The unrelenting cocaine epidemic constitutes a major cause of life-threatening cardiovascular emergencies, including hypertensive crises and acute myocardial infarcts. While these emergencies clearly are related to excessive adrenergic stimulation of the cardiovascular system, our understanding of the underlying mechanisms mediating cocaine’s sympathomimetic effects is incomplete and current therapies are unsatisfactory. Utilizing rigorously-defined cardiovascular phenotypes in a controlled laboratory setting, we will test whether the efficacy of potent α2 AR agonist (i.v. dexmedetomidine) to reverse the sympathomimetic actions of cocaine is maintained even under conditions in which either (a) the sympatholytic effects of α2 ARs might be attenuated (black ethnicity, loss-of- function mutation in α2C AR, chronic cocaine exposure), or (b) postjunctional α2 AR mediated vasoconstriction might be augmented (coronary artery disease, gain-of-function mutations in the α2B AR or its post-receptor G-protein signaling). ` Hypertension in Black Men
Non-Hispanic Black men suffer and die disproportionately from undetected, untreated, and uncontrolled hypertension?a chronic asymptomatic medical condition that requires frequent surveillance, prescription medication, and continuity of care by a regular medical provider. Despite comparable levels of healthcare access and perceived healthcare discrimination among hypertensive Black men and Black women in our county, we found that proportionately far fewer hypertensive men perceive a need for on-going healthcare with a regular provider. Even among hypertensive men with a regular provider, most do not realize that to reduce health risks their blood pressure (BP) requires continued monitoring and adjustment in medication. To improve hypertension detection, treatment, and control in Black men, we propose a theory-based intervention conducted by barbers, influential peers who will continually monitor their customers? BP, deliver health messages designed to change risk perception and social norms about healthcare utilization, and provide social support for desired changes in healthcare-seeking behavior and BP.
Cyclosporine A as an important new cause of secondary hypertension
The immunosuppressant drug cyclosporine A (CsA) has emerged as an important new cause of secondary hypertension and our previous work implicated a major neurogenic component in the pathogenesis. In the first grant cycle, we used anesthetized rats to prove that acute CsA-induced hypertension can be caused by sympathetic activation. This large sympathetic effect was somehow linked to the inhibition of calcineurin, the Ca2+-dependent phosphatase that is plentiful in brain. In the second grant cycle, we were surprised to discover that calcineurin inhibitors such as CsA reflexively increase sympathetic activity and blood pressure by a novel action localized mainly to renal sensory nerve endings rather than to nerve cell bodies or synapses. Using genetic mouse models, we showed that CsA raises blood pressure by stimulating renal sensory nerve endings containing synapsins, a family of vesicle-associated phosphoproteins that constitute putative substrates for calcineurin. In double knock out (DKO) mice lacking synapsins I and II, renal sensory endings were normally developed but they were unresponsive to CsA, and the resultant reflex increases in sympathetic activity and blood pressure were greatly attenuated compared with wild type (WT). We now want to (1) explore the molecular mechanism by which synapsins mediate CsA-induced renal afferent activation, and (2) determine if targeted interruption of this novel mechanism confers protection against not only acute more importantly chronic CsA-induced hypertension.
RESEARCH INTERESTS
Neural Control of Circulation
Hypertension in African Americans
Hypertension in Type 2 Diabetes
Blood Pressure Regulation in Chronic Renal Disease
Cocaine-Induced Acute Hypertension
RECENT PUBLICATIONS
Shafiq MM, Menon DV, Victor RG, "Oral direct renin inhibition: premis, promise, and potential limitations of a new antihyperetensive drug" Am J Med, 121(4):265-71, April 2008
Shafiq MM, Menon DV, Victor RG, "Oral direct renin inhibition: premise, promise, and potential limitations of a new antihypertensive drug" Am J Med, 121(4):265-71, April 2008
Victor RG, "Pathophysiology of target-organ disease: does angiotensin II remain the key?" J Clin Hypertens (Greenwich), 9(22 Suppl 4):4-10, November 2007
Victor RG, "Treating high blood pressure in patients with stable coronary artery disease: how low should we go?" Curr Cardiol Rep, 9(6):437-40, November 2007
Menon DV, Wang Z, Fadel PJ, Arbique D, Leonard D, Li JL, Victor RG, Vongpatanasin W, "Central sympatholysis as a novel countermeasure for cocaine-induced sympathetic activation and vasoconstriction in humans" J Am Coll Cardiol, 50(7):626-33, August 2007
Hess PL, Reingold JS, Jones J, Fellman MA, Knowles P, Ravenell JE, Kim S, Raju J, Ruger E, Clark S, Okoro C, Ogunji O, Knowles P, Leonard D, Wilson RP, Haley RW, Ferdinand KC, Freeman A, Victor RG, "Barbershops as hypertension detection, referral, and follow-up centers for black men" Hypertension, 49(5):1040-6, May 2007
SIGNIFICANT PUBLICATIONS
Converse RL, Jacobsen TN, Toto RD, Jost CMT, Cosentino F, Fouad-Tarazi F, and RG Victor, "Sympathetic Overactivity in Patients with Chronic Renal Failure" The New England Journal of Medicine, 327:1912-1918, 1992
Jacobsen TN, Grayburn PA, Snyder RW III, Hansen J, Chavoshan B, Landau C, Lange RA, Hillis LD, and RG Victor, "Effects of Intranasal Cocaine on Sympathetic Nerve Discharge in Humans" The Journal of Clinical Investigation, 99:628-634, 1997
Zhang W, Li J-L, Hosaka M, Janz R, Shelton JM, Albright GM, Richardson JA, Sudhof TC, , and Victor RG, "Cyclosporine A-Induced Hypertension Involves Synapsin in Renal Sensory Nerve Endings" Proceedings of the National Academy of Sciences USA, 97:9765-9770, 2000
Converse RL, Jacobsen TN, Fouad-Tarazi F, Obregon TM, Toto RD, and RG Victor, "Paradoxical Withdrawal of Reflex Vasoconstriction as a Cause of Hemodialysis-Induced Hypotension" The Journal of Clinical Investigation, 90:1657-1665, 1992
Sander M, Chavoshan B, Harris SA, Iannaccone ST, Stull JT, Thomas GD, and Victor RG, "Functional Muscle Ischemia in Neuronal NOS-Deficient Skeletal Muscle of Children with Duchenne Muscular Ddystrophy" Proceedings of the National Academy of Sciences USA,, 97:13818-13823, 2000
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