Research under this grant has shown that chronic surgical sympathectomy of the canine ventricles affords a protective effect during coronary artery occlusion and that this effect is due to improved collateral perfusion and reduced blood flow requirement. These findings are extremely important to the understanding and treatment of coronary artery disease and are directly applicable to the transplanted heart patient. These findings have been challenged by studies using other sympathectomy procedures (e.g. chemical) and other animal species (e.g. rabbit). Therefore, this renewal is focused both on advancement of our understanding of chronic sympathectomy and exploration of the physiological bases for reported differences. Four new studies are proposed: Study 10 will use conscious dogs and will examine whether chronic chemical sympathectomy [by topical application of phenol] exerts the same influence on the coronary collateral circulation as does surgical sympathectomy. Through a consortial arrangement with an independent laboratory, these experiments conducted """"""""blind"""""""". Study 11 will examine whether the surgical sympathectomy-induced collateral effects in the dog heart can be demonstrated in the pig heart, which like the human has a smaller native collateral bed. An improved collateral circulation in the pig heart after chronic sympathectomy would suggest an actual collateral development rather than a wider opening of existing channels. These experiments will also be conducted blind. Study 12 will systematically examine the influences of changes in heart rate and diastolic pressure on collateral blood flow during coronary occlusion. Evidence indicates that absence of a protective effect in the chronic, totally denervated heart of the conscious dog may be due to lack of reflex tachycardia, such as seen with only ventricular sympathectomy, such that diastolic pressure rises and opposes collateral perfusion. Study 13 will examine an apparent cardiocoronary reflex causing coronary constriction during myocardial ischemia. What are the roles of a local ischemia-induced release of norepinephrine or of a neural reflex affecting ischemic and nonischemic muscle? This study will also examine whether chronic ventricular sympathectomy alters this reflex in conscious dogs.
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