Norepinephrine transporter is involved in down-regulation of beta1-adrenergic receptors caused by adjuvant arthritis.
OBJECTIVE
Inflammation in forms of rheumatoid and experimental arthritis cause not only joint pain but also excessive cardiovascular mortality. The condition also reduces response to calcium channel and beta-adrenergic (beta1-AR) antagonists. For calcium channel inhibitors, the reduced response is shown to be due to the reduced expression of target proteins. Hydroxymethylglutaryl CoA reductase inhibitors (statins) restore response to propranolol and verapamil. We tested the effect of adjuvant arthritis on the norepinephrine (NE) transporter (NET) density since altered sympathetic nervous system innervation has been observed in rheumatoid arthritis.


METHODS
Male Sprague-Dawley rats were divided into the following groups: Healthy/Placebo, Healthy/Statin, Pre-AA/Placebo, and Pre-AA/Statin (n=7-8/group). On Day 0, to the Pre-AA and Healthy groups, was injected Mycobacterium butyricum or saline, respectively. On Days 4-8, Statin and Placebo groups received either pravastatin (6 mg/kg) or placebo twice daily, respectively. On day 8, heart and blood samples were collected. The density of NET and 1-AR in heart homogenate; NE in plasma and heart and inflammatory mediators (nitrite and interferon-gamma) in serum were determined.


RESULTS
Inflammation was associated with a significant reduction in both beta1-AR and NET density with a positive correlation between the two proteins (r=0.978, p<0.0001). The down-regulating effect of inflammation was not reversed by pravastatin. Inflammation had no significant effect on the plasma or heart NE concentration.


CONCLUSIONS
The close relations of NET and beta1-AR implicates altered sympathetic innervation and/or local NE handling in pharmacotherapeutic desensitization observed in arthritis.
Clements
John D
JD
University of Alberta, Faculty of Pharmacy and Pharmaceutical Sciences, Edmonton, Alberta T6G 2N8, Canada.
Jamali
Fakhreddin
F
D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism*; D015153:Blotting, Western; D015536:Down-Regulation; D006321:Heart / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000097:blood; D007371:Interferon-gamma / Q000097:blood; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009573:Nitrites / Q000097:blood; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D017035:Pravastatin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D009573:Nitrites; D050484:Norepinephrine Plasma Membrane Transport Proteins; D018342:Receptors, Adrenergic, beta-1; D007371:Interferon-gamma; D017035:Pravastatin; D009638:Norepinephrine