Different effects of St John's wort on the pharmacokinetics of simvastatin and pravastatin.

OBJECTIVE: St John's Wort, a widely used herbal product, is an inducer of CYP3A4 and it decreases blood concentrations of CYP3A4 substrates. The effects of St John's Wort on the pharmacokinetics of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors simvastatin (an inactive lactone pro-drug) and pravastatin were determined in this study. METHODS: Sixteen healthy male subjects (n = 8 in group 1 and n = 8 in group 2) took a St John's Wort caplet (300 mg) or matching placebo three times a day for 14 days in a double-blind, crossover study. On day 14, a single oral dose of 10 mg simvastatin and 20 mg pravastatin was given to subjects in group 1 and group 2, respectively. Blood samples were obtained during a 24-hour period after the administration of each drug. RESULTS: Repeated St John's Wort treatment tended to lower plasma simvastatin concentration and significantly (P <.05) lowered concentrations of simvastatin hydroxy acid, its active metabolite. The peak concentration in plasma (ratio, 0.72 of placebo) of simvastatin hydroxy acid tended to be decreased and its area under the plasma concentration-time curve between time zero and 24 hours after administration (ratio, 0.48 of placebo) was significantly decreased (P <.05) by St John's Wort. On the other hand, St John's Wort did not influence plasma pravastatin concentration. No significant differences were observed in the elimination half-life of simvastatin or pravastatin between the placebo and St John's Wort trials. CONCLUSIONS: This study showed that St John's Wort decreases plasma concentrations of simvastatin but not of pravastatin. Because simvastatin is extensively metabolized by CYP3A4 in the intestinal wall and liver, which are induced by St John's Wort, it is likely that this interaction is partly caused by the enhancement of the CYP3A4-mediated first-pass metabolism of simvastatin in the small intestine and liver.

11beta-hydroxysteroid dehydrogenase in human vascular cells.

Aldosterone selectivity in mineralocorticoid target tissues is mainly due to 11beta-hydroxysteroid dehydrogenase (11betaHSD), which converts cortisol to its inactive metabolite cortisone in humans. The defect of dehydrogenase activity would thus allow type 1 mineralocorticoid receptor (MR) to be occupied mostly by cortisol. It has been postulated that 11betaHSD type 2 (11betaHSD2) plays a significant role in conferring ligand specificity on the MR. We have demonstrated the diminished dehydrogenase activity in resistance vessels of genetically hypertensive rats. However, the mechanism that could link impaired vascular 11betaHSD activity and elevated blood pressure has been unclear. In this study, we showed the enzyme activity in human coronary artery smooth muscle cells. Glucocorticoids and mineralocorticoids increase vascular tone by up-regulating the receptors of pressor hormones such as angiotensin II (Ang II). Next, we found that physiological concentrations of a cortisol-induced increase in Ang II binding were significantly enhanced by the inhibition of dehydrogenase activity with an antisense DNA complementary to 11betaHSD2 mRNA, and the enhancement was partially but significantly abolished by a selective aldosterone receptor antagonist. This may indicate that impaired dehydrogenase activity in vascular wall results in increased vascular tone by the contribution of cortisol, which acts as a mineralocorticoid. In congenital 11betaHSD deficiency and after the administration of 11betaHSD inhibitors, suppression of dehydrogenase activity in the kidney has been believed to cause renal mineralocorticoid excess, resulting in sodium retention and hypertension. These results show that vascular 11betaHSD activity could influence blood pressure without invoking renal sodium retention.

11beta-hydroxysteroid dehydrogenase in cultured human vascular cells. Possible role in the development of hypertension.

11beta-Hydroxysteroid dehydrogenases (11beta-HSD) interconvert cortisol, the physiological glucocorticoid, and its inactive metabolite cortisone in humans. The diminished dehydrogenase activity (cortisol to cortisone) has been demonstrated in patients with essential hypertension and in resistance vessels of genetically hypertensive rats. 11beta-Hydroxysteroid dehydrogenase type 2 (11beta-HSD2) catalyzes only 11beta-dehydrogenation. However, a functional relationship between diminished vascular 11beta-HSD2 activity and elevated blood pressure has been unclear. In this study we showed the expression and enzyme activity of 11beta-HSD2 and 11beta-HSD type 1 (which is mainly oxoreductase, converting cortisone to cortisol) in human vascular smooth muscle cells. Glucocorticoids and mineralocorticoids increase vascular tone by upregulating the receptors of pressor hormones such as angiotensin II. We found that physiological concentrations of cortisol-induced increase in angiotensin II binding were significantly enhanced by the inhibition of 11beta-HSD2 activity with an antisense DNA complementary to 11beta-HSD2 mRNA, and the enhancement was partially but significantly abolished by a selective aldosterone receptor antagonist. This may indicate that impaired 11beta-HSD2 activity in vascular wall results in increased vascular tone by the contribution of cortisol, which acts as a mineralocorticoid. In congenital 11beta-HSD deficiency and after administration of 11beta-HSD inhibitors, suppression of 11beta-HSD2 activity in the kidney has been believed to cause renal mineralocorticoid excess, resulting in sodium retention and hypertension. In the present study we provide evidence for a mechanism that could link impaired vascular 11beta-HSD2 activity, increased vascular tone, and elevated blood pressure without invoking renal sodium retention.

Elevated endogenous digitalis-like substance in hypertensive diabetic patients with a family history of hypertension.

Endogenous digital-like substance (DLS) is increased in patients with essential hypertension and is hypothesized to play a role in the pathogenesis of high blood pressure. Whether an increase in DLS in diabetic patients with hypertension is associated with a family history of hypertension or diabetic nephropathy was investigated. Plasma DLS was measured as Na(+)-K(+)-ATPase inhibitory activity (ATPI) in 100 Type 2 diabetic patients. Ouabain was used as a standard of Na-K-ATPase inhibition. Diabetic patients with hypertension demonstrated a greater ATPI level than normotensive diabetic patients (p less than 0.05). In patients with hypertension groups, the positive family history group had a higher ATPI level than the negative family history group (p less than 0.01). Microalbuminuria was not correlated with the ATPI level in diabetic patients. These results suggest that ATPI might play a role in the pathogenesis of hereditary hypertension associated with diabetes mellitus, but not have etiologic significance in diabetic nephropathy.

Effects of a calcium entry blocker on cerebral circulation in essential hypertension.

The acute effects of the calcium entry blocker, nifedipine, on cerebral circulation were studied in 22 patients (56 +/- 5 years) with essential hypertension (EHT, WHO I-II) and 12 age-matched normal subjects. Cerebral effects were reevaluated in sixteen EHT patients after 8 weeks of treatment. The cerebrovascular resistance (Rp), cerebral capacitance (Cp), carotid velocity, and flow volume were measured by a newly developed ultrasonic volume flow meter coupled with a built-in computer which calculates Rp and Cp based on a simulated model. In EHT, acute administration of nifedipine (10 mg orally) decreased Rp from 13.5 +/- 1.8 to 8.0 +/- 0.3 (p less than 0.01) and increased Cp from 22.8 +/- 3.3 to 54.9 +/- 5.2 mFc (p less than 0.01). The carotid blood flow and velocity increased by 25.7% and 22.9%, respectively (p less than 0.05) in the face of lowered arterial pressure. In normal subjects, nifedipine also decreased Rp and increased Cp but to a lesser degree compared with EHT. The acute changes in cerebrovascular circulation in EHT were maintained at 8 weeks of treatment. These results suggest that nifedipine reduces Rp, possibly as the consequence of systemic hypotension and direct vasodilation of the cerebral arteries. This may be beneficial for hypertensive patients.

Effect of 9 alpha-fluorocortisol on the excretion of urinary digoxin-like substance in normotensive men.

In order to investigate the possible role of mineralocorticoid in the regulation of digoxin-like substance (DLS), 9 alpha-fluorocortisol (9-F) was administered to 6 healthy men and urinary excretion of DLS was measured. The administration of 0.6 mg of 9-F caused slight increases in body weight and blood pressure and significant decreases in urinary Na excretion, plasma renin activity and plasma aldosterone, which indicate the expansion of extracellular fluid (ECF) volume by 9-F administration. Urinary excretion of DLS decreased significantly from the baseline level of 43.3 +/- 2.6 (SEM) to 29.8 +/- 5.1 (SEM) ng/day; digoxin equiv. after 9-F. These results suggest that a large dose of mineralocorticoid may suppress DLS despite an increase in the ECF volume.

Reduced response of plasma aldosterone to acute ACTH stimulation during long-term treatment with spironolactone in essential hypertension.

The response of plasma aldosterone (PA) to ACTH administration (250 micrograms alpha 1-24 ACTH i.m.) before and during treatment with spironolactone (Sp, 75--100 mg/day) for at least 8 months was studied in 11 patients with essential hypertension. These responses were compared with those before and during prolonged treatment with hydrochlorothiazide (Th, 50--75 mg/day), with or without potassium supplement, in 14 hypertensives. PA and plasma cortisol (PC) were determined by radioimmunoassay in which Sp showed minimal cross-reactivity. Both Sp and Th treatments caused similar increases in plasma renin activity accompanied by nearly identical decreases in blood pressure and body weight. PA was also increased by both treatments, but to a significantly greater extent in the Sp-treated group. Serum potassium concentration was increased only by Sp treatment. The response of PA, but not of PC, to acute ACTH stimulation was blunted in the Sp-treated group. That is, the maximal increment of PA above the baseline level was significantly lower during Sp treatment than either before Sp treatment of during Th treatment. These results demonstrate that long-term treatment with Sp can inhibit aldosterone production by acute ACTH stimulation in patients with essential hypertension.