MECHANISMS OF ACTION

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This new component was developed in response to a perceived need to focus additional experiments on exploring mechanisms that will improve our understanding of systemic opioid agonist actions in 3 areas: the role of peripheral opioid receptors, the non opioid effects of delta-selective agonists, and clinically relevant side effects of a promising agonist. The goal of this component is to identify the mechanism(s) which underlie the physiological responses observed following iv bolus administration of selective mu and delta opioid peptide analogs that have been identified in the pharmacodynamic studies conducted in Component 3. Three specific quests are asked in this proposal. First, how are the cardiovascular responses to iv DALDA (H-Tyr-Arg-Phe-Lys) mediated? Second, are the immediate cardiovascular responses to iv DELT (H-Tyr-D-Ala-Phe-Asp-Val- Val-Gly-NH/2) the result of direct myocardial contractility or are they vagal in origin? Third, are the pregnancy-associated changes in the magnitude of the cardiovascular responses to DALDA and DELT mediated by a change in either estrogen and/or progesterone levels? The specific aims are: 1) determine if the pressor effect of iv DALDA is due to elevated cardiac output or increased peripheral vascular resistance; 2) determine if the cardiovascular effects of iv DALDA are mediated by enhanced sympathetic activity or decrease parasympathetic activity or decrease parasympathetic activity; 3) determine if the bradycardia to DELT is mediated by vagal stimulation; 4) determine the influence of estrogen and progesterone on the cardiovascular effects of DALDA and DELT; 5) determine if DALDA has direct positive inotropic and chronotropic action in the hear and/or whether DALDA alters vagal or sympathetic nerve transmission to the heart; 6) determine if DELT has direct negative chronotropic and inotropic action in the heart and/or whether DELT increases vagal nerve transmission to the heart; 7) determine the role of estrogen and progesterone in mediating the effects of pregnancy on the cardiac effects of DALDA and DELT. A combination of in vivo (chronically-instrumented sheep model; aims 1-4) and in vitro (isolated perfused guinea pig heart; aims 5-7) approaches will be used in this project. These specific aims will be carried out jointly by Dr. Clapp ( in vivo studies) and Dr. Szeto (in vitro studies) in their respective laboratories. We feel that understanding in these areas is necessary to ensure safety and identify important structure-function relationships for future drug development.