Superior antihypertensive and cardioprotective effects of chlorthalidone compared with hydrochlorothiazide.

Diuretics are the most commonly used drugs for the treatment of hypertension, either alone or in combination with other antihypertensive drugs. Of all diuretics, hydrochlorothiazide (HCTZ) and chlorthalidone (CTD) are the most commonly used, with HCTZ being the most widely prescribed diuretic. Recent studies have shown that CTD is a better diuretic with superior antihypertensive effectiveness and cardiovascular protection. Although these diuretics are chemically, pharmacokinetically and pharmacodynamically different, CTD continues to be called a "thiazide-like" diuretic. The only common features they both share are a sulfhydryl group in their molecules and their common mechanism and site of diuretic action. In order to get a better understanding of the true pharmacologic actions as well as the benefits and risks of these diuretics, a MEDLINE search of the English language literature between 1964 and January 2021 was conducted, using the terms "diuretics", "hydrochlorothiazide", "chlorthalidone", "hypertension", "cardiovascular disease" and "treatment". From this search, 28 pertinent papers were selected and they will be discussed in this review together with collateral literature. The analysis of results revealed that CTD is superior to HCTZ in antihypertensive effectiveness and cardioprotection and should be the preferred diuretic for the treatment of hypertension.

Unintended consequences of the new ACC/AHA blood pressure treatment guidelines.

Hypertension is a major risk factor for cardiovascular disease, heart failure, chronic kidney disease and stroke. Therefore, its early detection and treatment are very important according to blood pressure (BP) treatment guidelines issued by the various scientific societies. Over the years, BP treatment guidelines have changed from strict control of BP to more relaxed control, and lately to a strict BP control influenced by the results of the SPRINT trial. The recently published BP treatment guidelines by the American College of Cardiology/American Heart Association (ACC/AHA) recommend a systolic BP (SBP) and diastolic BP reduction to less than 130 mmHg and less than 80 mmHg, respectively, for all ages, and have also changed the classification of hypertension by changing the term "prehypertension" of the JNC 7 (7th Joint National Committee) guidelines to "stage 1 hypertension". These changes could have significant social and economic consequences for the patients. In order to get a better perspective of the current status of SBP control, we conducted a MEDLINE search of the English language literature from 2014 to 2018 in connection with recent (2014-2018) BP treatment guidelines, using the terms 'hypertension', 'blood pressure control', 'intensive blood pressure control', 'blood pressure treatment guidelines', and 'benefits and risks of intensive blood pressure control', and 26 pertinent papers were retrieved. These papers together with collateral literature, which goes beyond the year 2014, will be discussed in this review.

Controversies regarding the cardiovascular effects of testosterone replacement therapy in older men.

Testosterone (T) levels decline with the advancement of age and have been associated with increased incidence of cardiovascular disease (CVD). Indeed, several epidemiologic and prospective cohort studies have suggested that low T levels (lower tertile or quartile) are associated with increased incidence of CVD, type 2 diabetes mellitus (T2DM), obesity and dyslipidemia. In contrast, correction of low T levels with testosterone replacement therapy (TRT) is associated with a decrease in the incidence of CVD, T2DM and dyslipidemia as has been demonstrated by several randomized, controlled trials as well as prospective cohort studies. However, recent studies have shown that TRT is associated with an increased incidence of adverse CV events and these studies have created a great controversy regarding the CV benefits of TRT. In order to get a better perspective on the current status of TRT, a focused MEDLINE and Cochrane database search of the recent English language literature between 2010 and 2017 was conducted and 29 pertinent papers were retrieved. The studies reviewed could not definitely confirm the beneficial or adverse CV effects of TRT. Therefore, on the basis of the current stage of knowledge, older male subjects with low T levels could continue to receive TRT, but this decision should be discussed with their physicians.

Treatment of hypertension with olmesartan medoxomil, alone and in combination with a diuretic: an update.

Olmesartan medoxomil is an angiotensin II (Ang II) receptor blocker (ARB) that has been approved by the US Food and Drug Administration (FDA) for the treatment of hypertension. It is a prodrug that is hydrolysed in the gut into its active metabolite, olmesartan (RNH-6270). Olmesartan is highly selective for the Ang II type 1 receptor (AT1) to which it binds completely and insurmountably and has very little affinity for the other receptor subtypes AT2 and AT4. After oral administration, in animals and humans, it achieves a maximal blood drug concentration within a maximal time of approximately 2 h. It is then slowly eliminated in the urine and faeces. His half-life is approximately 13 h, which makes it suitable for once-daily administration. Olmesartan medoxomil given orally in single daily doses of 20-40 mg has demonstrated significant blood pressure (BP) lowering effects in hypertensive patients. A medline search for the preparation of this manuscript was conducted and revealed 128 references, from 2000 to 2007. Of these, only 16 well-designed prospective clinical trials were selected. The remaining were either animal studies, reviews or studies in progress. In well-designed clinical trials, olmesartan medoxomil has demonstrated similar antihypertensive actions to the other antihypertensive drugs, as well as other members of its class given the highest recommended doses. In addition, the BP lowering effect of olmesartan, like the other members of its class, is greatly enhanced in combination with a diuretic. Its safety profile is similar to the other ARBs and no different than placebo.

Promising cardiovascular and blood pressure effects of the SGLT2 inhibitors: a new class of antidiabetic drugs.

Patients with type 2 diabetes mellitus (T2DM) exhibit an increased risk of cardiovascular (CV) events. Treatment of these patients with traditional as well as newer glucose-lowering drugs has not demonstrated superiority in CV outcomes compared to placebo, despite effective control of diabetes. However, the recently FDA-approved sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of T2DM have demonstrated promising CV-protecting and blood pressure-lowering effects in addition to their effectiveness in glucose lowering, making them a novel class of drugs for the treatment of T2DM. So far, there are three SGLT2 inhibitors approved by the FDA and EMA for the treatment of T2DM: canagliflozin, dapagliflozin and empagliflozin. They exert their antihyperglycemic effect through inhibition of SGLT2 in the kidney and significantly reduce glucose reabsorption from the proximal renal tubule. By blocking glucose reabsorption, they lead to loss of calories, weight, abdominal and total body fat, blood pressure and CV complications. One CV outcomes randomized trial and several short-term studies have shown reductions in CV events and blood pressure in patients with T2DM. It is the hope that large ongoing long-term outcome studies will provide further much-needed information, when they are completed.

The impact of SPRINT on the future treatment of hypertension: a mini review.

Blood pressure (BP) control is associated with a significant decrease in the risk of coronary artery disease (CAD), stroke and chronic kidney disease (CKD), and U.S. treatment guidelines in 2003 and 2007 recommended a BP reduction to <140/90 mmHg for uncomplicated hypertension and to <130/80 mmHg for hypertension complicated by CAD, diabetes mellitus (DM) or CKD. In hopes of further decreasing the adverse effects of hypertension, more aggressive lowering of systolic blood pressure (SBP) was tested. However, this aggressive control of SBP did not materialize in additional cardiac benefits, and in fact resulted in worsening of cardiovascular and renal complications with the exception of stroke. These findings led national committees in 2014 and 2015 to draw up new guidelines recommending a relaxation of BP control based on recent clinical evidence, until publication of SPRINT. This National Institutes of Health (NIH)-sponsored study showed that aggressive SBP lowering to <120 mmHg was beneficial in further decreasing the risk of CVD, CVD mortality and strokes. The results of this study will most likely lead to the revision of current guidelines and to the recommendation of stricter BP control. However, the results of SPRINT are not final and still are in contrast with other recent studies. Until new guidelines become available, we should follow the current ones, or move closer to older guidelines depending on the clinical situation. A return to BP <140/90 mmHg for older subjects or uncomplicated hypertension and to <130/80 mmHg for hypertension complicated by CAD, DM and CKD may be appropriate.

The clinical significance and costs of herbs and food supplements used by complementary and alternative medicine for the treatment of cardiovascular diseases and hypertension.

Complementary and alternative medicine (CAM) is widely used by people in the United States and other countries for the treatment of health conditions that include hypertension (HTN), cardiovascular disease (CVD), heart failure, hyperlipidemia and other condtions. The visits to CAM practitioners result in significant out-of-pocket expenses, as CAM is not covered by health insurance in the majority of cases. The reasons for this are that the products used are not closely regulated by governmental regulatory agencies and lack scientific evidence about their effectiveness and safety. The people regard these products as being 'natural' and, consequently, safe. However, there is evidence that these products can be contaminated and adulterated with other substances and could cause harm to the persons who take them. The responsibility falls on the health professionals, who should become familiar with the various CAM products, inquire their patients whether they taking any of these products and advise them accordingly. This review is based on a recent statement issued by the American Medical for the use of CAM for the treatment of HTN. For its preparation, a Medline search of the English language literature was performed between 2010 and 2014 restricted in the use of CAM for CVD and HTN, and from the 88 abstracts reviewed, 23 pertinent papers were selected. These papers together with collateral literature will be discussed in this review regarding CAM and CAM products on their effectiveness and safety for the treatment of CVD and HTN.

Phase III multicenter trial comparing the efficacy of 2% dodecafluoropentane emulsion (EchoGen) and sonicated 5% human albumin (Albunex) as ultrasound contrast agents in patients with suboptimal echocardiograms.

OBJECTIVES: This study was performed to compare the safety and efficacy of intravenous 2% dodecafluoropentane (DDFP) emulsion (EchoGen) with that of active control (sonicated human albumin [Albunex]) for left ventricular (LV) cavity opacification in adult patients with a suboptimal echocardiogram. BACKGROUND: The development of new fluorocarbon-based echocardiographic contrast agents such as DDFP has allowed opacification of the left ventricle after peripheral venous injection. We hypothesized that DDFP was clinically superior to the Food and Drug Administration-approved active control. METHODS: This was a Phase III, multicenter, single-blind, active controlled trial. Sequential intravenous injections of active control and DDFP were given 30 min apart to 254 patients with a suboptimal echocardiogram, defined as one in which the endocardial borders were not visible in at least two segments in either the apical two- or four-chamber views. Studies were interpreted in blinded manner by two readers and the investigators. RESULTS: Full or intermediate LV cavity opacification was more frequently observed after DDFP than after active control (78% vs. 31% for reader A; 69% vs. 34% for reader B; 83% vs. 55% for the investigators, p < 0.0001). LV cavity opacification scores were higher with DDFP (2.0 to 2.5 vs. 1.1 to 1.5, p < 0.0001). Endocardial border delineation was improved by DDFP in 88% of patients versus 45% with active control (p < 0.001). Similar improvement was seen for duration of contrast effect, salvage of suboptimal echocardiograms, diagnostic confidence and potential to affect patient management. There was no difference between agents in the number of patients with adverse events attributed to the test agent (9% for DDFP vs. 6% for active control, p = 0.92). CONCLUSIONS: This Phase III multicenter trial demonstrates that DDFP is superior to sonicated human albumin for LV cavity opacification, endocardial border definition, duration of effect, salvage of suboptimal echocardiograms, diagnostic confidence and potential to influence patient management. The two agents had similar safety profiles.

Possible pathophysiologic mechanisms supporting the superior stroke protection of angiotensin receptor blockers compared to angiotensin-converting enzyme inhibitors: clinical and experimental evidence.

Stroke is a major cause of death and disability and its incidence increases linearly with age and the level of systolic and diastolic blood pressure. Stroke, besides being a cause of long-term disability for the affected person, also imposes a significant burden on society and healthcare costs. Although good blood pressure control is very critical for stroke prevention, angiotensin receptor blockers (ARBs) may be superior to angiotensin-converting enzyme inhibitors (ACEIs) for the same degree of blood pressure control. This hypothesis has clinical and experimental support. ARBs prevent stroke incidence by blocking the angiotensin II (AII), AT1 receptors preventing brain ischaemia and allowing AII to stimulate the unoccupied AT2 receptors, which improve brain ischaemia. ACEIs, by reducing AII generation, are less effective in preventing stroke. This hypothesis provides evidence that AII plays an important role in the prevention of stroke. Certain ARBs like losartan, and telmisartan, irbesartan and candesartan possess additional properties which may play a role in stroke prevention, which is independent of AII. These include antiplatelet aggregating, hypouricemic, antidiabetic and atrial antifibrillatory effects. However, the most critical factor in stroke prevention is good blood pressure control irrespective of drug used.

Current status of angiotensin receptor blockers for the treatment of cardiovascular diseases: focus on telmisartan.

Poorly controlled hypertension is a major risk for cardiovascular morbidity and mortality, strokes, heart failure and renal failure. Despite these devastating complications, blood pressure control of

Antihypertensive effectiveness of low-dose lisinopril-hydrochlorothiazide combination. A large multicenter study. Lisinopril-Hydrochlorothiazide Group.

OBJECTIVE: To test the antihypertensive and metabolic effects of lisinopril, 10 mg/d (L); hydrochlorothiazide, 12.5 and 25 mg/d (H12.5 and H25); and its combination with lisinopril (L/H12.5 and L/H25) against placebo in patients with mild to moderate (stage I and stage II) hypertension. DESIGN: Multicenter, double-blind, placebo-controlled outpatient study of 12 weeks' duration. PATIENTS: After 4 weeks of single-blind placebo treatment, 505 patients whose sitting diastolic blood pressure was 100 to 114 mm Hg were randomized into the study--467 patients completed it (placebo, 71; L, 80; H12.5, 79; H25, 77; L/H12.5, 79; and L/H25, 81). The patients were seen in the clinic every 2 weeks, where measurements of their sitting and upright blood pressure and heart rate were taken 24 +/- 2 hours after drug administration. Complete blood cell counts with differential cell counts, blood chemistry studies, urinalyses, and electrocardiograms were done at baseline and during the study. Roentgenograms were done once at baseline. RESULTS: Compared with placebo, all drug regimens decreased sitting and upright blood pressure (P < .001) and had no effect on sitting and upright heart rate. The greatest effect was obtained with the combinations of L/H12.5 and L/H25. There was no difference between L/H12.5 and L/H25 or between H12.5 and H25. There were no serious clinical side effects except cough, which was slightly higher with L, L/H12.5, and L/H25. The only metabolic side effects were in serum potassium level, which was lower with H25 (P < .01), and serum glucose level, which was higher with H25 and L/H25 (P < .01). CONCLUSIONS: The data suggest that (1) monotherapy of hypertension with L, H12.5, H25, L/H12.5, and L/H25 was effective and well tolerated; (2) the best results were achieved with L/H12.5 and L/H25; (3) lower doses of hydrochlorothiazide either alone or in combination with lisinopril were equipotent with higher doses and were free of metabolic side effects.

Severe reversible azotemia from captopril therapy. Report of three cases and review of the literature.

We saw three cases of severe reversible azotemia secondary to captopril therapy in hypertension. All patients had extensive peripheral vascular disease involving the renal arteries, and two patients (patients 2 and 3) had high levels of peripheral plasma renin activity. The azotemia occurred approximately two weeks after exposure to captopril, and fever, a maculopapular pruritic cutaneous rash, and eosinophilia developed in two patients (patients 2 and 3). The cause of the azotemia in our patients is not clearly known, since renal biopsies were not performed. The most likely cause for the azotemia was volume contraction with reduction in the glomerular filtration rate, although a direct insult to the kidney could not be excluded.

Ticrynafen: a novel uricosuric antihypertensive natriuretic agent.

Interest in new diuretics with less side effects has led to the synthesis of ticrynafen, an uricosuric diuretic. This agent was compared with hydrochlorothiazide in a crossover design study involving 12 hypertensive men. Both agents significantly decreased mean arterial pressure from 8% to 18% in eight of the 12 patients. In addition to reducing body weight, these diuretics induced reversible changes in BUN and carbon dioxide content (increased) and plasma concentration of potassium and chloride ions (decreased). The most important change in renal function was a 2.5-fold increase in fractional urate clearance by ticrynafen associated with reduction of serum uric acid by 62%. Thus, ticrynafen is a promising therapeutic agent in hypertension, adding a unique uricosuric effect that should improve patient compliance.

Action of Nitroglycerin and amyl nitrite in labile and essential hypertension: hemodynamic differences.

Seventeen patients with labile hypertension received nitroglycerin and 18 received amyl nitrite. Twelve patients with established essential hypertension received nitroglycerin and 12 received amyl nitrite. Nitroglycerin reduced the systolic and mean arterial pressures and cardiac output in both groups, but had no effect on diastolic pressure and total peripheral resistance. Amyl nitrite decreased systolic, diastolic, and mean arterial pressures and peripheral vascular resistance and increased heart rate and cardiac output in labile hypertensives. In established hypertensive patients, amyl nitrite decreased systolic, diastolic, and mean arterial pressures and cardiac output, and had little effect on peripheral vascular resistance. Nitroglycerin reduced arterial pressure in labile and established hypertensives through venodilation and peripheral venous pooling. Amyl nitrite and effects similar to nitroglycerin in established hypertensives; in labile hypertensives it reduced arterial pressure through arterial dilation and a decrease in peripheral vascular resistance.

There are no racial, age, sex, or weight differences in the effect of salt on blood pressure in salt-sensitive hypertensive patients.

BACKGROUND: This report is part of a larger, multicenter, placebo-controlled study designed to test the effects of low and high salt intake on the antihypertensive action of enalapril maleate or isradipine in salt-sensitive, hypertensive patients. OBJECTIVE: To present our findings with respect to the effects of race, age, sex, and weight on the blood pressure response to low and high salt intake in salt-sensitive hypertensive patients before randomization into the larger study. PATIENTS AND METHODS: After 3 week (weeks -9 to -6) of ad lib salt intake (100-200 mmol/d of sodium), 1916 patients whose sitting diastolic blood pressure was between 95 and 115 mm Hg entered a 3-week period (week -6 to -3) of low salt intake (50-80 mmol/d of sodium) and then a 3-week period (week -3 to 0) of high salt intake (200-250 mmol/d of sodium). Of the 1916 patients, 624 were identified as being sensitive to salt by demonstrating an increase in sitting diastolic blood pressure of equal to or more than 5 mm Hg from the low to high salt intake. Of these patients, 367 were white, 156 were black, 92 were Hispanic, 8 were Asian, and 1 was American Indian. Also, 315 were men and 309, women; 351 were 55 years or younger and 273 were older than 55 years; and 195 had a body mass index of 27 or less and 429 had a body mass index higher than 27. RESULTS: The sitting blood pressure decreased with salt restriction and increased with salt load in all groups of patients (P < .001). There were no statistically significant differences in the blood pressure changes to salt changes by race, age, sex, and weight. CONCLUSIONS: This large, multicenter study did not demonstrate any statistically significant effect of race, age, sex, and weight on blood pressure response to salt changes in salt-sensitive hypertensive patients.

Cardiovascular complications from consumption of high energy drinks: recent evidence.

The energy drinks (ED) are caffeinated beverages that are popular among teenagers and young adults. They are aggressively marketed as providing alertness, energy and sex prowess. The EDs in addition to caffeine contain several plant stimulants and simple sugars, which increase their caloric content. The caffeine concentration in these drinks is high and their overconsumption could lead to insomnia, agitation, tremors and cardiovascular complications including sudden death. Alcohol is often mixed with EDs (AMEDs) in the wrong perception that the caffeine in the EDs will prevent the drowsiness and sleepiness from alcohol and allow the person to consume more alcohol. This false perception, could lead to alcohol intoxication and the taking of risky decisions, like driving under the influence of alcohol and the risk of serious physical harm to themselves and others. To prevent the problem of consumption of EDs and AMEDs, the caring physician could help by advising the parents and his young patients about the serious health risks from the consumption of these drinks. In order to grasp the extend of the problem of ED and AMED consumption, we did a Medline search of the English language literature from January 2010 to December 2013, using the terms EDs and alcohol-mixed EDs. All the findings from the recent studies regarding the cardiovascular complications from the consumption of EDs and AMEDs together with collateral literature will be discussed in this review.

Captopril stimulation of differential renins in renovascular hypertension.

Twenty-six patients being evaluated for renovascular hypertension were studied to assess the diagnostic value of enhancing the differential between renal venous renins (PRA) by a single 25 mg oral dose of converting enzyme inhibitor (CEI, captopril). Antihypertensive medications were not discontinued prior to the study, and renal venous effluent was sampled before and 30 minutes after CEI. Eight patients without stenosis who did not have surgery had post-CEI ratios of less than 3.0. The other 18 patients had operative intervention, with 14 subsequently having improved blood pressure control. Of these 14, seven patients with unilateral stenosis, four patients with bilateral stenosis, and one patient without overt stenosis but with other evidence of reduced renal blood flow had 30-minute PRA ratios of 3.0 or greater. Five of these 14 patients had prestimulation ratios of less than 1.5 and might not be considered operative candidates by conventional criteria. Four other patients unimproved by surgery had post-CEI ratios of less than 3.0 despite a baseline ratio of greater than 1.5 in two of four. Only two patients with post-CEI ratios of less than 3.0 were improved with surgery. We conclude that a 30-minute post-CEI renal venous ratio of 3.0 or greater enhances the probability that patients with renovascular disease, and hypertension will respond to surgical intervention with improved blood pressure control.

Racial differences in pressure, volume and renin interrelationships in essential hypertension.

The interrelationships of arterial pressure, plasma volume (PV), and plasma renin activity were studied in 152 consecutive male patients with uncomplicated essential hypertension. Of these, 22 (17 white and 5 black) subjects had normal plasma volumes and because of the small number were not included in the analysis of results. The remaining 130 (35 black and 95 white) patients were classified as having either expanded or contracted plasma volume. A higher percentage of black (43%) than white (21%) subjects were volume expanded (PV > 19 ml/cm) and a lower percentage of blacks (57%) than whites (79%) were volume contracted (PV < 17 ml/cm). There was not significant difference in mean arterial pressure and plasma renin activity between the volume expanded and contracted black patients. In contrast, the white patients with contracted plasma volume had significantly higher arterial pressures (p < 0.05) and plasma renin activity (p < 0.001) than those with expanded plasma volume. More blacks than whites had low plasma renin activity and did not manifest the inverse relationship of plasma renin activity to plasma volume as did the whites. These data confirm and extend previous observations that the relationship between plasma volume and plasma renin activity (PRA) in the male patient with essential hypertension seems to differ between the black and white race. Efforts to explain the low PRA in black patients might be best directed toward those patients with suppressed PRA and with contracted intravascular volume.

Influence of race and dietary salt on the antihypertensive efficacy of an angiotensin-converting enzyme inhibitor or a calcium channel antagonist in salt-sensitive hypertensives.

Dietary salt restriction is a recommended adjunct with antihypertensive therapy. There may be racial differences in blood pressure response to salt restriction while on antihypertensive therapy. We performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial (black, n=96; Hispanic, n=63; white, n=232). Participants were initially preselected for stage I to III hypertension and then further selected for salt sensitivity (> or = 5 mm Hg increase in diastolic blood pressure after 3 weeks of low salt [< or = 88 mmol/d Na+] and high salt [>190 mmol/d Na+] diet). We compared the antihypertensive effect of an angiotensin-converting enzyme inhibitor (enalapril 5 or 20 mg BID) or a calcium channel antagonist (isradipine 5 or 10 mg BID) during alternating periods of high and low salt intake. The main outcome measure was blood pressure change and absolute blood pressure level achieved with therapy. During the high salt diet (314.7+/-107.5 mmol/d urinary Na+) there was greater downward change in blood pressure with both enalapril and isradipine compared with the low salt diet (90.1+/-50.8 mmol/d Na+); however, the absolute blood pressure achieved in all races was consistently lower on a low salt diet for both agents. Black, white, and Hispanic isradipine-treated salt-sensitive hypertensives demonstrated a smaller difference between high and low salt diets (black, -3.6/-1.6 mmHg; white, -6.2/-3.9 mmHg; Hispanic, -8.1/-5.3 mm Hg) than did enalapril-treated patients (black, -9.0/-5.3 mm Hg; white, -11.8/-7.0 mm Hg; Hispanic, -11.1/-5.6 mm Hg). On the low salt diet, blacks, whites, and Hispanics had similar blood pressure control with enalapril and isradipine. On the high salt diet, blacks had better blood pressure control with isradipine than with enalapril, whereas there was no difference in the blood pressure control in whites and Hispanics treated with either drug. Dietary salt reduction helps reduce blood pressure in salt-sensitive hypertensive blacks, whites, and Hispanics treated with enalapril or isradipine. These data demonstrate that controlling for salt sensitivity diminishes race-related differences in antihypertensive activity.

Long-term hemodynamic and metabolic effects of trimazosin in essential hypertension.

The long-term effects of trimazosin (TMZ) were studied in 26 male patients with mild essential hypertension. After a 2 wk single-blind placebo (P) period, 13 patients were randomly selected to receive TMZ and 13 P; they were followed for an additional 8 wk. TMZ was given in incremental doses of 25 to 50, 100 to 200, and finally 300 mg three times a day. The patients were seen at the clinic every 2 wk and their arterial pressures (AP) and heart rates (HRs) were measured in the supine (5 min) and upright (2 min) position. Blood chemistries, blood count, plasma volume (PV), plasma renin activity (PRA), plasma aldosterone (PA), and cardiac output (CO) were determined by ultrasound at the end of P and TMZ periods. TMZ decreased the AP and total peripheral resistance (TPR) at the higher dosages, but had no effect on PV, PRA, PA, CO, HR, or blood chemistry determinations. No effects were observed on any of the above parameters after P. We conclude that (1) TMZ is an effective and safe antihypertensive, (2) it lowers AP through reduction of TPR, and (3) its effect is dose related.