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Background: Drospirenone (DRSP) is a novel progestin with aldosterone receptor antagonist activity developed for hormone therapy as DRSP /17-beta estradiol (DRSP/E2). Because of a significant aldosterone antagonist activity, we studied the effects of DRSP/E2 on serum potassium (K) and blood pressure (BP) in hypertensive postmenopausal women with and without diabetes mellitus., Methods: This was a multicenter trial in postmenopausal women 44 to 70 years of age, either with type 2 diabetes mellitus (n = 82) or without type 2 diabetes mellitus (n = 148) and using an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist. Patients were randomized to 28 days of DRSP/E2 or placebo. Study endpoints were the number and percentage subjects who developed hyperkalemia (K >or= 5.5 mEq/L) and changes from baseline in clinic systolic and diastolic BP. To increase the likelihood of unmasking hyperkalemia, the nondiabetic group was also administered ibuprofen for 5 days., Results: There were no statistical differences in the overall number and percentage of subjects with hyperkalemia for DRSP/E2 versus placebo. No subject had symptoms or electrocardiographic changes related to hyperkalemia. Blood pressure was reduced by -8.6/-5.8 mm Hg in patients receiving DRSP/E2 versus -3.7/-2.9 mm Hg in those receiving placebo (P < .01 for both SBP and DBP)., Conclusions: In hypertensive postmenopausal women, treatment with DRSP/E2 was not associated with a greater incidence of hyperkalemia than with placebo in patients with and without type 2 diabetes mellitus and concomitant use of ACE inhibitors, angiotensin receptor antagonists, or ibuprofen. Furthermore, DRSP/E2 was found to have a significant antihypertensive effect in this high-risk population.

Advanced glycation end product (AGE) formation that occurs with aging and diabetes leads to the cross-linking of proteins and subsequent changes in the physicochemical properties of tissues. Cellular responses to AGE that lead to either pathological conditions or removal of AGE are mediated by a number of receptors that have been identified on various cell types such as macrophages, endothelial cells, and smooth-muscle cells. Mechanisms by which AGE affect the cardiovascular system include AGE cross-linking of long-lived proteins such as collagen and elastin and altered cellular responses. Alagebrium (3-phenacyl-4,5-dimethylthiazolium chloride, ALT-711) is the first drug in a new class of thiazolium therapeutic agents that break established AGE cross-links between proteins. In animal studies, alagebrium was effective in reducing large artery stiffness, slowing pulse-wave velocity, enhancing cardiac output, and improving left ventricular diastolic distensibility. In human studies to determine safety and efficacy, alagebrium was safe and well tolerated. In the first phase 2 clinical study, alagebrium improved arterial compliance in elderly patients with vascular stiffening. In two subsequent phase 2 clinical studies, one addressing diastolic heart failure and the other addressing systolic hypertension, alagebrium was effective in improving cardiac function and uncontrolled systolic blood pressure, particularly in more severely affected patients. Additional clinical studies to determine the utility of alagebrium in treating cardiovascular disorders associated with aging are in progress.

Background: Aldosterone has been implicated in the pathogenesis of progressive cardiovascular disease. Drospirenone (DRSP) is a novel progestin with aldosterone receptor antagonist activity developed for hormone replacement therapy (HRT) as DRSP/17beta-estradiol (DRSP/ E2). We investigated the additive effect of DRSP/E2 versus placebo on 24-h ambulatory blood pressure (BP) in postmenopausal women with hypertension treated with enalapril maleate (ENA)., Methods: This was a double-blind, randomized, two-parallel group trial. Twenty-four nonsmoking postmenopausal women receiving 10 mg of ENA twice a day before study were randomized to DRSP/E2 + ENA (n = 12) or placebo (P) + ENA (n = 12) for 14 days. Twenty-four-hour ambulatory BP, plasma renin activity, and serum aldosterone were determined at baseline and on day 14., Results: Compared to placebo, 24-h mean [SD] BP in the DRSP/E2 + ENA group decreased significantly from baseline (139/80 mm Hg), systolic (-9 [51 mm Hg, P = .014) and diastolic (-5 [4] mm Hg, P = .007). Essentially no change from baseline (139/83 mm Hg) in systolic or diastolic 24-h ambulatory BP were observed in the P + ENA group. Aldosterone (mean [SD]) increased from baseline by 2.6 [4.5] ng/dL in the DRSP/E2 + ENA group, and decreased by 0.3 [5.5] ng/dL in the P + ENA group (P = .08) consistent with an antimineralocorticoid effect., Conclusions: Our results suggest a significant additive BP-lowering effect of DRSP/E2 on both systolic and diastolic BP in hypertensive postmenopausal women receiving ENA, consistent with an antimineralocorticoid effect. DRSP/E2, a HRT with antimineralocorticoid effects, could offer a novel potential mechanism for reducing cardiovascular end points in postmenopausal women.

Regardless of the specific antihypertensive agent used, the most important aspect of the management of the patient with coexistent hypertension and renal disease is adequate control of the blood pressure. The current JNC VI recommendation is for a reduction to a target blood pressure of 130/85 mm Hg, or to a lower value of 125/75 in patients with greater than 1 g proteinuria per day. Impaired renal sodium excretion leading to extracellular fluid volume (ECFV) expansion is the most clinically important mechanism leading to renal parenchymal hypertension. Sodium restriction and loop diuretics constitute the cornerstone of effective antihypertensive therapy. Control of blood pressure in patients with chronic renal disease may be difficult without measures that address ECFV. JNC VI recommends the use of angiotensin converting enzyme (ACE) inhibitors in patients with hypertension and chronic renal disease to control hypertension and to slow progressive renal failure. ACE inhibitors have been found by clinical trials to be useful agents in the settings of established insulin-dependent diabetes mellitus (IDDM) nephropathy, non-insulin-dependent diabetes mellitus (NIDDM) nephropathy, IDDM patients with normal blood pressures and microalbuminuria, NIDDM patients with microalbuminuria and normal renal function, and a variety of nondiabetic renal diseases, especially in the setting of significant proteinuria. Calcium antagonists are effective for treating hypertensive patients with chronic renal impairment but have not been studied as intensively as ACE inhibitors with regard to their ability to slow the progression of renal insufficiency independently of their blood-pressure-lowering effects. The initial results for calcium antagonists and for combination calcium antagonist-ACE inhibitor therapy have been promising. The angiotensin II antagonists have theoretical advantages for use in renal impairment, and seem to have similar renal hemodynamic and antiproteinuric effects to ACE inhibitors, but further clinical study is needed.

A metaanalysis of the major clinical trials on the benefits of antihypertensive therapy revealed that there is an overall reduction of coronary events by treatment, but that it is only about one-half of the reduction predicted. The reduction in stroke achieved the predicted number. This "failure" has been attributed to study design, patient age at entry, preexisting disease, high-lipid diets, drug-associated cardiac dysrhythmias, and the "J-curve" effect. It is also possible that the drugs used in these trials did not suppress the morning acceleration of blood pressure during which most coronary and cerebrovascular events occur. Ambulatory blood pressure monitoring studies suggest that antihypertensive drugs reduce overall blood pressure throughout the 24-h period, but do not change the circadian curve. The beneficial effect of antihypertensive therapy probably rests with the magnitude of blood pressure reduction. It is unlikely that lack of suppression of morning acceleration alone accounted for the failure of "older" drugs to prevent as much cardiac mortality as expected.