The future of antihypertensive treatment.

Despite progress in recent years in the prevention, detection, and treatment of high blood pressure (BP), hypertension remains an important public health challenge. Hypertension affects approximately 1 billion individuals worldwide. High BP is associated with an increased risk of mortality and morbidity from stroke, coronary heart disease, congestive heart failure, and end-stage renal disease; it also has a negative impact on the quality of life. Hypertension cannot be eliminated because there are no vaccines to prevent the development of hypertension, but, its incidence can be decreased by reducing the risk factors for its development, which include obesity, high dietary intake of fat and sodium and low intake of potassium, physical inactivity, smoking, and excessive alcohol intake. For established hypertension, efforts are to be directed to control BP by lifestyle modification (LSM). However, if BP cannot be adequately controlled with LSM, then pharmacotherapy can be instituted along with LSM. Normalization of BP reduces cardiovascular risk (for cardiovascular death, myocardial infarction, and cardiac arrest), provides renoprotection (prevention of the onset or slowing of proteinuria and progression of renal dysfunction to end-stage renal disease in patients with hypertension, diabetes mellitus types 1 and 2, and chronic renal disease), and decreases the risk of cerebrovascular events (stroke and cognition impairment), as has been amply demonstrated by a large number of randomized clinical trials. In spite of the availability of more than 75 antihypertensive agents in 9 classes, BP control in the general population is at best inadequate. Therefore, antihypertensive therapy in the future or near future should be directed toward improving BP control in treated hypertensive patients with the available drugs by using the right combinations at optimum doses, individually tailored gene-polymorphism directed therapy, or development of new modalities such as gene therapy and vaccines. Several studies have shown that BP can be reduced by lifestyle/behavior modification. Although, the reductions appear to be trivial, even small reductions in systolic BP (for example, 3-5 mm Hg) produce dramatic reduction in adverse cardiac events and stroke. On the basis of the results of clinical and clinical/observational studies, it has been recommended that more emphasis be placed on lifestyle/behavior modification (obesity, high dietary intake of fat and sodium, physical inactivity, smoking, excessive alcohol intake, low dietary potassium intake) to control BP and also to improve the efficacy of pharmacologic treatment of high BP. New classes of antihypertensive drugs and new compounds in the established drug classes are likely to widen the armamentarium available to combat hypertension. These include the aldosterone receptor blockers, vasodilator beta-blockers, renin inhibitors, endothelin receptor antagonists, and dual endopeptidase inhibitors. The use of fixed-dose combination drug therapy is likely to increase. There is a conceptual possibility that gene therapy may yield long-lasting antihypertensive effects by influencing the genes associated with hypertension. But, the treatment of human essential hypertension requires sustained over-expression of genes. Some of the challenging tasks for successful gene therapy that need to be mastered include identification of target genes, ideal gene transfer vector, precise delivery of genes into the required site (target), efficient transfer of genes into the cells of the target, and prompt assessment of gene expression over time. Targeting the RAS by antisense gene therapy appears to be a viable strategy for the long-term control of hypertension. Several problems that are encountered in the delivery of gene therapy include 1) low efficiency for gene transfer into vascular cells; 2) a lack of selectivity; 3) problem in determining how to prolong and control transgene expression or antisense inhibition; and 4) difficulty in minimizing the adverse effects of viral or nonviral vectors. In spite of the hurdles that face gene therapy administration in humans, studies in animals indicate that gene therapy may be feasible in treating human hypertension, albeit not in the near future. DNA testing for genetic polymorphism and determining the genotype of a patient may predict response to a certain class of antihypertensive agent and thus optimize therapy in individual patients. In this regard, there are some studies that report the effectiveness of antihypertensive therapy based upon the genotype of selected patients. Treatment of human hypertension with vaccines is feasible but is not likely to be available in the near future.

Effect of losartan therapy on endothelial function in hypertensive patients.

The aim of the study was to evaluate the effect of losartan therapy on endothelial function by measuring serum nitric oxide (NO) levels and urinary excretion of NO in patients with essential hypertension. A group of 30 untreated stage 2 hypertensive patients (15 males and 15 females; age, 51.3 +/- 1.5 years) were included in the study. Office systolic and diastolic blood pressure (BP) was measured by using a mercury sphygmomanometer according to phase I and V of Korotkoff sounds. NO levels in serum and 24-hour urine were determined at baseline and after 6 weeks of daily dosing with losartan (50-100 mg). Losartan therapy resulted in a significant fall in systolic/diastolic BP (from 169.7 +/- 4.1/105 +/- 1.8 mm Hg at baseline to 146 +/- 2.7/91 +/- 1.9 mm Hg at the end of losartan treatment; P < 0.001). The therapy also caused significant increases in both serum NO level (32.74 +/- 3.01 microM/L at baseline versus 79.04 +/- 5.17 microM/L; P < 0.001 after therapy) and urinary NO excretion (58.21 +/- 3.72 microM/L at baseline versus 113.21 +/- 8.63 microM/L; P < 0.001 after therapy). Losartan therapy also reduced serum malondialdehyde (MDA), which is a measure of oxidative stress, by 0.201 nM (15.3%; P = 0.009). Losartan at a dose of 50 to 100 mg per day was effective in reducing elevated BP. The increase in serum NO levels and urinary NO excretion and a decrease in serum MDA levels by losartan treatment indicate a reduction in oxidative stress and enhances NO availability, both of which improve endothelial function. Thus, losartan therapy improves endothelial function in hypertensive patients with essential hypertension.

Update of diuretics in the treatment of hypertension.

Diuretics, which are primarily used to modify the volume and the composition of body fluids, are widely used to treat hypertension. The diuretics include a) the thiazides and thiazide-like agents, which are the most common drugs used to treat high blood pressure (these drugs inhibit sodium reabsorption in the early distal convoluted tubule); b) loop diuretics, such as furosemide, block chloride and sodium reabsorption by inhibition of the Na/K/2Cl cotransport system in the thick ascending limb of the loop of Henle; and c) potassium-sparing (retaining) diuretics, including aldosterone receptor blockers (such as spironolactone and eplerenone) and epithelial sodium channel blockers (such as amiloride and triamterene, which interfere with the reabsorption of sodium and excretion of potassium and hydrogen that takes place in the late distal tubule, the connecting tubule, and the cortical collecting duct). Hydrochlorothiazide 12.5 mg once daily or equivalent low dosages of other similar agents reduce blood pressure in approximately one-half to two-thirds of patients who are responsive to this class of drugs; higher doses add little to the effect on blood pressure and also increase side effects. Some combinations of very small doses of thiazide diuretics - for example, 6.25 mg hydrochlorothiazide or 0.625 mg indapamide, with a low dose of an antihypertensive drug of a different class - have average antihypertensive efficacy when used once daily. Furosemide is used in patients with renal failure or severe heart failure and is best given by continuous intravenous infusion. The potassium-sparing diuretics are generally used in combination with thiazide diuretics to treat hypertension. Side effects occur at about the same frequency and severity with equipotent doses of all diuretics. The incidence of side effects is dose-dependent and also increases as a function of the duration of the renal excretory and antihypertensive actions. However, longer-acting diuretics provide better 24-hour control of blood pressure and increase compliance and adherence to the treatment regimen.

Nitric oxide and malondialdehyde in human hypertension.

Nitric oxide (NO), a multifunctional effector molecule that plays a central role in the maintenance of vascular homeostasis, regulates vascular tone and inhibits platelet and leukocyte adhesion to endothelial cells. NO status is related to the endothelial function. Patients with hypertension have lower levels of NO, increased free radical production, higher oxidative stress, augmented platelet aggregation, and a change in the arachidonic acid cascade metabolism, all leading to the acceleration of the atherosclerotic process. The study subjects included a group of 21 normotensive healthy subjects (8 males and 13 females) with a mean age of 39.2 +/- 1.8 years and a body mass index of 27.9 kg/m, and another group of 42 patients (19 males and 23 females) with untreated essential hypertension with a mean age of 47.6 +/- 1.7 years and a body mass index of 28.3 kg/m. Serum levels and urinary excretion of NO determined as combined nitrate/nitrite (NOx) and serum malondialdehyde (MDA) concentrations were measured in the 2 groups of subjects. The serum levels and 24-hour urinary excretion of NOx were significantly higher and the renal clearance of NO was lower in the normotensive group than in the hypertensive patients, indicating decreased NO status in hypertension. There was a negative correlation between serum NO levels and mean arterial pressure, suggesting that a decrease in NO availability is related to increase in blood pressure. Serum concentrations of MDA were higher in the hypertensive patients as compared with the normotensive individuals, suggesting increased oxidative stress in hypertensive patients. These results are in agreement with previous studies showing decreased NO and increased oxidative stress in hypertension. In conclusion, patients with essential hypertension as compared with normotensive individuals have lower NO status, which may contribute to the endothelial dysfunction in hypertension. Increased serum malondialdehyde in hypertensives suggests an association between increased oxidative stress with higher blood pressure.

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.

Effect of cigarette smoking on the oxidant/antioxidant balance in healthy subjects.

BACKGROUND AND PURPOSE: Cigarette smoking has been associated with the development of cardiovascular disease and cancer. Even though the molecular mechanism(s) are not clear, the pathology has been related to oxygen free radicals present in cigarette smoke. Thus, the main objective of this study was to establish the changes in the oxidation/antioxidation balance induced by cigarette smoking. METHODS: Thirty healthy subjects (15 smokers and 15 nonsmokers) of both sexes were studied. The smokers group had smoked a mean of 14 cigarettes per day for an average of 4.5 years. Fasting serum levels of malondialdehyde (MDA), a marker of oxidative stress, nitric oxide (NO), reduced glutathione (GSH), and vitamin C (ascorbic and dehydroascorbic acids) were measured. RESULTS: Fasting NO concentration was significantly higher in smokers (51.3 +/- 5.3 microM) than in nonsmokers (35.2 +/- 4.8 microM, P < 0.05). The smokers had significantly higher serum dehydroascorbic acid levels (2.4 +/- 0.5 mg/dL, P < 0.03) than the nonsmokers (1.08 +/- 0.08 mg/dL). No significant differences were observed in the levels of ascorbic acid, MDA, and GSH between the smokers and nonsmokers. CONCLUSIONS: Our results suggest that exposure to cigarette smoke increases NO synthesis, such that NO may act in a compensatory way as an inhibitor of lipid peroxidation. Smoking also activates other antioxidative mechanisms such as involving vitamin C. These protective mechanisms appear to be enough in preventing accumulation of oxidative products such as MDA and avoiding oxidative damage.

Metformin plus low-dose glimeperide significantly improves Homeostasis Model Assessment for insulin resistance (HOMA(IR)) and beta-cell function (HOMA(beta-cell)) without hyperinsulinemia in patients with type 2 diabetes mellitus.

OBJECTIVE: Type 2 diabetes mellitus is characterized by insulin resistance and defects in insulin secretion from pancreatic beta-cells, which have been studied by using euglycemic/hyperinsulinemic clamps. However, it is difficult to study insulin resistance and beta-cell failure by these techniques in humans. Therefore, the aim of this study was to evaluate the effect of three different antidiabetic therapeutic regimens on insulin resistance and beta-cell activity by using a mathematical model, Homeostasis Model Assessment for insulin resistance (HOMA(IR)) and beta-cell function (HOMA(beta-cell)). RESEARCH DESIGN AND METHODS: Seventy type 2 diabetic patients were randomly assigned to one of three therapeutic regimens: (A) metformin + American Diabetic Association (ADA)-recommended diet + physical activity; (B) metformin + low-dose glimepiride + ADA diet + physical activity; or (C) ADA diet + physical activity (no drugs). Blood samples were obtained before and after the treatment to determine serum levels of fasting and post-prandial blood glucose, fasting insulin, and glycosylated hemoglobin (HbA1c), and HOMA(IR) and HOMA(beta-cell) were calculated. RESULTS: Fasting and post-prandial levels of glucose, HbA1c, and fasting insulin and calculated HOMA(IR) and HOMA(beta-cell) values before treatment were significantly higher than the respective values after treatment for all groups of patients (P < 0.01). Significant differences were also found when comparing the treatment-induced reduction in fasting blood glucose (51.8%; P < 0.01), post-prandial blood glucose (55.0%; P < 0.05), and HOMA(IR) (65.3%; P < 0.01) in patients of Group B with that in patients receiving other therapeutic options (Groups A and C). CONCLUSIONS: Metformin plus low-dose glimepiride (plus ADA diet and physical activity) is a more effective treatment for type 2 diabetes than either metformin plus ADA diet and physical activity or ADA diet and physical activity alone. Determination of HOMA(IR) and HOMA(beta-cell) values is an inexpensive, reliable, less invasive, and less labor-intensive method than other tests to estimate insulin resistance and beta-cell function in patients with type 2 diabetes mellitus.

Oat-derived beta-glucan significantly improves HDLC and diminishes LDLC and non-HDL cholesterol in overweight individuals with mild hypercholesterolemia.

OBJECTIVE: To investigate the effect of bread formulated with 6 g of beta-glucan (oat soluble fiber) on serum lipids in overweight normotensive subjects with mild to moderate hypercholesterolemia. DESIGN: Thirty-eight male subjects [mean age 59.8 +/- 0.6 yr, mean body mass index (BMI) 28.3 +/- 0.6 kg/m(2)] who were eligible for the study ate an isocaloric diet for a 1-week period. They were then divided into 2 groups: group A (n = 19), who were maintained on American Heart Association (AHA) Step II diet, including whole wheat bread, and group B (n = 19), who were maintained on AHA Step II diet containing high levels of monounsaturated fatty acids plus bread containing 6 g of beta-glucan (Nutrim-OB) for 8 weeks. Plasma lipids and glucose were measured at baseline and after weeks 8 in all subjects. All subjects were advised to walk for 60 minutes every day. RESULTS: There was a significant increase (upward arrow 27.8%) in plasma high density lipoprotein (HDL) cholesterol in the beta-glucan group (group A) from 39.4 +/- 2.0 to 49.5 +/- 2.1 mg/dL (P < 0.001), but there was no change in group B. There was a significant reduction in total cholesterol in the 2 groups to approximately the same extent: group A, from 232.8 +/- 2.7 mg/dL to 202.7 +/- 6.7 mg/dL; P < 0.001; and group B, from 231.8 +/- 4.3 mg/dL to 194.2 +/- 4.3 mg dL; P < 0.001. Plasma low density lipoprotein (LDL) cholesterol also decreased significantly in the two groups: group A, from 160.3 +/- 2.8 mg/dL to 133.2 +/- 5.4 mg/dL; P < 0.001; group B, from 167.9 +/- 4.3 mg/dL to 120.9 +/- 4.3 mg/dL; P < 0.001; however, the beta-glucan fortified diet was significantly more effective (downward arrow 27.3% vs. downward arrow 16.8%; P < 0.04). There was a small and insignificant reduction in plasma very LDL (VLDL) cholesterol and triglycerides in the two groups. Similarly, non-HDL cholesterol levels were also decreased, with beta-glucan diet producing significantly higher effect (downward arrow 24.5% vs. downward arrow 16.1%; P < 0.04). The beta-glucan diet also produced higher reduction in total cholesterol/HDL cholesterol ratio (downward arrow 33.3% vs. downward arrow 8.4%; P < 0.003) and LDL cholesterol/HDL cholesterol ratio (downward arrow 42.1% vs. downward arrow 13.3%; P < 0.001) than the diet without beta-glucan. The beta-glucan diet also decreased fasting plasma glucose (P < 0.4), whereas the other diet had no effect. Interestingly, both diets reduced body weight and BMI significantly, with beta-glucan diet having a greater effect. CONCLUSIONS: Six grams of beta-glucan from oats added to the AHA Step II diet and moderate physical activity improved lipid profile and caused a decrease in weight and, thus, reduced the risk of cardiovascular events in overweight male individuals with mild to moderate hypercholesterolemia. The diet with added beta-glucan was well accepted and tolerated.

Fibrinolytic system in normotensive subjects and hypertensive patients.

The aim of this study was to evaluate the fibrinolytic system by measurement of fibrinogen, plasminogen, tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) in healthy normotensive subjects and in patients with essential hypertension. A group of 21 healthy normotensive subjects [age, 39.2 +/- 1.8 years; 8 males, 13 females; body mass index (BMI) = 27.9 kg/m] and 42 patients with untreated essential hypertension (age, 47.6 +/- 1.7 years; 19 males, 23 females; BMI = 28.3 kg/m) were studied. Blood samples and clinical measurement were taken between 7 am and 9 am by an observer in a blind fashion. The systolic/diastolic blood pressure of normotensive subjects was 121.3 +/- 2.5/78.4 +/- 1.3 mm Hg and that of hypertensive patients was 166.4 +/- 4.3/102.9 +/- 1.83 mm Hg, measured in the sitting position. Plasma fibrinogen levels in the normotensive and hypertensive individuals were 295.7 +/- 9.4 mg/dL and 305.67 +/- 10.9 mg/dL, respectively (P = 0.456). The corresponding values for plasminogen were 71.4 +/- 3.8% and 89.5 +/- 2.5%, (P = 0.0031), for t-PA were 6.3 +/- 0.5 ng/mL and 7.6 +/- 0.4 ng/mL (P = 0.0487), and for PAI-1 were 46.9 +/- 5.1 ng/mL and 63.0 +/- 5.6 ng/mL (P = 0.0324), respectively. In conclusion, patients with essential hypertension have disequilibrium in the fibrinolytic system with a tendency toward a hypercoagulability state when compared with normotensive subjects. This state could explain, in part, the thrombotic complications that occur with a higher frequency in hypertensive patients as compared with normotensive subjects.

Ciprofibrate treatment decreases non-high density lipoprotein cholesterol and triglycerides and increases high density lipoprotein cholesterol in patients with Frederickson type IV dyslipidemia phenotype.

OBJECTIVE: The combination of hypertriglyceridemia and low high density lipoprotein (HDL) cholesterol is one of the most common lipid abnormalities. Thus, the aim of this study was to determine the effects of ciprofibrate on lipid profile in patients with Frederickson's type IV dyslipidemia phenotype. RESEARCH DESIGN AND METHODS: Seventy-five patients with type IV dyslipidemia were assigned at random to 1 of 2 therapeutic options: group A (control), American Heart Association (AHA) Step II diet and physical activity; and group B, AHA diet, physical activity, and ciprofibrate 100 mg daily for 8 weeks. The lipid profile of all patients was determined at baseline and after therapeutic intervention. RESULTS: Patients in group B (treated with ciprofibrate) compared with group A (control) had significantly higher reductions in total cholesterol (downward arrow 14.2% vs. downward arrow 4.8%; P < 0.02), triglycerides (downward arrow 38.0% vs. downward arrow 21.6%; P < 0.007), very low density lipoprotein cholesterol (downward arrow 38.0% vs. downward arrow 21.6%; P < 0.007), non-HDL cholesterol (downward arrow 20.5% vs. downward arrow 7.1%; P < 0.007), and total cholesterol/high density cholesterol ratio (downward arrow 25.6% vs. downward arrow 9.4%; P < 0.01). The ciprofibrate group had a significantly higher increase in HDL cholesterol levels compared with the other group (upward arrow 25.0% vs. upward arrow 9.6%, P < 0.02). CONCLUSIONS: Ciprofibrate treatment effectively reduced triglyceride-rich particles and non-HDL cholesterol, and significantly increased HDL cholesterol, proving its effectiveness in patients with low HDL cholesterol and type IV Frederickson's hyperlipidemia.