The aim of this project was to study changes in cardiovascular responses brought about by long term oral treatment of Wistar rats with beta adrenoceptor antagonists. After chronic treatment with propranolol (12 or 60 mg/kg/day for up to 6 weeks) or timolol (1.2, 2.5, 5 or 25 mg/kg/day for up to 17 weeks), the log dose-response curves for mean rises in heart rate and mean arterial pressure on stimulation of the postsynaptic adrenoceptors of the pithed rat by I.V. noradrenaline or isoprenaline were not significantly changed. Chronic propranolol treatment significantly reduced the response of the heart to electrical stimulation of the whole sympathetic outflow but treatment with timolol failed to alter the cardiac chronotropic response. The rises in mean arterial pressure on stimulation of the whole sympathetic outflow were not altered by long term treatment with either propranolol or timolol. The high dose of propranolol significantly reduced the heart rate of conscious rats. However neither the lower dose of propranolol nor any dose of timolol affected heart rate. The systolic pressure of conscious rats was unaltered by treatment with the beta adrenoceptor blockers. The threshold for release of tritiated noradrenaline from the sympathetic nerves on stimulation of the whole spinal outflow was raised by chronic treatment with propranolol or timolol. Timolol significantly increased the concentration of 3H noradrenaline in the blood and decreased the heart content of tritium. Chronic propranolol treatment did not alter the blood or heart levels of 3H noradrenaline. Thus, although the plasma levels of the beta adrenoceptor blocking drugs were probably insufficient to ensure prolonged blockade of postsynaptic receptors, significant changes in presynaptic function were observed. It remains to be seen whether these changes play any significant part in cardiovascular responses to beta adrenoceptor antagonists in clinical practice.
|Date of Award||1985|