Involvement of endothelium-dependent and -independent mechanisms in midazolam-induced vasodilation.

Benzodiazepine (BDZ) infusion has been shown to reduce blood pressure in both humans and animals. Although the inhibitory effects of BDZ on the central nervous system have been well documented, less is known about the direct effects of BDZ on the vascular bed. The aims of this study were to assess the effects of the BDZ midazolam on the vascular system in C57/BL6 mouse aortic rings and to investigate the mechanisms of its direct vascular action. We found that midazolam induced reversible, dose-dependent vasodilation in potassium- and phenylephrine-precontracted rings. In rings that were precontracted with potassium or phenylephrine, treatment with 10 µmol l(-1) midazolam increased vasodilation by 15 and 60%, respectively, compared with baseline. Vasodilation increased by 80 and 87%, respectively, after treatment with 50 µmol l(-1) midazolam. Only the low concentration of midazolam (10 µmol l(-1)) induced endothelium-dependent vasodilation in phenylephrine-precontracted rings. Vasodilation increased by 60% in rings with endothelium and by 20% in rings without endothelium. Conversely, only the high concentration of midazolam (50 µmol l(-1)) reduced the CaCl(2)-induced vasoconstriction of aortic rings with EC(50) (the concentration giving 50% of the maximal effect) values of 1 and 6 mmol l(-1) for vehicle- and midazolam-treated rings, respectively. Furthermore, the incubation of phenylephrine-precontracted rings with an inhibitor of the nitric oxide synthase (NOS) NG-nitro-L-arginine methyl ester or the inhibitors of central or peripheral type BDZ receptors (flumazenil or PK 11195, respectively) produced no change in midazolam-induced vasodilation. Thus, low concentrations of midazolam induce vasodilation via an endothelium-dependent mechanism that does not involve NO production. In contrast, high concentrations of midazolam induce vasodilation via an endothelium-independent mechanism that implies reduced sensitivity of aortic rings to calcium ions. Additionally, neither the central γ-amino-butyric acid receptor type A nor the peripheral type BDZ receptors seem to be involved in the mechanism of midazolam-induced vasodilation.

Relationship of plasma renin with a prothrombotic state in hypertension: relevance for organ damage.

BACKGROUND: Components of the renin-angiotensin-aldosterone system (RAAS) and a prothrombotic state are predictors of cardiovascular events in hypertensive patients. A relationship between the RAAS and the coagulation/fibrinolytic systems has been demonstrated, but its clinical relevance in hypertension is unclear. We investigated the relationships of the RAAS and the hemostatic system with hypertensive organ damage. METHODS: Plasma components of the RAAS and parameters that directly assess the activation of coagulation and fibrinolysis were measured in 247 essential hypertensive patients in whom the extent of organ damage had been characterized at the cardiac, renal, and vascular level. RESULTS: Positive association with increasing plasma renin activity (PRA) was demonstrated for plasma fibrinogen, D-dimer, and plasminogen activator inhibitor-1 (PAI-1) levels. PRA was directly correlated with plasma aldosterone, fibrinogen, d-dimer, and PAI-1. The relationship of PRA with fibrinogen and PAI-1 remained significant after correction for age, gender, duration of hypertension, and smoking status. Plasma aldosterone levels were directly correlated with fibrinogen, D-dimer, and PAI-1, whereas plasma angiotensin-converting enzyme was not related with any of the coagulation parameters. Elevated PRA, aldosterone, fibrinogen, D-dimer, prothrombin fragment 1+2, and PAI-1 levels were associated with clinical and/or instrumental evidence of hypertension-related cardiac and renal damage. Both fibrinogen and PAI-1 were independent predictors of the presence of organ damage and their inclusion in a multivariate model eliminated PRA and aldosterone as independent predictors. CONCLUSIONS: A strong and independent association exists between renin, aldosterone, and markers of a prothrombotic state in essential hypertension. This relationship might contribute to the development of hypertensive organ damage.

Cardiovascular outcomes in patients with primary aldosteronism after treatment.

BACKGROUND: Experimental and human studies demonstrate that long-term exposure to elevated aldosterone levels results in cardiac and vascular damage. METHODS: We investigated long-term cardiovascular outcomes in patients with primary aldosteronism after surgical or medical treatment. Fifty-four patients with or without evidence of adrenal adenomas were prospectively followed up for a mean of 7.4 years after treatment with adrenalectomy or spironolactone. Patients with primary aldosteronism were compared with patients with essential hypertension and were treated to reach a blood pressure of less than 140/90 mm Hg. The main outcome measure was a combined cardiovascular end point comprising myocardial infarction, stroke, any type of revascularization procedure, and sustained arrhythmias. RESULTS: At baseline, the prevalence of cardiovascular events was greater in primary aldosteronism (35%) than in essential hypertension (11%) (odds ratio, 4.61; 95% confidence interval, 2.38-8.95; P< .001), with odds ratios of 4.93, 4.36, and 2.80 for sustained arrhythmias, cerebrovascular events, and coronary heart disease, respectively. Blood pressure during follow-up was comparable in the primary aldosteronism and essential hypertension groups. Ten patients in the primary aldosteronism group and 19 in the essential hypertension group reached the primary end point (P= .85). Cox analysis indicated that older age and longer duration of hypertension were factors independently associated with the cardiovascular end point. Cardiovascular outcome was comparable in patients with aldosteronism treated with adrenalectomy vs aldosterone antagonists (P= .71). CONCLUSION: Primary aldosteronism is associated with a cardiovascular complication rate out of proportion to blood pressure levels that benefits substantially from surgical and medical treatment in the long term.

Long-term cardiac effects of adrenalectomy or mineralocorticoid antagonists in patients with primary aldosteronism.

Exposure to excess aldosterone results in cardiac damage in hypertensive states. We evaluated the long-term cardiac structural and functional evolution in patients with primary aldosteronism after surgical or medical treatment. Fifty-four patients with primary aldosteronism were enrolled in a prospective study and were followed for a mean of 6.4 years after treatment with adrenalectomy (n=24) or spironolactone (n=30). At baseline, echocardiographic measurements of patients with primary aldosteronism were compared with those of 274 patients with essential hypertension. Patients with primary aldosteronism had greater left ventricular mass, more prevalent left ventricular hypertrophy, lower early:late-wave diastolic filling velocities ratio, and longer deceleration time than patients with essential hypertension but no differences in relative wall thickness and systolic function. During follow-up, average blood pressure was 135/82 and 137/82 mm Hg in patients treated with adrenalectomy and spironolactone, respectively. In the initial 1-year period, left ventricular mass decreased significantly only in adrenalectomized patients. Subsequent changes in left ventricular mass were greater in patients treated with spironolactone, with an overall change from baseline to the end of follow-up that was comparable in the 2 groups. Prevalence of hypertrophy decreased in both treatment groups, whereas diastolic parameters had only mild and nonsignificant improvement. Changes in blood pressure and pretreatment plasma aldosterone were independent predictors of left ventricular mass decrease in both treatment groups. Thus, in the long-term, both adrenalectomy and spironolactone are effective in reducing left ventricular mass in patients with primary aldosteronism, with effects that are partially independent of blood pressure changes.

Relationships of plasma renin levels with renal function in patients with primary aldosteronism.

BACKGROUND: The renal damage that is present in primary aldosteronism might reflect functional and potentially reversible abnormalities that are initiated by glomerular hyperfiltration. The aim of this study was to investigate the relationships of plasma renin and aldosterone concentrations with renal outcomes after treatment of primary aldosteronism. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Fifty-six consecutive patients who had primary aldosteronism and were recruited in a university center were studied. Patients were prospectively followed after either surgical or medical treatment for a mean of 6.2 yr, during which they received antihypertensive drugs to reach a target BP of <140/90 mmHg. RESULTS: At baseline, patients with primary aldosteronism had higher creatinine clearance and albuminuria than 323 patients with essential hypertension and 113 normotensive individuals. In patients with primary aldosteronism, plasma active renin levels that were higher than the lower limit of detection (2.5 pg/ml) were associated with higher BP, plasma potassium, and albuminuria and lower creatinine clearance. Plasma aldosterone concentrations that were higher than the median value (225 pg/ml) were associated with lower plasma potassium and higher creatinine clearance. Creatinine clearance was correlated directly with plasma aldosterone and inversely with renin. During follow-up, patients with higher baseline plasma renin required use of more antihypertensive drugs to obtain BP control and had a smaller early decline in albuminuria than did patients with suppressed renin. CONCLUSIONS: Escape of renin from suppression by excess aldosterone is associated with evidence of more severe renal damage in patients with primary aldosteronism and predicts less favorable outcomes after treatment.

Insulin resistance and hyperinsulinemia are related to plasma aldosterone levels in hypertensive patients.

OBJECTIVE: An association between aldosterone and insulin resistance has been demonstrated in obesity and primary aldosteronism and in blacks with the metabolic syndrome. The aim of this study was to evaluate the relationship of plasma aldosterone with insulin sensitivity in white subjects. RESEARCH DESIGN AND METHODS: In 356 patients with essential hypertension and 102 normotensive control subjects of comparable age and BMI, we measured, after discontinuation of treatment, plasma active renin, aldosterone, cortisol, glucose, insulin, and C-peptide levels and calculated markers of insulin sensitivity. Direct assessment of insulin sensitivity was obtained in a subset of 64 hypertensive patients by a hyperinsulinemic clamp. RESULTS: Hypertensive patients had significantly greater fasting plasma insulin and C-peptide concentrations and homeostasis model assessment (HOMA) indexes than normotensive control subjects. A positive association with increasing plasma aldosterone concentrations was demonstrated for plasma glucose, insulin, C-peptides, and HOMA. Assessment of insulin sensitivity by clamp showed a significant decrease of the metabolic clearance rate of glucose with increasing aldosterone levels. Significant correlations were found between plasma aldosterone, plasma insulin, and C-peptide levels, HOMA, and glucose metabolic clearance rate. Blood pressure and plasma potassium, plasma cortisol, and renin levels, but not BMI, were also directly correlated with plasma aldosterone. Multiple regression analysis showed that HOMA, together with plasma potassium, cortisol, and renin levels, was independently correlated with plasma aldosterone. CONCLUSIONS: This study demonstrates a direct relationship between aldosterone, insulin resistance, and hyperinsulinemia in white subjects. In patients with hypertension, this relationship might contribute to maintenance of high blood pressure and increased cardiovascular risk.

Renal cysts and hypokalemia in primary aldosteronism: results of long-term follow-up after treatment.

BACKGROUND: Cross-sectional studies have reported an elevated prevalence of renal cysts in patients with primary aldosteronism. The nature of this association could be related to hypokalemia and/or hypertension and has never been evaluated in prospective studies. METHODS: A consecutive sample of 54 patients with tumoral or idiopathic primary aldosteronism was followed after adrenalectomy or treatment with aldosterone antagonists. At baseline, renal cysts were evaluated by renal ultrasound and patients with primary aldosteronism were compared with 323 essential hypertension patients with the same severity and duration of disease, and 113 age- and sex-matched normotensive subjects. RESULTS: The adjusted prevalence and average number of renal cysts were significantly greater in patients with primary aldosteronism than in patients with essential hypertension and normotensive subjects. Multivariate analysis revealed that age and plasma potassium levels were independently associated with the presence of renal cysts in patients with primary aldosteronism. Treatment of primary aldosteronism decreased blood pressure (BP) and restored normal potassium concentrations. After a median follow-up of 6.2 years, no significant change from baseline of cyst number and cyst total volume was observed in patients with both tumoral and idiopathic aldosteronism and in a subset of 100 patients with essential hypertension. In patients with primary aldosteronism, stepwise logistic analysis showed that the presence of renal cysts was associated with worse BP outcome after treatment. CONCLUSION: Renal cystic disease is highly frequent in patients with primary aldosteronism and either surgical or medical treatment halt its progression, supporting the contention that hypokalemia and its severity are the main contributors to cyst formation in these patients.

Omega-3 fatty acids: from biochemistry to their clinical use in the prevention of cardiovascular disease.

Omega-3 and omega-6 Polyunsaturated fatty acids (PUFA) are the major families of PUFA that can be found as components of the human diet. After ingestion, both omega-3 and omega-6 PUFA are distributed to every cell in the body where they are involved in a myriad of physiological processes, including regulation of cardiovascular, immune, hormonal, metabolic, neuronal, and visual functions. At the cell level, these effects are mediated by changes in membrane phospholipids structure, interference with eicosanoid intracellular signaling, and regulation of gene expression. Two long-chain omega-3 PUFAs, the docosahexaenoic (DHA) and eicosapentaenoic (EPA) acid, are found in fatty fish and other marine sources and might be the putative dietary components thought to modify the cardiovascular risk in subjects consuming high amounts of such food. Evidence of an inverse relationship between fatty fish intake and cardiovascular risk has, in fact, emerged in studies performed more than twenty years ago in Eskimos and has been subsequently confirmed in other ethnic groups. The benefits of omega-3 PUFA might relate principally to prevention of coronary heart disease, coronary artery restenosis after angioplasty, and sudden arrhythmic death. In this brief review, we will cover the general biochemical aspects of omega-3 PUFA, summarize the evidence relating these fatty acids with control of cardiovascular risk factors and prevention of cardiovascular events, and overview the most recent and relevant patents that are related to these issues. More specifically, we will deal with the possibility to use PUFA in association with other molecules that can potentiate their antiinflammatory and antiatherogenic effects.