This proposal focuses on the function and regulation of the vascular heme-heme oxygenase-carbon monoxide system in relation to peripheral mechanisms of vasomotor control in normotensive and hypertensive rats. Four major hypotheses will be examined. First, heme oxygenase-derived carbon monoxide is manufactured tonically, by small monoxide of vascular origin inhibits myogenic behavior and responsiveness to constrictor hormones in arterioles and small arteries. Third, the heme- heme oxygenase-carbon monoxide system contributes to the implementation of peripheral anti-hypertensive mechanisms. Fourth, the heme-heme oxygenase-carbon monoxide system contributes to the implementation of peripheral anti-hypertensive mechanisms. Fourth, high oxidative stress in arterial tissues of rats with angiotensin-dependent hypertension promotes vascular production of heme oxygenase products which, in turn, subserve adaptive anti-hypertensive and anti-oxidative functions. In testing these hypotheses, the following the following specific aims will be addressed in normotensive and hypertensive rats.
AIM 1 : To Characterize the Status of the Heme-Heme Oxygenase System of Arterial Vessels in Terms of Heme Oxygenase(s) Protein Level and Activity and Ability to Manufacture Carbon Monoxide. We will contrast small and large arterial vessels of normotensive and hypertensive rats in terms of ability to manufacture carbon monoxide and levels heme oxygenase protein and activity.
AIM 2 : To Define the Influence of Vascular Heme Oxygenase Product Formation on Vasomoter Function. We will examine the effect of interventions that increase or decrease the activity of the vascular heme-heme oxygenase system on myogenic responses and reactivity to constrictor agonist in small arteries and arterioles.
AIM 3 : To Determine the Effect of Interventions that Alter Heme-Oxygenase Product Formation on the Blood Pressure on Normotensive Rats and Spontaneously Hypertensive Rats. We will examine the hemodynamic response to interventions that decrease (heme oxygenase inhibitor; heme oxygenase antisense oligodeoxynucleotides) heme oxygenase activity or level of expression on blood pressure.
Aim 4 : To Explore Relationships Between Vascular Heme Oxygenase Product Formation and Oxidative Stress in Rats with Angiotensin-Dependent Hypertension. We will explore the effect of anti-oxidants on the vascular heme-heme oxygenase system and of heme oxygenase inhibitors on indices of oxidative stress in hypertensive rats.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Lin, Michael
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York Medical College
Schools of Medicine
United States
Zip Code
Lamon, Brian D; Zhang, Frank F; Puri, Nitin et al. (2009) Dual pathways of carbon monoxide-mediated vasoregulation: modulation by redox mechanisms. Circ Res 105:775-83
Botros, F T; Olszanecki, R; Prieto-Carrasquero, M C et al. (2007) Induction of heme oxygenase-1 in renovascular hypertension is associated with inhibition of apoptosis. Cell Mol Biol (Noisy-le-grand) 53:51-60
Zhang, Fan; Deng, Huan; Kemp, Rowena et al. (2005) Decreased levels of cytochrome P450 2E1-derived eicosanoids sensitize renal arteries to constrictor agonists in spontaneously hypertensive rats. Hypertension 45:103-8
Botros, Fady T; Schwartzman, Michal L; Stier Jr, Charles T et al. (2005) Increase in heme oxygenase-1 levels ameliorates renovascular hypertension. Kidney Int 68:2745-55
Zhang, Fan; Kaide, Jun Ichi; Yang, LiMing et al. (2004) CO modulates pulmonary vascular response to acute hypoxia: relation to endothelin. Am J Physiol Heart Circ Physiol 286:H137-44
Li, Ping; Jiang, Houli; Yang, LiMing et al. (2004) Angiotensin II induces carbon monoxide production in the perfused kidney: relationship to protein kinase C activation. Am J Physiol Renal Physiol 287:F914-20
Zhang, Fan; Wang, Mong-Heng; Wang, Ji-Shi et al. (2004) Transfection of CYP4A1 cDNA decreases diameter and increases responsiveness of gracilis muscle arterioles to constrictor stimuli. Am J Physiol Heart Circ Physiol 287:H1089-95
Rodriguez, Francisca; Lamon, Brian D; Gong, Weiying et al. (2004) Nitric oxide synthesis inhibition promotes renal production of carbon monoxide. Hypertension 43:347-51
Brodsky, Sergey V; Zhang, Fan; Nasjletti, Alberto et al. (2004) Endothelium-derived microparticles impair endothelial function in vitro. Am J Physiol Heart Circ Physiol 286:H1910-5
DelliPizzi, A; Guan, H; Dinocca, S et al. (2004) Prostaglandin I2 does not contribute to the hypotensive effect of the superoxide dismutase mimetic Tempo in rats with aortic coarctation-induced hypertension. Clin Exp Hypertens 26:191-8

Showing the most recent 10 out of 76 publications