Divergent biological actions of coronary endothelial nitric oxide during progression of cardiac hypertrophy

Coronary endothelial NO synthase expression and NO bioactivity were investi gated at sequential stages during the progression of left ventricular hyper trophy. Male guinea pigs underwent abdominal aortic banding or sham operati on. Left ventricular contractile function was quantified in isolated ejecti ng hearts. Coronary endothelial and vasodilator function were assessed in i solated isovolumic hearts in response to boluses of bradykinin (0.001 to 10 mu mol/L), substance P (0.01 to 100 mu mol/L), diethylamine NONOate (DEA-N O) (0.1 to 1000/mu mol/L), N-G-monomethyl-L-arginine monoacetate (L-NMMA) ( 10 mmol/L), and adenosine (10 mmol/L). At a stage of compensated left ventr icular hypertrophy (3 weeks), left ventricular endothelial NO synthase prot ein expression was unaltered (Western blot and immunocytochemistry). Vasoco nstriction in response to L-NMMA was increased in banded animals compared w ith sham-operated animals (13.8 +/-2.1% versus 6.2 +/-1.3%, n=10; P<0.05), but agonist- and DEA-NO-induced vasodilation was similar in the 2 groups. A t a stage of decompensated left ventricular hypertrophy (8 to 10 weeks), le ft ventricular endothelial NO synthase protein expression was significantly lower in banded animals (on Western analysis: banded animals, 7.8<plus/min us>0.4 densitometric units; sham-operated animals, 12.2 +/-1.7 densitometri c units; n=5; P<0.05). At this time point, vasoconstriction in response to L-NMMA was similar in the 2 groups, but vasodilatation in response to brady kinin (30.9<plus/minus>2.4% versus 39.7 +/-2.2%, n=10; P<0.05), DEA-NO (26. 2<plus/minus>1.8% versus 34.6 +/-1.8%, n=10; P<0.05), and adenosine (24.3<p lus/minus>2.0% versus 35.7 +/-2.0%, n=10; P<0.01) was attenuated in banded animals. These findings indicate that there is an increase in the basal act ivity of NO (without a significant change in endothelial NO synthase expres sion) in early compensated left ventricular hypertrophy, followed by a decr ease in both endothelial NO synthase expression and NO bioactivity during t he transition to myocardial failure.