Human response to α-adrenergic agonist stimulation studied in an isolated vascular bed in vivo: Biphasic influence of dose, age, gender, and receptor genotype

King, Danuta; Etzel, Jason P.; Chopra, Shagun; Smith, Joshua R.; Cadman, Peter E.; Rao, Fangwen; Funk, Stephen D.; Rana, Brinda K.; Schork, Nicholas J.; Insel, Paul A.; O’Connor, Daniel T.

doi:10.1016/j.clpt.2005.02.008

Cited by 27 publications

(18 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, we have noted that aging-dependent changes in sympathetic activity differ between the sexes, 11 as do vascular responses to adrenergic agonists. 31 The Gly364Ser genotype-by-sex interaction results (Figure 4b), however, have potential implications. Because sex is a necessary modifier of the Gly364Ser effect on BP, it will be an essential part of any Gly364Ser role in the diagnosis, pathogenesis, or treatment of hypertension.…”

Section: Chga Gly364ser: Association With Hypertensionmentioning

confidence: 86%

Catecholamine Release–Inhibitory Peptide Catestatin (Chromogranin A _352–372 )

et al. 2007

View full text Add to dashboard Cite

Background-Chromogranin A, coreleased with catecholamines by exocytosis, is cleaved to the catecholamine release-inhibitory fragment catestatin. We identified a natural nonsynonymous variant of catestatin, Gly364Ser, that alters human autonomic function and blood pressure. Methods and Results-Gly364Ser heterozygotes and controls underwent physiological and biochemical phenotyping, including catecholamine production, chromogranin A precursor, and its catestatin product. Case-control studies replicated effects of the gene on blood pressure in the population. Gly364Ser displayed diminished inhibition of catecholamine secretion from cultured neurons. Gly/Ser heterozygotes displayed increased baroreceptor slope during upward deflections (by Ϸ47%) and downward deflections (by Ϸ44%), increased cardiac parasympathetic index (by Ϸ2.4-fold), and decreased cardiac sympathetic index (by Ϸ26%). Renal norepinephrine excretion was diminished by Ϸ26% and epinephrine excretion by Ϸ34% in Gly/Ser heterozygotes. The coalescent dated emergence of the variant to Ϸ70 000 years ago. Gly364Ser was in linkage disequilibrium with 1 major Chromogranin A promoter haplotype, although promoter haplotypes did not predict autonomic phenotypes. The 364Ser variant was associated with lower diastolic blood pressure in 2 independent/confirmatory groups of patients with hypertension; genotype groups differed by Ϸ5 to 6 mm Hg, and the polymorphism accounted for Ϸ1.8% of population diastolic blood pressure variance, although a significant gene-by-sex interaction existed, with an enhanced effect in men. Conclusions-The catestatin Gly364Ser variant causes profound changes in human autonomic activity, both parasympathetic and sympathetic, and seems to reduce risk of developing hypertension, especially in men. A model for catestatin action in the baroreceptor center of the nucleus of the tractus solitarius accounts for these actions.

show abstract

Section: Chga Gly364ser: Association With Hypertensionmentioning

confidence: 86%

Catecholamine Release–Inhibitory Peptide Catestatin (Chromogranin A _352–372 )

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Indeed, we have noted that aging-dependent changes in sympathetic activity differ between the sexes, 43 as do vascular responses to adrenergic agonists. 44 The C-824T genotype-bysex interaction has potential implications. Since sex may modify the C-824T effect on BP, sex may contribute to the role of genotype in the diagnosis, pathogenesis, or treatment of hypertension.…”

Section: Th and Sexmentioning

confidence: 99%

Tyrosine Hydroxylase, the Rate-Limiting Enzyme in Catecholamine Biosynthesis

et al. 2007

View full text Add to dashboard Cite

Background-Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. Does common genetic variation at human TH alter autonomic activity and predispose to cardiovascular disease? We undertook systematic polymorphism discovery at the TH locus and then tested variants for contributions to sympathetic function and blood pressure. Methods and Results-We resequenced 80 ethnically diverse individuals across the TH locus. One hundred seventy-two twin pairs were evaluated for sympathetic traits, including catecholamine production, reflex control of the circulation, and environmental (cold) stress responses. To evaluate hypertension, we genotyped subjects selected from the most extreme diastolic blood pressure percentiles in the population. Human TH promoter haplotype/reporter plasmids were transfected into chromaffin cells. Forty-nine single-nucleotide polymorphisms were discovered, but coding region polymorphism did not account for common phenotypic variation. A block of linkage disequilibrium spanned 4 common variants in the proximal promoter. Catecholamine secretory traits were significantly heritable (h 2 ), as were stressinduced blood pressure changes. In the TH promoter, significant associations were found for urinary catecholamine excretion and for blood pressure response to stress. TH promoter haplotype 2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. Coalescent simulations suggest that TH haplotype 2 likely arose Ϸ380 000 years ago. In hypertension, 2 independent case-control studies (1266 subjects with 53% women and 927 subjects with 24% women) replicated the effect of C-824T in the determination of blood pressure. Conclusions-We conclude that human catecholamine secretory traits are heritable, displaying joint genetic determination (pleiotropy) with autonomic activity and finally with blood pressure in the population. Catecholamine secretion is influenced by genetic variation in the adrenergic pathway encoding catecholamine synthesis, especially at the classically rate-limiting step, TH. The results suggest novel pathophysiological links between a key adrenergic locus, catecholamine metabolism, and blood pressure and suggest new strategies to approach the mechanism, diagnosis, and treatment of systemic hypertension. (Circulation. 2007;116:993-1006.)Key Words: catecholamines Ⅲ genetics Ⅲ nervous system, autonomic Ⅲ nervous system, sympathetic Ⅲ norepinephrine T yrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. 1,2 Substantial loss of TH enzymatic activity as a consequence of rare inactivating mutations has profound consequences in humans 1 and in mice with targeted ablation of the TH locus. 3 Editorial p 970 Clinical Perspective p 1006The human TH locus also displays more common natural allelic variation such as the tetranucleotide repeat [or microReceived January 18, 2007; accepted May 8, 2007. satellite polymorphism (TCAT) n ] in its first intron, 4 which has been used to probe the role of TH in ...

show abstract

“…61 Indeed, heredity and genetic polymorphism are already known to play substantial roles in the response to ␣ 2 -adrenergic ligands in humans. 75,76 Whether CHGA polymorphisms can effectively guide therapy in this setting remains to be evaluated.…”

Section: Discussionmentioning

confidence: 99%

Chromogranin A Polymorphisms Are Associated With Hypertensive Renal Disease

Salem

Cadman²,

Chen³

et al. 2008

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Chromogranin A is released together with epinephrine and norepinephrine from catecholaminergic cells. Specific endopeptidases cleave chromogranin A into biologically active peptide fragments, including catestatin, which inhibits catecholamine release. Previous studies have suggested that a deficit in this sympathetic "braking" system might be an early event in the pathogenesis of human hypertension. Whether chromogranin A (CHGA) polymorphisms predict end-organ complications of hypertension, such as end-stage renal disease, is unknown. Among blacks, we studied common genetic variants spanning the CHGA locus in 2 independent case-control studies of hypertensive ESRD. Two haplotypes were significantly more frequent among subjects with hypertensive ESRD: 1) in the promoter (5Ј) region, G-462A3T-415C3C-89A, haplotype ATC (adjusted odds ratio ϭ 2.65; P ϭ 0.037), and 2) at the 3Ј-end, C11825T (3Ј-UTR, Cϩ87T)3G12602C, haplotype TC (adjusted odds ratio ϭ 2.73, P ϭ 0.0196). Circulating levels of catestatin were lower among those with hypertensive ESRD than controls, an unexpected finding given that peptide levels are usually elevated in ESRD because of reduced renal elimination. We found that the 3Ј-UTR ϩ 87T variant decreased reporter gene expression, providing a possible mechanistic explanation for diminished catestatin. In summary, common variants in chromogranin A associate with the risk of hypertensive ESRD in blacks.

show abstract

Human response to α-adrenergic agonist stimulation studied in an isolated vascular bed in vivo: Biphasic influence of dose, age, gender, and receptor genotype

Cited by 27 publications

References 56 publications

Catecholamine Release–Inhibitory Peptide Catestatin (Chromogranin A _352–372 )

Catecholamine Release–Inhibitory Peptide Catestatin (Chromogranin A _352–372 )

Tyrosine Hydroxylase, the Rate-Limiting Enzyme in Catecholamine Biosynthesis

Chromogranin A Polymorphisms Are Associated With Hypertensive Renal Disease

Contact Info

Product

Resources

About

Human response to α-adrenergic agonist stimulation studied in an isolated vascular bed in vivo: Biphasic influence of dose, age, gender, and receptor genotype

Cited by 27 publications

References 56 publications

Catecholamine Release–Inhibitory Peptide Catestatin (Chromogranin A 352–372 )

Catecholamine Release–Inhibitory Peptide Catestatin (Chromogranin A 352–372 )

Tyrosine Hydroxylase, the Rate-Limiting Enzyme in Catecholamine Biosynthesis

Chromogranin A Polymorphisms Are Associated With Hypertensive Renal Disease

Contact Info

Product

Resources

About

Catecholamine Release–Inhibitory Peptide Catestatin (Chromogranin A _352–372 )

Catecholamine Release–Inhibitory Peptide Catestatin (Chromogranin A _352–372 )