l‐Arginine: Effect on Reperfusion Injury after Heart Transplantation

Abstract

Global myocardial ischemia and reperfusion injury play a major role in early postoperative myocardial graft dysfunction. The aim of the present study was to investigate the effects of the nitric oxide (NO) precursor L-arginine on myocardial and endothelial function after hypothermic ischemia and reperfusion in a heterotopic rat heart transplantation model. After 1 hour ischemic preservation, reperfusion was started after application of placebo (control, n = 12) or L-arginine (L-Arg 40 mg/kg, n = 12), a substrate of NO synthesis. Myocardial blood flow (MBF) was assessed by the hydrogen clearance method. An implanted balloon was used to obtain pressure-volume relations of the transplanted heart. Left ventricular developed pressure (LVDP), rate of pressure development (dP/dt), end-diastolic pressure (LVEDP), isovolumic relaxation constant (TE), and MBF were measured after 60 minutes and 24 hours of reperfusion. endothelium-dependent vasodilatation in response to acetylcholine (ACh) and endothelium-independent vasodilatation in response to sodium nitroprusside (SNP) were also determined. After 1 hour the MBF was significantly higher in the L-Arg group (3.6 +/- 0.6 vs. 1.9 +/- 0.2 ml/min/g, p < 0.05). The L-Arg group showed better recovery of systolic function and myocardial relaxation (LVDP 106 +/- 6 VS. 70 +/- 7 mmHg, p < 0.05; maximal dP/dt 5145 +/- 498 vs. 3410 +/- 257 mmHg/s, P < 0.05; TE 12.1 +/- 0.9 vs. 16.1 +/- 1.5 ms, p < 0.05, at an intraventricular volume of 80 microliters). LVEDP was similar in the two groups. After 24 hours no difference was found between the groups for basal MBF, LVP dP/dt, TE, LVEDP, or the response of MBF to SNP. However, ACh led to a significantly higher increase in MBF in the L-Arg group (52 +/- 8% vs. 29 +/- 7%, p < 0.05). These results indicate that (1) NO donation improves myocardial and endothelial functional recovery during early reperfusion after heart transplantation; and (2) initial treatment with L-Arg has a persisting beneficial effect against reperfusion-induced graft coronary endothelial dysfunction during late reperfusion.

Poly(ADP-Ribose) Polymerase Inhibition Reduces Reperfusion Injury After Heart Transplantation

“…On the other hand, the control group showed a recovery after 24 hours with similar values to the PJ34 group, suggesting that that the applied cardiac preservation time and reperfusion lead to only reversible changes of functional status of the heart. 16,17 Although no differences were found between the groups in systolic and diastolic function and baseline coronary blood flow after 24 hours of reperfusion, endothelial function was still depressed in the control group as indicated by the lower CBF response to acetylcholine and bradykinin. The fact that after 24 hours reperfusion the histological specimens from both control and PJ34 showed only little PARP activation suggested that delayed endothelial dysfunction in the control animals may be a late consequence of a transient, earlier burst of PARP activation and subsequent cellular alterations.…”

“…16,17,27,30,31 Summarizing the data of these studies, a biphasic recovery pattern is characteristic for this model with an early phase (Ͻ1 hour) followed by a further improvement during the next 24 hours. Furthermore, different agents such as adenosine, 30 endothelin receptor antagonists, 17 the NOprecursor L-arginine, 16 the NO-donor SIN-1 (unpublished data), and free radical scavengers 31 effectively reduced reperfusion injury. Taking into account that in some of the studies ischemic time 30,31 or assessment protocol 30 was different, PARP inhibition seems to be an effective therapeutic modality for reducing reperfusion injury in comparison to other, previously tested agents.…”

“…16,17 Total coronary blood flow (CBF) was measured by a perivascular ultrasonic flow probe on the donor aorta. After baseline measurement, the endothelium-dependent vasodilator acetylcholine (ACH, 1 nmol/L, 0.2 mL) and bradykinin (BK 0.1 nmol/L, 0.2 mL) as well as the endothelium-independent vasodilator sodiumnitroprusside (SNP, 10 nmol/L, 0.2 mL) were administered directly into the coronary arteries of the graft via the donor aorta.…”

“…16,17 Briefly, donor hearts were explanted from Lewis rats. After 1 hour of ischemic preservation at 4°C, the hearts were implanted intraabdominally anastomosing the aorta and the pulmonary artery of the donor heart with the abdominal aorta or the vena cava of the recipient rat, respectively.…”

624 Acute Ethanol Exposure Increases the Susceptibility of the Donor Hearts to Ischemia/Reperfusion Injury after Transplantation in Rats

“…In our laboratory, we previously showed in canine orthotopic heart transplantation [37] and cardiopulmonary bypass models of global ischemia/reperfusion [38] and in a rat model of transplantation-induced ischemia/reperfusion injury [14] decreased LV contractility. However, we and others have already demonstrated that 24 h after transplantation systolic and diastolic function return to normal [39,40]. In the present study persistence of graft dysfunction 24 h after transplantation needs to be considered during heart transplantation when hearts from donor with alcohol abuse are used.…”