Nicotine exacerbates postischemic contractile dysfunction of 'stunned' myocardium in the canine model. Possible role of free radicals.
BACKGROUND
There is no doubt that high doses of nicotine have deleterious effects on cardiovascular function. However, the effects of lower and more clinically relevant doses of nicotine have received little attention, and the consequences of nicotine in the setting of ischemia/reperfusion are virtually unknown. The first objective of this study was to determine whether nicotine, given either before or after ischemia and at a dose mimicking that absorbed by humans during inhalation of one cigarette, exacerbated contractile dysfunction of canine myocardium "stunned" by brief transient ischemia. The second aim was to provide preliminary insight into the mechanism of action of nicotine on the stunned myocardium.


RESULTS
Anesthetized open chest dogs underwent 15 minutes of left anterior descending coronary artery (LAD) occlusion and 3 hours of reperfusion. In protocol 1, each dog was randomized to receive nicotine at 30 minutes before LAD occlusion (80 micrograms/kg dissolved in 15 mL of saline, given i.v. over 10 minutes), nicotine at 1 hour after reperfusion (80 micrograms/kg as above), or saline. Segment shortening (assessed by sonomicrometry) in both the LAD and circumflex beds, heart rate, arterial pressure, and coronary blood flow were monitored throughout the protocol, and regional myocardial blood flow (by injection of radiolabeled microspheres) was measured during LAD occlusion and at 5 minutes after nicotine/saline infusion. All groups were equally ischemic during LAD occlusion. As expected, segment shortening in the LAD bed of control animals was depressed after reperfusion, averaging 54 +/- 6% and 50 +/- 4% of baseline at 1 and 3 hours after reflow. Nicotine given before occlusion did not alter segment shortening before LAD occlusion and did not exacerbate dyskinesis during occlusion. However, segment shortening in the LAD bed recovered to only 29 +/- 9% and 22 +/- 5% of baseline at 1 and 3 hours after reperfusion (P < .01 versus corresponding control values). Furthermore, nicotine given at 1 hour after reperfusion caused a significant deterioration in segment shortening, from 47 +/- 11% immediately before infusion (P = NS versus control at 1 hour after reflow) to 7 +/- 13% at 3 hours after reperfusion (P < .01 versus 1 hour after reperfusion; P < .01 versus control at 3 hours after reflow). This dose of nicotine did not alter heart rate, arterial pressure, or blood flow; did not cause myocyte necrosis; and did not impair contractile function in the normally perfused circumflex bed. In protocol 2, all dogs received a continuous infusion of the free radical scavenging agent N-2-mercaptopropionyl glycine (MPG; 50 mg.kg-1 x h-1) beginning 45 minutes after reperfusion and, at 1 hour after reflow, received either nicotine or saline as described in protocol 1. MPG given after reperfusion did not alter contractile function in control animals. However, MPG prevented the deterioration in postischemic function observed with nicotine in protocol 1; segment shortening averaged 54 +/- 11% and 56 +/- 9% of baseline at 1 and 3 hours after reperfusion (P = NS).


CONCLUSIONS
Nicotine, given before occlusion or after reflow, significantly exacerbated contractile dysfunction of post-ischemic stunned myocardium in this canine model. This exacerbated dysfunction was not a secondary consequence of unfavorable alterations in hemodynamics or coronary blood flow and may be mediated by free radicals acting on myocytes that had been reversibly injured by the brief ischemic insult.
Przyklenk
K
K
Heart Institute, Hospital of the Good Samaritan, Los Angeles, Calif. 90017.
D000818:Animals; D004285:Dogs; D005609:Free Radicals; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D017682:Myocardial Stunning / Q000139:chemically induced* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D009538:Nicotine / Q000009:adverse effects*; D008625:Tiopronin / Q000494:pharmacology
D005609:Free Radicals; D009538:Nicotine; D008625:Tiopronin