Mechanisms of improved ischemic regional dysfunction by bradycardia. Studies on UL-FS 49 in swine.
In anesthetized swine, the left anterior descending coronary artery was cannulated and perfused at constant blood flow levels during two grades of ischemia. In one group (n = 10), moderate ischemia reduced percent systolic wall thickening (by sonomicrometry) from 25 +/- 7% to 6 +/- 2%, whereas in the other group (n = 7), severe ischemia reduced percent wall thickening from 24 +/- 6% to -0.5 +/- 4%. Heart rate was paced in both groups at 91 beats/min. After reperfusion and complete return to control conditions, administration of the bradycardic agent UL-FS 49 (0.37 mg/kg i.v.) decreased the heart rate to 55 +/- 5 beats/min. During subsequent ischemia at the same coronary inflow as before bradycardia, percent wall thickening in the ischemic zone during moderate ischemia was increased from 6 +/- 2% to 25 +/- 6% (p less than 0.01) (not significantly different from control without ischemia), and during severe ischemia, percent wall thickening increased from -0.5 +/- 4% to 13 +/- 7% (p less than 0.01). During moderate ischemia, bradycardia caused an increase in the subendocardial blood flow from 0.24 +/- 0.60 to 0.42 +/- 0.17 (ml/min)/g (p less than 0.009) and during severe ischemia, bradycardia caused an increase from 0.14 +/- 0.08 to 0.2 +/- 0.1 (ml/min)/g (p less than 0.001). At each level of ischemia, a more marked improvement occurred in subendocardial blood flow per beat ([(ml/min)/g]/heart rate). The relation between myocardial blood flow and wall function at a heart rate of 55 beats/min (n = 14) was plotted and compared with that studied at a heart rate of 122 beats/min in another group of pigs (n = 14). The increase in subendocardial blood flow per minute during bradycardia was not sufficient to explain the striking increase in function; thus, an independent relation (p less than 0.05) between blood flow per minute and contractile function (percent wall thickening) was found for for each heart rate. In contrast, when myocardial blood flow was normalized for heart rate and expressed per beat, data from both heart rate groups could be described by a single relation. Thus, the subendocardial blood flow per beat predicted wall function independently of heart rate and accounted for changes in both oxygen supply and demand.
Indolfi
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Department of Medicine, University of California, San Diego, La Jolla 92093.
Guth
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BD
Miura
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Miyazaki
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S
Schulz
R
R
Ross
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J
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use*; D001696:Biomechanical Phenomena; D002317:Cardiovascular Agents / Q000627:therapeutic use; D003326:Coronary Circulation; D003327:Coronary Disease / Q000188:drug therapy* / Q000503:physiopathology; D003864:Depression, Chemical; D006321:Heart / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D013552:Swine
D001552:Benzazepines; D002317:Cardiovascular Agents; C043636:zatebradine