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A recent proposal is that the alpha₁-adrenoceptor may mediate the arrhythmogenic effect of catecholamines during acute myocardial ischaernia. The purpose of this thesis was to explore the role of alpha₁ and alpha₂-adrenoceptor stimulation on vulnerability to ventricular fibrillation in the norrnoxic rat ventricular myocardium and further to evaluate the possible underlying cellular mechanism. The model used was the isolated perfused rat heart (Langendorff technique) in which ventricular fibrillation was electrically induced. The amount of current required to produce ventricular fibrillation was measured as the ventricular fibrillation threshold. Alpha₁-adrenoceptor stirnμlation with methoxamine to 10⁻⁶M to 10⁻⁵M increased the vulnerability to ventricular fibrillation. The arrhythmogenic effect of methoxamine could not be attributed to beta-adrenoceptor stimulation as it occurred in the setting of the beta-adrenoceptor antagonist agent, atenolol; furthermore no accumulation of cyclic AMP, the proposed arrhythmogenic second messenger of beta-adrenoceptor stimulation, occurred. Similarly no alteration in heart rate, coronary flow rate or myocardial high energy phosphate content accompanied the arrhythrnogenic effect of methoxamine. The QT interval increased with alpha₁-adrenoceptor stimulation, this being an indirect index of prolongation of the action potential duration. The arrhythmogenic action of methoxamine was associated with a positive inotropic effect. Prazosin 10⁻⁸M (an alpha₁-adrenoceptor antagonist agent) produced a tenfold displacement to the right of the log concentration response curve of the positive inotropic effect of methoxamine. Prazosin 10⁻⁸M prevented the methoxamine induced fall in ventricular fibrillation threshold. Alpha₂-adrenoceptor stimulation with B-HT 920 and B-HT 933 (azepexole), in the presence of the beta-adrenoceptor antagonist agent atenolol, did not alter the vulnerability to ventricular fibrillation. Alpha₂-adrenoceptor stimulation produced no alteration in heart rate, coronary flow rate or metabolic status. We next explored the possible mechanism underlying the arrhythmogenic effect of methoxamine. Alpha₁-adrenoceptor stimulation enhances transsarcolemmal calcium ion influx and may induce sarcoplasmic reticulum calcium release. To assess the role of transsarcolemmal calcium movement in alpha₁-adrenoceptor mediated effects experiments were undertaken with nisoldipine and low extracellular calcium. To evaluate the role of sarcoplasmic reticulum calcium release, experiments were undertaken with ryanodine (an agent reputed to inhibit sarcoplasmic reticulum calcium release without effecting the slow inward current). Nisoldipine 10⁻⁸M, reducing extracellular calcium (2.5 mM to 1.25 mM) and ryanodine 10⁻⁹M to 10⁻⁸M, prevented the arrhythmogenic and positive inotropic effect of methoxamine. Heart rate, metabolic status and cyclic AMP levels we're unchanged with these procedures. The mechanism underlying the arrhythmogenic action of alpha₁-adrenoceptor stimulation might be an increase in cytosolic calcium concentration. This increase may be secondary to (i) an enhanced transsarcolemmal calcium influx or (ii) an increase in the phasic release of calcium from the sarcoplasmic reticulum.

Myocardial ischemia, infarction, heart failure and arrhythmias are the manifestations of coronary artery disease. Reduction of ischemic damage is a major concern of cardiovascular biology research. As per recent studies, the mitochondrial ATP-sensitive potassium channel (mitoKATP) opening is believed to play key role in the physiology of cardioprotection, protection against ischemia-reperfusion injury or apoptosis. However, the structural information of mitoKATP is not precisely known. Elucidating the structural integrity and functioning of the mitoKATP is therefore a major goal of cardiovascular biology research. The known structure and function of the cell ATP-sensitive potassium channel (cellKATP) is functional in interpreting the structural and functional properties of mitoKATP. The primary goal of my research was to characterize the activity of mitoKATP in the isolated mitochondria from the control mouse heart. The mitoKATP activity, if preliminarily characterized in the control strains through the light scattering technique, then the structure of the channel could possibly be established and analyzed by means of the transgenic model and with the help of immunological techniques such as western blotting and immunoflorescence. With this experimental model it was possible to demonstrate that the mitoKATP activity in control mouse heart mitochondria is activated by potassium channel openers (KCOs) such as diazoxide and cromakalim and activators of mitoKATP such as PMA (phorbol12 myristate-13-acetate), and inhibited by KATP inhibitors such as glibenc1amide and 5-hydroxydecanoate (5 HD). It was evident that the KATP activity in mouse heart mitochondria was comparable to that exhibited by the rat heart mitochondria. The various selective and non-selective activators and inhibitors of the channel elicited their activity at a similar concentration used for the rat heart mitochondria. The results were reproducible in five independent experiments for each combination, further reinforcing the significance of existing channel activity in the mouse heart mitochondria.

M.A. / It is a well-known fact that South Africans of all races are a high risk population for the development of coronary heart disease and hypertension . More recent statistics indicate that cardiovascular disease caused 12 % of deaths amongst black South Africans in 1994 (Webster, 1996). Risk factors for CHI) can be grouped into four domains : Biomedical (e.g. hypertension, family history), behavioural (e.g. substance intake), sociodemographic (e.g. socio - economic status) and personality (e.g. Type A Behaviour). While there is a general agreement on many of the risk factors for CHIC, there are many more which are still being debated such as the influence of offspring parental heart disease and hypertension and coronary - prone behaviour. In a developing country, such as South Africa, with its heterogeneous population, it seemed that cardiovascular diseases are assuming epidemiological proportions among both White and Black South Africans, and thus appears necessary to establish whether Black patients with cardiovascular disease exhibits the TABP, closely related with diseases of the cardiovascular system among Whites. Els (1987) noted that stress associated with lifestyle changes in Black urbanisation in South Africa, not only showed psychological markers of CHD, but also physiological markers, such as substance intake. A cohort of 67 Black South African university students (38 male & 29 female), with a mean age of 23 was selected. The experimental groups being children of parents with hypertension and heart disease and the controls being children of normotensive parents and without a history of heart disease. A battery of tests were used to measure TAB, depression, hostility, anger and substance consumption. Results indicated that the experimental groups showed a significantly higher index of Type A Behaviour (p < 0, 01) than the controls and there was a significant correlation in terms of Parental hypertension and parental heart disease with coronary - prone behaviour (anger, hostility and depression) as well as substance consumption.