title: Drug-induced delayed cardiac protection against the effects of myocardial ischemia.
abstract: Drug-induced delayed cardiac protection (DCP) against the effects of acute myocardial ischemia was first described 22 years ago by the author and his coworkers. It can be initiated by noninjurious pharmacological doses of prostacyclin (PGI2), its stable analogues, and by catecholamines. DCP protects against many consequences of ischemia, attenuating early morphological changes, limiting infarct size and suppressing arrhythmias, and can also protect against ouabain intoxication. DCP operates under a variety of pathological conditions (atherosclerosis, hypercholesterolaemia, and diabetes). DCP can also be evoked by transient myocardial ischemia and by exercise and is known in this context as "ischemic preconditioning", specifically the "second window of protection"; transient ischemia also evokes an immediate but short-lived protection known as "classical preconditioning". DCP is fundamentally different in concept to conventional drug therapy because the process appears to depend on the duration of the trigger and be related in a bell-shaped manner to the strength of the trigger. The exact mechanism is uncertain. Prolongation of the effective refractory period (ERP) and of the action potential duration (APD) may contribute to DCP suppression of arrhythmias. The protection is time and dose dependent, with optimal effects 24 to 48 hr after treatment. It can be sustained by intermittent administration of low maintenance doses. Stimulation of the adenylate-cyclase/cyclic adenosine monophosphate (cAMP) system appears to be a common feature of DCP. Responses to beta-adrenergic stimuli are also diminished. Cardiac cAMP triggers the induction of phosphodiesterase (PDE) 1 and 4 isoforms and of Na/K-ATPase. Increased amount and activity of PDE isoforms subsequently reduces excess myocardial cAMP production. Changes in Na/K-ATPase moderate ischemic myocardial potassium loss, sodium, and calcium accumulation, as well as the toxicity of ouabain. The future therapeutic challenge is to identify new drugs that can mimic DCP.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical Center, University of Szeged, Szeged, Hungary. L.Szekeres@iif.u-szeged.hu
authors.forename: László
authors.initials: L
authors.lastname: Szekeres
mesh_terms: D000222:Adaptation, Physiological; D018674:Adrenergic Antagonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D018674:Adrenergic Antagonists; D000889:Anti-Arrhythmia Agents; C033705:7-oxoprostaglandin I2; D011464:Epoprostenol