ABSTRACT
As cannabis use has legalized for medical and recreational use in several states, the medical community has become more aware of the drug's potential toxicities. First described in 2004, cannabinoid hyperemesis syndrome is increasingly recognized as a cause of hospitalization among drug users. However, little information is available in the medical literature regarding electrolyte abnormalities in this syndrome. Between 2011 and 2014, six men were treated for cannabinoid hyperemesis syndrome at the Veterans Affairs Medical Center in San Diego, CA, and found to have significant hypophosphatemia (phosphate range, <1-1.3mg/dL). The 6 cases are presented here and possible causes of hypophosphatemia are discussed. In 3 patients, serum phosphate levels normalized spontaneously within hours, suggesting redistribution of phosphate as a potential mechanism. Hyperventilation, which can lead to phosphate redistribution, was observed in 4 of the 6 individuals and may have contributed. Hypophosphatemia is a presenting feature of cannabinoid hyperemesis syndrome in some patients.
Subject(s)
Hypophosphatemia/chemically induced , Marijuana Abuse/complications , Adult , Aged , Humans , Male , Middle Aged , Young AdultABSTRACT
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 (5') region, G-462A-->T-415C-->C-89A, haplotype ATC (adjusted odds ratio = 2.65; P = 0.037), and 2) at the 3'-end, C11825T (3'-UTR, C+87T)-->G12602C, haplotype TC (adjusted odds ratio = 2.73, P = 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 3'-UTR + 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.
Subject(s)
Black or African American/genetics , Chromogranin A/genetics , Hypertension, Renal/genetics , Kidney Failure, Chronic/genetics , 3' Untranslated Regions , Chromogranin A/blood , Epistasis, Genetic , Female , Gene Expression , Gene Frequency , Genetic Predisposition to Disease/ethnology , Genotype , Haplotypes , Humans , Hypertension, Renal/ethnology , Kidney Failure, Chronic/ethnology , Linkage Disequilibrium , Male , Middle Aged , Odds Ratio , Peptide Fragments/blood , Polymorphism, Single NucleotideABSTRACT
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 (h2), as were stress-induced 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 approximately 380,000 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.
Subject(s)
Autonomic Nervous System/physiology , Blood Pressure , Cardiovascular Diseases/genetics , Catecholamines/biosynthesis , Transcription, Genetic , Tyrosine 3-Monooxygenase/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Algorithms , Cardiovascular Diseases/epidemiology , Genetic Predisposition to Disease , Genetic Variation , Humans , Kinetics , Middle Aged , Polymorphism, Single Nucleotide , Twins, Dizygotic , Twins, MonozygoticABSTRACT
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.
Subject(s)
Diabetes Mellitus, Type 2/metabolism , Glucose/metabolism , Obesity/metabolism , Pancreatic Hormones/genetics , Pancreatic Hormones/metabolism , Polymorphism, Genetic , Amino Acid Sequence , Amino Acids/metabolism , Base Sequence , Case-Control Studies , Chromogranin A , Diabetes Mellitus, Type 2/complications , Fatty Acids, Nonesterified/metabolism , Forearm , Genetic Variation , Humans , Injections, Intra-Articular , Male , Middle Aged , Molecular Sequence Data , Obesity/blood , Obesity/complications , Obesity/therapy , Pancreatic Hormones/administration & dosage , Pancreatic Hormones/pharmacology , Weight LossABSTRACT
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.
Subject(s)
Adrenergic alpha-Agonists/pharmacokinetics , Genotype , Veins/drug effects , Adrenergic alpha-Agonists/administration & dosage , Adult , Age Factors , Azepines/administration & dosage , Azepines/pharmacokinetics , Dose-Response Relationship, Drug , Female , Hand/blood supply , Humans , Infusions, Intravenous , Male , Pharmacogenetics/methods , Receptors, Adrenergic, alpha-2/drug effects , Receptors, Adrenergic, alpha-2/genetics , Sex Factors , Vasoconstriction , Vasodilation , Veins/pathology , Veins/physiologyABSTRACT
Chromogranin B (CgB), a major member of the chromogranin/secretogranin family of catecholamine storage vesicle secretory proteins, plays both intracellular (vesiculogenic) and extracellular (prohormone) roles in the neuroendocrine system, and its biosynthesis and release are under the control of efferent sympathetic nerve traffic ("stimulus-transcription coupling"). To explore the role of heredity in control of CgB, we conducted a genome-wide linkage analysis of CgB release in 12 extended CEPH (Centre d'Etude du Polymorphisme Humain) pedigrees. Region-specific radioimmunoassays were used to measure five CgB fragments in plasma: CgB1-16, CgB312-331, CgB439-451, CgB568-577, and CgB647-657. Substantial heritability, as measured by h2r, was observed for three of the fragment concentrations, CgB312-331, CgB439-451, and CgB568-577, which yielded h2r estimates ranging from 0.378 (P = 0.002) to 0.910 (P < 0.0000001). Variance-component genome-wide linkage analysis with 654 microsatellite markers at 5 cM spacing identified a major quantitative trait locus for CgB312-331 on chromosome 11q24-q25 with a maximum multipoint LOD score of 5.84. Significant allelic associations between markers in the region and CgB levels were also observed. Although the 2-LOD confidence interval for linkage did not include the CgB locus itself, known trans-activators of the CgB gene promoter, or prohormone cleaving proteases, examination of positional candidate loci within this region yielded novel and plausible physiological candidates for further exploration. Allelic variation in this region may thus influence effects of sympathetic outflow on target organs in humans.
Subject(s)
Chromogranins/biosynthesis , Chromosomes, Human, Pair 20/genetics , Peptide Fragments/blood , Alleles , Animals , Barium/pharmacology , Catecholamines/metabolism , Chromogranin B , Chromogranins/blood , Chromogranins/genetics , Chromosomes, Human, Pair 11/genetics , Cohort Studies , Exocytosis/drug effects , Genetic Variation , Humans , Lod Score , Microsatellite Repeats , PC12 Cells/drug effects , PC12 Cells/metabolism , Parents , Pedigree , Potassium Channel Blockers/pharmacology , Potassium Channels/drug effects , Potassium Channels/genetics , Protein Structure, Tertiary , Quantitative Trait Loci , Rats , SiblingsABSTRACT
The physiologic effects of the chromogranin A peptide fragment, pancreastatin, were studied in six healthy Caucasian men, ages 25-46 years. Synthetic pancreastatin (human chromogranin A(273-301)-amide) was infused into the brachial artery of each subject to achieve a local concentration of approximately 200 nM over 15 minutes. Forearm blood flow was measured by strain-gauge plethysmography while (A-V)(glucose) was monitored by arterial and venous sampling. Pancreastatin infusion significantly reduced forearm glucose uptake (mean reduction +/- 1 SEM, 54 +/- 15%; P = 0.028) but did not alter forearm blood flow-indicating a metabolic, rather than hemodynamic, effect. Simultaneous infusion of pancreastatin with insulin (0.1 mU/kg/min) did not diminish insulin-induced forearm glucose uptake, suggesting pancreastatin is not simply a negative insulin modulator. The results of this study suggest that pancreastatin may contribute to the dysglycemia associated with type 2 diabetes and essential hypertension, two common human disease states in which plasma pancreastatin levels are elevated.
Subject(s)
Arm/blood supply , Pancreatic Hormones/chemistry , Pancreatic Hormones/physiology , Adult , Blood Flow Velocity/drug effects , Blood Glucose/metabolism , Chromogranin A , Diabetes Mellitus, Type 2/physiopathology , Glucose/pharmacokinetics , Hemodynamics , Humans , Male , Middle Aged , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolismABSTRACT
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. We resequenced 80 ethnically diverse individuals across the TH locus. One hundred seventy-two twin pairs were evaluated for sympathetic traits, including catecholamine production 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 (SNPs) and one tetranucleotide repeat were discovered, but coding region polymorphism did not account for common phenotypic variation. A block of linkage disequilibrium spanned four common variants in the proximal promoter. Catecholamine secretory traits were significantly heritable, as were stress-induced blood pressure changes. In the TH promoter, significant associations were found for urinary catecholamine excretion, as well as blood pressure response to stress. TH promoter haplotype #2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. In hypertension, a case-control study (1266 subjects, 53% women) established the effect of C-824T in determination of blood pressure. 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.
Subject(s)
Cardiovascular Diseases/genetics , Genetic Predisposition to Disease , Polymorphism, Genetic , Stress, Psychological , Tyrosine 3-Monooxygenase/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Autonomic Nervous System/physiology , Blood Pressure/genetics , Catecholamines/genetics , Catecholamines/metabolism , Female , Genotype , Haplotypes , Humans , Hypertension/genetics , Hypertension/physiopathology , Linkage Disequilibrium , Middle Aged , PC12 Cells , Physiological Phenomena/genetics , Promoter Regions, Genetic , Rats , Twins/genetics , Tyrosine 3-Monooxygenase/metabolism , Young AdultABSTRACT
Chromogranins or secretogranins (granins), present in secretory granules of virtually all neuroendocrine cells and neurones, are structurally related proteins encoded by different genetic loci: chromogranins A and B, and secretogranins II through VI. Compelling evidence supports both intracellular and extracellular functions for this protein family. Within the cells of origin, a granulogenic or sorting role in the regulated pathway of hormone or neurotransmitter secretion has been documented, especially for chromogranin A (CHGA). Granins also function as pro-hormones, giving rise by proteolytic processing to an array of peptide fragments for which diverse autocrine, paracrine, and endocrine activities have been demonstrated. CHGA measurements yield insight into the pathogenesis of such human diseases as essential hypertension, in which deficiency of the catecholamine release-inhibitory CHGA fragment catestatin may trigger sympathoadrenal overactivity as an aetiologic culprit in the syndrome. The CHGA dysglycaemic fragment pancreastatin is functional in humans in vivo, affecting both carbohydrate (glucose) and lipid (fatty acid) metabolism. Pancreastatin is cleaved from CHGA in hormone storage granules in vivo, and its plasma concentration varies in human disease. The pancreastatin region of CHGA gives rise to three naturally occurring human variants, one of which (Gly297Ser) occurs in the functionally important carboxy-terminus of the peptide, and substantially increases the peptide's potency to inhibit cellular glucose uptake. These observations establish a role for pancreastatin in human intermediary metabolism and disease, and suggest that qualitative hereditary alterations in pancreastatin's primary structure may give rise to interindividual differences in glucose disposition.
Subject(s)
Catecholamines/metabolism , Metabolic Syndrome/metabolism , Pancreatic Hormones/physiology , Secretory Vesicles/metabolism , Amino Acid Sequence , Animals , Biological Transport , Blood Glucose/metabolism , Cattle , Chromogranin A/physiology , Diabetes Mellitus, Type 2/blood , Humans , Mice , Molecular Sequence Data , Pancreatic Hormones/genetics , Rats , Sequence AlignmentABSTRACT
PURPOSE OF REVIEW: The emerging field of pharmacogenomics has the potential to fundamentally change the management of essential hypertension, a common, perhaps polygenic syndrome characterized by substantial inter-individual variability in drug responsiveness. As understanding of sequence diversity in the human genome progresses, the prospect grows for tailoring the prescription of antihypertensive drugs to complement common genetic variations among individual patients, allowing optimization of blood pressure control and improved avoidance of drug side effects. Some principles of pharmacogenomics are presented here, along with a review of the most recent literature on genetic determinants of antihypertensive drug responses, with a preview of likely developments to come. RECENT FINDINGS: Polymorphisms at candidate pharmacodynamic loci (such as angiotensinogen, angiotensin converting enzyme, and the angiotensin II receptor) have already been shown to predict responses to such specific treatments as angiotensin converting enzyme inhibition and angiotensin II blockade. The National Institutes of Health have established a multi-institutional pharmacogenetics network and knowledge base, whose goals include understanding how common polymorphisms influence therapeutic responses to a variety of drugs, including antihypertensive agents. SUMMARY: The study of genetic determinants of drug responses, particularly at the pharmacodynamic (drug target/receptor and post-receptor) level, is likely to allow us to more precisely tailor therapy to the individual patient, as well as to promote the creation of novel therapies.