Time course of cardiac inflammation during nitric oxide synthase inhibition in SHR: impact of prior transient ACE inhibition.
We have previously demonstrated that angiotensin-converting enzyme (ACE) inhibition with enalapril produces persistent effects that protect against future nitric oxide synthase (NOS) inhibitor (L-arginine methyl ester, L-NAME)-induced cardiac dysfunction and outer wall collagen deposition in spontaneously hypertensive rats (SHR). In the present study, we dissect the cytokine/chemokine release profile during NOS inhibition, its correlation to pathological cardiac remodeling and the impact of transient ACE inhibition on these effects. Adult male SHR were treated with enalapril (E+L) or tap water (C+L) for 2 weeks followed by a 2-week washout period. Rats were then subjected to 0, 3, 7 or 10 days of L-NAME treatment. The temporal response to NOS inhibition was evaluated by measuring arterial pressure, cardiac remodeling and cytokine/chemokine levels. L-NAME equivalently increased blood pressure and myocardial and vascular injury in C+L and E+L rats. However, pulse pressure (PP) was only transiently altered in C+L rats. The levels of several inflammatory mediators were increased during L-NAME treatment. However, interleukin-6 (IL-6) and IL-10 and monocyte chemoattractant protein-1 were uniquely increased in C+L hearts; whereas IL-4 and fractalkine were only elevated in E+L hearts. By days 7 and 10 of L-NAME treatment, there was a significant increase in the cardiac density of macrophages and proliferating cells, respectively only in C+L rats. Although myocardial injury was similar in both treatment groups, PP was not changed and there was a distinct cardiac chemokine/cytokine signature in rats previously treated with enalapril that may be related to the lack of proliferative response and macrophage infiltration in these hearts.
Department of Basic Medical Sciences, University of Arizona, College of Medicine-Phoenix, Phoenix AZ, USA.
Lauren A
LA
Biwer
Department of Basic Medical Sciences, University of Arizona, College of Medicine-Phoenix, Phoenix AZ, USA.
Karen M
KM
D'souza
Department of Basic Medical Sciences, University of Arizona, College of Medicine-Phoenix, Phoenix AZ, USA.
Ali
A
Abidali
Department of Basic Medical Sciences, University of Arizona, College of Medicine-Phoenix, Phoenix AZ, USA.
Danni
D
Tu
Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.
Ashley L
AL
Siniard
Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.
Matthew
M
DeBoth
Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.
Matthew
M
Huentelman
Department of Basic Medical Sciences, University of Arizona, College of Medicine-Phoenix, Phoenix AZ, USA.
Taben M
TM
Hale
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000097:blood; D018925:Chemokines; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D004656:Enalapril / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008264:Macrophages / Q000187:drug effects; D008297:Male; D009205:Myocarditis / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D011918:Rats, Inbred SHR
D000806:Angiotensin-Converting Enzyme Inhibitors; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D016753:Interleukin-10; D004656:Enalapril; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester