Stephen Farrow

α2-Adrenergic receptor gene polymorphism and hypertension in blacks

alpha 2-Adrenergic receptors are found on presynaptic neurons of the central and peripheral nervous systems, on blood vessels, on platelets, on adipocytes, and in the kidney and pancreas. Activation of these ubiquitous adrenoreceptors results in decreased neuronal norepinephrine release, vasodilation, a fall in blood pressure, platelet aggregation, increased sodium excretion, and decreased insulin release. We hypothesized that defects in alpha 2-adrenergic receptors, or postreceptor defects, could explain the increased prevalence of hypertension in blacks. To test our hypothesis, we first determined whether or not a polymorphism of the alpha 2-adrenergic receptor gene was associated with pathologic elevations in blood pressure in American blacks. Dra-I identified a restriction fragment-length polymorphism (RFLP) of 6.3 and 6.7 kb of the alpha 2-adrenergic receptor gene on chromosome 10 in humans. Of 227 patients studied, 13/107 hypertensive subjects were homozygous for the 6.3-kb allele, whereas only 3/120 normotensive volunteers were homozygotes (P = .008). When analyzed by race, 13/82 black hypertensive subjects were homozygous for the 6.3-kb allele, whereas only 2/59 normotensive blacks were homozygous for the 6.3-kb alleles (P = .02). However, only 1/61 white normotensive and 0/25 white hypertensive subjects were homozygous for the 6.3-kb allele (P = 1.00). Ethnic variation among blacks may explain our findings. Alternatively, a genetic polymorphism in, or near, the alpha 2-adrenergic receptor on chromosome 10 can contribute to the development of hypertension in blacks.

Genetic polymorphism of the α2-adrenergic receptor is associated with increased platelet aggregation, baroreceptor sensitivity, and salt excretion in normotensive humans

It is likely that a number of independent heritable traits, each encoded by a singular gene, contribute to pathologic elevations in blood pressure in humans. Genetic polymorphisms of individual genes may result in intermediate phenotypes which, by themselves, do not raise blood pressure, but, coupled with environmental or epistatic forces, contribute to the prevalence of human hypertension. The gene for the alpha 2-adrenergic receptor encoded by chromosome 10 (C10 A2AR) is polymorphic, and Southern blotting with a cDNA probe following restriction enzyme digest of this gene results in fragments of either 6.3 kb or 6.7 kb in size. We reported an association between homozygosity for the 6.3 kb allele and hypertension in blacks. Blacks with hypertension also have an increased risk for thrombotic stroke, increased baroreceptor sensitivity, and decreased sodium excretion. We noted that the C10 A2AR, which modulates norepinephrine release in blood-pressure-regulating regions of the brain, is also expressed on platelets and in the kidney. We postulated that functional changes associated with the C10 A2AR gene polymorphism could be responsible for increased baroreceptor sensitivity, epinephrine-mediated platelet aggregation, and decreased sodium excretion in some individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Ethnic differences in titratable acid excretion and bone mineralization.

PURPOSE To test our hypothesis that differences in urinary calcium excretion among blacks and whites may be secondary to ethnic variations in acid (H(+)) metabolism and to prove that increases in titratable acid excretion would be found among individuals predisposed to the development of stress fractures. METHODS We administered 8 g NH(4)Cl acutely to 11 black and 18 white healthy volunteers and measured urinary sodium, calcium, and acid excretions. We measured the Na(+)/H(+) antiporter activity using acid-loaded platelets as surrogate markers for this exchanger expressed in renal epithelial cells. We also compared differences in titratable acid excretion among a cohort of subjects with, and without, a history of stress fracture. RESULTS NH(4)Cl-induced increases in titratable urinary acid correlated with changes in the renal excretion of calcium and sodium, and stimulated acid excretion correlated with basal acid loss. Despite comparable changes in plasma pH, whites, when compared to blacks, had much greater basal acid excretion and NH(4)Cl-induced acid excretion. Whites also had much greater baseline calcium excretion rates when compared to blacks. Following acid loading, whites continued to exhibit greater calcium excretion rates than blacks. Acid loading significantly decreased sodium excretion in whites but not in blacks. Blacks also had significantly attenuated Na(+)/H(+) exchange activity. In a cohort of resting, athletic students, we found enhanced basal H(+) and phosphate excretion among subjects who experienced stress fractures during their rigorous physical training when compared to those individuals who did not. CONCLUSION Blacks may have a greater endogenous buffering capacity than whites, or the reported ethnic differences in sodium and calcium excretion rates between blacks and whites may be secondary to racial variations in renal H(+) excretion. We conclude that both ethnic differences in bone mineralization and bone integrity in athletes are mediated by heritable differences in titratable acid excretion.

Effect of the alpha 2-adrenergic antagonist yohimbine on orthostatic tolerance.

We studied the effect of yohimbine, a drug that inhibits presynaptic Oj-adrenergic receptors and increases the neuronal release of norepinephrine from the central and sympathetic nervous systems, on tolerance to cardiovascular stress in 10 untrained, healthy subjects. Using radioligand binding of tritiated yohimbine to platelets, these subjects were found to have a normal complement of a<2-adrenergic receptors (174±18 [±SM] receptors/platelet) with normal X, (1.93±0.17 nmol/1). Lower body negative pressure was used to test responses to cardiovascular stress in the subjects after they received either placebo or 20 mg yohimbine. Graded lower body negative pressure from 0 to −40 mm Hg significantly decreased systolic blood pressure from 116±3.7 to 106±5.8 mm Hg, increased heart rate from 54±3 to 68±7 beats/min, decreased forearm blood flow from 1.8 ±0.21 to 1.36±0.25 ml/100 ml/min, and increased forearm vascular resistance from 55.76±12.1 to 77.26±15.8 mm Hg/ml/min. Yohimbine increased the blood pressure at rest and during lower body negative pressure, but these changes were not significantly different from values recorded from the individuals when they were given placebo. Compared with placebo, however, yohimbine significantly increased forearm blood flow at rest (1.80±0.21 vs. 2.66±OJ1 ml/100 ml/min, p < 0.05) and during −40 mm Hg of lower body negative pressure (U6±0.25 vs. 1.91±0.28 ml/100 ml/min, p < 0.05). We also found that yohimbine significantly increased the plasma insulin concentration in these fasted subjects (9.4±2.4 vs. 14.5±1.4 ng/ml,/?<0.05) without inducing hypoglycemia. Because this agent increases forearm blood flow, yohimbine might be useful in treating the orthostatic hypotension and ischemic vascular disease that results from the autonomic insufficiency common in patients with diabetes mellitus.

α2-Adrenergic Agonists Increase Cellular Lactate Efflux

We reported previously that genetic polymorphisms of the alpha 2-adrenergic receptor are associated with hyperinsulinemia, diabetes mellitus, and hypertension in blacks. The evolutionary driving force for maintaining such deleterious mutations in the black population is unknown. Recognizing that vascular alpha 2-adrenergic receptors mediate cold-induced vasoconstriction and that temperature maintenance is a primary thrust of cellular metabolism, we postulated that vascular alpha 2-adrenergic receptors contribute significantly to metabolic heat generation in homeotherms such as humans. Using aerobic lactate production as an indicator of thermogenesis, we measured metabolic heat production in HT29 cells that expressed the gene encoding human vascular alpha 2-adrenergic receptors. Epinephrine, an alpha 2-adrenergic receptor agonist, increased net lactate efflux from 226 +/- 20 to 280 +/- 20 nmol/min (mean +/- SE) (P = .06). Clonidine, a more specific alpha 2-adrenergic agonist, increased lactate efflux from 110 +/- 6 to 156 +/- 8 nmol/min (P < .01). Similarly, in the presence of physiological concentrations of glucose (5.5 mmol/L), insulin increased lactate production from 123 +/- 6 to 175 +/- 10 nmol/min (P < .01). Because differences in aerobic glycolysis may also explain the heat intolerance and abnormal fuel homeostasis found in genetically hypertensive rats, we also measured lactate production in cultured vascular smooth muscle cells isolated from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive control Wistar-Kyoto rats (WKY). Vascular smooth muscle cells from SHRSP had significantly greater lactate efflux compared with cells from normotensive WKY (296 +/- 4 versus 172 +/- 2 nmol/min, P < .001). These differences were not due to abnormalities in glucose uptake, as lactate efflux was greater in SHRSP cells compared with WKY cells when dextrose was replaced with equimolar concentrations of fructose (230 +/- 6 versus 138 +/- 2 nmol/min, P < .001). alpha 2-Adrenergic agonists increase lactate efflux in HT29 cells, and abnormalities in vascular smooth muscle lactate metabolism in genetically hypertensive rats is independent of altered glucose uptake. These data provide support for our hypothesis that balanced polymorphisms of the alpha 2-adrenergic receptor could offer protection against cold stress by increasing the thermogenic response associated with aerobic lactate production.

Metabolic and Cardiovascular Manifestations of Hypertension in the Elderly

Aging in industrialized societies is associated with an increasing prevalence of hypertension, type II diabetes mellitus, renal disease and atherosclerotic vascular disease. This increase in chronic disease processes in industrialized societies is related, in part, to increasing obesity, reduced physical activity, medications such as non-steroidal anti-inflammatory agents, and other environmental influences. Hypertension in the elderly is characterized by high peripheral vascular resistance, reduced baroreflex sensitivity, a low renin state with reduced cardiac output / increased hypertrophy, reduced intravascular volume, and an increased propensity to salt-sensitivity. Type II diabetes commonly accompanies hypertension in the elderly, in part related to reduction in lean body mass and relative increase in adiposity. Lipid abnormalities are also relatively common in the elderly and should generally be treated in a similar fashion to those in the middle-aged individual.