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Background and Objectives: Activation of α2-adrenergic receptors regulates a broad spectrum of physiologic responses, including blood pressure (centrally and peripherally), sedation, analgesia, insulin release, renal function, cognition, and behavior. The purpose of this study was to explore systematically the local vascular responses in humans triggered by a highly selective α2-adrenergic agonist (azepexole [B-HT 933]) and whether such responses are dose-dependent or influenced by age, gender, or allelic variation at the drug's receptor. Methods: We evaluated dorsal hand vein vascular responses to the infusion of a wide spectrum of doses of azepexole, assessing any venodilation, as well as the maximal extent of venoconstriction (Bmax) and the dose that produced a half-maximal effect (Kd), in 50 healthy normotensive adults of both genders and 4 ethnicities. Genomic deoxyribonucleic acid from the study subjects was evaluated at polymorphisms of the α2B-adrenergic receptor gene (ADRA2B). Results: We found previously unreported initial venodilation to low doses (10-100 ng/min) of azepexole, followed by progressive, intense venoconstriction to higher doses (200-100,000 ng/min) of the drug. Younger individuals (aged <30 years) had less venodilation than older individuals (aged >30 years) with low doses of azepexole but had a greater extent of venoconstriction at higher doses of azepexole (ANOVA, P = .001). Men had less venodilation than women with low doses of azepexole but greater venoconstriction with higher doses (ANOVA, P = .036). Several common polymorphisms (>10% minor allele frequency) at ADRA2B (insertion/deletion polymorphism [Glu322-325],G-98C, C1182A, and C1776A) did not show an association with either Bmax or Kd for the drug response. The A36G (Thr12Thr) synonymous single nucleotide polymorphism displayed a nonsignificant trend (P = .073) toward higher Kd in A/G heterozygotes compared with A/A homozygotes. Conclusions: Local infusion into the human dorsal hand vein of a highly selective α2-adrenergic agonist, azepexole, produces biphasic responses, with venodilation at a low dose and intense venoconstriction at a higher concentration. These responses to azepexole show prominent differences as a function of age and gender but appear not to depend on common allelic variations at the ADRA2B receptor. [ABSTRACT FROM AUTHOR]

Rationale: The chromogranin A (CHGA) fragment pancreastatin (human CHGA250-301) impairs glucose metabolism, but the role of human pancreastatin in vivo remains unexplored., Methods: We studied brachial arterial infusion of pancreastatin (CHGA273-301-amide at approximately 200 nm) on forearm metabolism of glucose, free fatty acids, and amino acids. Plasma pancreastatin was measured in obesity or type 2 diabetes. Systematic discovery of amino acid variation was performed, and the potency of one variant in the active carboxyl terminus (Gly297Ser) was tested., Results: Pancreastatin decreased glucose uptake by approximately 48-50%; the lack of change in forearm plasma flow indicated a metabolic, rather than hemodynamic, mechanism. A control CHGA peptide (catestatin, CHGA352-372) did not affect glucose. Insulin increased glucose uptake, but pancreastatin did not antagonize this action. Pancreastatin increased spillover of free fatty acids by about 4.5- to 6.4-fold, but not spillover of amino acids. Insulin diminished spillover of both free fatty acids and amino acids, but these actions were not reversed by pancreastatin. Plasma pancreastatin was elevated approximately 3.7-fold in diabetes, but was unchanged during weight loss. Proteolytic cleavage sites for pancreastatin in vivo were documented by matrix-assisted laser desorption ionization/time of flight mass spectrometry. Three pancreastatin variants were discovered: Arg253Trp, Ala256Gly, and Gly297Ser. The Gly297Ser variant had unexpectedly increased potency to inhibit glucose uptake., Conclusions: The dysglycemic peptide pancreastatin is specifically and potently active in humans on multiple facets of intermediary metabolism, although it did not antagonize insulin. Pancreastatin is elevated in diabetes, and the variant Gly297Ser had increased potency to inhibit glucose uptake. The importance of human pancreastatin in vivo as well as its natural variants is established.

Background and Objectives: Activation of alpha 2 -adrenergic receptors regulates a broad spectrum of physiologic responses, including blood pressure (centrally and peripherally), sedation, analgesia, insulin release, renal function, cognition, and behavior. The purpose of this study was to explore systematically the local vascular responses in humans triggered by a highly selective alpha 2 -adrenergic agonist (azepexole [B-HT 933]) and whether such responses are dose-dependent or influenced by age, gender, or allelic variation at the drug's receptor., Methods: We evaluated dorsal hand vein vascular responses to the infusion of a wide spectrum of doses of azepexole, assessing any venodilation, as well as the maximal extent of venoconstriction (B max ) and the dose that produced a half-maximal effect (K d ), in 50 healthy normotensive adults of both genders and 4 ethnicities. Genomic deoxyribonucleic acid from the study subjects was evaluated at polymorphisms of the alpha 2B -adrenergic receptor gene (ADRA2B)., Results: We found previously unreported initial venodilation to low doses (10-100 ng/min) of azepexole, followed by progressive, intense venoconstriction to higher doses (200-100,000 ng/min) of the drug. Younger individuals (aged <30 years) had less venodilation than older individuals (aged >30 years) with low doses of azepexole but had a greater extent of venoconstriction at higher doses of azepexole (ANOVA, P = .001). Men had less venodilation than women with low doses of azepexole but greater venoconstriction with higher doses (ANOVA, P = .036). Several common polymorphisms (>10% minor allele frequency) at ADRA2B (insertion/deletion polymorphism [Glu 322-325 ], G-98C, C1182A, and C1776A) did not show an association with either B max or K d for the drug response. The A36G (Thr12Thr) synonymous single nucleotide polymorphism displayed a nonsignificant trend (P = .073) toward higher K d in A/G heterozygotes compared with A/A homozygotes., Conclusions: Local infusion into the human dorsal hand vein of a highly selective alpha 2 -adrenergic agonist, azepexole, produces biphasic responses, with venodilation at a low dose and intense venoconstriction at a higher concentration. These responses to azepexole show prominent differences as a function of age and gender but appear not to depend on common allelic variations at the ADRA2B receptor.