Department of Pharmacology
Basic Sciences Building
New York Medical College
Valhalla, NY 10595
Our research projects are focused in the area of cardiovascular disease, in particular, we study the role of lipid mediators, produced by the kidneys, in the regulation of blood pressure. Although salt is essential to human health, excessive sodium chloride intake is one of the main environmental factors responsible for the development of high blood pressure:-hypertension and salt sensitivity accounts for a significant portion of adult hypertension. If the kidneys are functioning properly, increased sodium chloride intake results in increased renal sodium chloride excretion (natriuresis). This adaptive process prevents progressive salt retention, volume expansion with elevation of blood pressure. However, an impaired ability of the kidney to excrete sodium requires an increase in blood pressure to increase natriuresis, resulting in hypertension. The mechanisms underlying salt sensitive hypertension and tissue injury remain to be defined and the elucidation of the mechanisms and more effective treatments are needed.
We are studying the function of cytochrome P450 derived eicosanoids, epoxyeicosatrienoic acids (EETs), generated by epoxygenases, and have shown that this pathway occupies a key position in the regulation of renal function. It has become increasingly recognized that EETs have important biological effects in the kidneys, including inhibition of sodium transport in the nephron, 11, 12-EET having a direct inhibitory effect on the epithelial sodium channel (ENaC) and vasodilatation of the renal arterioles. In addition, adenosine, a metabolite of ATP, modulates cellular and organ function by binding to specific cell-surface adenosine receptors, of which there are four known subtypes (A1, A2A, A2B and A3). The physiological effects of adenosine are observed in nearly every tissue and organ and in the kidney, activation of A1 R and A2 R participate in the regulation of renal vascular tone and tubular function.
The adenosine –EET pathway
We have shown that the A2A R selective agonists stimulate EET release from rat kidneys and that the renal vasodilator action of A2A R agonists is inhibited by a selective epoxygenase inhibitor. As EETs are vasodilators and natriuretic and can account for the biological actions of adenosine acting on A2A R, we suggest an interdependency involving the adenosine and CYP-derived AA metabolites in renal microcirculatory regulation and propose 1) that the EETs are mediators / messengers of the biological functions of adenosine acting via A2A R and 2) this signaling pathway via A2A R/EETs is involved in the adaptive response to increased dietary salt intake.
Salt sensitive hypertension
High salt intake is a powerful stimulus of the production of EETs in normotensive animals. The inability to upregulate CYP2C epoxygenases in response to salt-loading has been associated with the development of salt-sensitive hypertension. The Dahl salt-sensitive (SS) rat is a genetic model of salt-dependent hypertension, that exhibits a rightward shift in the pressure-natriuresis curve, the hallmark of salt-sensitive hypertension. We have shown that in kidneys from normotensive animals and Dahl salt resistant (SR) rats, but not hypertensive Dahl SS rats, high salt intake augments vascular responses to a stable adenosine analog, increases the production of natriuretic EETs, and upregulates the renal protein expression of A2AR, as well as CYP2C23 a salt-inducible epoxygenases. The inability of Dahl SS rats to upregulate the A2AR-epoxygenase pathway may contribute to the development of salt-sensitive hypertension. Selective A2A R agonists may provide a novel therapeutic approach to controlling blood pressure.
Post Graduate Studies
Graduate Degree: M.Sc., Ph.D.
Graduate Degree Institution: Chelsea College, University of London, England; King's College, University of London, England
Undergraduate Institution: Manchester Polytechnic, England
Liclican, E.L., Doumad A.B., Wang J., Li, J., Falck, J.R., Stier, C.T. and Carroll, M.A. Inhibition of the adenosine 2A receptor-epoxyeicosatrienoic acid pathway renders Dahl salt-resistant rats hypertensive. Hypertension, 54(6):1284-90, 2009.
Liclican, E.L., McGiff, J.C., Falck, J.R., and Carroll, M.A. Failure to upregulate the adenosine 2A receptor-epoxyeicosatrienoic acid pathway contributes to the development of hypertension in Dahl salt-sensitive rats. Am. J. Physiol. Renal Physiol. 295: F1696–F1704, 2008.
Carroll, M.A., Doumad A.B., Li J., Cheng M.K., Falck J.R. and McGiff J.C. Adenosine 2A receptor vasodilation of rat preglomerular microvessels is mediated by epoxyeicosatrienoic acids that activate the cAMP/protein kinase A pathway. Am. J. Physiol. Renal Physiol. 291:F155-F161, 2006.
Liclican, E.L., McGiff, J.C., Pedraza, P.L., Ferreri, N.R., Falck, J.R. and Carroll, M.A. Exaggerated response to adenosine in kidneys from high salt-fed rats: role of epoxyeicosatrienoic acids. Am. J. Physiol. Renal Physiol. 289:F386-F392, 2005.
Cheng, M.K., Doumad, A.B., Jiang, H., Falck, J.R., McGiff, J.C. and Carroll, M.A. Epoxyeicosatrienoic acids mediate adenosine-induced vasodilation in rat preglomerular microvessels (PGMV) via A2A receptors. Br. J. Pharmacol., 141(3):441-8, 2004.