ABSTRACT
Coronary endothelial NO synthase expression and NO bioactivity were investigated at sequential stages during the progression of left ventricular hypertrophy. Male guinea pigs underwent abdominal aortic banding or sham operation. Left ventricular contractile function was quantified in isolated ejecting hearts. Coronary endothelial and vasodilator function were assessed in isolated isovolumic hearts in response to boluses of bradykinin (0.001 to 10 micromol/L), substance P (0.01 to 100 micromol/L), diethylamine NONOate (DEA-NO) (0.1 to 1000 micromol/L), N(G)-monomethyl-L-arginine monoacetate (L-NMMA) (10 mmol/L), and adenosine (10 mmol/L). At a stage of compensated left ventricular hypertrophy (3 weeks), left ventricular endothelial NO synthase protein expression was unaltered (Western blot and immunocytochemistry). Vasoconstriction in response to L-NMMA was increased in banded animals compared with 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. At a stage of decompensated left ventricular hypertrophy (8 to 10 weeks), left ventricular endothelial NO synthase protein expression was significantly lower in banded animals (on Western analysis: banded animals, 7.8+/-0.4 densitometric units; sham-operated animals, 12.2+/-1.7 densitometric 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 bradykinin (30.9+/-2.4% versus 39.7+/-2.2%, n=10; P<0.05), DEA-NO (26.2+/-1.8% versus 34.6+/-1.8%, n=10; P<0.05), and adenosine (24.3+/-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 activity of NO (without a significant change in endothelial NO synthase expression) in early compensated left ventricular hypertrophy, followed by a decrease in both endothelial NO synthase expression and NO bioactivity during the transition to myocardial failure.
Subject(s)
Endothelium, Vascular/metabolism , Hypertrophy, Left Ventricular/metabolism , Nitric Oxide/physiology , Animals , Disease Progression , Enzyme Inhibitors/pharmacology , Guinea Pigs , Heart/drug effects , Heart/physiopathology , Hypertrophy, Left Ventricular/pathology , Hypertrophy, Left Ventricular/physiopathology , Male , Myocardial Contraction , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type III , Organ Culture Techniques , Organ Size , Vasoconstriction/drug effects , Vasodilation/drug effects , Vasodilator Agents/pharmacology , Ventricular Pressure , omega-N-Methylarginine/pharmacologyABSTRACT
Immunohistochemistry of human atherosclerotic arteries demonstrates expression of the intercellular adhesion molecule-1 (ICAM-1) on endothelial cells, macrophages, and smooth muscle cells of the plaques. Normal arterial endothelial cells and intimal smooth muscle outside plaques give weaker or negative reactions; these differ from the strong endothelial expression in small vessels. Quantitative color-image analysis of the endothelial layer shows increased expression of ICAM-1 in all subtypes of atherosclerotic lesions, except fibrous plaques. Endothelial expression of ICAM-1 may be involved in the recruitment of monocytes to the lesion, as suggested by its role in the entry of leukocytes, including monocytes, into foci of inflammation. Collaboration with other mechanisms, particularly chemoattractant factors, may be important for this effect. ICAM-1 enhanced monocyte recruitment is a potential mechanism for the growth of an atherosclerotic plaque.
