title: Cyclic fluctuations in the cardiac performance of the isolated Langendorff-perfused mouse heart: pyruvate abolishes the fluctuations and has an anti-ischaemic effect.
abstract: During the development of a Langendorff preparation of isolated mouse hearts, hitherto undescribed cyclic fluctuations in left ventricular pressure and coronary flow were independently observed in three laboratories. Isolated mouse hearts were perfused with crystalloid glucose-containing Krebs-Hensleit buffer in a constant pressure model, and left ventricular pressures were measured via an intraventricular balloon catheter. After acquiring technical skill in preparing the mouse hearts, the perfusionists observed that fluctuations in cardiac performance with a cycle period lasting 5-10 min occurred shortly after initiation of perfusion. Each fluctuation cycle consisted of a phase of increase and a phase of decrease. Synchronized with the fluctuations in left ventricular pressure, increases and decreases in dP/dt max took place. Analogous fluctuations in coronary flow occurred, with onset 1-2 min later than changes in left ventricular systolic pressure. In some preparations a gradual ST-segment elevation was seen on the electrocardiogram during the systolic pressure increase phase. The amplitude of the fluctuations could be augmented by increasing the perfusion pressure, and reduced, but not abolished, by lowering the pressure. Changes in buffer calcium, magnesium, or sodium concentration did not alter the fluctuations, nor did any change of anaesthetics, mouse strain, or left ventricular drainage. Altering the perfusion mode from constant pressure to constant flow did not prevent the occurrence of the cyclic fluctuations. The hearts became stable and the fluctuations disappeared when the buffer was supplemented with 2 mm pyruvate. In the present study, pyruvate given throughout stabilization and reperfusion also markedly attenuated the ischaemic insult, as evidenced by the delayed ischaemic contracture and a reduced magnitude of ischaemic contracture. A cardioprotective effect was only visible at early reperfusion, did not affect the final functional recovery. In conclusion, a phenomenon of cyclic fluctuations in left ventricular pressure followed by fluctuations in coronary flow was observed in isolated mouse hearts. These could be abolished by adding 2 mm pyruvate to the perfusion buffer. Pyruvate in the buffer also markedly attenuated the post-ischaemic deterioration of cardiac performance seen in this mouse model.
authors.affiliation: Integrative Pharmacology, AstraZeneca R & D, Mölndal, Sweden.
authors.forename: Q-D
authors.initials: QD
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Tokuno
authors.forename: G
authors.initials: G
authors.lastname: Valen
authors.forename: P-O
authors.initials: PO
authors.lastname: Sjöquist
authors.forename: P
authors.initials: P
authors.lastname: Thorén
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000032:analysis; D004562:Electrocardiography / Q000379:methods; D005260:Female; D008274:Magnesium / Q000032:analysis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D010424:Pentobarbital / Q000494:pharmacology; D010477:Perfusion; D019289:Pyruvic Acid / Q000494:pharmacology*; D012964:Sodium / Q000032:analysis; D016276:Ventricular Function
chemical_list: D019289:Pyruvic Acid; D012964:Sodium; D008274:Magnesium; D010424:Pentobarbital; D002118:Calcium