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.

AIMS:To examine the hypothesis that sildenafil, a phosphodiesterase type 5 inhibitor that inhibits cGMP breakdown, could enhance nitric oxide-mediated vasodilation and reverse endothelial dysfunction in chronic smokers.METHODS:Flow-mediated dilation of the brachial artery and forearm postischemic reactive hyperemia (both nitric oxide-mediated responses) were measured before and after sildenafil 50 mg and placebo in a double-blind, randomized, crossover study in 9 men who were chronic smokers (21 +/- 3 pack years).RESULTS:There was no significant change in flow-mediated dilation after either sildenafil (0.18%, 95%CI -1.7-2%) or placebo (0.24%, 95%CI -2.8-3.3%) (P = 0.88 and 0.8, respectively). Sildenafil had no significant effect on resting forearm blood flow or postischemic reactive hyperemia (P = 0.39 and 0.7, respectively). Resting heart rate and blood pressure were unaffected by sildenafil.CONCLUSIONS:Acute sildenafil administration did not improve endothelial function in chronic smoking men.

Objective The α1A-adrenergic receptor is highly expressed in human vasculature including resistance arteries and veins, and its stimulation is primarily responsible for adrenergically mediated smooth muscle contraction. Variability in sensitivity to phenylephrine, an α1A adrenergic agonist, has a large genetic component. We examined the hypothesis that a common polymorphism of α1A-adrenergic receptor (Arg347Cys) affects in vivo response. Methods We measured vascular sensitivity to phenylephrine using the dorsal hand vein linear variable differential transformer technique and determined α1A-adrenergic receptor genotype in 74 healthy, nonsmoking adults (28 Arg/Arg, 30 Arg/Cys, and 16 Cys/Cys). Results Sensitivity to phenylephrine, expressed as the dose of phenylephrine resulting in 50% venoconstriction (Phe50), was not significantly different in subjects with the 3 α1A adrenergic receptor genotypes: Phe50 geometric mean (95% confidence interval) was 513 ng/min (287–9–8 ng/min) for Arg/Arg, 431 ng/min (274–680 ng/min) for Arg/Cys, and 471 ng/min (197–1124 ng/min) for Cys/Cys (P = .90). Conclusion We conclude that the Arg347Cys receptor polymorphism does not alter agonist-mediated venoconstriction in vivo. Clinical Pharmacology & Therapeutics (2004) 75, 539–545; doi: 10.1016/j.clpt.2004.02.006

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.

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