AM Prasan*, HCK McCarron, Y Zhang and RW Jeremy

Department of Medicine, University of Sydney, Sydney

Background: Nitric oxide (NO) may affect myocardial ischemia/reperfusion (I/R) injury, but effects of hypercholesterolemia on myocardial NO release during I/R are unknown.

Methods: Isovolumic rabbit hearts, perfused at 37^oC with Krebs-Henseleit solution were assigned to control (n=9), L-arginine (200mM) added (n=7), L-NAME (8mM) added (n=7), or cholesterol-fed (0.5% for 16 weeks) (n=7) groups.   A NO specific quartz electrode (30mM) placed in the coronary sinus continuously measured [NO] by differential amperometry.   Hearts had 20 mins control perfusion before 60 mins low flow (1ml/min) ischemia and 60 mins reperfusion.

Results: Control hearts had an early increase in cumulative NO release (5.6 ± 1.1 nmol, 0-15 min ischemia) which then gradually decreased (3.5 ± 0.4 nmol, 45-60 mins ischemia, p< 0.05). L-arginine hearts had a similar pattern of NO release. Treatment with L-NAME reduced early NO release (1.1 ± 1.1 nmol, p<0.05 v controls) but did not change late NO release (3.4 ± 0.5 nmol, NS v controls). Cholesterol hearts had markedly attenuated NO release (1.1 ± 0.4 nmol at 0-15 mins, p<0.01 v control, 0.8 ± 0.3 nmol at 45-60 mins, p<0.05 v control). [NO] decreased below baseline during reperfusion and did not differ between groups.   Rate pressure product (% pre-ischemia) at 60 mins reperfusion in L-arginine (66 ± 7%, p<0.01 v control) and L-NAME (54 ± 7%, p<0.05 v control) hearts was higher than in controls (33 ± 6%) but the cholesterol hearts did not differ from control (35 ± 10%).

Conclusions: Myocardial NO release during I/R includes both early cNOS-dependent and later enzyme-independent components.   Hypercholesterolemia is associated with absence of the early component and reduction of later enzyme-independent NO release.

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