Intrinsic sympathomimetic activity and beta-adrenoceptor blockade: Clinical and metabolic studies in ischaemic heart disease

The studies which form the basis of this thesis were performed over the course of two and a half years from May 1982 until October 1984, during the tenure of my post of Research Fellow in Cardiology at the Victoria Infirmary, Glasgow. The main object has been to establish the clinical importance of intrinsic sympathomimetic activity possessed by beta blockers during the treatment of chronic stable angina pectoris. Despite their widespread use, the longterm clinical effects of beta blockers with and without ISA are poorly documented. Thus, I have investigated the influence of beta blockers with and without this property on left ventricular performance, plasma lipoproteins, symptomatic and asymptomatic myocardial ischaemia, respiratory function and adverse effects. In addition, the experiments involved presented an opportunity to evaluate the role of radionuclide ventriculography in the detection of coronary artery disease, and an assessment of cold pressor stress and isometric handgrip exercise used in conjunction with this technique. This thesis consists of eight sections of which Section 1 is the introduction. Sections 2-7 comprise the investigations conducted by the author and Section 8 contains the final commentary and references. Where necessary each section has been divided into subsections covering particular topics or experiments. Each table or figure is described by a section number and a number corresponding to it's appearance in that section. In the first section I have developed the concept of beta-adrenoceptor blockade and intrinsic sympathomimetic activity. In this introduction I have attempted to describe the current understanding of ISA and the known clinical effects and adverse reactions of beta blockers with this property in as brief a review as is commensurate with an understanding of the main topics of this thesis. This section lays the foundation for the following experiments and attempts to pinpoint important gaps in our knowledge of the clinical effects of these agents. Section 2 describes briefly how patients with chronic stable angina were recruited for the experiments to follow and includes an assessment of patient compliance with the beta blockers used in each experiment and their adverse reactions. Sections 3 and 4 contain the results of investigations using radionuclide ventriculography to determine left ventricular function. Section 3 investigates the role of ISA in the long-term treatment of chronic stable angina with beta blockers and Section 4 evaluates the reproducibility of radionuclide ventriculography in our laboratory and its use in the detection of coronary artery disease. In addition, the cardiovascular effects and application of cold pressor stress and isometric handgrip exercise are explored. All of the measurements of heart rate and blood pressure in this thesis necessitated the use of a semi-automatic recorder, and the Hitachi HME-20 pulse and blood pressure monitor was chosen for this purpose and it's evaluation is contained in Section 4. Section 5 contains the results from a long-term investigation into the effects of pure beta blockers and one with ISA on plasma lipoproteins and contains an extensive review of the current literature. The study contained in Section 6 was designed to evaluate the effect of beta blockers with and without ISA on the frequency of symptomatic and asymptomatic myocardial ischaemia in chronic stable angina pectoris and their effect on heart rate and rhythm. This was carried out using ambulatory ECG recorders designed for the purpose. One of the long established concerns when using beta blockers is their effect on respiratory function. There is considerable evidence of increased airway narrowing following their administration. In Section 7, this is investigated with particular reference to the possible influence of ISA which may aleviate this effect. In the final section (Section 8), I have attempted to construct a concise resume of my findings and place them in perspective to previous knowledge