ALPHA(2)-ADRENERGIC AGONISTS INCREASE CELLULAR LACTATE EFFLUX

We reported previously that genetic polymorphisms of the alpha(2)-adre nergic receptor are associated with hyperinsulinemia, diabetes mellitu s, and hypertension in blacks. The evolutionary driving force for main taining 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)-a drenergic receptors contribute significantly to metabolic heat generat ion in homeotherms such as humans. Using aerobic lactate production as an indicator of thermogenesis, we measured metabolic heat produc lion in HT29 cells that expressed the gene encoding human vascular alpha(2 )-adrenergic receptors. Epinephrine, an alpha(2)-adrenergic receptor a gonist, increased net lactate efflux from 226+/-20 to 280+/-20 nmol/mi n (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 gl ucose (5.5 mmol/L), insulin increased lactate production from 123+/-6 to 175+/-10 nmolimin (P<.01). Because differences in aerobic glycolysi s may also explain the heat intolerance and abnormal fuel homeostasis found in genetically hypertensive rats, we also measured lactate produ ction in cultured vascular smooth muscle cells isolated from stroke-pr one spontaneously hypertensive rats (SHRSP) and normotensive control W istar-Kyoto rats (WKY). Vascular smooth muscle cells from SHRSP had si gnificantly greater lactate efflux compared with cells from normotensi ve WKY (296+/-4 versus 172+/-2 nmol/min, P<.001). These differences we re not due to abnormalities in glucose uptake, as lactate efflux was g reater in SHRSP cells compared with WKY cells when dextrose was replac ed with equimolar concentrations of fructose (230+/-6 versus 138+/-2 n mol/min, P<.001). alpha(2)-Adrenergic agonists increase lactate efflux in HT29 cells, and abnormalities in vascular smooth muscle lactate me tabolism in genetically hypertensive rats is independent of altered gl ucose uptake. These data provide support for our hypothesis that balan ced polymorphisms of the alpha(2)-adrenegic receptor could offer prote ction against cold stress by increasing the thermogenic response assoc iated with aerobic lactate production.