Neuropeptide depletion impairs postischemic recovery of the isolated rat heart: role of substance P.
OBJECTIVE
Ischemia of the myocardium stimulates cardiac sensory nerve endings resulting in the local release of neuropeptides. The significance of the release of neuropeptides, such as substance P (SP), for the function of the heart during ischemia and reperfusion is not known. We examined the effects of both chronic and acute neuropeptide depletion and of SP administration on contractile function and rhythmicity of the isolated rat heart during global ischemia and subsequent reperfusion.


METHODS
Experiments were conducted on the isolated perfused heart from vehicle and capsaicin-pretreated rats (100 mg/kg) to deplete neuropeptides from peripheral nerve terminals. The hearts were perfused with Krebs-Henseleit solution (95%O2 + 5% CO2, 37 degrees C, at constant pressure of 90 cmH2O). Left ventricular developed and diastolic pressures (LVDevP and LVEDP), heart rate (HR) and coronary flow (CF) were measured. Hearts were subjected to 20 min global no-flow ischemia and 30 min reperfusion.


RESULTS
Prior to interrupting coronary flow, LV pressures, HR and CF did not differ between vehicle and capsaicin-pretreated rats. However, throughout the reperfusion period, the recovery of LVDevP, HR and CF in hearts from capsaicin-pretreated rats was consistently less than in control hearts (P < 0.05), and the incidence of fibrillation during reperfusion was higher (P < 0.05). In other experiments, acute perfusion of isolated hearts with capsaicin (10(-6) M) for 5 min before ischemia had a similar limiting effect during reperfusion. Administration of SP (10(-6)-10(-9) M) to capsaicin-pretreated hearts before ischemia restored their ability to recover contractile function and CF during reperfusion. Administration of SP to untreated hearts before ischemia also improved their recovery above normal during reperfusion and decreased the incidence of fibrillation without affecting postischemic CF. The beneficial effects of SP were abolished by an NK-1 receptor antagonist, CP-96,345 (10(-6) M).


CONCLUSIONS
These data indicate that sensory neuropeptides play a role in protection of the isolated heart against ischemic damage and suggest a role of SP in the resistance of the myocardium to ischemia and reperfusion injury.
Ustinova
E E
EE
Department of Physiology and Biophysics, University of Nebraska College of Medicine, Omaha 68198, USA.
Bergren
D
D
Schultz
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HD
D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000378:metabolism*; D015425:Myocardial Reperfusion; D009479:Neuropeptides / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000494:pharmacology / Q000502:physiology*
D009479:Neuropeptides; D013373:Substance P; D002211:Capsaicin