Natriuretic peptides as therapy in cardiac ischaemia/reperfusion.
Natriuretic peptides elicit vasodilation, increased sodium excretion and concomitant diuresis, and counteract the RAAS. In the heart itself, natriuretic peptides may also act anti-inflammatory and antifibrotic. This has led to the pursuit of natriuretic peptides and chemically modified peptides as adjunctive therapy in myocardial ischaemia. However, natriuretic peptide infusion may also influence the endogenous natriuretic peptide response and lipid accumulation. We hypothesised that a) natriuretic peptide infusion (BNP and CD-NP) is cardiomyocyte protective, b) affects the endogenous response, and c) facilitate cardiac lipid accumulation. We examined these effects in a minimally invasive porcine model of regional cardiac ischaemia and reperfusion. The studies were supplemented by a 48-hour porcine model of ischemia and reperfusion as well as an in vitro study of BNP administered in a HL-1 cell model of "ischaemia/reperfusion". Infarct size was determined by TTC staining, plasma troponin T release, and total RNA integrity in cardiac tissue samples. The endogenous response was assessed by a processing-independent proANP immunoassay and mRNA quantitation. Lipids in plasma and myocardial tissue were determined by TLC. The studies show that natriuretic peptides decrease cardiomyocyte damage, possibly partly through indirect mechanisms. Furthermore, BNP infusion completely inverts the endogenous response, whereas CD-NP infusion does not. Finally, both natriuretic peptides increase plasma free fatty acids, which is associated with an increased cardiac lipid accumulation in non-ischaemic myocardium. In conclusion, the studies suggest that natriuretic peptides are beneficial in terms of reduced cardiac injury. In addition, the endogenous natriuretic peptide response is inverted. The results advocate for pursuing natriuretic peptide treatment in ischaemia/reperfusion damage. However, the metabolic consequences in a cardiac tissue challenged by ischaemia should be pursued before testing the peptides in patients.
Department of Cardiothoracic and Vascular Surgery, T-research, Aarhus University Hospital, Brendstrupgaardvej 100, 8200 Aarhus N, Denmark. birgitte.kousholt@ki.au.dk
Birgitte Saima
BS
Kousholt
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D020170:Caspase 1 / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D006152:Cyclic GMP / Q000378:metabolism; D004231:Diuresis / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005990:Glycerol / Q000097:blood; D051379:Mice; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000097:blood / Q000188:drug therapy*; D032383:Myocytes, Cardiac / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology / Q000627:therapeutic use*; D020098:Natriuretic Peptide, C-Type / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D045265:Natriuretic Peptides / Q000096:biosynthesis / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000097:blood / Q000517:prevention & control*; D013552:Swine; D014280:Triglycerides / Q000097:blood; D020107:Troponin T / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; D045265:Natriuretic Peptides; D012333:RNA, Messenger; D014280:Triglycerides; D020107:Troponin T; D042461:Vascular Endothelial Growth Factor A; D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type; D002784:Cholesterol; D020170:Caspase 1; D006152:Cyclic GMP; D005990:Glycerol