Effect of norepinephrine on myocardial collagen gene expression and response of cardiac fibroblasts after norepinephrine treatment.

Biosynthesis of the collagen matrix of the heart has been shown to be regulated under various physiologic and pathologic conditions. Biogenic amines have known effects on myocardial function. The authors studied the effects of norepinephrine on myocardial collagen gene expression in the rat heart. Norepinephrine was administered intravenously in a sustained-release manner. Within 1 hour after treatment, the abundance of mRNA for pro alpha 2 (I) collagen increased by 212% (P = 0.05), TGF-beta 1 by 91% (P = 0.05), and cytoskeletal actin by 429% (P less than 0.01) in the ventricular myocardium of the treated rats compared with that in control untreated rats. In extended period of treatment, the abundance of mRNA for pro alpha 2 (I) collagen reached a peak (206% increase, P less than 0.01) at day 3, remained elevated through day 6, and returned to the control levels at 2 weeks after treatment. The expression of mRNA for TGF-beta 1 was coregulated with that of pro alpha 2 (I) collagen. The abundance of mRNA for cytoskeletal actin showed a sharp increase (323%, P less than 0.05) at day 1 and remained elevated through day 6 in treated hearts compared with that in control hearts and returned to the control levels at 2 weeks after treatment. Coadministration of alpha-receptor blocker, phentolamine, led to modest reversal, whereas coadministration of beta-receptor blocker, propranolol, led to about 50% reversal of norepinephrine effects on the abundance of mRNAs. At day 3 of treatment, collagen content of ventricular tissue, as determined by hydroxyproline measurement was increased by 13% (P less than 0.05) in treated hearts. Immunofluorescent light microscopy showed increased collagen deposition and focal areas of necrosis in the endocardial regions in hearts of animals treated with norepinephrine for 2 weeks. In vitro studies on cultured cardiac fibroblasts showed that although norepinephrine treatment does not lead to significant changes in the abundance of mRNA for pro alpha 2 (I) collagen, it leads to increased mRNA for cytoskeletal actin and increased (113%, P less than 0.05) 3H-thymidine incorporation into the cell nuclei of treated cells compared with that in untreated cells. The authors conclude that although norepinephrine has no direct in vitro effects on collagen type I biosynthesis, its in vivo effects may lead to a cascade of events such as induction of growth factors that ultimately result in increased expression of collagen type I in the myocardium.