Postischemic dysfunction of the heart induced by small numbers of neutrophils via formation of hypochlorous acid.
The role of polymorphonuclear neutrophils (PMN) in the injury of the heart following ischemia and reperfusion is still controversial. The aim of this study was to investigate whether small numbers of PMN may cause myocardial dysfunction in an isolated system, how the resulting loss of function can be characterized and whether the formation of hypochlorous acid (HOCl) can be responsible for the PMN-mediated effect. Isolated working guinea pig hearts were subjected to a 90% reduction of coronary flow for 30 min, with or without intracoronary infusion of homologous PMN (approximately 1-2 x 10(5) cells/min, i.e. about 5-10% of normal blood count). This ischemia was followed by a 15 min reflow period in a non-working ("Langendorff") mode before work was resumed. In hearts perfused only with buffer, post-hypoxic heart function recovered to 75-80% of the initial value. Inclusion of unstimulated PMN did not further attenuate cardiac function. However, cardiac output was decreased to 42% of the initial value, provided thrombin (0.3 U/ml) and H2O2 (10(-5) M) were also present, and the retained PMN (about 10% of those infused) were additionally stimulated during reflow by application of FMLP (10(-6) M for 1 min). In these instances, coronary flow at any time of the experiment and release of lactate or purines during ischemia and reflow did not differ significantly between hearts perfused with or without PMN. There was no substantial release of myoglobin in controls and in PMN-treated hearts. Inotropic stimulation of the hearts with noradrenaline or exogenous Ca2+ caused a sustained increase in contractile force. However, the response was significantly reduced in PMN-perfused hearts in comparison to control hearts. The myocardial contents of high-energy phosphates with and without inotropic stimulation proved to be identical irrespective of whether experiments had been performed in the absence or presence of PMN. A similar loss of myocardial function as mediated by PMN could be produced by infusing chemically generated hypochlorous acid (HOCl, 5 x 10(-7) M for 10 min). Strikingly, that portion of the infused HOCl which actually reacted with cardiac tissue was comparable to the amount shown to be generated by stimulating 10(6) PMN retained in the coronary system (about 7 nmoles). Supplementing the perfusate with the scavengers L-methionine (10(-4) M) or uric acid (5 x 10(-4) M) prevented the attenuation of heart function provoked by PMN. The results indicate that small numbers of PMN, sufficiently activated, can depress cardiac function after 30 min of ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)
Raschke
P
P
Physiologisches Institut, Universität München, Germany.
Becker
B F
BF
Leipert
B
B
Schwartz
L M
LM
Zahler
S
S
Gerlach
E
E
D000818:Animals; D004734:Energy Metabolism; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics; D006997:Hypochlorous Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism* / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D010710:Phosphates / Q000378:metabolism; D010865:Pilot Projects
D010710:Phosphates; D006997:Hypochlorous Acid; D009638:Norepinephrine