Effects of indomethacin on furosemide induced renal prostaglandin synthesis and action in man

We had previously shown that the early increment in plasma renin activity occurring within ten minutes of intravenous furosemide is accompanied by an increase in urine 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) the hydrolysis product of prostacyclin. Renal prostacyclin and thromboxane A2 synthesis are apparently limited to the cortex. To assess whether indomethacin would inhibit renal cortical eicosanoid synthesis and whether such reduction correlated with reduced early renin release, we assessed responses to intravenous furosemide (0.5 mg/kg) before and after indomethacin (150 mg/day for seven days) in ten normal male volunteers. Indomethacin did not change blood pressure but increased weight slightly (79.7 +/- 2.5 kg to 80.4 +/- 2.4 kg, p less than 0.05). Serum thromboxane B2 (TXB2), a measure of platelet thromboxane A2 production, was profoundly depressed (142 +/- 29 ng/ml to 4.8 +/- 1.6 ng/ml, p less than 0.001). Neither diuresis nor natriuresis were changed by indomethacin but potassium excretion was reduced (33 +/- 4 mmol/4 hr to 27 +/- 3 mmol/4 hr, p less than 0.05). Basal as well as furosemide stimulated plasma renin activity (at 10, 30 and 240 minutes) was reduced, as well as the transient increase in excretion rates of 6-keto-PGF1 alpha and TXB2. We conclude that the reduction in furosemide stimulated renin release by indomethacin is due to renal cyclo-oxygenase inhibition which is reflected in decreased excretion rates of hydrolysis products of renal eicosanoids.     

Inhibition of prostaglandin synthesis by indomethacin interacts with the antihypertensive effect of atenolol

The interaction of inhibition of prostaglandin (PG) synthesis by indomethacin (75 mg/day) with the antihypertensive effect of atenolol (50 mg b.i.d.) was studied in 11 untreated otherwise healthy men 35 to 45 years old with essential hypertension. Atenolol for 3 weeks decreased supine blood pressure (BP) from 157/109 mm Hg during placebo to 148/97 mm Hg. Indomethacin alone for 1 week slightly increased BP and antagonized the antihypertensive action of atenolol. Atenolol reduced plasma renin activity (PRA) to 40% but did not modify either the urinary excretion of vasodilatory PGs (PGE2 and prostacyclin measured as 6-keto-PGF1 alpha) or plasma kininogen and urine kallikrein. Indomethacin suppressed PRA to 27% and PG excretion to approximately 70% but did not markedly change plasma kininogen and urine kallikrein excretion. The decreased excretion of 6-keto-PGF1 alpha, the metabolite of the main vasodilatory prostanoid prostacyclin, correlated with the increased BP measured in standing subjects. The effects of indomethacin were practically the same when given with atenolol as when given alone. We conclude that the slight increase in BP by indomethacin in essential hypertension is associated with the reduced production of vasodilatory PGs but not with alterations in activities of the renin-angiotensin or kallikrein-kinin systems.     

The antihypertensive action of hydrochlorothiazide and renal prostacyclin

To investigate whether chronic hydrochlorothiazide (HCTZ) therapy increases synthesis of tissue vasodilator prostaglandins (PG), we used intravenous furosemide as a standardized stimulus of renal PG synthesis before and after HCTZ dosing. Sixteen subjects with mild hypertension received placebo for 4 weeks, followed by HCTZ, 50 mg/day, and potassium chloride, 60 mmol/day, for 4 weeks. Nine subjects had decreased mean arterial pressure (-12.2 +/- 0.9 mm Hg) after HCTZ (responders), while seven others had no antihypertensive effect (nonresponders). Responders increased their excretion of the prostacyclin (PGI2) hydrolysis product 6-keto-PGF1 alpha in the first 10 minutes after furosemide, from 17.8 +/- 2.7 ng after placebo to 34.9 +/- 7.5 ng (P less than 0.05) after HCTZ, whereas nonresponders showed no such increase. These groups could not be distinguished on the basis of sex, age, or pretreatment plasma renin activity. After HCTZ dosing, responders showed evidence of increased action of PGI2 by increased plasma renin activity 10 minutes after furosemide (6.10 +/- 1.06 vs. 3.39 +/- 0.4 ng/ml/hr; P less than 0.05). Furthermore, creatinine clearance was maintained in responders (while decreasing slightly in nonresponders) despite lower blood pressure, a finding consistent with increased vasodilator effect. We conclude that an antihypertensive response to HCTZ is accompanied by an increase in renal PGI2 synthesis and action.     

Usefulness of moexipril and hydrochlorothiazide in moderately severe essential hypertension.

The purpose of this study was to assess the efficacy and tolerability of the angiotensin-converting enzyme inhibitor moexipril alone and in combination with hydrochlorothiazide versus hydrochlorothiazide monotherapy in patients with stage II and III essential hypertension. This was a double-blind, randomized, multicenter trial that evaluated moexipril (15 and 30 mg once daily), hydrochlorothiazide (25 and 50 mg once daily), and combinations of the drugs (15 mg moexipril/25 mg hydrochlorothiazide and 30 mg moexipril/50 mg hydrochlorothiazide) in 272 hypertensive patients whose seated diastolic blood pressure (BP) was 100 to 114 mm Hg. The primary efficacy variable was the mean change from baseline in seated diastolic BP at the end of the dosing period. Secondary efficacy measures included changes in systolic BP and standing BP. The lower doses of moexipril and hydrochlorothiazide reduced diastolic BP similarly (-8.0 +/- 1.4 versus -8.1 +/- 1.4 mm Hg; p = NS) as did higher doses of the monotherapeutic regimens (moexipril, -9.7 +/- 1.2 mm Hg versus hydrochlorothiazide, -11.0 +/- 1.2 mm Hg, p = NS). Combinations of moexipril and hydrochlorothiazide reduced diastolic BP significantly more than either monotherapy (lower doses, -16.0 +/- 1.4 mm Hg; p < 0.001; higher doses, -17.9 +/- 1.2 mm Hg; p < 0.001). Similar trends were observed for the systolic BP. Discontinuation rates due to adverse events were 0% for the moexipril monotherapy patients and 3% to 5% in patients on diuretic or combination treatment. These data demonstrate that 15 and 30 mg moexipril once daily lower BP similarly to hydrochlorothiazide in patients with stage II and III hypertension. There is also an additive effect when combining the two agents that lowers BP more significantly than either monotherapy.     

Treatment of hypertension in the elderly

We have evaluated the effectiveness of antihypertensive therapy for predominant systolic hypertension in 55 patients, aged 61 to 76 years, with untreated systolic blood pressures of at least 160 mm Hg and diastolic blood pressures less than 100 mm Hg. In this retrospective analysis, 41 of the patients had been treated with the centrally acting agent guanabenz (average dose 24 +/- 14 [SD] mg daily) given alone, and 14 had received a combination of guanabenz (17 +/- 10 mg daily) and hydrochlorothiazide (60 +/- 30 mg daily). After six months of therapy, each regimen significantly decreased both systolic and diastolic blood pressures. Moreover, there were no differences between the two treatment regimens in their antihypertensive efficacy, and there was no evidence of orthostatic effects. In both treatment groups, approximately 50% of the patients had excellent therapeutic responses (decrease in supine systolic blood pressure of at least 20 mm Hg). The main side effects of treatment were drowsiness and dry mouth, though these tended to be mild and of short duration. Thus, in predominant systolic hypertension in elderly patients, guanabenz, either alone or in combination with a diuretic, appears to be an effective and well tolerated form of treatment.     

Estimated rate of prostacyclin secretion into the circulation of normal man.

The rate of secretion of prostacyclin (PGI2) into the circulation of normal man was estimated by measurement of the 2,3-dinor-6-keto-PGF1 alpha (D) and 15-keto-13,14-dihydro-2,3-dinor-6-keto-PGF1 alpha (KDD) urinary metabolites of PGI2. Subjects received 6-h intravenous infusions of vehicle alone and PGI2 at 0.1, 0.4, and 2.0 ng/kg per min in random order. The fractional elimination of the metabolites was independent of the rate of PGI2 infusion. 6.8 +/- 0.3% of the infused PGI2 appeared as D and 4.1 +/- 0.4% as KDD. The regression of infused PGI2 upon the quantities of the two metabolites excreted in excess of control values permitted estimation of the rate of entry of endogenous PGI2 into the circulation corresponding to a given quantity of metabolite excreted. Using the quantities excreted in the 24 h from commencement of the infusions the estimated rates were 0.08 +/- 0.02 ng/kg per min from D and 0.10 +/- 0.03 from KDD. Studies with exogenous PGI2 suggest that infusion rates 2--4 ng/kg per min are required to achieve the threshold for inhibition of platelet function (ex vivo) in man. Although not precluding a role for PGI2 in local platelet-vessel wall interactions, the much lower estimates obtained in this study suggest that endogenous PGI2 is unlikely to act as a circulating antiplatelet agent in healthy man.     

In vivo production of thromboxane and prostacyclin in patients following total hip arthroplasty

The in vivo production of thromboxane and prostacyclin was studied by measurements of their major urinary metabolites in eight patients undergoing total hip arthroplasty. Specific methods based on gas chromatography-mass spectrometry were used to measure the urinary excretion of 2,3-dinor-TxB2 and 2,3-dinor-6-keto-PGF1 alpha. The excretion of these metabolites increased about 10-fold during the intra and immediate postoperative period and 4 days after surgery was still higher than during the preoperative period. The increased thromboxane formation reflects probable activation of platelets whereas the increased prostacyclin could be part of a vascular defense against induced thrombotic activity. These findings may have pathophysiological implications.     

Nifedipine tablet vs. hydralazine in patients with persisting hypertension who receive combined diuretic and beta-blocker therapy

The antihypertensive effects of a 20 mg tablet of nifedipine were compared with those of hydralazine in a randomized, double-blind, placebo-controlled study. Nineteen patients with a diastolic blood pressure (BP) between 95 and 120 mm Hg despite combined diuretic and beta-blocker therapy completed the protocol. After 2 weeks of placebo each subject received increasing doses of nifedipine (20, 40, and 60 mg b.i.d.) and hydralazine (25, 50, and 100 mg b.i.d.) if tolerated or until goal BP (supine and standing diastolic BP less than 85 mm Hg) was achieved. Both nifedipine and hydralazine significantly lowered supine BP from placebo baseline (146 +/- 3/96 +/- 2 mm Hg) to 119 +/- 3/80 +/- 2 and 129 +/- 2/81 +/- 2 mm Hg, respectively. The decrease in systolic BP with nifedipine was significantly lower than that with hydralazine at 9 weeks. Neither drug significantly altered heart rate. Mean left ventricular ejection fractions were similar for nifedipine (67% +/- 2%), hydralazine (69% +/- 3%), and placebo (66% +/- 2%). The nifedipine tablet appears to be an effective antihypertensive agent in patients whose BP remains high despite combined diuretic and beta-blocker therapy.     

Effect of losartan plus hydrochlorothiazide on nitric oxide status in 'nondipper' hypertensive patients

The objective of this study was to investigate the effects of losartan (100 mg) plus hydrochlorothiazide (HCTZ; 25 mg) on nitric oxide (NO) production and blood pressure (BP) in "nondipper" severe hypertensive patients. Twelve hypertensive "nondipper patients" (6 of each gender) with sitting systolic/diastolic BP of 188.0 +/- 5.2/116.2 +/- 1.2 mm Hg were studied by 24-hour ambulatory blood pressure monitoring (ABPM) after daily administration of 100 mg losartan plus 25 mg HCTZ for a period of 12 weeks. Office and mean 24-hour, as well as mean awake- and sleep-time systolic/diastolic BP, serum NO levels, and urinary excretion of NO were measured after the placebo period (3 weeks) and after 12 weeks of therapy. At the end of the 12-week treatment period, the mean 24-hour systolic/diastolic BP decreased significantly from 158.6 +/- 4.7/102.2 +/- 2.6 mm Hg (placebo period) to 140.3 +/- 4.8/90.9 +/- 3.3 mm Hg (P = 0.001/< or = 0.002). The mean BP (systolic/diastolic) during the waking period was reduced from 159.3 +/- 4.4/103.0 +/- 2.5 mm Hg to 135.0 +/- 4.4/88.2 +/- 3.1 (P < or = 0.007/P < or = 0.002), whereas the mean BP (systolic/diastolic) during the sleeping hours changed from 154.9 +/- 5.3/98.9 +/- 3.1 to 140.9 +/- 4.6 (P = 0.035)/91.7 +/- 3.2 mm Hg (P = 0.035/P = 0.051). Serum NO levels increased from 40.89 +/- 5.69 microM/L (placebo period) to 67.35 +/- 6.96 microM/L (posttreatment; P < or = 0.007), whereas the 24-hour urinary NO excretion did not change significantly (69.71 +/- 3.68 microM/L [placebo period] vs 79.64 +/- 4.25 microM/L [posttreatment]; P < or = 0.16). Urinary clearance of NO also did not change. Serum NO levels increased significantly without a significant change in urinary NO excretion. BP was significantly reduced but without modifying the nondipper pattern in these patients.     

Synthetic arterial grafts cause prolonged increase in the in vivo formation of thromboxane and prostacyclin in humans

To evaluate the in vivo production of thromboxane A2 and prostacyclin their major urinary metabolites were measured in patients following graft replacement of the abdominal aorta. Specific methods based on gas chromatography-mass spectrometry were used to measure the urinary excretion of 2,3-dinor-TxB2 and 2,3-dinor-6-keto-PGF1 alpha. The excretion of these metabolites increased tenfold and almost fortyfold during post-operative Day 1 and remained elevated 6-10 days p.o. In a group undergoing cholecystectomy smaller changes of shorter duration were seen. It is concluded from this study that synthetic grafts cause prolonged increase in the in vivo formation of thromboxane A2 and prostacyclin. The reason for the increased TxA2 formation is probably platelet interaction with the foreign surface, whereas the increase of PGI2 could be part of a vascular defense against induced thrombotic activity. Those increases may have pathophysiologic implications.     

2,3-Dinor metabolites of thromboxane A2 and prostacyclin in urine from healthy human subjects: diurnal variation and relation to 24h excretion.

1. Urinary levels of the 2,3-dinor metabolites of thromboxane A2 (2,3-dinor-thromboxane A2, Tx-M) and prostacyclin (2,3-dinor-6-keto-prostaglandin F1 alpha, PGI-M) are frequently analysed as indices of platelet and endothelial activity and interaction in vivo. Despite this, little is known about the possible diurnal variations in urinary Tx-M and PGI-M in healthy human subjects, and how the urinary levels of Tx-M and PGI-M in single samples reflect their respective 24 h excretion rates. We addressed this by determining Tx-M, PGI-M and creatinine in consecutive portions of urine collected during 24 h in 15 healthy non-smoking subjects. 2. The total 24 h excretion of Tx-M and PGI-M did not differ between men (223 +/- 31 and 132 +/- 27 ng, respectively) and women (215 +/- 44 and 127 +/- 29 ng, respectively). Neither the excretion of Tx-M nor that of PGI-M displayed any significant diurnal variation. 3. The excretion of Tx-M during a 3 h period and the Tx-M/creatinine ratio in a urine sample accurately reflected the 24 h excretion of Tx-M (correlation coefficient ranges 0.74-0.94 and 0.74-0.86, respectively). The excretion of PGI-M during a 3 h period and the PGI-M/creatinine ratio in a urinary sample were accurate measures of 24 h excretion of PGI-M (correlation coefficient ranges 0.76-0.94 and 0.72-0.83, respectively). Urinary Tx-M and PGI-M expressed as simple concentrations were poor indices of their respective 24 h excretion. 4. We conclude that time-related excretions of Tx-M and PGI-M may be the best indices ex vivo of the cardiovascular formation of thromboxane A2 and prostacyclin, but that urinary creatinine-related concentrations of Tx-M and PGI-M in a urine sample are accurate measures as well.     

Experimental atherosclerosis: effects of oestrogen and atherosclerosis on thromboxane and prostacyclin formation

We evaluated the effect of oestrogen and experimental atherosclerosis on the in vivo formation of thromboxane and prostacyclin in rabbits. Twenty-four New Zealand White rabbits were divided into four groups. One group received control diet, one group received control diet and oestrogen, one group received control diet supplemented with 1% cholesterol and one group received cholesterol supplemented diet and oestrogen during 3 months. The in vivo formation of thromboxane and prostacyclin were measured as 2,3-dinor-TxB2 and 2,3-dinor-6-keto-PGF1 alpha in urine by gas chromatography/mass spectrometry. All rabbits on cholesterol diet became hypercholesterolaemic and developed atherosclerosis. As in previous experiments cholesterol and oestrogen-treated rabbits had only minor atherosclerosis compared to purely cholesterol-fed rabbits. The in vivo production of thromboxane in oestrogen-treated rabbits decreased from 1641 +/- 162 pg mg-1 creatinine pretreatment to 808 +/- 92 pg mg-1 creatine at 12 weeks (P = 0.0001). In contrast, the in vivo production of prostacyclin increased during oestrogen treatment (P = 0.0027). The in vivo production of prostacyclin decreased during pure cholesterol feeding without oestrogen 1384 +/- 219 pg mg-1 creatinine to 702 +/- 142 pg mg-1 creatinine (P = 0.0091). The ratio of in vivo prostacyclin to thromboxane formation increased 2-3-fold during oestrogen therapy (P = 0.0007).(ABSTRACT TRUNCATED AT 250 WORDS)     

Angiotensin II-induced hypertension in the rat. Effects on the plasma concentration, renal excretion, and tissue release of prostaglandins.

We examined in rats the effects of intraperitoneal angiotensin II (AII) infusion for 12 d on urinary excretion, plasma concentration, and in vitro release of prostaglandin (PG) E2 and 6-keto-PGF1 alpha, a PGI2 metabolite. AII at 200 ng/min increased systolic blood pressure (SBP) progressively from 125 +/- 3 to 170 +/- 9 mmHg (P less than 0.01) and elevated fluid intake and urine volume. Urinary 6-keto-PGF1 alpha excretion increased from 38 +/- 6 to 55 +/- 5 and 51 +/- 7 ng/d (P less than 0.05) on days 8 and 11, respectively, of AII infusion, but urinary PGE2 excretion did not change. Relative to a control value of 129 +/- 12 pg/ml in vehicle-infused (V) rats, arterial plasma 6-keto-PGF1 alpha concentration increased by 133% (P less than 0.01) with AII infusion. Aortic rings from AII-infused rats released more 6-keto-PGF1 alpha (68 +/- 7 ng/mg) during 15-min incubation in Krebs solution than did rings from V rats (40 +/- 3 ng/mg); release of PGE2, which was less than 1% of that of 6-keto-PGF1 alpha, was also increased. Slices of inner renal medulla from AII-infused rats released more 6-keto-PGF1 alpha (14 +/- 1 ng/mg) during incubation than did slices from V rats (8 +/- 1 ng/mg, P less than 0.05), but PGE2 release was not altered. In contrast, AII infusion did not alter release of 6-keto-PGF1 alpha or PGE2 from inferior vena cava segments or from renal cortex slices. Infusion of AII at 125 ng/min also increased SBP, plasma 6-keto-PGF1 alpha concentration, and in vitro release of 6-keto-PGF1 alpha from rings of aorta and renal inner medulla slices; at 75 ng/min AII had no effect. SBP on AII infusion day 11 correlated positively with both 6-keto-PGF1 alpha plasma concentration (r = 0.54) and net aortic ring release (r = 0.70) when data from all rats were combined. We conclude that augmentation of PGI2 production is a feature of AII-induced hypertension. The enhancement of PGI2 production may be an expression of nonspecific alteration in vascular structure and metabolic functions during AII-induced hypertension, as well as the result of a specific effect of the peptide on the arachidonate-prostaglandin system.     

Experience in the use of valsartan with the aim to inhibit progression of kidney failure in patients with chronic glomerulonephritis

AIM: To assess the effect of valsartan, angiotensin-II receptor blocker type 1, on key factors of progression of chronic renal failure (CRF)--arterial hypertension (AH), proteinuria (PU), sodium excretion (SE)--in patients with chronic glomerulonephritis (CGN) and initial affection of renal function. MATERIAL AND METHODS: 11 patients (mean age 33.7 +/- 13.3 years, mean duration of nephritis 8.6 +/- 6.4 years, male to female ratio 8:3) with AH (AP > 140/90 mm Hg) and marked PU (> 1 g/day) who had not received immunosuppressive drugs for at least 6 months before the trial were given valsartan. It was administered after the period of "washing out" at the initial dose 80 mg/day with further addition of diuretics or raising the dose twice (in hyperuricemia) to decrease AP under 140/90 mm Hg. The duration of the treatment was 3 months. RESULTS: After 3 months of valsartan therapy systolic arterial pressure fell from 162 +/- 18 to 138 +/- 20 mm Hg (p < 0.05), diastolic pressure from 100 +/- 8 to 92 +/- 15 mm Hg (single measurements). 24-h monitoring of AP showed a significant lowering of mean 24-h and night systolic and diastolic AP, day-time diastolic AP, 24-h time index of systolic and diastolic AP. Initial antiproteinuric effect was observed after 1 month of the treatment and after 3 months of therapy PU reduced significantly (from 5.7 +/- 6.0 g/day to 3.3 +/- 3.3 g/day). After 3 months sodium excretion significantly rose, while creatinine level and glomerular filtration rate did not. Potassium rose in one patient. CONCLUSION: In CGN with initial CRF valsartan in a dose 80-160 mg/day produces a pronounced antihypertensive and antiproteinuric actions, stimulates sodium excretion. No serious side effects were noted. It is necessary to continue studies on the ability of valsartan to inhibit progression of CRF.     

Cigarette smoking and urinary excretion of markers for platelet/vessel wall interaction in healthy women.

1. Cigarette smoking is known to increase the risk of cardiovascular disease in both men and women. Experimental and epidemiological studies have demonstrated that cigarette smoking is associated with several indices of increased platelet activation and platelet/vessel wall interaction in men. The aim of the present study was to test the hypothesis that cigarette smoking is linked to an increased platelet activity in women also. 2. In 26 healthy smoking and non-smoking women (age 21-49 years) the urinary excretion of the thromboxane A2 metabolite 2,3-dinor-thromboxane B2 (an index of platelet activation) and of the prostacyclin metabolite 2,3-dinor-6-keto-prostaglandin F1 alpha (an index of platelet/vessel wall interaction) were analysed by g.c.-m.s. in samples collected on days 3, 10 and 20 of their respective menstrual cycles. 3. The urinary excretion of 2,3-dinor-thromboxane B2 did not vary significantly during the menstrual cycle, either in the smokers or in the non-smokers. It was consistently higher (P less than 0.004) in the group of smokers (average of day 3, 10 and 20, 395 +/- 61 pg/mg of creatinine; mean +/- SEM) than in the group of non-smokers (average 188 +/- 22 pg/mg of creatinine). 4. The urinary excretion of 2,3-dinor-6-keto-prostaglandin F1 alpha did not differ between the groups on any of the days studied (average on days 3, 10 and 20 in the smokers and non-smokers was 281 +/- 50 and 227 +/- 30 pg/mg of creatinine, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of delapril in combination with indapamide on blood pressure and left ventricular mass in elderly hypertensive patients

We present a single-blinded, placebo-controlled trial of the effects on blood pressure and left ventricular mass and of the safety of a combined antihypertensive treatment with delapril, a new nonsulfhydryl angiotensin-converting enzyme inhibitor, and indapamide, a sulfonamide diuretic. We studied 28 elderly patients aged 65-85 years (mean age, 69 +/- 1) with sitting systolic/diastolic blood pressure of 160-200/95-115 mm Hg (at the end of the placebo period). After a 2-week placebo run-in, patients took 30 mg delapril in combination with 1.25 mg indapamide once daily for 24 weeks. Twenty-four-hour ambulatory blood pressure was monitored and M- and B-mode echocardiography were performed before and after 24 weeks of treatment. Blood pressure decreased from 156 +/- 1.5/101 +/- 1 mm Hg before treatment to 133 +/- 1/73 +/- 1 mm Hg after treatment. The total blood pressure burden also decreased; the percentage of measurements with a systolic blood pressure > or = 140 mm Hg and a diastolic blood pressure > or = 90 mm Hg decreased from 48.7% +/- 5%/31.5% +/- 4.3% to 23.5% +/- 4%/20.5% +/- 2.9% (p < 0.0005 and p < 0.05). The area under the curve of the 24-hour blood pressure decreased from 250 +/- 41/103 +/- 21 mm Hg to 97 +/- 21/37 +/- 8.5 mm Hg (p < 0.001 and p < 0.005). The left ventricular mass index (LVMI) in the 15 patients with pretreatment left ventricular hypertrophy was reduced after therapy from 167.5 +/- 8.5 g/m 2 to 152.2 +/- 7.6 g/m 2 (p < 0.05). A positive correlation was observed between percent changes of the area under the curve of the 24-hour diastolic blood pressure and percent changes of LVMI (r = 0.6; p < 0. 05) in the 15 patients with left ventricular hypertrophy. Only 2 patients reported side effects: 1 developed skin rash and 1 developed headache. The safety of the treatment was confirmed by laboratory tests. In elderly hypertensive patients, the combination of delapril and indapamide at low doses reduced blood pressure and had favorable effects on LVMI with few side effects.     

Stimulation of prostacyclin synthesis by physical exercise in type I diabetes

We examined the effect of short- and long-term exercise on prostacyclin (prostaglandin I2 [PGI2]) and thromboxane A2 (TXA2) synthesis in type I (insulin-dependent) diabetic patients and healthy control subjects. PGI2 synthesis was assessed by determining the urinary excretion of 6-keto-PGF1 alpha and 2,3-dinor-6-keto-PGF1 alpha and TX synthesis by measuring TXB2 in serum and urine. In the resting state, prostanoid excretion and concentrations were similar in diabetic and control subjects. During 40 min of ergometric cycling exercise, the urinary excretion of 6-keto-PGF1 alpha (a hydration product of vasodilatory PGI2) increased 5.8-fold more in the 12 control subjects than in the 15 diabetic patients (P less than .02). Serum TXB2 concentration rose similarly in diabetic patients and control subjects (P less than .05). During a 75-km competitive cross-country ski race (7 h, 30 min), urinary excretion of 6-keto-PGF1 alpha rose 1.9-fold in 7 diabetic (P less than .05) and 3.3-fold in 10 control (P less than .001) subjects, whereas urinary dinor excretion, reflecting vascular PGI2 synthesis more closely, increased only in the control subjects (P less than .01). Urinary TXB2 excretion remained unchanged in both groups during long-term exercise. These data suggest that diabetic patients have normal PGI2 and TXA2 synthesis in the resting state but diminished PGI2 response to both acute and prolonged exercise.     

Chronic treatment with propranolol enhances the synthesis of prostaglandins E2 and I2 by the aorta of spontaneously hypertensive rats

The effects of treatment with dl, d- or l-propranolol (subcutaneously for 1 week) on arterial blood pressure and on 6-keto prostaglandin (PG) F1 alpha (stable metabolite of PGI2) and PGE2 production by aorta, renal medulla and renal cortex were examined in spontaneously hypertensive rats. dl-Propranolol and l-propranolol significantly (P less than .05) lowered blood pressures from 148 +/- 9/113 +/- 5 (n = 6) and 133 +/- 4/100 +/- 2 (n = 12) mm Hg to 112 +/- 3/80 +/- 3 and 121 +/- 3/81 +/- 3 mm Hg, respectively. Comparable treatment of spontaneously hypertensive rats with inactive d-propranolol was without effect. Basal immunoreactive (i) i6-keto-PGF1 alpha and iPGE2 production by isolated aorta, renal medulla and cortex was not different in vehicle compared to the dl-propranolol-treated rats. In contrast, norepinephrine (1 microM)-stimulated synthesis of i6-keto PGF1 alpha and iPGE2 by the aorta in the dl-propranolol-treated group was significantly (P less than .05) enhanced compared with the vehicle-treated group. Aortic i6-keto-PGF1 alpha and iPGE2 synthesis stimulated by norepinephrine in l-propranolol-treated rats was also significantly (P less than .05) higher than that observed in vehicle and d-propranolol-treated rats. dl-Propranolol treatment did not alter norepinephrine-stimulated renal cortical or medullary i6-keto-PGF1 alpha or iPGE2 synthesis. Indomethacin (5 mg/kg i.p.) given on the last 2 days of dl-propranolol treatment, significantly inhibited aortic i6-keto-PGF1 alpha and iPGE2 production and blunted the antihypertensive effect of dl-propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)     

The antiproteinuric action of enalapril in stroke-prone spontaneously hypertensive rats is unrelated to alterations in urinary prostaglandins.

We examined whether the renal protective effect of the angiotensin I converting enzyme inhibitor enalapril in stroke-prone spontaneously hypertensive rats (SHRSP) is dose-related and associated with alterations in the urinary excretion of prostaglandin (PG) E2 and 6-keto-PGF1 alpha, a stable breakdown product of prostacyclin. Enalapril maleate at 1.5, 5 and 15 mg/kg/day or vehicle was chronically administered to saline-drinking SHRSP (six per group) starting at 8.1 weeks of age. Vehicle-treated SHRSP developed severe hypertension, proteinuria and strokes (age at death, 14 +/- 1 weeks; mean +/- S.E.). Enalapril prolonged survival dose-dependently and reduced proteinuria; all SHRSP given 15 mg/kg/day lived beyond 23 weeks of age without evidence of stroke or proteinuria. There was no effect of enalapril at any dose on systolic arterial blood pressure in spite of variable levels of urinary protein excretion and onset of stroke in the different groups. Likewise, urinary 6-keto-PGF1 alpha and PGE2 excretion did not differ among the groups except for an increase in 6-keto-PGF1 alpha in the 15 mg/kg/day group at one week after initiation of enalapril therapy. These results are consistent with a dose-related renal protective action of enalapril in saline-drinking SHRSP that is not closely associated with sustained alterations in urinary excretion of renal vasodilatory PGs.     

Human pharmacology of naproxen sodium

We compared the variability in degree and recovery from steady-state inhibition of cyclooxygenase (COX)-1 and COX-2 ex vivo and in vivo and platelet aggregation by naproxen sodium at 220 versus 440 mg b.i.d. and low-dose aspirin in healthy subjects. Six healthy subjects received consecutively naproxen sodium (220 and 440 mg b.i.d.) and aspirin (100 mg daily) for 6 days, separated by washout periods of 2 weeks. COX-1 and COX-2 inhibition was determined using ex vivo and in vivo indices of enzymatic activity: 1) the measurement of serum thromboxane (TX)B(2) levels and whole-blood lipopolysaccharide-stimulated prostaglandin (PG)E(2) levels, markers of COX-1 in platelets and COX-2 in monocytes, respectively; 2) the measurement of urinary 11-dehydro-TXB(2) and 2,3-dinor-6-keto-PGF(1alpha) levels, markers of systemic TXA(2) biosynthesis (mostly COX-1-derived) and prostacyclin biosynthesis (mostly COX-2-derived), respectively. Arachidonic acid (AA)-induced platelet aggregation was also studied. The maximal inhibition of platelet COX-1 (95.9 +/- 5.1 and 99.2 +/- 0.4%) and AA-induced platelet aggregation (92 +/- 3.5 and 93.7 +/- 1.5%) obtained at 2 h after dosing with naproxen sodium at 220 and 440 mg b.i.d., respectively, was indistinguishable from aspirin, but at 12 and 24 h after dosing, we detected marked variability, which was higher with naproxen sodium at 220 mg than at 440 mg b.i.d. Assessment of the ratio of inhibition of urinary 11-dehydro-TXB(2) versus 2,3-dinor-6-keto-PGF(1alpha) showed that the treatments caused a more profound inhibition of TXA(2) than prostacyclin biosynthesis in vivo throughout dosing interval. In conclusion, neither of the two naproxen doses mimed the persistent and complete inhibition of platelet COX-1 activity obtained by aspirin, but marked heterogeneity was mitigated by the higher dose of the drug.