Effects of captopril on prostaglandin and natriuresis in patients with essential hypertension.

The antihypertensive, renal and hormonal effects of captopril were studied in 10 patients with essential hypertension. Captopril significantly decreased arterial blood pressure with a concomitant increase in glomerular filtration rate, natriuresis and kaliuresis and a significant selective increase in urinary (renal) prostaglandin E2; other plasma and urinary prostaglandin (F2 alpha, 6-keto-prostaglandin F1 alpha; thromboxane B2) were not significantly changed. The urinary prostaglandin E2 increase was observed even in patients with pretreatment subnormal prostaglandin E2 excretion. Increases in urinary prostaglandin E2 were significantly positively correlated with increases in urinary sodium concentration. It is concluded that the antihypertensive effect of captopril is mediated, at least partially, by prostaglandin E2 release from renal and extrarenal tissues. Captopril enhances natriuresis at a lower perfusion pressure.

The influence of age on renal prostaglandin synthesis in man.

The purpose of our study was to determine influence of age on renal prostaglandin (PG) synthesis in man. Urinary prostaglandins 6-Keto-PGF1 alpha, TxB2, PGE2 and PGF2 alpha were measured in 45 normotensive subjects aged from 20-95 years. Urinary 6-Keto-PGF1 alpha excretion, reflecting mainly renal cortical prostacyclin synthesis, decreased significantly with age, while urinary TxB2 showed the opposite development. The ratio of urinary 6-Keto-PGF1 alpha/TxB2 decreased with age. PGE2 excretion was preserved in old subjects probably because the age-dependent decrease in renal function concerns mainly the cortex and spares the medulla. PGF2 alpha synthesis was least influenced by age. This age-dependent decrease in renal prostacyclin synthesis may play a role in the renal alterations of the elderly.

Effects of OKY-046 and nifedipine in cyclosporine-induced renal dysfunction in rats.

Cyclosporine (CsA) (37.4 mumol/kg per day for 7 days) treated female Wistar rats exhibited significantly decreased creatinine clearance (Ccr) and body weight loss (BWL), but had neither proteinuria (PU) nor alteration in their urine volume (V). Light microscopic (LM) sections of rat kidneys showed that all kidneys were affected by lesions, mainly diffuse vacuolization. These changes were associated with decreased urinary excretion ratios of 6-ketoprostaglandin F1 alpha to thromboxane B2 (6kPGF1 alpha/TXB2) and prostaglandin E2 to TXB2 (PGE2/TXB2). When OKY-046, a TXA2-synthetase inhibitor or nifedipine (NFD), a calcium channel blocker and an antagonist of endotheline (ET), were administered in addition to CsA, they restored Ccr and increased urine V but they did not prevent BWL. LM sections showed that only 5 or 7 out of 9 kidneys of animals were affected, respectively. These changes were associated with prevention of the diminished ratios of urinary PGE2/TXB2 and 6kPGF1 alpha/TXB2 mainly in the OKY-046 treated animals. In conclusion, our results suggest that inhibitors of TXA2 or antagonists and/or inhibitors of endothelin play a protective role in the development of the dysfunction induced by CsA. However, the protection observed using OKY-046 and NFD did not reach that obtained by evening primrose oil (EPO) or Ketanserine (KTS), substances which prevented the fall of Ccr and BWL. Furthermore, with these protective agents only 5 out of 9 kidneys were affected and the lesions were of minor importance.

The effect of high density lipoprotein subfractions on endothelial eicosanoid secretion.

Epidemiological, clinical, and experimental studies have demonstrated that high density lipoproteins (HDL) are protective against atherosclerosis. However, the respective influence of two main HDL subfractions (HDL2 and HDL3) on atherosclerosis process is not yet clear. The present study was designed to determine, which HDL subfraction was antiatherogenic in terms of eicosanoid release by human umbilical vein endothelial cells (HUVEC). Endothelial cells were incubated for 4 hours with HDL2 or HDL3 and prostaglandins 6-keto-PGF1alpha, thromboxane B2 and prostaglandin E2 were measured by RIA in culture supernatant. HDL2 has a dose dependent stimulatory effect on 6-keto-PGF1alpha release without stimulatory effect on thromboxane B2 secretion. The 6-keto-PGF1alpha/thromboxane B2 ratio increased progressively from 1.65 to 4.65 for 0.39 to 6.25 mg HDL protein/ml. The pattern of prostanoid secretion under influence of HDL3 showed a predominant response in 6-keto-PGF1alpha and TxB2 release. As regards PGE2, both HDL subfractions stimulated considerably secretion of this prostanoid in a dose dependent manner. In terms of PGI2/TxA2 balance the better antiatherogenic effect was observed with HDL2 subfraction.

Prostaglandins and hypertension in chronic renal diseases.

The role of prostaglandin A (PG A) in the pathogenesis of renal hypertension has been studied. The concentration of endogenous PG A was measured in the peripheral plasma by radioimmunoassay in patients with chronic renal disease and in control subjects. The mean plasma concentration of PG A1 equivalents was as follows: 1. normotensive healthy volunteers (n=23): 115 +/- 15 pg/ml 2. patients in terminal renal failure on regular hemodialysis a) anephric patients (n=6): 51+/- 21 pg/ml b) patients retaining their own kidneys, all but one with hypertension (n=9): 231 +/- 51 pg/ml (P less than 0.01 versus control) 3. patients with chronic renal disease a) with hypertension (n=7): 204 +/- 60 pg/ml (P less than 0.01 versus control) b) without hypertension (n=11): 136 +/- 30 pg/ml. Renal hypertension was associated with high levels of PG A in peripheral blood. This increase is probably a secondary adaptative mechanism for the excretion of a greater fraction of the glomerular filtrate at a lower blood pressure. PG A may represent a circulating "antihypertensive hormones".

[Reduction of kidney prostaglandin synthesis in patients with essential hypertension. Stimulating effect of cicletanine]. / Diminution de la synthèse rénale des prostaglandines chez l'hypertendu essentiel. Effet stimulateur du ciclétanine.

The purpose of this study was to evaluate the level of renal synthesis of vasodilator and natriuretic prostaglandins I2 and E2 in patients with essential hypertension and to test the effect of cicletanine, a new antihypertensive drug, on the renal synthesis of these prostanoids in hypertensive patients. The first part of the study was carried out in 12 healthy normotensive subjects and in 25 patients of both sexes with essential hypertension. The effect of cicletanine administered in dose of 150 mg was assessed in 10 healthy volunteers and 12 hypertensive patients. The urinary levels of prostaglandins 6-keto-PGF1 alpha (a metabolite of prostacyclin PGI2) and PGE2 were measured (HPLC) by radioimmunoassay after extraction and chromatographic separation. In normal subjects the urinary excretion rate of 6-keto-PGF1 alpha was 134 +/- 26 pg/min and that of PGE2 was 180 +/- 25 pg/min. The corresponding values were significantly lower in hypertensive patients. This defect of PGI2 and PGE2 renal synthesis was found in 64 p. 100 and 72 p. 100 respectively of patients with hypertension. Cicletanine increased the urinary excretion of 6-keto-PGF1 alpha by 45 p. 100 and that of PGE2 by 59 p. 100 in hypertensive patients. It also brought to normal limits the secretion of these prostanoids in these subjects. At the dose of 150 mg the drug stimulated natriuresis significantly and increased glomerular filtration in patients with essential hypertension. This renal effect of cicletanine was acutely reduced by the presence of indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)

[Prostaglandins in renovascular arterial hypertension]. / Les prostaglandines dans l'hypertension artérielle réno-vasculaire.

Prostaglandins (PG) A1, B1, E2, F2 alpha and plasma renin activity (PRA) were measured by radioimmunoassay in 8 patients with unilateral artery stenosis, 7 hypertensive patients with unilateral renal atrophy without stenosis ans 20 controls. The measurement of the PG and PRA in the hypertensive group was performed in the infra-renal inferior vena cava and in the two renal veins. PRA and PGA1 were significantly raised in the renovascular hypertensive patients but no significant change was observed in the group with unilateral renal atrophy. On the other hand, the PGE2 and PGF2 alpha were raised in both groups, especially in the renal veins on the stenosed or atrophic side. There was a positive significant correlation between PRA and PGA1 and PGB, but none with PGE2 or PGF2 alpha. This study suggests that the increase in PGA1 and PGE2 represents a secondary hypertensive mechanism which is diuretic and natiuretic. The increase of PGF2 alpha represents a direct mechanism of hypertension. Simultaneous measurement of the vasopressor (PRA and PGF2 alpha) and vasodepressor (PGA and PGE) systems may give a better diagnostic and prognostic approach to renovascular hypertension.

[Microabluminuria in arterial hypertension. Measurement, variables, interpretation, recommendations]. / Micro-albuminurie dans l'hypertension artérielle. Mesure, variations, interprétations, recommandations.

Permanent hypertension is frequently associated with increased glomerular permeability to albumin at an early stage, indicating renal involvement and endothelial dysfunction. The definition of microalbuminuria is an urinary albumin excretion of 30-300 mg/24 hrs, confirmed on two occasions over a 3 month period. It may also be expressed in microgram/min, m/l or mg/mmol of creatinine. Radio-immunological, immunonephelometric methods and Elisa are specific and the most sensitive methods of measurement. There is a large intra-individual variability (25-60%) making it essential to repeat measurements always by the same technique. The prevalence of microalbuminuria is 5-8% in the general population and 6-24% in hypertensive patients. When present, it is a marker of increased cardiovascular risk. Clinical recommendations suggest adaptation of urinary collection according to the context: screening, diagnosis or clinical research. It is always necessary to start by dip-stick detection of proteinuria, haematuria or urinary infection. Clinical research requires repeated measurement of 24 hour microalbuminuria, sometimes divided into two periods of day and night, often associated with ambulatory blood pressure recordings and renal function tests. Studies of the effects of anti-hypertensive drugs on microalbuminuria could provide better evaluation. In conclusion, measurement of microalbuminuria remains a tool of clinical research allowing an assessment of cardiovascular and renal risk of hypertensive patients.

[Urinary thromboxane B2 in hypertensive patients]. / Thromboxane B2 urinaire chez les malades hypertendus.

UNLABELLED: Thromboxane A2 (TxA2) is a vasoconstrictor synthetized by the kidney. Its role in hypertension is unknown. We measured urinary TxB2 (the metabolite of renal TxA2) by radioimmunoassay and studied renal functions in 15 borderline, 15 sustained essential hypertensive patients and 12 age-matched normotensive subjects (6 young and 6 older adults). Results were as follows: Normotensive subjects: Mean arterial blood pressure (MBP) 97 +/- 2 mmHg, urinary TxB2 (UTxB2V) 159 +/- 12 pg/min, glomerular filtration rate (GFR) 120 +/- 8 ml/min, sodium excretion (UNaV) 73 +/- 9 mueq/min. Hypertensive patients: MBP 115 +/- 2 mmHg (p less than 0,001 vs controls), UTxB2V 298 +/- 24 pg/min (p less than 0,005), GFR 128 +/- 6 ml/min, UNaV 51 +/- 4 mueq/min (p less than 0.02). There was a positive significant correlation between UTxB2V and GFR (p less than 0,005) and between UTxB2V and UNaV (p less than 0,005) in hypertensive but not in normotensive subjects. There was no correlation between GFR and UNaV in either group. CONCLUSION: 1. Urinary (i.e. renal) TxB2 is significantly elevated in hypertensive patients; 2. TxA2 may be a mediator of pressure natriuresis.

[Microalbuminuria and arterial hypertension]. / Microalbuminurie et hypertension artérielle.

UNLABELLED: IMPACT OF HYPERTENSION ON THE KIDNEY: Permanent uncontrolled hypertension affects target organs, particularly the kidney. Infraclinical renal dysfunction can be detected by early measurements of microalbuminuria which is an expression of the increased glomerular permeability related to increased arterial pressure, endothelial dysfunction and hormonal factors. Trace albumin can be detected in the urine of normal subjects. Although the amount of albumin in the urine increases with exercise, output should not exceed 20 mg/24 h. DEFINITIONS: Microalbuminuria is defined as urinary excretion of albumin in the 30-300 mg/24 h or 20-200 micrograms/min range. Due to the wide variability, tests should be repeated 2 or 3 times to confirm the persistent nature of the microalbuminuria. In hypertensive patients, microalbuminuria can be reversible if blood pressure levels are normalized. Urinary secretion of albumin above 300 mg/24 h is considered to be a macroalbuminuria expressing a more severe renal condition. INCIDENCE: The incidence of microalbuminuria in patients with borderline hypertension is 12-15%, in those with mild or moderate hypertension, it is 15-30%, and in those with severe hypertension, the percentages exceed 50%. RISKS: Albuminuria is positively correlated with blood pressure levels measured in inpatients; the correlation is even tighter with ambulatory recordings. Microalbuminuria is a risk factor for cardiovascular disease and for the development of nephroangiosclerosis. It should be searched for in all patients with persistently high blood pressure. Monitoring urine albumin is an effective tool for assessing the efficacy of an antihypertensive treatment and is useful for preventing renal damage.

[Changes in plasma prostaglandins in normal subjects in an orthostatic position. Comparison with the response of the renin-aldosterone system]. / Modifications des prostaglandines plasmatiques chez les sujets normaux en orthostatisme. Comparaison avec la réponse du système rénine-aldostérone.

Changes in blood pressure, plasma concentrations of PGE2, PGF2 alpha, G-keto-PGF1 alpha, thromboxane B2, aldosterone and plasma renin activity were evaluated in 13 normotensive subjects passing from supine to upright position. Orthostatism resulted in slight elevation of blood pressure and increase of all plasma prostaglandins (except PGE2), plasma aldosterone and plasma renin activity. A positive correlation was found in supine position between systolic arterial pressure and thromboxane B2 level (p less than 0.001). In upright position, however, blood pressure did not correlate with any of the hormones assayed. Orthostatism is a powerful stimulant of renin and aldosterone secretion but not so much of prostaglandin secretion. Basal arterial pressure is significantly influenced by thromboxane A2.

The effect of gamma-linolenic acid on plasma and membrane lipids and renal prostaglandin synthesis in older subjects.

UNLABELLED: Senescence is associated with a decreased activity of enzyme delta-6 desaturase, which converts linoleic acid to gamma-linolenic acid. This enzymatic defect may alter the composition of plasma and membrane lipids, and influences the biosynthesis of renal prostaglandins. Exogenous supplementation of GLA during 3 months increases the plasma level of dihomo-gamma-linolenic acid (p < 0.002), and to a smaller degree, the level in erythrocyte membrane lipids. This treatment was associated with a beneficial reduction of cardiovascular risk factors (arterial hypertension, total cholesterol, apolipoprotein B, HDL-cholesterol, apolipoprotein A-I) and the renal function has become stable reached. Epogam treatment also increased the biosynthesis of renal prostaglandins, especially that of prostaglandin E2, which has a vasodilatory effect on vessel walls and reduces the elevated blood pressure. CONCLUSION: Dietary supplementation of essential fatty acids such as gamma-linolenic acid to old subjects has beneficial effect on their health condition. (Tab. 6, Fig. 5, Ref. 37.)

[Atherogenic and anti-atherogenic plasma lipoproteins modulate secretion of prostanoids by endothelial cells in vitro]. / Aterogénne a antiaterogénne lipoproteíny plazmy modulujú sekréciu prostanoidov endotelovou bunkou in vitro.

The authors present the evidence of atherogenic properties of VLDL and LDL potentiation on the model of endothelial cells-human umbilical vein endothelial cells, by preferable stimulation of the endothelial cell to thromboxane A1 production at in vitro conditions by atherogenic lipoproteins. The vasoconstrictive, thrombogenic and atherogenic effects of TXA2 are exerted on the vessel in this way. The ratio prostacycline/thromboxane, decisive for the maintenance of vascular homeostasis, is less than 1, this means the beneficial effect of prostacycline can not be applied. Protective, antiatherogenic effect of HDL and its subfractions HDL2 and HDL3/predominantly through their function in the reverse cholesterol transport from the periphery to the liver, antioxidative influence on LDL, as far as antiaggregation and fibrinolytic effects of HDL/is multiplied by the fact that HDL preferably stimulates the secretion of prostacycline by the endothelial cell. The ratio prostacycline/thromboxane A2 is higher than 1, that means beneficial vasodilative, antiaggregation and antiatherogenic effect of prostacycline on the vessel wall predominate. Quantitative evaluation of antiatherogenic effects of HDL subfractions (HDL2 and HDL3) revealed more significant antiatherogenic effect in HDL2 subfraction-in the sense of prostacycline secretion stimulation and exertion of its beneficial effects on the vessel. (Fig. 5, Ref. 33.)

Detection of paroxysmal atrial fibrillation with transtelephonic EKG in TIA or stroke patients.

BACKGROUND: Paroxysmal atrial fibrillation (PAF) may remain underdiagnosed after stroke, as suggested by long-duration EKG monitoring. Here we report the sensitivity of transtelephonic EKG monitoring (TTM) for detection of PAF in patients following a recent stroke or TIA and a negative 24-hour Holter. METHODS: We analyzed data from 98 consecutive patients with TTM and noncardioembolic TOAST stroke (n = 78) or TIA (n = 20). Most were cryptogenic events (82%). Patients started TTM 0.8 months (interquartile range 0.4-2.5) after the indexed event and randomly recorded about 1 EKG per day for 1 month. Univariate and multivariate analyses were run to identify PAF predictors. RESULTS: Seventeen PAF episodes were detected in 9.2% (9/98) of the patients. The estimated duration of PAF episodes ranged from 4 to 72 hours. Two predictors were identified: premature atrial ectopic beats (more than 100) in 24-hour routine Holter (odds ratio [OR] = 11.0; 95% confidence interval [CI] 1.9-62; p = 0.007) and nonlacunar anterior circulation DWI hypersignals (OR = 9.9; 95% CI 1.1-90.6; p = 0.04). The PAF detection rate varied from 42.6% for patients meeting both criteria to 0% for patients with neither of them. CONCLUSIONS: Transtelephonic EKG monitoring increases detection rate of paroxysmal atrial fibrillation in stroke and TIA patients whose 24-hour Holter result was negative, especially if they had frequent premature atrial ectopic beats, recent anterior circulation infarct on MRI, or both.