A key pathologic event in cardiac ischemia reperfusion (I-R) injury is mitochondrial energetic dysfunction, and several studies have attributed this to complex I (CxI) inhibition. In isolated perfused rat hearts, following I-R, we found that CxI-linked respiration was inhibited, but isolated CxI enzymatic activity was not. Using the mitochondrial thiol probe iodobutyl-triphenylphosphonium in conjunction with proteomic tools, thiol modifications were identified in several subunits of the matrix-facing 1alpha sub-complex of CxI. These thiol modifications were accompanied by enhanced ROS generation from CxI, but not complex III. Implications for the pathology of cardiac I-R injury are discussed.

The purpose of this study was to compare the degree of ischemic and hypoxic injury in normal versus hypertrophied rat hearts to investigate basic mechanisms responsible for irreversible myocardial ischemic injury. Hearts from rats with bands placed on the aortic arch at 23 days of age (BAND) and sham-operated rats (SHAM, 8 weeks postoperative) were isolated, perfused with Krebs buffer, and had a left ventricular balloon to measure developed pressure. Hearts were made globally ischemic until they developed peak ischemic contracture and were reperfused for 30 minutes. Additional hearts were perfused for 15 minutes with glucose-free hypoxic buffer followed by 20 minutes of oxygenated perfusion. There was an 87% increase in heart weight of BAND compared with SHAM (p less than 0.01). During ischemia, lactate levels increased faster in BAND compared with SHAM, ischemic contracture occurred earlier in BAND than in SHAM despite no difference in ATP levels, and postischemic recovery of left ventricular pressure was less in BAND (26.8 +/- 5.6% of control left ventricular pressure, mean +/- SEM) compared with SHAM (40 +/- 4.6%, p less than 0.05). During hypoxic perfusion, lactate release was greater in BAND than in SHAM (48.8 +/- 1.2 versus 26.6 +/- 0.97 mumols/g, p less than 0.01), and with reoxygenation, lactate dehydrogenase release was less in BAND than in SHAM (13.2 +/- 0.7 versus 19.5 +/- 0.2 IU/g, p less than 0.01). After hypoxia and reoxygenation, left ventricular pressure recovery was greater in BAND than in SHAM (93 +/- 8.4% versus 66 +/- 5.3%, p less than 0.01). Thus, this study suggests that hypertrophied hearts have a greater potential for glycolytic metabolism, resulting in an increased rate of by-product accumulation during ischemia, which may be responsible for the increased susceptibility of hypertrophied hearts to ischemic injury.

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We induced reverse passive Arthus (RPA) reactions in the skin of rodents and found that the contribution of complement to immune complex-mediated inflammation is species specific. Complement was found to be necessary in rats and guinea pigs but not in C57BL/6J mice. In rats, within 4 h after initiation of an RPA reaction, serum alternative pathway hemolytic titers decreased significantly below basal levels, whereas classical pathway titers were unchanged. Thus the dermal reaction proceeds coincident with systemic activation of complement. The serine protease inhibitor BCX 1470, which blocks the esterolytic and hemolytic activities of the complement enzymes Cls and factor D in vitro, also blocked development of RPA-induced edema in the rat. These data support the proposal that complement-mediated processes are of major importance in the Arthus reaction in rats and guinea pigs, and suggest that BCX 1470 will be useful as an anti-inflammatory agent in diseases where complement activation is known to be detrimental.

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The purpose of these studies was to evaluate cardiovascular structural and functional changes in a model of hypertension-induced myocardial hypertrophy in which vasodilator therapy decreased blood pressure to normal levels. Thus, we determined the separate contributions of hypertension and hypertrophy on myocardial and coronary vascular function and structure. Twelve-month-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) with and without 12 weeks of vasodilator antihypertensive treatment (hydralazine) were studied using an isolated perfused rat heart model. Hydralazine treatment normalized blood pressure in SHR but did not cause regression of cardiac hypertrophy (heart weight to body weight ratio of SHR + hydralazine 4.33 +/- 0.098 vs. SHR 4.66 +/- 0.091; WKY 3.21 +/- 0.092 and WKY + hydralazine 3.38 +/- 0.152; mean +/- SEM). Coronary flow reserve, elicited by adenosine vasodilation in the perfused heart, was decreased in SHR (29%) compared with WKY (105%) and WKY + hydralazine (100%) and was significantly improved in SHR + hydralazine (75%). Morphometric evaluation of perfusion-fixed coronary arteries and arterioles (30-400 microns diameter) demonstrated a significant increase in the slope of the regression line comparing the square root of medial area versus outer diameter in SHR (0.444) compared with WKY (0.335) and WKY + hydralazine (0.336, p less than 0.05). Blood vessels from SHR + hydralazine were not different from control (0.338). Cardiac oxygen consumption was decreased in SHR (10.9 +/- 0.74 mumols oxygen/min/g/60 mm Hg left ventricular pressure) compared with WKY (22.4 +/- 1.47) and WKY + hydralazine (23.4 +/- 1.90; p less than 0.01), while SHR + hydralazine was intermediate (16.0 +/- 1.60). These studies suggest that significant alterations in myocardial and coronary vascular structure and function occur in hypertension-induced cardiac hypertrophy. The coronary vasculature is responsive to blood pressure, independent of cardiac hypertrophy, although moderate coronary deficits do remain after chronic antihypertensive therapy.