The long term goal of the present proposal is to continue an analysis of drug actions on regional myocardial blood flow and cardiac muscle function in different models of ischemia. One major objective will be to determine mechanisms whereby specific pharmacological agents increase coronary collateral blood flow and influence its transmural distribution between subendocardium and subepicardium in dogs with single or multiple coronary occlusions and/or stenoses. Dogs with immature or poorly developed collateral vessels (acute occlusion) and ones with mature or well developed collateral vessels (chronic occlusion) will be used. Myocardial segment function (sonomicrometry) will be monitored in normal, partially ischemic and central ischemic areas and changes in segment shortening (% SS) will be correlated with changes in regional blood flow (radioactive microspheres). By using selective beta and alpha receptor agonists and antagonists, specific bradycardic agents and vagal stimulation, the importance of a number of variables which are thought to influence collateral perfusion, i.e., heart rate, arteriolar resistance in nonischemic myocardium, alpha1 and alpha2 adrenergic receptors, will be investigated. In the multiple occlusion studies, the effectiveness of beta receptor blocking agents, vagal stimulation and specific bradycardic drugs to increase coronary perfusion pressure distal to a partially occluded coronary vessel, thereby increasing collateral blood flow to a totally occluded area will be studied in dogs with immature or well-developed collateral vessels. A second major objective will be to determine the effect of different slow channel calcium entry blockers on collateral function in dogs with well developed collateral vessels. In addition, the relative selectivity of these agents to dilate coronary resistance vessels versus large epicardial conductance and collateral vessels will be assessed. Radioactive microspheres, retrograde pressure and flow will be used as indices of collateral function and dose-response curves to different calcium channel blockers will be obtained by intracoronary or intravenous infusion. Nitroglycerin and adenosine, agents known to selectively dilate collateral vessels or arteriolar resistance vessels, respectively, will be used for purposes of comparison. Since patients with ischemic heart disease often have multiple occlusion and/or stenoses and have widely varying degrees of collateral development, these studies should lend important insight as to mechanisms by which certain pharmacological agents relieve myocardial ischemia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL008311-21
Application #
3334222
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1979-06-01
Project End
1990-05-31
Budget Start
1985-06-01
Budget End
1986-05-31
Support Year
21
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Auchampach, John A; Maas, Jason E; Wan, Tina C et al. (2011) Are we putting too much stock in mice? J Mol Cell Cardiol 50:584-5
Gumina, Richard J; Newman, Peter J; Gross, Garrett J (2011) Effect on ex vivo platelet aggregation and in vivo cyclic flow with Na+/H+ exchange inhibition: Gumina, NHE-1 inhibition and platelet aggregation. J Thromb Thrombolysis 31:431-5
Peart, Jason N; Hoe, Louise E See; Gross, Garrett J et al. (2011) Sustained ligand-activated preconditioning via ýý-opioid receptors. J Pharmacol Exp Ther 336:274-81
Maas, Jason E; Wan, Tina C; Figler, Robert A et al. (2010) Evidence that the acute phase of ischemic preconditioning does not require signaling by the A 2B adenosine receptor. J Mol Cell Cardiol 49:886-93
Gross, Garrett J; Baker, John E; Hsu, Anna et al. (2010) Evidence for a role of opioids in epoxyeicosatrienoic acid-induced cardioprotection in rat hearts. Am J Physiol Heart Circ Physiol 298:H2201-7
Gross, Eric R; Hsu, Anna K; Gross, Garrett J (2009) Acute methadone treatment reduces myocardial infarct size via the delta-opioid receptor in rats during reperfusion. Anesth Analg 109:1395-402
Gross, Eric R; Gross, Garrett J (2007) Ischemic Preconditioning And Myocardial Infarction: An Update and Perspective. Drug Discov Today Dis Mech 4:165-174
Gross, Garrett J; Auchampach, John A (2007) Reperfusion injury: does it exist? J Mol Cell Cardiol 42:12-8
Bolte, Craig S; Liao, Siyun; Gross, Garrett J et al. (2007) Remote preconditioning-endocrine factors in organ protection against ischemic injury. Endocr Metab Immune Disord Drug Targets 7:167-75
Auchampach, John A; Jin, Xiaowei; Moore, Jeannine et al. (2004) Comparison of three different A1 adenosine receptor antagonists on infarct size and multiple cycle ischemic preconditioning in anesthetized dogs. J Pharmacol Exp Ther 308:846-56

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