Cardiac Ca2+ signaling and Ca2+ sensitizers.
The role of Ca2+ in cardiac excitation-contraction (E-C) coupling has been established by simultaneous measurements of contractility and Ca2+ transients by means of aequorin in intact myocardium and Ca2+ sensitive fluorescent dyes in single myocytes. The E-C coupling process can be classified into 3 processes: upstream (Ca2+ mobilization), central (Ca2+ binding to troponin C) and downstream mechanism (thin filament regulation and crossbridge cycling). These mechanisms are regulated differentially by various inotropic interventions. Positive force-frequency relationship and effects of beta-adrenoceptor stimulation, phosphodiesterase 3 inhibitors and digitalis are essentially exerted via upstream mechanism. Alpha-adrenoceptor stimulation, endothelin-1, angiotensin II, and clinically available Ca2+ sensitizers, such as levosimendan and pimobendan, act by a combination of the upstream and central/downstream mechanism. The Frank-Starling mechanism and effects of Ca2+ sensitizers such as EMD 57033 and Org 30029 are primarily induced via the central/downstream mechanism. Whereas the upstream and central mechanisms are markedly suppressed in failing myocytes and under acidotic conditions, Ca2+ sensitizers such as EMD 57033 and Org 30029 can induce cardiotonic effects under such conditions. Ca2+ sensitizers have high therapeutic potential for the treatment of contractile dysfunction in congestive heart failure and ischemic heart diseases, because they have energetic advantages and less risk of Ca2+ overload and can maintain effectiveness under pathological conditions.
Endoh
Masao
M
Department of Cardiovascular Pharmacology, Yamagata University School of Medicine, Yamagata, Japan. mendou@med.id.yamagata-u.ac.jp
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001392:Azocines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D018679:Cholinergic Agonists / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology; D016232:Endothelins / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D000077464:Simendan; D013829:Thiadiazines / Q000494:pharmacology; D019209:Troponin C / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D001392:Azocines; D002316:Cardiotonic Agents; D018679:Cholinergic Agonists; D004095:Dihydropyridines; D016232:Endothelins; D006835:Hydrazones; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011804:Quinolines; C115124:Sch 00013; D013829:Thiadiazines; D019209:Troponin C; D000804:Angiotensin II; C070609:EMD 53998; C095056:BA 41899; D000077464:Simendan; C041648:pimobendan; D002118:Calcium