Long-Term Antioxidant Intervention Improves Myocardial Microvascular Function in Experimental Hypertension

Abstract

Abstract-Hypertension increases oxidative stress, which can impair myocardial microvascular function and integrity.However, it is yet unclear whether long-term antioxidant intervention in early hypertension would preserve myocardial perfusion and vascular permeability responses to challenge. Pigs were studied after 12 weeks of renovascular hypertension without (nϭ8) or with daily supplementation of antioxidants (100 IU/kg vitamin E and 1 g vitamin C, nϭ6), and compared with normal controls (nϭ7). Myocardial perfusion and microvascular permeability were measured in vivo by electron beam computed tomography before and after 2 cardiac challenges (intravenous adenosine and dobutamine). Basal left ventricular muscle mass was also obtained. 4,5 In addition to its effect on vascular reactivity, HT has effects on other functions of the vascular wall. Increases in blood pressure can also lead to alterations in thrombogenesis 6 and increased permeability of the endothelium. 7,8 One of the mechanisms that might be responsible for HT-induced myocardial dysfunction is an increase in oxidative stress, which has been demonstrated in both humans 9 and animal models. 10 Indeed, short-term antioxidant administration improved coronary epicardial endothelial function. 9,11 However, whether long-term antioxidant supplementation might preserve HT-induced myocardial microvascular dysfunction remains unclear.Electron beam computed tomography (EBCT), a fast CT scanner, provides a unique tool to accurately 12 and reproducibly 13 study in vivo transmural myocardial perfusion 14 -16 and myocardial microvascular permeability (MVP) 15-17 noninvasively. This tool provides an opportunity to explore noninvasively the effect of long-term therapeutic interventions on myocardial vascular function. Thus, the present study was designed to test the hypothesis that long-term antioxidant blockade would preserve myocardial vascular function in early HT. Methods AnimalsAll of the study procedures were approved by the Institutional Animal Care and Use Committee. Twenty-one female, domestic crossbred pigs (Pork Partners, Stewartville, Minn; 55 to 65 kg each) were studied after a 12-week preparation: one group (normal, nϭ7) was untreated, and in the second (HT, nϭ8), renovascular HT was induced by placing a local-irritant stent in the left renal artery, as previously described. 16,18 In addition to induction of renal artery stenosis, animals from group 3 (HTϩantioxidants [Ao], nϭ6) received daily oral antioxidant supplementation (combination of 100 IU/kg vitamin E and 1 g vitamin C). This dosage was based on our previous studies in pigs that showed that this combination provided

Role of Oxidative Stress in Remodeling of the Myocardial Microcirculation in Hypertension

“…We have previously shown that this antioxidant combination was effective in decreasing oxidative stress and normalizing vascular function. 1,11 Mean arterial pressure (MAP) was measured in all animals by a PhysioTel telemetry system (Data Sciences) implanted at baseline in the left femoral artery. 10 After 12 weeks of observation, the animals were anesthetized (ketamine 17.5 mg/kg/h and xylazine 2.3 mg/kg/h in saline), and catheters were placed in the right atrium for electron beam CT (EBCT) scanning.…”

“…1 Initially, 40 consecutive ECGtriggered end-diastolic scans were acquired at 1 to 3 heartbeat intervals after a bolus injection of the contrast medium iopamidol (0.5 mL/kg over 2 seconds). After a 15-minute recovery, the flow study was repeated toward the end of a 15-minute infusion of adenosine (400 g/kg/min).…”

“…We have previously demonstrated that early experimental HT was associated with impaired myocardial perfusion, partly mediated by increased oxidative stress, which was corrected with chronic antioxidant supplementation. 1 However, the potential effect of antioxidants on coronary microvascular remodeling in early HT remains unclear.…”

Relation of Nonperfused Myocardial Volume and Surface Area to Left Ventricular Performance in Coronary Microembolization

“…Regional myocardial perfusion, [15][16][17] cardiac output, and stroke volume (SV; cardiac output/heart rate) were calculated as others 19 and we 20 have previously shown. In 10 of the 36 animals, the EBCT scanner was also used in cine mode for geometric analysis of LV dynamics.…”

Relationship between surface area of nonperfused myocardium and extravascular extraction of contrast agent following coronary microembolization

“…However, it has been shown that myocardial microvascular permeability can change under various pathologic and metabolic circumstances such as diabetes mellitus (24,41), hypercholesterolemia (32), hypertension (31), and acute myocardial ischemia followed by reperfusion (29). Embolization of microscopic plaque debris into the distal coronary bed during coronary interventions is a common and frequent event (9,10,35) that might be associated with microinfarctions and with adverse clinical outcome (7,10).…”