Human sympathetic activation by alpha2-adrenergic blockade with yohimbine: Bimodal, epistatic influence of cytochrome P450-mediated drug metabolism.

BACKGROUND: alpha2-Adrenergic blockade responses suggest adrenergic dysfunction in hypertension. alpha2-Blockade is also used to treat autonomic dysfunction. However, pharmacokinetic determinants of yohimbine disposition are not understood. METHODS: We evaluated alpha2-blockade with intravenous yohimbine in 172 individuals. Specific cytochrome P450 (CYP) isoform-mediated metabolism was investigated. Results were evaluated by ANOVA and by maximum likelihood analysis for bimodality of response distributions. RESULTS: Yohimbine metabolism to 11-hydroxy-yohimbine displayed greater than 1000-fold variability, with 17 individuals showing no metabolism. Nonmetabolizers differed from others in ethnicity but not in age, sex, body habitus, blood pressure, heart rate, or family history of hypertension. Bimodality of metabolism was suggested by frequency histogram, as well as maximum likelihood and cluster analysis. Among ethnic groups, subjects of European ancestry had the highest frequency of nonmetabolism. In vitro oxidation suggested that the major route of metabolism (lowest Michaelis-Menten constant and greatest intrinsic clearance) was likely via CYP2D6 to 11-hydroxy-yohimbine. In vivo genotypes at both CYP2D6 and CYP3A4 were necessary to predict metabolism (overall F = 3.03, P =.005); an interaction of alleles at these 2 loci (interaction F = 3.05, P =.033) suggested an epistatic effect on drug metabolism in vivo. Nonmetabolizers had greater activation of sympathetic nervous system activity. Yohimbine increased blood pressure, an effect mediated hemodynamically by elevation of cardiac output rather than systemic vascular resistance. Blood pressure and cardiac output responses did not differ by metabolizer group. CONCLUSIONS: We conclude that heterogeneous, bimodally distributed yohimbine metabolism depends on common genetic variation in both CYP2D6 and CYP3A4 and contributes to differences in sympathetic neuronal response to alpha2-blockade. These results have implications for both diagnostic and therapeutic uses of this alpha2-antagonist.

Diminished renal kallikrein responses to mineralocorticoid stimulation in African Americans: determinants of an intermediate phenotype for hypertension.

BACKGROUND: Hypertension is a complex trait with an ill-defined genetic predisposition, in which renal mechanisms seem to be involved even at the early stages. Renal kallikrein excretion is diminished in patients with hypertension, and perhaps even in the early, prehypertensive phases of the syndrome. African Americans, a group at increased risk of developing hypertension, have especially diminished kallikrein expression, coupled with decreased renal excretion of K(+), a known stimulant of kallikrein expression, suggesting an environmental mechanism for their kallikrein deficit. We, therefore, tested whether short-term indirect (K(+)) or direct (fludrocortisone) stimulation of mineralocorticoid activity might be capable of restoring kallikrein excretion in African Americans. METHODS: Nineteen healthy normotensive young men (n = 10 white, n = 9 African Americans) were treated with the following sequence of four oral medications, each for 1 week: placebo, KCl (120 mEq/day), placebo, and the mineralocorticoid fludrocortisone (0.4 mg/day). At each stage, we measured vital signs, excretion of kallikrein, aldosterone and electrolytes, and serum renin. Results were evaluated by two-way, repeated measures ANOVA. RESULTS: African Americans had diminished urinary excretion of not only kallikrein (P =.007), but also K(+) (P <.001) and aldosterone (P =.015). Kallikrein responses to mineralocorticoid stimulation were substantially blunted in African Americans, whether achieved indirectly (by supplemental K(+); P =.019) or directly (by the exogenous mineralocorticoid fludrocortisone; P =.027), despite achievement of substantial increments in K(+) excretion after KCl (P =.002), and multiple other mineralocorticoid effects after fludrocortisone (P =.005). The kallikrein increment after KCl was best predicted by renin activity (P =.001) rather than ethnicity. Potassium chloride did not lower blood pressure (BP) in either group (P >.4). CONCLUSIONS: Restoration of K(+) and aldosterone secretion to levels found in whites does not normalize kallikrein excretion or lower BP in African Americans, at least in the short term. Nor does exogenous mineralocorticoid stimulation fully restore kallikrein expression in African Americans. Therefore, the diminution of kallikrein biosynthesis in African Americans seems to involve mechanisms at or distal to the aldosterone receptor, and perhaps at the level of the kallikrein gene itself.

Utility of HbA(1c) levels for diabetes case finding in hospitalized patients with hyperglycemia.

OBJECTIVE: We evaluated the role of a single measurement of HbA(1c) in a diabetes case finding in hospitalized patients with random hyperglycemia at admission. RESEARCH DESIGN AND METHODS: From 20 March to 31 July 2000, 508 patients admitted through the emergency department of one hospital were tested for random hyperglycemia (plasma glucose [PG] >125 mg/dl). Consenting patients with hyperglycemia (without preexisting diabetes or on corticosteroids) underwent testing for HbA(1c) levels, two fasting PG levels, and an outpatient oral glucose tolerance test (OGTT) if necessary. RESULTS: Of the patients, 50 (9.8%) met the inclusion criteria. Of these, 70% (n = 35) completed the study, and 60% (n = 21) were diagnosed with diabetes. Patients with diabetes had higher HbA(1c) levels than subjects without diabetes (6.8 +/- 0.4 vs. 5.3 +/- 0.1%, P = 0.002). An HbA(1c) level >6.0% was 100% specific (14/14) and 57% sensitive (12/21) for the diagnosis of diabetes. When a lower cutoff value of HbA(1c) at 5.2% was used, specificity was 50% (10/21) and sensitivity was 100% (7/14). CONCLUSIONS: In acutely ill patients with random hyperglycemia at hospital admission, an HbA(1c) >6.0% reliably diagnoses diabetes, and an HbA(1c) level <5.2% reliably excludes it (paralleling the operating characteristics of the standard fasting glucose measurements); however, the rapidity of the HbA(1c) level can be useful for diabetes case finding and treatment initiation early in the hospital course.

Early decline in the catecholamine release-inhibitory peptide catestatin in humans at genetic risk of hypertension.

BACKGROUND: Hypertension is a complex trait with an ill-defined genetic predisposition, in which adrenergic mechanisms seem to be involved even at the early stages. Chromogranin A is a pro-hormone stored and released with catecholamines by exocytosis; its fragment catestatin, formed in vivo, inhibits further catecholamine release as an antagonist at the physiologic trigger for secretion, the neuronal nicotinic cholinergic receptor. METHODS: We measured catestatin by radioimmunoassay in n = 277 subjects stratified by blood pressure (n = 61 hypertensive, n = 216 normotensive), and if normotensive by genetic risk of developing hypertension: family history positive (n = 176) versus negative (n = 40). Maximum likelihood analysis tested for bimodality. Involvement of catestatin in pathophysiology was probed by measurements of catecholamines and leptin, and the hemodynamic responses to environmental (cold) stress. RESULTS: The normotensive offspring of patients with hypertension already had diminished catestatin (P = 0.024), and family history was a better predictor of catestatin than age, ethnicity or gender (P = 0.014). Greater catestatin variance among family history-positive individuals (P = 0.021) suggested heterogeneity in this group, and a bimodal distribution (P < 0.001) identified 4.3% of individuals in a lower mode of catestatin values, all with positive family histories (P = 0.05). Catestatin correlated inversely with body mass index (r = -0.215, r(2) = 0.046, n = 276, P < 0.001) and plasma leptin (r = -0.203, r(2) = 0.041, n = 212, P = 0.003), while body mass index and leptin correlated directly (r = 0.59, r(2) = 0.350, n = 212, P < 0.001). Family history-positive individuals had greater epinephrine excretion (P = 0.037) in addition to diminished catestatin, suggesting an inhibitory effect of catestatin on chromaffin cells in vivo. Low plasma catestatin predicted enhanced pressor response to a sympathoadrenal stressor (cold stress; r = -0.184, r(2) = 0.034, n = 211, P = 0.007), suggesting an adrenergic mechanism whereby diminished catestatin might predispose to later development of hypertension. In white subjects, diminished catestatin also predicted greater systemic vascular resistance responses to cold stress (r = -0.307, r(2) = 0.094, n = 75, P = 0.007), a relationship not found in Blacks (r = 0.122, r(2) = 0.015, n = 94, P = 0.243). CONCLUSIONS: We conclude that catestatin is diminished early in the course of development of hypertension, even in the normotensive offspring of patients with the disease. Low catestatin predicts augmented adrenergic pressor responses, suggesting a mechanism whereby diminished catestatin might increase the risk for later development of hypertension.