1.00). In conclusion, captopril has no effect on the GFR and UAER of normoalbuminuric normotensive IDDM patients irrespective of the presence of glomerular hyperfiltration.     

Increased plasma endothelin concentration in atherosclerotic renovascular hypertension

The aim was to investigate circulating levels of immunoreactive endothelin (ir-ET) in atherosclerotic renovascular hypertension (RVH), and to assess the role of the kidneys in its overall plasma concentration. We studied 16 hypertensive patients with renal artery stenosis evidenced by angiography and admitted to hospital for the diagnostic evaluation of RVH by renal vein plasma renin activity (PRA) determinations. The right femoral vein was catheterized to simultaneously measure PRA and ir-ET in both renal veins and inferior vena cava below the origin of the renal veins. RVH was present in 9 patients as indicated by diagnostic PRA renal vein ratios and the remaining 7 patients were considered to have essential hypertension (EH). Patients with RVH showed a marked increase in systemic plasma ir-ET concentration (10.3 +/- 0.9 pg/ml). Despite a significant increase of PRA in the vein of the ischemic (IK) versus the contralateral (CK) kidney in patients with RVH, no significant differences in ir-ET concentration were observed between both kidneys. These results indicate that patients with RVH have increased circulating levels of ir-ET. However, the higher systemic plasma ir-ET do not arise from the renal circulation, since plasma ir-ET is significantly higher in systemic circulation than in renal veins.     

Comparative study of the effects of ouabain and digoxin on blood pressure of rats

OBJECTIVE: To compare the effect of ouabain on the blood pressure of rats with that of digoxin to find the evidences of the relationship between endogenous ouabain (EO) and development of hypertension. METHODS: Sprague-Dawley rats, which were divided into 3 groups, were infused with ouabain (23 x 75 micrograms.kg-1/day, i.p.), digoxin (36 x 84 micrograms.kg-1/day, i.p.) and normal saline (NS) once a day respectively. Systolic blood pressure and body weight were recorded weekly. Five weeks later, rats of ouabain group were randomly assigned to three infusion subgroups: Oc group, continued with ouabain infusion; Od group, added digoxin (73 x 68 micrograms.kg-1/day, i.p.) and Os group, stopped administration of ouabain. Another week later, direct blood pressure was recorded in aorta. Systolic and diastolic cardiac function, plasma renin activity and aldosterone levels of all the rats were measured. RESULTS: After a latent period of one week, blood pressure of Ouabain group increased significantly [95.4 +/- 11.8 mmHg (1 mmHg = 0.133 kPa) at the beginning of the experiment vs 122.5 +/- 16.9 mmHg at the end of week 6, P < 0.05] with normal plasma renin activity and higher aldosterone (1.28 +/- 0.45 ng/ml vs 0.69 +/- 0.27 ng/ml, P < 0.05). The blood pressure decreased after either withdrawal of ouabain or addition of digoxin (116.3 +/- 14.4 mmHg vs 100 +/- 10.7 mmHg, P < 0.05; 123.9 +/- 13.9 vs 103.3 +/- 10.5 mmHg, P < 0.05, respectively). No difference of blood pressure was found between the digoxin and NS group. CONCLUSIONS: Our results suggested that EO might be one of the causes of the development of hypertension. Aldosterone might play some role in the mechanism of ouabain-induced hypertension. Digoxin can not induce hypertension. There is a great difference between the effect of ouabain and digoxin on the blood pressure. Moreover, digoxin can reverse the hypertension induced by ouabain.     

Hypertension treatable with glucocorticoids: report of a case

Lately, a series of hypertensive syndromes of unknown etiology that respond to new forms of therapy, have been described. One of these is glucocorticoid remediable hypertension, that evolves with suppressed plasma renin activity and normal or high serum aldosterone levels, that lead to an aldosterone/plasma renin activity ratio over 30. We report a 45 years old woman with a severe hypertension, despite the use of antihypertensive medications. She had a plasma renin activity of less than 0.3 ng/ml/h, normal serum aldosterone levels (10 ng/ml) and thus a high aldosterone/plasma renin activity ratio. She had normal serum potassium and sodium levels. Due to the bad results of conventional antihypertensive medications, a treatment with dexamethasone was started, that normalized blood pressure and allowed to discontinue other antihypertensive medications. This type of hypertension must be sought since non conventional treatments could be used for refractory hypertensive syndromes.     

Accidental intake of tritiated water: a cytogenetic follow-up case on translocation stability and dose reconstruction

OBJECTIVE: To evaluate the renin-aldosterone system and insulin secretion in hyperparathyroidism and their effects on blood pressure regulation. DESIGN: Studies were carried out on patients with primary hyperparathyroidism (PHPT) prior to and following removal of the parathyroid tumor. METHODS: Sixteen normotensive and euglycemic patients with PHPT were studied. The following parameters were measured: basal and stimulated plasma renin activity (PRA) and aldosterone (ALD) secretion: parathormone (PTH) and serum electrolytes. Insulin and glucose levels were measured during an oral glucose tolerance test. RESULTS: Systolic but not diastolic blood pressure showed a decrease following surgery, from 123.3+/-13.0/80+/-8.6 to 116.7+/-13.5/77.3+/-8.8 mmHg. The decrease in the systolic pressure was not clinically significant. After surgery, both the basal and stimulated PRA and ALD values decreased, and the preoperative pathological values returned to normal: PRA basal: 1.79 --> 0.70 ng/ml/h, P=0.0049; PRA stimulated: 7.76 --> 1.90 ng/ml/h, P=0.0031; ALD basal: 111.5 --> 73.0 pg/ml, P=0.0258; ALD stimulated: 392.5 --> 236.0 pg/ml, P=0.0157. The postoperative decrease in the PRA correlated with the changes in PTH levels (r=0.5442, P < 0.05, n=16) but did not correlate with the changes in serum calcium concentrations. Both the fasting and stimulated insulin levels decreased after surgery but remained within the normal range: insulin fasting: 10.2 --> 5.0 mIU/l, P=0.0218; insulin area under the curve: 5555 --> 3296 mIU/l*min, P=0.0218. There was no correlation between the changes in insulin levels and PTH or ion levels. Sodium, potassium and blood glucose levels remained unaffected by parathyroid surgery. CONCLUSIONS: In a population of normotensive hyperparathyroid patients an increased activity of the renin-aldosterone system related to PTH was found and surgery resulted in a small and insignificant decrease in blood pressure. This change was accompanied by a significant decrease in the activity of the renin-aldosterone system indicating the role of the renin-aldosterone system in the regulation of blood pressure in PHPT. Both fasting and stimulated insulin values decreased following removal of the parathyroid tumor, but with no individual correlation with PTH and calcium levels.     

Bovine serum albumin and lysophosphatidic acid stimulate calcium mobilization and reversal of cAMP-induced stellation in rat spinal cord astrocytes

We conducted studies in conscious chronically catheterized, trained young (3-5 months) and old (18-20 months) rats to assess the impact of aging on baseline renin activity (PRA) and metabolic clearance rate (MCR) of angiotensin II (ANG II). We observed that under unstressed conditions the baseline values of PRA and plasma ANG II were no different in young versus old rats (1.8 +/- 0.2 versus 1.5 +/- 0.2 ng Al/ml/h and 18 +/- 3 versus 15 +/- 2 fmol/ml, respectively). Values of PRA in the present study were similar to those reported by others for old rats, but our young rat values were lower than usually reported. This probably reflects our use of an unstressed preparation. We also observed a blunted increase in PRA in old rats in response to acute converting enzyme inhibition. Overall, our observations suggest that old rats may lose their ability to increase PRA in response to acute stimuli, including perhaps, the stress of blood drawing in emotionally or surgically stressed preparations. We also observed that the MCR of ANG II increased with age, despite similar baseline plasma ANG II concentrations in young and old. This suggests that with aging, an increase occurs in the rate of synthesis of ANG II. These results emphasize the importance of establishing true baseline values for indices of the renin-ANG II system in aging.     

Role of cyclic GMP-inhibitable phosphodiesterase and nitric oxide in the beta adrenoceptor control of renin secretion

We have reported that inhibition of nitric oxide synthesis with N(G)-nitro-L-arginine methyl ester (L-NAME) attenuates the renin secretory response to beta adrenoceptor stimulation. We proposed that the attenuation results from disinhibition of the cyclic GMP-inhibitable isoform of phosphodiesterase (PDE III) with a resultant increase in cyclic AMP hydrolysis in the juxtaglomerular cells. In our investigation, experiments were performed in conscious rabbits to test the effects of the specific PDE III inhibitor milrinone on resting renin secretion and on the renin responses to isoproterenol and L-NAME. In the first series of experiments, infusion of milrinone increased plasma renin activity from 5.4 +/- 0.6 to 10.2 +/- 1.4 ng/ml/2 hr (P < .01). Heart rate increased markedly, but arterial pressure did not change. In the second series, infusion of isoproterenol increased plasma renin activity from 6.3 +/- 1.1 to 15.0 +/- 1.0 ng/ml/2 hr (P < .01). The renin response to isoproterenol was increased (P < .01) in the presence of milrinone (15.3 +/- 3.7 to 38.4 +/- 6.2 ng/ml/2 hr, P < .01). In the third series, L-NAME alone decreased plasma renin activity from 5.0 +/- 1.0 to 3.3 +/- 1.0 ng/ml/2 hr (P < .01). Milrinone again increased plasma renin activity and prevented the suppression of plasma renin activity by L-NAME. By contrast, milrinone did not alter the suppression of plasma renin activity produced by infusion of phenylephrine. In addition, a PDE IV inhibitor failed to prevent the suppression of PRA by L-NAME. Finally, administration of milrinone completely reversed the L-NAME-induced suppression of the renin response to isoproterenol. These results provide evidence that PDE III participates in the regulation of renin secretion, and support the proposal that the L-NAME-induced reductions in renin secretion and in the renin response to beta adrenoceptor stimulation result from disinhibition of PDE III and increased hydrolysis of cyclic AMP in the juxtaglomerular cells.     

Heparin-induced hyperkalemia in chronic hemodialysis patients: comparison of low molecular weight and unfractionated heparin

Aldosterone suppression and subsequent hyperkalemia are well described reversible side effects of prolonged treatment with heparin. This study was designed to examine whether the discontinuous use of heparin three times a week to prevent thrombosis formation during hemodialysis sessions could also induce hypoaldosteronism and might contribute to increased predialysis kalemia in hemodialysis patients. Two different heparinization regimens were prospectively compared in a crossover study of 11 chronic hemodialysis patients. During 2 consecutive weeks, the patients were dialyzed each week with either their usual doses of unfractionated heparin (UH) (6,160 IU +/- 1,350 IU) or low molecular weight heparin (LMWH) (15 anti-Xa activity [aXa] U/kg + 5 aXa U/kg/h). In all but 2 patients, the predialysis level of plasma K+ was higher with UH than with LMWH, and the mean value was higher (5.66+/-0.83 versus 5.15+/-0.68 mM, p = 0.01) while no differences in the predialysis plasma concentrations of creatinine, phosphate, urea, and bicarbonate were observed, excluding the potential role of differences in diet and dialysis efficacy in explaining the higher plasma K+ concentration with UH. The mean plasma aldosterone to plasma renin activity (pRA) ratio was higher with LMWH than with UH (149.54+/-123.1 versus 111.91+/-86.22 pg/ng/ h, p < 0.05). Individual plasma aldosterone values were found to be correlated to pRAs both during the UH period and the LMWH period, and the slope of the positive linear relation between plasma aldosterone and pRA was lower during the UH treatment period (63 versus 105 pg/ng/h). Finally, a negative linear correlation was found between the differences in individual predialysis plasma K+ observed during the 2 protocols and the differences in the corresponding plasma aldosterone levels, suggesting a link between the higher kalemia and the lower aldosterone responsiveness to angiotensin with unfractionated heparin. Although it cannot be concluded whether or not LMWH inhibits aldosterone synthesis, should LMWH decrease aldosterone production, this side effect is 33% less marked than that of UH so that the predialysis plasma K+ levels are 10% lower. This property makes LMWH use preferable to that of UH in patients with elevated predialysis kalemia.     

The importance of studying the renin-angiotensin-aldosterone system in essential arterial hypertension in clinical practice. Activity of the renin-angiotensin-aldosterone system during treatment of hypertension with ACE-inhibitors and beta blockers

The authors assessed in 20 subjects with mild or medium severe arterial hypertension basal and stimulated values of plasma renin activity (PRA) and aldosterone before onset of treatment and after 6-week therapy with enalapril (ENAP KRKA) or metoprolol (Vasocardin Slovakofarma). PRA and aldosterone secretion was stimulated by a vertical position and by administration of 40 mg furosemide by the i.v. This test proved suitable for assessment of secondary arterial hypertension in different forms of primary hyperaldosteronism and for expressing suspicion of renovascular hypertension and hypertension with affection of the renal arteries resp. Based on PRA levels, arterial hypertension can be divided into normorenin, high-renin and low-renin hypertension. This classification is, however, of no value for selection of treatment and the prognosis of hypertension. Each level of PRA can be associated with three different aldosterone levels. PRA and aldosterone did not correlate with urinary K, Na excretion nor with blood pressure. During treatment with ACE inhibitor PRA rose while basal as well as stimulated aldosterone levels declined. After administration of betablockers basal as well as stimulated PRA and aldosterone levels declined.     

Effect of atrial natriuretic hormone on hypertonic saline-induced suppression of the renin-aldosterone system

To evaluate the effect of physiologic doses of atrial natriuretic hormone (ANH) on hypertonic saline-induced renin-aldosterone system suppression, nine healthy subjects were studied three times: 1) on a low-salt (LS) diet with a 2 h placebo infusion; 2) on LS with 2 h infusion of human Ser-Tyr28 ANH (0.6 pmol/kg/min)(LS+ANH); and 3) on a high-salt (HS) diet with a 2 h placebo infusion. On each study day during the second hour of infusion, subjects also received 3% saline (0.1 mL/kg/min) infusion. Data from eight subjects were used for analysis because of a sampling error in one subject. During ANH infusion, plasma ANH levels increased about twofold and reached levels similar to ANH levels on HS. Serum sodium increased by 3-4 mEq/L, and serum osmolality increased by 7-8 mOsm/L during 3% saline infusion on all study days. ANH levels remained stable during 3% saline infusion. During the first hour of ANH infusion, plasma renin activity (PRA) decreased by about 24% and aldosterone levels by about 27%. Hypertonic saline caused further suppression of PRA and aldosterone. The extent of the suppression was similar under each condition, and the levels at the end of hypertonic saline infusion reached about 60% of the levels at the beginning of the saline infusion. We conclude that low-dose ANH infusion does not seem to have any major influence on PRA and aldosterone response to hypertonic saline.     

Plasma renin activity in patients with coronary arteriosclerosis with different types of hyperlipoproteinemia

The examination was conducted in 142 patients with coronary atherosclerosis, aged 33 to 74 years, and in 40 normal persons, aged 25 to 48 years. The pain form of the disease was observed in 96 patients, the arrhythmic one--in 38, the painless one--in 8 patients. The arterial pressure was within the normal limits in the examined patients. In 67.6% of the patients hypercholesterolemia was diagnosed, in 47.3%--hypertriglyceridemia. Type II hyperlipoproteinemia was found in 67.6% of the cases, types III and IV--in 5.3 and 9.1%, respectively, type V--in 0.5% of the patients; the type of hyperlipoproteinemia could not be identified in 10.6%, and in 6.9% of the cases the blood level of lipoproteins did not differ from the normal. The plasma renin activity examined by the radioimmunoassay in normals comprised 1.26 +/- 0.21 ng/ml/hour; in patients with the pain form of coronary atherosclerosis--6.67 +/- 0.72 ng/ml/hour; in those with arrhythmias--6.89 +/- 1.20 ng/ml/hour; in those with the painless form--2.39 +/- 1.02 ng/ml/hour. The highest renin activity was revealed in types IIa, IIb and III hyperlipoproteinemia, as well as in paroxysmal arrhythmia and cardiac fibrillation.     

Reversible metabolism of clozapine and clozapine N-oxide in schizophrenic patients

1. To characterize the interconversion process between clozapine and its metabolite clozapine N-oxide (CNO), eight healthy male schizophrenics were administered a single dose of clozapine or CNO in a randomized crossover manner. 2. Using a general pharmacokinetic model for the interconversion process, the mean total clearances of clozapine and CNO were 28.45 L/hr and 45.30 L/hr, respectively. These values were similar to the values obtained by the usual model-independent method of pharmacokinetic analysis. 3. When administered clozapine, mean CNO plasma concentrations of 17.7 +/- 16.4 ng/ml were slightly lower than the other clozapine metabolite-desmethylclozapine (DCLOZ) plasma levels of 24.4 +/- 8.6 ng/ml at the 12 hour time point. When CNO was administered, plasma concentrations at the 12 hour time point of clozapine were twice the amount of CNO (28.1 +/- 8.9 ng/ml vs 14.4 +/- 8.8 ng/ml). 4. DCLOZ plasma concentrations were detected in all patients upon clozapine administration. Upon CNO administration, only one patient had detectable plasma DCLOZ levels. 5. The interconversion process of clozapine and CNO could partially account for the wide interpatient variability reported for clozapine plasma concentrations in schizophrenic patients.     

Malignant hypertension in a patient with primary aldosteronism with elevated active renin concentration

A 40-year-old male, with a past history of hypertension but receiving no medical treatment, was referred. He manifested malignant hypertension (190/130 mmHg; Keith-Wagener III), renal dysfunction (serum creatinine, 3.8 mg/dl), and elevated plasma aldosterone (450 pg/ml) and active renin concentration (ARC, 104 pg/ml). His blood pressure was controlled with multiple antihypertensive agents and ARC thus decreased (4.3 pg/ml), but aldosterone remained elevated. Abdominal magnetic resonance imaging (MRI) revealed a right adrenal adenoma, and aldosterone-producing adenoma was confirmed by adrenal venous sampling. Primary aldosteronism very rarely develops to malignant hypertension, and even in that case ARC is suppressed. Therefore this is a rare case of primary aldosteronism complicated with malignant hypertension and high ARC.