(Verbatim from the application): Abnormalities in sympathetic nervous system activity have been reported for many patients with salt-sensitive, essential hypertension. Autonomic responsiveness is mediated by alpha-2 adrenergic receptors (A2ARs). During the previous funding cycle, we performed an extensive population-based association study. We reported that a common mutation of the A2AR was associated with severe hypertension in Detroit Blacks. This polymorphism was also associated with increased platelet aggregation, altered baroreceptor sensitivity, and diminished salt excretion in healthy, college-age students with no evidence of high blood pressure. We postulated that severe blood pressure elevations may be a """"""""marker"""""""" of individuals at risk for stroke due to a common gene defect encoding increased vascular resistance and platelet sensitivity. In this continuation, we will measure the proportion of the total variance of A2AR-mediated platelet aggregation and central baroreceptor activity that may be attributable to additive genetic factors in humans. A2AR-mediated platelet aggregation will be measured with standard laboratory techniques. Autonomic responses to increases and decreases in baroreceptor activity will be assessed by loading, and unloading, of the central blood volume with immersion in thermal-neutral water and graded lower body negative pressure (LBNP), respectively. We postulate that abnormal A2AR-mediated transport of chloride is a necessary link between the autonomic nervous system and salt-sensitive hypertension. Before that hypothesis can be proven, we must first establish the mechanism(s) by which A2AR agonists affect chloride transport. We documented a role for A2ARs in mediating intracellular chloride transport. We will now use microfluorometry to test our hypothesis that A2AR-dependent agonists mediate increases in intracellular chloride concentrations ([Cl-]i) in platelets and vascular smooth muscle by enhancing the activity of the chloride/bicarbonate exchanger and the Na/Cl and the Na/K/2Cl-coupled cotransporters in these effector cells. We predict: (1) a significant heritable component exists for platelet aggregation, heart rate responses to LBNP, and immersion-induced salt excretion; (2) the squared difference of measurements for a particular phenotype between sibs negatively correlate with the number of alleles shared at the C10 A2AR locus; and (3) agonist-induced increases in platelet calcium and aggregation are enhanced by A2AR-dependent increases in {Cl-]i mediated by the chloride/bicarbonate exchanger.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Velletri, Paul A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wayne State University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Fox, W Christopher; Watson, Rex; Lockette, Warren (2006) Acute hypoxemia increases cardiovascular baroreceptor sensitivity in humans. Am J Hypertens 19:958-63
Finley Jr, J Clayton; O'Leary, Michael; Wester, Derin et al. (2004) A genetic polymorphism of the alpha2-adrenergic receptor increases autonomic responses to stress. J Appl Physiol 96:2231-9
Fox, W Christopher; Hall, Charlotte; Hall, Eric et al. (2003) Cardiovascular baroreceptors mediate susceptibility to hypothermia. Aviat Space Environ Med 74:132-7
Fox, W Chris; Lockette, Warren (2003) Unexpected syncope and death during intense physical training: evolving role of molecular genetics. Aviat Space Environ Med 74:1223-30
Vaitkevicius, Henrikas; Turner, Immanuel; Spalding, Aaron et al. (2002) Chloride increases adrenergic receptor-mediated platelet and vascular responses. Am J Hypertens 15:492-8
Vaitkevicius, Henrikas; Witt, Richard; Maasdam, Matthew et al. (2002) Ethnic differences in titratable acid excretion and bone mineralization. Med Sci Sports Exerc 34:295-302
MacKenzie, S; Vaitkevicius, H; Lockette, W (2001) Sequencing and characterization of the human thiazide-sensitive Na-Cl cotransporter (SLC12A3) gene promoter. Biochem Biophys Res Commun 282:991-1000
Spalding, A; Vaitkevicius, H; Dill, S et al. (1998) Mechanism of epinephrine-induced platelet aggregation. Hypertension 31:603-7
Lockette, W; Kirkland, K; Farrow, S (1996) Alpha 2-adrenergic agonists increase cellular lactate efflux. Hypertension 27:1104-7
Freeman, K; Farrow, S; Schmaier, A et al. (1995) Genetic polymorphism of the alpha 2-adrenergic receptor is associated with increased platelet aggregation, baroreceptor sensitivity, and salt excretion in normotensive humans. Am J Hypertens 8:863-9