AJP - Cell Physiology, Vol 265, Issue 2 C412-C421, Copyright © 1993 by American Physiological Society

ARTICLES

Mechanism of diltiazem's immunomodulatory effects after hemorrhage and resuscitation

D. R. Meldrum, A. Ayala and I. H. Chaudry
Department of Surgery, Michigan State University, East Lansing 48824.

Although diltiazem improves immune responses after hemorrhage and resuscitation, its mechanism remains unknown. To study this, C3H/HeN mice were bled to a mean blood pressure of 35 mmHg, maintained at that level for 1 h, and then adequately resuscitated and treated with diltiazem (400 micrograms/kg body wt) or saline (vehicle). One hour after hemorrhage and resuscitation, splenic microvascular blood flow was determined by laser Doppler flowmetry. Splenocytes were also harvested and ATP levels and cytoplasmic free Ca2+ concentration ([Ca2+]i) were determined by 31P nuclear magnetic resonance and fluo 3 flow cytometry, respectively. Splenocyte functions were determined by measuring interleukin (IL)-1, IL-2, IL-3, IL-6, and tumor necrosis factor concentrations in concanavalin A-stimulated supernatant with cytokine-specific cellular assays. Hemorrhage and resuscitation caused a significant decrease in the splenocyte's ability to release cytokines, which was correlated with significant reductions in splenocyte ATP levels and splenic microvascular blood flow as well as a significant increase in splenocyte [Ca2+]i. Diltiazem significantly decreased splenocyte [Ca2+]i while improving splenocyte ATP levels, cytokine production, and splenic microvascular blood flow. Nitroglycerin (71 micrograms/kg body wt) administration improved splenic microvascular blood flow to diltiazem-treated levels but failed to concomitantly improve splenocyte ATP levels or cytokine production. Thus diltiazem's immunoprotective effects appear to be the result of decreased Ca(2+)-induced splenocyte injury.

This article has been cited by other articles:

				K. K. Meldrum, D. R. Meldrum, K. L. Hile, E. B. Yerkes, A. Ayala, M. P. Cain, R. C. Rink, A. J. Casale, and M. A. Kaefer p38 MAPK mediates renal tubular cell TNF-{alpha} production and TNF-{alpha}-dependent apoptosis during simulated ischemia Am J Physiol Cell Physiol, August 1, 2001; 281(2): C563 - C570. [Abstract] [Full Text] [PDF]

				K. K. Donnahoo, X. Meng, A. Ayala, M. P. Cain, A. H. Harken, and D. R. Meldrum Early kidney TNF-alpha expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion Am J Physiol Regulatory Integrative Comp Physiol, September 1, 1999; 277(3): R922 - R929. [Abstract] [Full Text] [PDF]

				M. K. Angele, N. Smail, M. W. Knoferl, A. Ayala, W. G. Cioffi, and I. H. Chaudry L-Arginine restores splenocyte functions after trauma and hemorrhage potentially by improving splenic blood flow Am J Physiol Cell Physiol, January 1, 1999; 276(1): C145 - C151. [Abstract] [Full Text] [PDF]

				D. R. Meldrum Tumor necrosis factor in the heart Am J Physiol Regulatory Integrative Comp Physiol, March 1, 1998; 274(3): R577 - R595. [Abstract] [Full Text] [PDF]

				D. R. Meldrum, J. C. Cleveland Jr., B. C. Sheridan, R. T. Rowland, A. Banerjee, and A. H. Harken CARDIAC PRECONDITIONING WITH CALCIUM: CLINICALLY ACCESSIBLE MYOCARDIAL PROTECTION J. Thorac. Cardiovasc. Surg., September 1, 1996; 112(3): 778 - 786. [Abstract] [Full Text]