Sodium-volume factor, cardiovascular reactivity and hypotensive mechanism of diuretic therapy in mild hypertension associated with diabetes mellitus

Diabetes mellitus is often associated with excess body sodium and frequently accompanied by hypertension. Relationships among blood pressure and various regulatory factors were studied before and after six weeks of diuretic therapy with chlorthalidone, 100 mg/day, in 17 diabetic subjects (aged 32 to 75 years) with borderline to moderate hypertension. Following a four-week placebo phase, mean supine blood pressure was 165/93 ± 26/15 (±SD) mm Hg and exchangeable sodium was increased (49 ± 4 versus 45 ± 4 meq/kg lean body mass in 90 normal subjects; p < 0.01). Blood volume, and supine and upright plasma renin, aldosterone, norepinephrine, epinephrine or dopamine levels were comparable to normal values. Measurements in eight diabetic subjects revealed an increased cardiovascular reactivity, as evidenced by decreased (p < 0.001) pressor doses of norepinephrine (68 ± 42 versus 151 ± 52 ng/kg/min) or angiotensin II (3.9 ± 1.2 versus 10.3 ± 5.5 ng/kg/min). Chlorthalidone decreased blood volume by 11 per cent, lowered body sodium (by 9 per cent) and cardiovascular sensitivity to norepinephrine (by 48 per cent) or angiotensin II (by 60 per cent) towards normal and reduced blood pressure by 11 per cent to 145/82 ± 13/12 mm Hg (11 per cent). Plasma renin and aldosterone were markedly increased by chlorthalidone, whereas plasma and urinary catecholamine levels were not significantly altered. These findings suggest that hypertension in patients with diabetes mellitus may partly depend on increased body sodium and/or an exaggerated cardiovascular reactivity to norepinephrine and angiotensin II. The blood pressure-lowering effect of diuretic therapy may be due to removal of excess sodium and the restoration of norepinephrine pressor sensitivity towards normal without an equivalent increase in adrenergic nervous activity.     

Celiprolol--review of airways studies

Celiprolol was compared with chlorthalidone in a double-blind randomized placebo-controlled study of 30 hypertensive or anginal patients with reversible bronchial obstruction. The study consisted of a 4-week placebo run-in period and a 12-week titration period during which the dose of both drugs was increased at 4-week intervals if blood pressure was not reduced adequately. The doses of celiprolol were 200, 400 or 600 mg once daily, whereas those for chlorthalidone were 12.5, 25 or 37.5 mg once daily. Entry criteria were a diastolic blood pressure between 90 to 115 mm Hg, forced expiratory volume in 1 second between 40 and 80% of predicted value, increasing by 15% or more after salbutamol inhalation and the need for occasional bronchodilator therapy. Prophylactic medication for asthma was given at a constant dosage for 1 month before the study and throughout the study. Clinical variables were not significantly changed by either drug, and neither celiprolol nor chlorthalidone had any significant effect on forced expiratory volume in 1 second.     

Long-Acting and Short-Acting Diuretics in Mild Essential Hypertension

A randomised, placebo-controlled, double-blind crossover study was conducted in 14 patients with mild essential hypertension comparing different regimens of administration of the “short-acting” diuretic, chlorothiazide and the “long-acting” diuretic, chlorthalidone. There were 6 randomised treatment phases each of 5 weeks duration. For blood pressure recorded both at the Clinic and at home the most prominent effects were seen with standing blood pressure, for which significant reductions of mean blood pressure compared to the placebo phase were observed with chlorthalidone 25 mg once daily (-5 ± 1 (SE) mm Hg - p < 0.05), chlorthalidone 50 mg once daily (-7 ± 1 mm Hg - p < 0.01) and chlorothiazide 500 mg twice daily (-4 ± 1 mm Hg - p < 0.05). Blood pressure reductions with chlorothiazide 500 mg once daily and 1000 mg once daily were not significant. About half of the patients completing the trial could be described as “non-responders”.

The observed biochemical changes (reduced plasma potassium and chloride concentrations and increased plasma bicarbonate and urate concentrations) were most marked in the phases with the most prominent blood pressure effects. The results support the suggestion that a sustained diuretic effect is desirable when diuretics are used in the treatment of hypertension. This can be obtained by selection of the appropriate dosage regimen for a particular diuretic, such as once daily administration for “long-acting” and twice daily for “short-acting” thiazide-type diuretics.     

Acute hypotensive and renin-stimulating actions of captopril before and during treatment with a beta-blocking drug

There is no general agreement on the relation between the hypotensive effect of captopril and the pretreatment plasma renin levels of hypertensive patients. To determine whether the hypotensive effect of captopril was directly related to plasma renin, the angiotensin-converting enzyme inhibitor was administered acutely to 10 essential hypertensive patients with normal or suppressed plasma renin activity before and after inhibition of renin secretion with propranolol. Captopril was equally effective in reducing blood pressure both when administered alone (25 mg: -29/-17; 50 mg: -37/-23 mm Hg) and after chronic treatment with propranolol (25 mg: -33/-20; 50 mg: -30/-20 mm Hg). The increase in renin induced by captopril was not decreased by propranolol therapy. The persistence of the hypotensive effect of captopril after renin suppression by propranolol suggests that this drug has some blood pressure decreasing properties independent of plasma renin.     

Role of renin classification for diuretic treatment of black hypertensive patients

Previous studies in white and mixed-race hypertensive patient populations have generally found patients with low renin activity more responsive to diuretic therapy than patients with normal renin activity. Twenty-nine black patients (26 women and three men) with placebo diastolic blood pressure of 90 to 115 mm Hg were treated with spironolactone (100 to 400 mg/day) and hydrochlorothiazide (100/mg/day). Renin status was categorized by (1) the intravenous furosemide test, (2) ambulation during placebo, and (3) ambulation during spironolactone and hydrochlorothiazide treatment. Only seven patients were categorized identically with all methods. No method identified a low renin subgroup that was more responsive to either spironolactone or hydrochlorothiazide. Diastolic blood pressure fall with hydrochlorothiazide (18 mm Hg) and 400 mg/day of spironolactone (15 mm Hg) was similar. Thus, since black women with both low and normal renin activity are quite responsive to diuretics, renin classification to guide initial antihypertensive selection is not warranted.     

Labetalol and Propranolol in Mild Hypertensives: Comparison of Blood Pressure and Plasma Volume Effects

Summary: Labetalol and propranolol in mild hypertensives: Comparison of blood pressure and plasma volume effects. S. N. Hunyor, G. E. Bauer, M. Ross and H. Larkin, Aust. N.Z. J. Med ., 1980, 10, pp. 162–166.
Labetalol administered in a small to moderate dose (first month 400 mg/day, second month average 585 mg/day) was effective in lowering blood pressure (BP) (-21/-18 mmHg, recumbent) in 11 of 13 mild essential hypertensives over an eight-week period, despite a significant (+294 ml) increase in plasma volume. The effect of propranolol (first month 160 mglday, second month average 234 mg/day) was significantly less on both blood pressure (-9/-9 mmHg) and plasma volume (+98 ml), although the pre-propranolol BP was lower and the final BP achieved on the two medications was comparable (labetalol 147/89 mmHg, propranolol 145/89
Six patients who continued labetalol for periods of up to 14 months had persistent plasma volume expansion. Three of these, taking a higher dose of labetalol, developed resistance to the drug's antihypertensive effect. Addition of a diuretic restored antihypertensive efficacy and led to a fall in plasma volume. No such plasma volume expansion was seen in six patients who were followed on long term propranolol therapy
Some plasma volume expansion with the combined alpha- beta-adrenoceptor blocker labetalol may be appropriate to its vasodilator action. Provided this effect is not excessive, it appears not to lead to resistance to its antihypertensive action. Small to moderate doses of labetalol would, therefore, seem effective without concomitant diuretic. Such sole use of labetalol could help minimise orthostatic symptoms which can be a major side effect of combination therapy     

Controlled treatment of primary hypertension with propranolol and spironolactone: A crossover study with special reference to initial plasma renin activity

Twenty-seven patients with hypertension were randomly allocated to a 10 month crossover study. Treatment consisted of spironolactone (200 mg/day for 2 months), propranolol (320 mg/day for 2 months) and combined administration of both drugs at half the dosage. Between treatment periods placebo was given for 2 months. Fourteen patients were previously untreated. The average pretreatment blood pressure for the entire group was 188/114 ± 16/7 (mean ± standard deviation) mm Hg supine and 188/118 ± 20/9 mm Hg standing. Both spironolactone and propranolol reduced blood pressure significantly in both the supine and standing positions.Upright plasma renin activity was determined by radioimmunoassay of angiotensin I. The average initial level was 1.9 ± 1.2 (range 0.4 to 5.0) ng/ml/hr. There was a close correlation between plasma renin activity and the effects of the drugs: With increasing renin level the response to propranolol was better whereas the opposite was true for spironolactone. The combination of spironolactone and propranolol decreased the blood pressure still further in the supine and standing positions, irrespective of initial plasma renin activity. All patients achieved a normal supine pressure. Blood pressure and plasma renin activity returned toward pretreatment values during placebo administration. It is concluded that pretreatment levels of plasma renin activity can predict the antihypertensive response to propranolol and spironolactone. The combination of the two drugs, which have different modes of action, will effectively reduce blood pressure in hypertension. The results support the concept that the renin-angiotensin-aldosterone system may be involved in primary hypertension.     

Different antihypertensive effect of beta-blocking drugs in low and normal-high renin hypertension.

The treatment response to beta-adrenoceptor blocking drugs was compared in two groups of patients with primary (essential) hypertension and different renin levels. Each group consisted of 25 patients and was equally distributed regarding age, severity and stage of hypertension. In the first group (group 1), the mean upright plasma renin activity was 0.8 ng ml-1h-1 (range 0.3 to 1.5) and the patients were considered to have low renin hypertension. In the other group (group 2) the patients had a mean plasma renin activity of 2.1 ng ml-1h-1 (range 1.1 to 5.1) and were considered to have normal to high renin hypertension. In both groups the patients were initially treated with beta-blocking drugs; in group 1 with a beta-blocker corresponding to an average dose of 311 mg propranolol a day for at least eight weeks and in group 2 with propranolol 320 mg a day in a fixed dose for eight weeks. The hypotensive response differed significantly between the two groups (p less than 0.001). In group 1 the pretreatment blood pressure was 197/117 mm Hg supine and 198/120 mm Hg standing. During treatment blood pressure decreased only 5/3 mm Hg supine and 9/5 mm Hg standing. The pretreatment blood pressure in group 2 was 187/114 mm Hg supine and 186/117 mm Hg standing. Beta-blocking therapy reduced blood pressure 36/23 and 34/18 mm Hg, respectively (both p less than 0.001). Pulse rates fell significantly in the two groups, both in the lying and standing positions. In 17 patients with low renin hypertension (group 1), a volume-depleting drug was added (spironolactone, 14 patients; thiazides, 3 patients) and this achieved a marked fall in blood pressure levels of 38/16 mm Hg supine and 37/19 mm Hg standing (both p less than 0.001). These results suggest the following: (1) Most patients with normal to high plasma renin activity respond well to moderate doses of propranolol. (2) Propranolol given in the same doses is almost without antihypertensive effect in patients with low renin hypertension. (3) A volume factor may be operating in patients with low renin hypertension since a hypotensive effect is demonstrated after the addition of volume-depleting drugs. (4) Determination of plasma renin activity with adequate methods can predict the treatment response to hypotensive agents.     

Effects of Indomethacin,Sulindac, Naproxen,Aspirin, and Paracetamol in Treated Hypertensive Patients

Four placebo controlled, randomised crossover studies were carried out to investigate the effects of non-steroidal antiinflammatory drugs and analgesics on blood pressure control in treated hypertensive patients. Twelve patients completed one study comparing indomethacin, 25 mg tds, with placebo in 2 six week phases; there were increases in mean blood pressure (p < 0.01) of 9 mm Hg (casual), 8 mm Hg (supine) and 10 mm Hg (standing) in the indomethacin phase accompanied by a 50% reduction in plasma renin activity (p < 0.05) and a 47% decrease in plasma aldosterone concentration (p < 0.05). Similar studies on aspirin-SR, 650 mg daily (19 patients), and paracetamol, 1 g 8th hourly (20 patients), revealed only small changes in blood pressure, with a 2 mm Hg increase in supine diastolic blood pressure during aspirin therapy and a 4 mm Hg increase in supine and standing systolic blood pressure during paracetamol therapy (p < 0.05 for both)

Nineteen patients completed a study with 4 three week phases, taking placebo, naproxen 250 mg mane and 500 mg nocte, sulndac 200 mg bd, and aspiring-SR 1950 mg bd. All threee active agents depressed plasma renin activity and plasma aldosterone concentration. Neither sulindac nor aspiring cuased any significant increases in blood pressure, and naproxen had little effect, though it did cause a 4 mm Hg increase in standing systolic pressure (p < 0.05). We conclude that the effects of indomethacin on control of blood pressure in treated hypertensive patients are not exhibited to the same extent by o ther durgs investigated, and that they are not dependent on the concomitant decreases in plasma renin activity or plasma aldosterone concentration. The importance of inhibition of prostaglandin sysnthesis remains unclear     

Echocardiographic assessment of the effect of an antihypertensive regimen on left ventricular performance.

A regimen consisting of chlorthalidone, hydralazine and propranolol would be useful in some hypertensive patients with coronary artery disease or aortic dissection if it could be shown that reflex cardiac stimulation induced by hydralazine is completely neutralized by propranolol. Nine hypertensive patients were treated with chlorthalidone during week 1, chlorthalidone and hydralazine during week 2 and a combination of chlorthalidone, hydralazine and propranolol during week 3. Blood pressure, heart rate, mean velocity of circumferential fiber shortening (VCF) measured echocardiographically and plasma renin activity were measured weekly. This potent three drug regimen reduced mean blood pressure from 142 to 102 mm Hg, and with the third drug, propranolol, heart rate, VCF and plasma renin activity returned to control levels from the greater elevated levels produced by the diuretic drug and hydralazine. In six additional patients VCF (an index of left ventricular contractility) was found to be proportionate to the rate of rise of aortic pressure (dP/dt) or aortic shearing force. This regimen appears safe for use in patients with ischemic heart disease and aortic dissection.     

左旋氨氯地平对血压控制不良患者微量白蛋白尿逆转作用的研究

目的观察不同联合治疗方案对高血压伴微量白蛋白尿(MAU)患者血压控制及白蛋白尿的逆转作用。方法选择使用血管紧张素转换酶抑制剂或血管紧张素Ⅱ受体拮抗剂后,血压仍>140/90 mm Hg(1 mm Hg=0.133 kPa)且MAU阳性的高血压患者94例,随机分为左旋氨氯地平组52例(2.5～5 mg/d)、氢氯噻嗪组42例(1 2.5～25 mg/d),干预12周。观察不同治疗方案对血压控制以及MAU的逆转作用。结果左旋氨氯地平组和氢氯噻嗪组干预1 2周后,血压达标分别为35例和27例(67.3%vs 64.3%,P>0.05)。MAU转阴率分别为53.8%和1 9.0%(P<0.01);血压<140/90 mm Hg同时MAU下降≥30%的比例分别为80.8%和64.3%(P<0.05)。结论肾素-血管紧张素阻滞剂联合钙拮抗剂或利尿剂(氢氯噻嗪)的治疗方案在血压降低以及达标率方面无显著差异。联合钙拮抗剂在降低MAU方面明显优于联合利尿剂方案。     

Alpha and beta adrenergic blockade with orally administered labetalol in hypertension. Studies on blood volume, plasma renin and aldosterone and catecholamine excretion.

Patients with essential hypertension were treated for 6 weeks with the alpha and beta adrenoceptor blocking agent labetalol alone (no. = 18) or in combination with the diuretic agent chlorthalidone (no. = 11). Maximal doses of labetalol during these trials averaged 1,460 and 650 mg/day, respectively. Significant (P < 0.05) changes during therapy with labetalol alone included a transient decrease in supine blood pressure reaching a maximum of 11 percent, persistent reduction in upright blood pressure, pulse rate (20 percent) and plasma renin activity (40 percent), a gain of 1.7 percent in body weight and of 17 percent in blood volume, a sevenfold rise in epinephrine excretion rate and a mild increase in plasma potassium; plasma aldosterone and norepinephrine excretion rate remained unaltered. After 6 weeks of combination therapy, blood pressure reduction was greater (P < 0.02) than after labetalol alone in both the supine (14.4 versus 4.3 percent) and upright (18.6 versus 11.6 percent) positions; blood volume and plasma potassium were decreased (P < 0.05), plasma renin was doubled (P < 0.02) and plasma aldosterone was unchanged. Orthostatic hypotension and several other side effects were common with large doses of labetalol but infrequent at doses used during combination therapy; moreover, these effects were often transient. These data indicate that combined alpha and beta adrenoceptor blockade with labetalol may effectively reduce blood pressure in patients with essential hypertension, with a somewhat more pronounced effect in the upright position. Extracell fluid retention may reduce the sensitivity of supine blood pressure to treatment, but this effect is avoided with concomitant diuretic therapy. Labetalol's antihypertensive action appears to be renin-independent and is associated with a marked increase in epinephrine excretion.     

Thermogenic synergism between ephedrine and caffeine in healthy volunteers: a double-blind, placebo-controlled study

Animal and human studies have suggested a thermogenic synergism between ephedrine (E), a beta-agonist, and caffeine (C), an adenosine antagonist, which may be suitable for the treatment of obesity. To study this phenomenon, the thermogenic effect of single doses of oral placebo, E 10 mg, E 20 mg, C 100 mg, and C 200 mg were compared with the effects of three different combinations of E + C, 10 mg/200 mg, 20 mg/100 mg, and 20 mg/200 mg, measured by indirect calorimetry in six healthy, lean subjects. The thermogenic effect after E + C 20 mg/200 mg was larger than that of any of the other combinations. In this dose ratio, ephedrine and caffeine exerted a supra-additive synergism, whereas the thermogenic effects of the other two combinations were only additive. The 3-hour postintake increase in systolic blood pressure after all three combinations averaged 5 to 7 mm Hg more than placebo (P less than .01), which exceeded the predicted additive effect fivefold to sevenfold. Diastolic blood pressure was not increased by E + C 20 mg/200 mg, whereas the other two combinations increased it by approximately 4 mm Hg more than placebo. E + C 20 mg/100 mg and 20 mg/200 mg increased heart rate more than placebo, while E + C 10 mg/200 mg had no effect on heart rate. As expected, all combinations increased plasma glucose, insulin, and C-peptide from their ephedrine content. No significant effects of the combinations were found on plasma lactate, glycerol, nonesterified fatty acids (NEFA), triglyceride, potassium, or sodium.(ABSTRACT TRUNCATED AT 250 WORDS)     

The captopril test for identifying renovascular disease in hypertensive patients

To develop a screening test for identifying renovascular hypertension, the blood pressure and plasma renin activity responses to an oral test dose of captopril were studied in 246 quietly seated hypertensive patients. The following criteria were developed that exploit the hyperresponsiveness of renin secretion in renovascular hypertensive patients: a 60-minute post-captopril plasma renin activity of 12 ng/ml per hour or more and an absolute plasma renin activity increase of 10 ng/ml per hour or more, along with a 150 percent increase in plasma renin activity (or a 400 percent increase if the baseline plasma renin activity was below 3 ng/ml per hour). Retrospectively, the test identified, among 200 hypertensive patients without evidence of renal dysfunction, all 56 patients with proved renovascular disease. In this group, false-positive results occurred only in two of 112 patients with essential hypertension and in six with secondary hypertension. Nine untreated patients had blood pressure levels of less than 160/100 mm Hg. The test was neither as sensitive nor specific in the 46 patients with renal insufficiency. This study demonstrates that the renin response to oral captopril is a useful screening test for identifying patients with unilateral or bilateral renovascular disease. Since the test also characterizes the renin dependency of the hypertension, it may have other diagnostic and therapeutic uses.     

Azilsartan medoxomil plus chlorthalidone reduces blood pressure more effectively than olmesartan plus hydrochlorothiazide in stage 2 systolic hypertension

Azilsartan medoxomil, an effective, long-acting angiotensin II receptor blocker, is a new treatment for hypertension that is also being developed in fixed-dose combinations with chlorthalidone, a potent, long-acting thiazide-like diuretic. We compared once-daily fixed-dose combinations of azilsartan medoxomil/chlorthalidone force titrated to a high dose of either 40/25 mg or 80/25 mg with a fixed-dose combination of the angiotensin II receptor blocker olmesartan medoxomil plus the thiazide diuretic hydrochlorothiazide force titrated to 40/25 mg. The design was a randomized, 3-arm, double-blind, 12-week study of 1071 participants with baseline clinic systolic blood pressure 160 to 190 mm Hg and diastolic blood pressure ≤119 mm Hg. Patients had a mean age of 57 years; 59% were men, 73% were white, and 22% were black. At baseline, mean clinic blood pressure was 165/96 mm Hg and 24-hour mean blood pressure was 150/88 mm Hg. Changes in clinic (primary end point) and ambulatory systolic blood pressures at week 12 were significantly greater in both azilsartan medoxomil/chlorthalidone arms than in the olmesartan/hydrochlorothiazide arm (P<0.001). Changes in clinic systolic blood pressure (mean±SE) were -42.5±0.8, -44.0±0.8, and -37.1±0.8 mm Hg, respectively. Changes in 24-hour ambulatory systolic blood pressure were -33.9±0.8, -36.3±0.8, and -27.5±0.8 mm Hg, respectively. Adverse events leading to permanent drug discontinuation occurred in 7.9%, 14.5%, and 7.1% of the groups given azilsartan medoxomil/chlorthalidone 40/25 mg, azilsartan medoxomil/chlorthalidone 80/25 mg, and olmesartan/hydrochlorothiazide 40/25 mg, respectively. This large, forced-titration study has demonstrated superior antihypertensive efficacy of azilsartan medoxomil/chlorthalidone fixed-dose combinations compared with the maximum approved dose of olmesartan/hydrochlorothiazide.     

Distinguishing the antihypertensive and electrolyte effects of eplerenone

In two clinical trials on the antihypertensive effects of the mineralocorticoid receptor antagonist eplerenone 397 essential hypertensives were dose titrated (50, 100, and 200 mg/d) over successive 4-wk periods until they reached target blood pressure levels. Of the total, 44% reached target on 50 mg/d, 17% on 100 mg/d, and 19% on 200 mg/d, with 20% failing to do so despite stepwise dose increases. At each dose level, those who reached target (responders) were compared with those who did not (nonresponders), with three major findings. First, at each dose level, the blood pressure fall in responders (systolic, 16-20 mm Hg; diastolic, approximately 15 mm Hg) was markedly more than mean values in nonresponders (systolic, 2-5 mm Hg; diastolic, 1-3 mm Hg). Second, sensitivity to eplerenone varied widely across the population studied in terms of blood pressure reduction. Third, there was no difference in plasma [K+] levels between responders and nonresponders at any dose level. We interpret these data as evidence for the major antihypertensive effect of eplerenone being via mechanisms other than those involving epithelial electrolyte and fluid transport. The modest (< or =0.2 mEq/liter at 200 mg/d) mean elevation in plasma [K+] suggests that titration to effect rather than forced titration may minimize the risk of hyperkalemia, even where relatively high (100-200 mg/d) doses of the specific mineralocorticoid receptor antagonist eplerenone may ultimately be required.     

Effect of antishock trouser inflation on plasma renin activity during hemorrhagic shock

The effect of antishock trouser inflation on plasma renin activity during hypovolemic shock was studied in dogs. Following anesthesia, six dogs were bled to a systolic blood pressure of 60 mm Hg. Antishock trousers were inflated to 40 to 100 mm Hg for 20 minutes each. Plasma renin activity was measured before phlebotomy, after phlebotomy, and after each 20-minute period of antishock trouser inflation. Three dogs without antishock trousers served as controls. Experimental animals had a significant rise in blood pressure when the antishock trousers were inflated to 100 mm Hg. Plasma renin activity showed a marked increase following phlebotomy (experimental, 1.55 ng/mL/h to 13.63 ng/mL/h; control, 2.71 ng/mL/h to 19.7 ng/mL/h). Both groups had a continued small, statistically insignificant rise in plasma renin levels throughout the remainder of the experiment. Plasma renin level changes did not explain the observed rise in blood pressure following antishock trouser inflation. Plasma renin levels remained elevated in spite of improvement of blood pressure after application of antishock trousers.     

The Trial of Antihypertensive Interventions and Management (TAIM) Study. Final results with regard to blood pressure, cardiovascular risk, and quality of life.

The Trial of Antihypertensives Interventions and Management (TAIM) was a multicenter double-blind placebo-controlled clinical trial of drug and diet combinations for the treatment of mild hypertension among 878 participants, ages 21 to 65, 110% to 160% ideal weight, and with baseline diastolic blood pressure 90 to 100 mm Hg. The drugs used were placebo, chlorthalidone (25 mg/daily) or atenolol (50 mg/daily). The diets studied were usual, weight loss, sodium reduction/potassium increase. Trial end points were 6-month diastolic blood pressure change, cardiovascular risk change, and quality of life change. Either drug combined with weight loss produced the greatest blood pressure reduction of 15 mm Hg, compared to 8 mm Hg on placebo/usual diet. Adding sodium restriction to either drug did not enhance blood pressure lowering effect. Drugs outperformed diet in terms of antihypertensive effect. However, those on placebo and assigned to weight reduction who lost more than 4.5 kg and those on sodium restriction who reduced sodium to less than 70 mEq daily lowered blood pressure to a similar extent as those on either of the two drugs alone. Cardiovascular risk at 6 months relative to baseline ranged from 0.85 in weight loss/atenolol subgroup to 1.04 in the usual diet/chlorthalidone subgroup. Blacks were more responsive to chlorthalidone plus weight loss and whites to atenolol plus weight loss. Quality of life, as measured by scales of distress and well-being, was favorably affected by weight reduction. Although there were few side effects of the drugs and most patients improved on most parameters, sexual complaints were worsened among those on chlorthalidone and usual diet compared to placebo.(ABSTRACT TRUNCATED AT 250 WORDS)     

Angiotensin II is a necessary component for the development of hypertension in the two kidney, one clip rat

The current study was undertaken to define the role of the renin-angiotensin system in the development of hypertension in the two kidney, one clip Goldblatt rat. Captopril was administered orally (100 mg/kg/day) to two groups of rats (n = 8 each) 24 hours before and each day after unilateral renal artery clipping (0.2 mm internal diameter): the drug was given for either 16 weeks (group I) or 24 weeks (group II). Sham-operated (n = 5) and Goldblatt (n = 8) rats not receiving captopril were prepared for comparisons of plasma renin activity and systolic blood pressure. Indomethacin (20 mg/kg/day subcutaneously) was administered for 48 hours concomitantly with captopril to the rats in group I. In group II, systolic blood pressure was monitored for 7 weeks after cessation of captopril. Continual captopril administration to Goldblatt rats completely prevented the rise in systolic blood pressure, a rise that was observed in Goldblatt rats not receiving captopril. Whereas systolic blood pressure of captopril-treated rats approximated 100 mm Hg throughout the study, that of Goldblatt rats not receiving the drug increased to nearly 180 mm Hg within 6 weeks after clipping. Systolic blood pressure of sham-operated rats remained normal. Indomethacin did not change systolic blood pressure in the drug-treated rats in group I. On cessation of captopril therapy in group II, systolic blood pressure increased gradually in a manner that paralleled the development of the disease in the Goldblatt rats that did not receive captopril. Plasma renin activity was determined in Goldblatt and sham-operated rats at either 16 weeks (group I) or 24 weeks (group II) after clipping; the rats from either group with mild hypertension (systolic blood pressure less than 180 mm Hg) had normal plasma renin activity whereas those with severe hypertension (systolic blood pressure greater than 180 mm Hg) had greatly elevated plasma renin activity. In summary, captopril can completely prevent the increase in systolic blood pressure for up to 24 weeks in Goldblatt rats, and this hypotensive effect is not mediated by the prostaglandins. It is concluded that the renin-angiotensin system is a necessary component of the hypertensive process in this experimental model.