Role of basal nitric oxide synthesis in vasoconstrictor hyporeactivity in the perfused rat hindlimb after myocardial infarction: effect of captopril.
OBJECTIVE
The contribution of vascular changes to the development of heart failure is largely unknown. In the present study, we evaluated endothelial and vascular contractile function in the rat hindlimb vascular bed after myocardial infarction (MI), including the modulatory role of basal nitric oxide (NO) production and the effects of treatment with the angiotensin converting enzyme inhibitor captopril on vascular function.


METHODS
MI was induced in male Wistar rats by ligation of the left coronary artery. Acetylcholine-induced dilatations were assessed in the ex vivo perfused hindlimb at various time points. At 2 and 5 weeks post-MI, vascular contractile function in the perfused hindlimb was assessed from resistance changes induced by 35 mM and 125 mM potassium (K+) and the maximum increase in resistance (delta Rmax, 125 mM K+ and 3 mg phenylephrine). Basal NO synthesis was blocked for 2 weeks with L-nitro-arginine methylester (L-NAME) in sham and MI rats and similar contractility experiments were performed. The effect of captopril treatment from 2 to 5 weeks post-MI on vasoconstrictor responses was also tested.


RESULTS
Acetylcholine-induced dilatations in the presence of 10 microM indomethacin were not different between sham and MI rats. Vasoconstrictor responses to K+ and delta Rmax were reduced at 2 weeks after MI. This reduction in vasoconstrictor ability was similar to that seen in L-NAME-treated sham rats, while chronic L-NAME treatment did not affect vasoconstrictor reactivity in MI rats. Similarly, L-NAME induced an increase in mean arterial pressure in sham rats, but not in MI rats. At 5 weeks after MI, vasoconstriction to 125 mM K+ and delta Rmax were still reduced in MI rats; this response was however partially restored after captopril treatment.


CONCLUSIONS
The development of vascular contractile hyporeactivity in the rat hindlimb after MI may be due to reduced basal NO production. Delayed treatment with captopril improves peripheral vascular contractile function in this setting.
Ceiler
D L
DL
Department of Pharmacology, Cardiovascular Research Institute Maastricht, Universiteit Maastricht, The Netherlands. D.Ceiler@Farmaco.Unimaas.nl
Nelissen-Vrancken
M
M
De Mey
J G
JG
Smits
J F
JF
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002216:Captopril / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology*; D006614:Hindlimb; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D009569:Nitric Oxide; D002216:Captopril; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester