Clinical Pharmacology & TherapeuticsVolume 78, Issue 1 p. 19-24 Commentary St John's wort-associated drug interactions: Short-term inhibition and long-term induction? Correction(s) for this article Correction Volume 78Issue 5Clinical Pharmacology & Therapeutics pages: 550-550 First Published online: November 18, 2005 Hong-Guang Xie MD, PhD, Corresponding Author Hong-Guang Xie MD, PhD Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TNDivision of Clinical Pharmacology, 552 Robinson Research Bldg, Vanderbilt University Medical Center, Nashville, TN 37232–6602 e-mail: [email protected]Search for more papers by this authorRichard B. Kim MD, Richard B. Kim MD Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TNSearch for more papers by this author Hong-Guang Xie MD, PhD, Corresponding Author Hong-Guang Xie MD, PhD Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TNDivision of Clinical Pharmacology, 552 Robinson Research Bldg, Vanderbilt University Medical Center, Nashville, TN 37232–6602 e-mail: [email protected]Search for more papers by this authorRichard B. Kim MD, Richard B. Kim MD Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TNSearch for more papers by this author First published: 25 July 2005 https://doi.org/10.1016/j.clpt.2005.04.002Citations: 8Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1Rengelshausen, J., Banfield, M., Riedel, K.-D., Burhenne, J., Weiss, J. and Thomsen, T., et al. (2005). 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Postsynaptic alpha2B adrenergic receptors (ARs) mediate vasoconstriction. There is more than 1000-fold variability in vascular sensitivity to an alpha2-AR agonist. Genetic variability may contribute to such interindividual differences in sensitivity. A 301-303 deletion (del) polymorphism has been identified in the coding region of the alpha2B-AR gene and has functional effects in vitro. Thus, we examined the hypothesis that the del301-303 polymorphism contributes to variability in vascular alpha2-AR responses in vivo. Healthy subjects were recruited based on their alpha2B-AR genotype. Their vascular sensitivity was determined using a linear variable differential transformer following the infusion of increasing doses (range 0.01-1000 ng/min) of the alpha2-AR agonist, dexmedetomidine, into a dorsal hand vein. The dose that produced 50% (ED50) of maximum venoconstriction (Emax) was determined for each subject. Vascular response was compared among the three genotypes. Forty-nine subjects were studied [28 wild-type wt/wt, 13 wt/del, 8 del/del]. There was no difference in dexmedetomidine ED50 and Emax among the alpha2B-AR del301-303 genotypes. The ED50 was 1.39 ng/min [95% confidence interval (CI) 0.03-63.0 ng/min] in wt/wt subjects, 1.63 ng/min (95% CI 0.01-177.8 ng/min) in wt/del and 2.37 ng/min (95% CI 0.17-33.7 ng/min) in del/del (P=0.80). The average Emax was 75.4+/-14.9% in wt/wt, 75.7+/-21.3% in wt/del and 82.2+/-12.9% in del/del subjects (P=0.26). These findings suggest that the del301-303 polymorphism does not contribute significantly to interindividual in vivo variability in response to alpha2-AR activation in the hand vein.

The genetic basis for salt-sensitive hypertension is not known. Altered regulatory mechanisms such as vascular reactivity and/or sodium excretion are thought to contribute to salt sensitivity. Linkage analysis indicates that the blood pressure response to sodium loading is associated with the beta-2 adrenergic receptor (BAR2) locus suggesting that this gene may be an important regulator of blood pressure responses to salt. The common Arg16Gly and Gln27Glu BAR2 polymorphisms have been associated with enhanced agonist mediated desensitization and increased agonist-mediated responsiveness, respectively but their effects on salt sensitivity are not known. Healthy subjects (n = 23) received a high (400meq) and a low (10meq) salt diet for 5 days in random order. Automated blood pressure monitoring was performed on the last day of each diet. The change in blood pressure between low and high salt days was calculated and compared among genotypes. There was no significant genotypic difference in salt induced changes in systolic (Arg16Gln27[n = 8] 2.3 ± 3.8 mmHg, Gly16Gln27 [n = 7] 3.1 ± 3.3 mmHg and Gly16Glu27 [n = 8] 6.1 ± 2.8 mmHg: P = 0.66) or diastolic (Arg16Gln27 −2.4 ± 1.7 mmHg, Gly16Gln27 1.1 ± 1.6 mmHg and Gly16Glu27 −1.5 ± 1.2 mmHg: P = 0.26) blood pressure. These findings suggest that the BAR2 Arg16Gly and Gln27Glu polymorphisms are not a significant determinant of blood pressure responses to salt. Clinical Pharmacology & Therapeutics (2004) 75, P13–P13; doi: 10.1016/j.clpt.2003.11.048

Salt-sensitivity is more common in AA and is associated with increased risk of hypertension, but its genetic basis is not known. Genetic variability in ADRA2's has been implicated in salt sensitivity. An ADRA2C deletion polymorphism (322–325) is common in AA and is associated with reduced responses to agonist in vitro. We examined the hypothesis that the ADRA2C deletion polymorphism (322–325) contributes to salt sensitivity. Nineteen healthy AA subjects received 5 days of low (10 meq/day, LS), and high sodium, (400 meq/day, HS) diet. 24 hour automated blood pressure was monitored on the last day of each diet. The mean arterial blood pressure difference (dMAP) between LS and HS was calculated. An increase of 3 mmHg or greater was regarded as salt sensitivity. Genotyping for ADRA2C 322–325 deletion was performed, and dMAP compared among the three genotypes [wt/wt (5), wt/del (9), del/del (5)]. There was no difference between genotypes in dMAP (p= 0.263) or frequency of salt sensitivity (p= 0.794). [dMAP mmHg (CI): −0.07 (−9.5 +9.4), −2.27 (−8.2 +3.7), 4.94 (−4.1 +14.0); salt sensitivity: 2/5, 4/9, 3/5, for wt/wt, wt/del and del/del, respectively]. These findings indicate that the ADRA2C 322–325 deletion is not a major determinant of blood pressure response to dietary Sodium in healthy AA subjects. Clinical Pharmacology & Therapeutics (2004) 75, P13–P13; doi: 10.1016/j.clpt.2003.11.049

Vascular alpha-2 adrenergic receptors (ADRA2) mediate vasoconstriction. There are 3 ADRA2 subtypes, A, B and C, each with genetic variation that alters function. The ADRA2C 322-325 deletion polymorphism (322-325del) was associated with reduced responses to agonist in vitro, but its effects in vivo are not known. We examined the hypothesis that 322-325del affects ADRA2 mediated vasoconstrictor response. Increasing doses (0.01-1000ng/min) of the selective ADRA2 agonist, dexmedetomidine, were infused into a dorsal hand vein and constriction measured using a linear variable differential transformer in 53 healthy subjects (28 men and 25 women), aged 18-45 years. A dose-response curve was constructed and ED50 and Emax calculated for each individual. Genotyping for the ADRA2C 322-325del was performed, and ED50 and Emax compared. The average maximal constriction (Emax) and the ED50 (geometric mean) did not differ significantly among genotypes [p (ANOVA) = 0.251 and 0.946, respectively]. The ADRA2C 322-325del polymorphism does not alter vascular response to an agonist. (See Table). Clinical Pharmacology & Therapeutics (2004) 75, P55–P55; doi: 10.1016/j.clpt.2003.11.207 ADRA2C 322–325 del wt/wt (n=31) wt/del (n=13) del/del (n=9) mean Emax (±SEM %constriction) 77.2 ± 3.3 70.9 ± 5.2 *p=0.575 84.0 ± 3.9 *p=0.613 mean ED50 (95% CI, ng/min) 1.84 (0.79–4.27) 2.27 (0.57–9.02) *p=0.962 2.29 (0.36–14.38) *p=0.969 * P value compared to wt/wt.