F. Padilla et al., Intravenous administration of the natriuretic peptide urodilatin at low doses during coronary reperfusion limits infarct size in anesthetized pigs, CARDIO RES, 51(3), 2001, pp. 592-600
Citations number
42
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Objective: It has been shown that cGMP content is reduced in post-ischemic
myocardium, and that stimulation of cGMP synthesis prevents cardiomyocyte h
ypercontracture and cell death in vitro. This study was aimed at determinin
g whether administration of the natriuretic peptide urodilatin (URO) at the
time of reperfusion could limit myocardial cell death secondary to transie
nt coronary occlusion. Methods: The relation between cGMP content in reperf
used myocardium and the extent of cell death was investigated in isolated r
at hearts (n=62) receiving different URO concentrations during initial repe
rfusion. The dose of intravenous URO necessary to obtain the targeted incre
ase in cGMP in reperfused myocardium was investigated in ten pigs submitted
to transient coronary occlusion (CO), and the effect of two selected doses
of URO on infarct size was investigated in 22 pigs. Results: cGMP was seve
rely reduced in post-ischemic rat hearts. Addition of 0.01 muM URO during t
he first 15 min of reperfusion had no effect on myocardial cGMP content, fu
nctional recovery or LDH release in hearts submitted to 40 or 60 min of isc
hemia. At 0.05 muM, URO increased myocardial cGMP to 111% of values in norm
oxic hearts, improved functional recovery (P=0.01) and reduced peak LDH rel
eased by 40% (P=0.02). The beneficial effect of urodilatin was abolished by
ANP receptor inhibition. At 1 muM URO increased cGMP in reperfused myocard
ium to 363% of normoxic controls and had no beneficial effect. In pigs allo
cated to 47 min of CO and 5 min of reperfusion, cGMP was markedly reduced i
n reperfused myocardium. Intravenous URO at 10 ng/kg per min during the fir
st 25 min of reperfusion normalized myocardial cGMP after 5 min of reflow (
95% of control myocardium), and reduced infarct size by 40% (P=0.04). At 50
ng/ka per min, urodilatin increased myocardial cGMP in reperfused myocardi
um to 335% of control myocardium and failed to significantly reduce infarct
size (46 vs. 66%, P=0.125). None of these doses had detectable hemodynamic
effects. Conclusions: Intravenous low-dose URO at the time of reperfusion
normalizes myocardial cGMP and limits necrosis. Large doses of URO increasi
ng myocardial cGMP well over normal values may lack this beneficial effect.
(C) 2001 Elsevier Science B.V. All rights reserved.