Orally administered nitrite attenuates cardiac allograft rejection in rats

Zhan, Jianghua; Nakao, Atsunori; Sugimoto, Ryujiro; Dhupar, Rajeev; Wang, Yinna; Wang, Zhiliang; Billiar, Timothy R.; McCurry, Kenneth R.

doi:10.1016/j.surg.2009.05.002

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Volume 146, Issue 2 , Pages 155-165, August 2009

Orally administered nitrite attenuates cardiac allograft rejection in rats

Jianghua Zhan, MD
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
- Department of Surgery, Tianjin Children's Hospital, Tianjin, China
Atsunori Nakao, MD, PhD
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
Ryujiro Sugimoto, MD
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
Rajeev Dhupar, MD
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
Yinna Wang, MD
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
Zhiliang Wang, MD
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
Timothy R. Billiar, MD
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
Kenneth R. McCurry, MD
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
- Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH
- Reprint requests: Kenneth R. McCurry, MD, Heart and Vascular Institute Cleveland Clinic, 9500 Euclid Avenue, J4-1, Cleveland, OH 44195.

Accepted 12 May 2009.

Background

Recent studies have shown that nitrite serves as an endogenous reservoir of nitric oxide (NO), particularly in the presence of hypoxia and ischemia. We hypothesized that exogenous nitrite supplementation would protect cardiac allografts.

Methods

Fully allogeneic heterotopic heart transplantation was performed in LEW to BN combination under tacrolimus. Animals were given either regular or nitrite/nitrate (NOx)-low chow combined with regular water or water containing nitrite (50 mg/L) for 120 days continuously beginning 7 days before transplant.

Results

Serum nitrite/nitrate levels were significantly higher in animals given nitrite water for 30 days, and lower in the animals fed with NOx-low diet than those in animals who received standard diet. Supplementation of drinking water with nitrite enhanced heart graft survival to a median of >120 days from 49.5 days in animals fed a standard diet. In contrast, dietary NOx insufficiency resulted in significantly earlier rejection of allografts (30.5 days). In correlation with graft survival, mRNA levels for interferon-γ in the spleen or tumor necrosis factor-α in the grafts were significantly less when animals were fed nitrite water compared with those without nitrite supplementation.