Rapid restoration of blood flow to ischemic myocardium is essential, however it causes further injury called reperfusion injury. Apoptosis contributes significantly to cardiomyocyte cell death during ischemia reperfusion injury, in which caspase family proteases play an essential role as they are the executioners of apoptosis. Caspase inhibitors showed promising cardioprotective results when administered before ischemia or at the start of reperfusion. However, before applying them in pre clinical studies of myocardial ischemia, several investigations needed to be taken to determine their therapeutic window post reperfusion, their effect on functional recovery of myocardium post ischemia, their mechanism of action. Methods Isolated perfused rat hearts were subjected to 35 min ischemia followed by 2 hr reperfusion where caspase inhibitors [broad spectrum caspase inhibitor (ZVAD, 0.1µM), specific caspase 3 inhibitor (DEVD, 0.07µM)] were added at the start of reperfusion, 15, 30 and 60 min after starting reperfusion at the presence or absence of Wortmannin (WORT, 100nM, PI3-kinase inhibitor). Hearts underwent triphenyl tetrazolium staining for infarct size assessment, or were frozen for Western blot analysis. Freshly isolated adult rat ventricular myocytes were subjected to 6 hr hypoxia followed by either 18 hr, where caspase inhibitors (ZVAD, 25µM and DEVD, 25µM) were added at the start of reoxygenation, 15, 30 and 60 min after starting reoxygenation at the presence or absence of Wortmannin (WORT, 100nM). Cardiomyocytes were analysed for viability, apoptosis, necrosis and intracellular caspase-3 activity using flow cytometry analysis. Isolated adult rat ventricular papillary muscles were subjected to 35 min hypoxia followed by 100 min reperfusion where caspase inhibitors [ZVAD (0.1 µM, 2.5µM) and DEVD (2.5µM)] were added at the start of reperfusion throughout. Power output was measured using work loop technique.

No description available.

University of Macau / Institute of Chinese Medical Sciences

No description available.

No description available.

No description available.

Clinically, the modified Bruce protocol is widely used to predict functional capacity in cardiac patients. However, it has been suggested that cardiac patients have lower oxygen uptakes for standard workloads. In order to study this, we measured oxygen uptake (V02) and venous bloodV02 derived from lactic acid concentration during a modified Bruce treadmill protocol in 12 pest myocardial infarction (MI) and 12 normal males. During three stages of the protocol mean oxygen uptake was significantly lower (1.42 - 6.2 ml/kg.min; p < .001) for the pest MI than the normal males.However, venous blood lactic acid concentrations were not different at these stages. The MI patients' measured V02 for three stages of the protocol ranged from 1.8 - 7.3 ml/kg.min lower than the Bruce predictions for cardiacs. In addition, measured V02 (max) for cardiac patients were from 3.68 to 11.15 ml/kg.min lower than the predicted the normal subjects. These data suggest myocardial damage may slow oxygen kinetics and results in lower actual V02during treadmill testing. However, blood lactic acid concentrations failed to demonstrate an anaerobic compensation for the lower V02 in pest MI patients.

Thesis (PhD) -- University of South Australia, 1994

The objective of this thesis is to investigate the pathophysiology of the coronary slow phenomenon (CSFP). The experimental work of this thesis has taken a 'bedside to benchtop' approach with clinical observations made in the second chapter guiding the application of basic research techniques in subsequent chapters. Chapter 1 ; The CSFP is a disorder of the coronary microcirculation ; hence chapter 1 specifically reviews the current understanding of this vascular territory and concludes with a summary of the clinical disorders affecting it, concentrating on the CSFP. Chapter 2 ; investigated the angiographic response of the CSFP to a calcium channel blocking agent with antianginal efficacy in this disorder ( mibefradil ). Mibefradil administration was associated with an acute improvement of coronary flow indices which occurred despite background vasodilator therapy with conventional calcium channel antagonists. Chapter 3 ; investigated the in vitro response of human microvessels to mibefradil in comparison to conventional calcium channel blockers. Mibefradil was found to be a more potent agent both in terms of vasodilatation and the prevention of vasoconstriction. Both findings support the clinical observations and point to its selective action on the calcium T channel subtype as a potential mechanism. Chapter 4 ; examined the expression of T type calcium channels at the level of the microvasculature and compared T channel expression in CSFP patients and controls. T channels were found to be expressed at two or more orders of magnitude greater than the L channels. No difference in T channel expression between patients and controls was found. Chapter 5 ; examined the vasomotor reactivity of isolated subcutaneous arterial microvessels to various vasoactive substances between controls and CSFP patients. CSFP patients were found to have a selective hyper reactivity to endothelin. Chapter 6 ; examined plasma endothelin levels in CSFP patients and controls and the relationship between endothelin levels and angina frequency in the CSFP cohort. A small but statistically significant elevation of endothelin-1 was present in patients with the CSFP. A positive association between plasma endothelin fluctuation and angina frequency was also found in the CSFP cohort but not between absolute endothelin levels and angina symptoms. / Thesis (Ph.D.)-- The University of Adelaide, School of Medical Sciences, 2006.

The objective of this thesis is to investigate the pathophysiology of the coronary slow phenomenon (CSFP). The experimental work of this thesis has taken a 'bedside to benchtop' approach with clinical observations made in the second chapter guiding the application of basic research techniques in subsequent chapters. Chapter 1 ; The CSFP is a disorder of the coronary microcirculation ; hence chapter 1 specifically reviews the current understanding of this vascular territory and concludes with a summary of the clinical disorders affecting it, concentrating on the CSFP. Chapter 2 ; investigated the angiographic response of the CSFP to a calcium channel blocking agent with antianginal efficacy in this disorder ( mibefradil ). Mibefradil administration was associated with an acute improvement of coronary flow indices which occurred despite background vasodilator therapy with conventional calcium channel antagonists. Chapter 3 ; investigated the in vitro response of human microvessels to mibefradil in comparison to conventional calcium channel blockers. Mibefradil was found to be a more potent agent both in terms of vasodilatation and the prevention of vasoconstriction. Both findings support the clinical observations and point to its selective action on the calcium T channel subtype as a potential mechanism. Chapter 4 ; examined the expression of T type calcium channels at the level of the microvasculature and compared T channel expression in CSFP patients and controls. T channels were found to be expressed at two or more orders of magnitude greater than the L channels. No difference in T channel expression between patients and controls was found. Chapter 5 ; examined the vasomotor reactivity of isolated subcutaneous arterial microvessels to various vasoactive substances between controls and CSFP patients. CSFP patients were found to have a selective hyper reactivity to endothelin. Chapter 6 ; examined plasma endothelin levels in CSFP patients and controls and the relationship between endothelin levels and angina frequency in the CSFP cohort. A small but statistically significant elevation of endothelin-1 was present in patients with the CSFP. A positive association between plasma endothelin fluctuation and angina frequency was also found in the CSFP cohort but not between absolute endothelin levels and angina symptoms. / Thesis (Ph.D.)-- The University of Adelaide, School of Medical Sciences, 2006.