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.
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