Effect of pravastatin on sympathetic reinnervation in postinfarcted rats.
We assessed whether pravastatin attenuates cardiac sympathetic reinnervation after myocardial infarction through the activation of ATP-sensitive K(+) (K(ATP)) channels. Epidemiological studies have shown that men treated with statins appear to have a lower incidence of sudden death than men without statins. However, the specific factor for this has remained disappointingly elusive. Twenty-four hours after ligation of the anterior descending artery, male Wistar rats were randomized to groups treated with either vehicle, nicorandil (a specific mitochondrial K(ATP) channel agonist), pinacidil (a nonspecific K(ATP) channel agonist), pravastatin, glibenclamide (a K(ATP) channel blocker), or a combination of nicorandil and glibenclamide, pinacidil and glibenclamide, or pravastatin and glibenclamide for 4 wk. Myocardial norepinephrine levels revealed a significant elevation in vehicle-treated rats at the remote zone compared with sham-operated rats (2.54 +/- 0.17 vs. 1.26 +/- 0.36 mug/g protein, P < 0.0001), consistent with excessive sympathetic reinnervation after infarction. Immunohistochemical analysis for tyrosine hydroxylase, growth-associated factor 43, and neurofilament also confirmed the change of myocardial norepinephrine. This was paralleled by a significant upregulation of tyrosine hydroxylase protein expression and mRNA in vehicle-treated rats, which was reduced after the administration of either nicorandil, pinacidil, or pravastatin. Arrhythmic scores during programmed stimulation in vehicle-treated rats were significantly higher than those treated with pravastatin. In contrast, the beneficial effects of pravastatin were reversed by the addition of glibenclamide, implicating K(ATP) channels as the relevant target. The sympathetic reinnervation after infarction is modulated by the activation of K(ATP) channels. Chronic use of pravastatin after infarction, resulting in attenuated sympathetic reinnervation by the activation of K(ATP) channels, may modify the arrhythomogenic response to programmed electrical stimulation.
Lee
Tsung-Ming
TM
Cardiology Section, Department of Medicine, Taipei Medical University, 252 Wu-Hsing Street, Taipei, Taiwan.
Lin
Mei-Shu
MS
Chang
Nen-Chung
NC
D000818:Animals; D015153:Blotting, Western; D002304:Cardiac Pacing, Artificial; D003331:Coronary Vessels / Q000601:surgery; D004195:Disease Models, Animal; D019922:GAP-43 Protein / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006321:Heart / Q000294:innervation*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007150:Immunohistochemistry; D054086:KATP Channels / Q000187:drug effects* / Q000378:metabolism; D008026:Ligation; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D016900:Neurofilament Proteins / Q000378:metabolism; D020108:Nicorandil / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D020110:Pinacidil / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D017180:Tachycardia, Ventricular / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D020257:Ventricular Remodeling / Q000187:drug effects
D019922:GAP-43 Protein; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D054086:KATP Channels; D016900:Neurofilament Proteins; D026902:Potassium Channel Blockers; D012333:RNA, Messenger; D020108:Nicorandil; D020110:Pinacidil; D014446:Tyrosine 3-Monooxygenase; D017035:Pravastatin; D005905:Glyburide; D009638:Norepinephrine