Divergent Biological Actions of Coronary Endothelial Nitric Oxide During Progression of Cardiac Hypertrophy

Abstract

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 mol/L), substance P (0.01 to 100 mol/L), diethylamine NONOate (DEA-NO) (0.1 to 1000 mol/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 (13.8Ϯ2.1% versus 6.2Ϯ1.3%, nϭ10; PϽ0.05), 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, 7.8Ϯ0.4 densitometric units; sham-operated animals, 12.2Ϯ1.7 densitometric units; nϭ5; PϽ0.05). At this time point, vasoconstriction in response to L-NMMA was similar in the 2 groups, but vasodilatation in response to bradykinin (30.9Ϯ2.4% versus 39.7Ϯ2.2%, nϭ10; PϽ0.05), DEA-NO (26.2Ϯ1.8% versus 34.6Ϯ1.8%, nϭ10; PϽ0.05), and adenosine (24.3Ϯ2.0% versus 35.7Ϯ2.0%, nϭ10; PϽ0.01) 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. Key Words: hypertrophy Ⅲ pressure overload Ⅲ nitric oxide Ⅲ arteries Ⅲ endothelium Ⅲ nitric oxide synthase I t is well established that the endothelium regulates coronary vascular tone via the controlled release of vasoactive agents. 1 NO appears to be the major endothelium-derived relaxing factor (EDRF) and is synthesized continuously under basal conditions by endothelial NO synthase (eNOS). Its production may be increased by agonists such as bradykinin and acetylcholine or by physiological stimuli such as shear stress. 1 Changes in the release and bioactivity of NO occur in many cardiovascular diseases and are thought to contribute to the associated vascular dysfunction. 1 There is much controversy as to whether coronary eNOS expression and the biological activity of NO are increased or decreased in left ventricular (LV) hypertrophy (LVH). Both impaired and enhanced NO-dependent coronary artery vasodilation has been found in LVH and heart failure, experimentally and clinically. [2][3][4][5][6][7] Likewise, other groups have reported increased, 8,9 d...

Activation of NADPH Oxidase During Progression of Cardiac Hypertrophy to Failure

“…As reported previously, 13 LV/body weight ratio was significantly higher by 3 weeks after surgery in the banded group compared with the sham group. Lung/body weight ratio was increased in the banded group by 10 weeks after surgery ( Figure 1A and 1B).…”

“…Male Dunkin-Hartley guinea pigs (200 to 250 g; Harlan UK Ltd, Bicestor, UK) underwent suprarenal abdominal aortic banding or sham banding. 13 Aortic banding in guinea pigs is a well-established model of pressure-overload LVH that has been preferred over small rodent models in several studies because guinea pig LV more closely resembles human myocardium with respect to myosin heavy-chain isoform expression and electrophysiological characteristics. In this model, compensated LVH is present from 2 weeks after surgery followed by a transition phase from 4 to 6 weeks and then overt LV decompensation at 8 to 10 weeks.…”

“…In this model, compensated LVH is present from 2 weeks after surgery followed by a transition phase from 4 to 6 weeks and then overt LV decompensation at 8 to 10 weeks. 13 Animals from the banded and sham groups were euthanized at 1, 3, 6, and 10 weeks postoperatively for harvesting of heart tissue. LV and right ventricular weights, lung weight, and body weight were determined, and tissue for immunoblotting, immunohistochemistry, or biochemistry was snapfrozen in liquid N 2 and stored at Ϫ70°C until study.…”

Simvastatin Prevents Load-Induced Protein Tyrosine Nitration in Overloaded Hearts

“…3,4 Although reactive oxygen species might be generated by diverse cellular mechanisms, abnormal activation and expression of myocardial NAD(P)H-oxidase have been suggested to be the main source of reactive oxygen species in the hypertrophic and failing myocardium. 3,5,6 Experimental data are accumulating, suggesting that the combination of superoxide (O 2 Ϫ ) and nitric oxide (NO), releasing peroxynitrite, may also contribute to the pathogenesis of myocardial dysfunction and damage triggered by a variety of stress, including ischemia, cytokines, and sepsis. 7 These detrimental effects are thought to be consequent of larger tissue concentrations of NO or O 2 Ϫ .…”

LA419, a Novel Nitric Oxide Donor, Prevents Pathological Cardiac Remodeling in Pressure-Overloaded Rats Via Endothelial Nitric Oxide Synthase Pathway Regulation

“…16 In this sense, previous studies have reported a selective decrease of eNOS cardiac protein in different models of cardiac hypertrophy. 17,18 The recent generation of transgenic mice models with a lack or an overexpression of eNOS protein has also demonstrated the importance of this enzyme in the process of cardiac remodeling. 19,20 More recently, Wenzel et al 21 have demonstrated that inhibition of eNOS-derived NO induces hypertrophy development in adult ventricular cardiomyocytes.…”