Objectives-Black subjects may be less responsive to β-blockers than whites. Genetic variants in the β 1 -adrenergic receptor (β 1 -AR) associated with lesser response to β-blockers are more common in blacks than whites. The purpose of this study was to determine whether ethnic differences in response to β-blockade can be explained by differing distributions of functional genetic variants in the β 1 -AR.Methods-We measured sensitivity to β-blockade by the attenuation of exercise-induced tachycardia in 165 subjects (92 whites) who performed a graded bicycle exercise test before and 2.75 hours after oral atenolol (25 mg). We determined heart rate at rest and at 3 exercise levels from continuous ECG recordings and calculated the area-under-the-curve (AUC). We also measured plasma atenolol concentrations and determined genotypes for variants of the β 1 -AR (Ser49Gly, Arg389Gly) and α 2C -AR (del322-325). The effects of ethnicity, genotype, and other covariates on the heart rate reduction after atenolol were estimated in multiple regression analyses.Results-Atenolol resulted in a greater reduction in exercise heart rate in whites than blacks (P=0.006). β 1 -AR Arg389 (P=0.003), but not the α 2C -AR 322-325 insertion allele (P=0.31), was independently associated with a greater reduction in heart rate AUC. Ethnic differences in sensitivity to atenolol remained significant (P=0.006) after adjustment for β 1 -AR and α 2C -AR genotypes.Conclusions-Ethnic differences in sensitivity to the β 1 -blocker atenolol persist even after accounting for different distributions of functional genetic β 1 -AR variants, suggesting that additional, as yet unidentified factors contribute to such ethnic differences.

This study demonstrates the feasibility of using olfactory receptor neurons to examine alterations in intracellular signaling in neuronal cells from living patients. Our results, although based on a small number of subjects, suggest that altered intracellular calcium signaling in olfactory receptor neurons may be a trait of bipolar disorder.

Purpose There is a large interindividual variability in dexmedetomidine dose requirements for sedation of patients in intensive care units (ICU). Cytochrome P450 2A6 (CYP2A6) mediates an important route of dexmedetomidine metabolism, and genetic variation in CYP2A6 affects the clearance of other substrate drugs. We examined whether CYP2A6 genotypes affect dexmedetomidine disposition. Methods In 43 critically ill ICU patients receiving dexmedetomidine infusions adjusted to achieve the desired level of sedation, we determined a median of 5 plasma dexmedetomidine concentrations each. Forty subjects were genotyped for five common CYP2A6 alleles and grouped into normal (n=33), intermediate (n=5), and slow metabolizers (n=2). Results Using a Bayesian hierarchical nonlinear mixture model, estimated dexmedetomidine clearance was 49.1 L/hr (posterior mean; 95% credible interval, 41.4 to 57.6 L/hr). There were no significant differences in dexmedetomidine clearance among normal, intermediate, and slow CYP2A6 metabolizer groups. Conclusion Genetic variation in CYP2A6 is not an important determinant of dexmedetomidine clearance in ICU patients.

Objectives: Cardiovascular responses to stressors are regulated by sympathetic activity, increased in black Americans, and associated with future cardiovascular morbidity. Our aim was to determine whether two functional variants in genes regulating sympathetic activity, a deletion in the α 2C -adrenergic receptor (ADRA2C del322-325) and a G-protein β3 subunit variant (GNB3 G825T), affect cardiovascular responses to physiologic stressors and contribute to their ethnic differences. Methods:We measured heart rate and blood pressure responses to a cold pressor test (CPT) in 79 healthy subjects (40 blacks, 39 whites), aged 25.7 ± 5.3 years, and determined genotypes for the ADRA2C and GNB3 variants. We examined the response variables (increase in heart rate and blood pressure) in multiple linear regression analyses adjusting first for baseline measures, ethnicity, and other covariates, and then additionally for genotypes. Results:Black subjects had a greater heart rate response to CPT than whites (mean difference, 9.9 bpm; 95% confidence interval (CI), 4.1 to 15.6; P=0.001). Both the ADRA2C del/del (15.8 bpm; 95% CI, 8.0 to 23.7; P<0.001) and GNB3 T/T genotypes (6.8 bpm; 95% CI, 0.9 to 12.7; P=0.026) were associated with greater heart rate response. After adjusting for genotypes, the ethnic difference was abrogated (1.3 bpm; 95% CI, −5.4 to 8.0; P=0.70), suggesting that the genetic variants contributed substantially to ethnic differences. Conclusions:Variation in genes that regulate sympathetic activity affects hemodynamic stress responses and contributes to their ethnic differences. This study elucidates how genetic factors may in part explain ethnic differences in cardiovascular regulation.

Bordetella pertussis, the causative organism of whooping cough, produces a calmodulin-sensitive adenylate cyclase. Confer & Eaton [(1982) Science 217, 948-950] have shown that an extract from B. pertussis increases intracellular cyclic AMP levels in neutrophils and suggested that this increase is caused by the bacterial adenylate cyclase which penetrates these cells. We demonstrate in the present study that adenylate cyclase activity in lysates from lymphocytes exposed to a partially purified preparation of the bacterial enzyme has properties completely different from those of the intrinsic membrane-bound enzyme. Adenylate cyclase activity in lysates from lymphocytes exposed to the invasive enzyme is insensitive to N-ethylmaleimide, readily inactivated by acetic anhydride and relatively stable to SDS. Similar properties are exhibited by the bacterial enzyme itself. By contrast, the intrinsic membrane-bound enzyme activated by forskolin and guanosine 5'-gamma-thiotriphosphate is sensitive to N-ethylmaleimide and SDS and relatively stable to acetic anhydride. This strongly supports the notion that B. pertussis adenylate cyclase penetrates cells. Using the partially purified preparation of the invasive enzyme, we have studied the kinetics of its penetration. The intracellular catalytic activity reaches a steady state within 20 min, irrespective of enzyme or cell concentration. Steady-state levels are maintained for at least 2 h provided that the invasive enzyme is present in the incubation medium. Upon its removal, a rapid decrease (t1/2 approximately equal to 15 min) in the intracellular cyclase level is observed. This decrease reflects intracellular inactivation of the bacterial enzyme and is not caused by the release of the enzyme to the cell medium.