Coronary response in the doxorubicin-induced cardiomyopathy

Abstract

Background:Coronary reserve and reactivity traits regarding doxorubicin (Dx) car-diotoxicity are less known comparatively to myocardial contraction and inotropiccapacities.Aim:the in vitro evaluation of coronary response to natural vasotropic agent actionin Dx-induced cardiomyopathy (Dx-CMP).Material and methods. Dx-CMP has been reproduced in white rats by Dx adminis-tration during 2 weeks (4 i/p Dx injections of 4 mg/kg, cumulative dose 16 mg/kg).The izovolumic isolated heart was perfused by standard Krebs solution accordingto Langendorff method, and the coronary flow (CF) changes were determined dur-ing action of acetylcholine (Ach), adenosine (As), bradykinin (Bk), hydrogen peroxide(H2O2), epoxyeicosatriens 11,12 (EET-11,12) and endothelin 1 (ET-1) in a concen-tration range of 10-7-10-5 M.Results:The basal CF in DxCMP did not differ from control index (12,7±0,08vs 13,4±0,09 ml/min). However, the endothelium dependent coronary functionalreserve is impaired, manifested by significant lowered CF value during stimulationby Ach (14,8±0,1 vs 17,3±0,12 ml/min), As (13,9±0,09 vs 15,5±0,11 ml/min) andBk (13,8±0,08 vs 15,3±0,12 ml/min). Remarkably, the coronarodilation mediatedby hyperpolarization was not compromised in Dx-CMP. The coronary reserve inher-ent to H2O2 action was as 15,7% in Dx-CMP (CF, 14,7±0,12 ml/min) and 14,9% incontrol series (CF, 15,4±0,13 ml/min). In a similar manner CF increased in responseto EET-11,12 action: 14,3% in Dx-CMP (CF, 14,52±0,13 ml/min) and 14,1% in con-trol (CF, 15,29±0,14 ml/min). Thus, the mediated by hyperpolarization coronaryartery dilatation could be an alternative tool of coronary functional reserve control inDx-CMP associated by endothelium dysfunction. Importantly, ET-1 in concentrationof 10-7 M determined in Dx-CMP o reduction of CF equal to control pattern (11,3%),but in condition of isolated heart pretreatment by apamin (selective blocker of KCachannels) the coronaroconstriction in Dx-CMP has been more pronounced vs con-trol (-17,1 vs -14,2%). In highest concentration (10-5 M) ET-1 led in Dx-CMP to abigger decline of coronary flow FC (-16,8 vs -14,5%).Conclusions:1. The coronary functional endothelium dependent reserve is signif-icantly reduced in Dx-CMP during Ach, As and Bk action averagely by 39-43,3%comparing to control, but the mediated by hyperpolarization coronarodilation properto H2O2 and EET-11,12 action is not compromised.2. In concentration of 10-5 M endoteline-1 induces a bigger fall of CF in Dx-CMP, butin concentration of 10-7 M the decline is similar to control, however CF decreasesmore if ET-1 action was preceded by KCa channels blocking.