Exercise preserves endothelium-dependent relaxation in coronary arteries of hypercholesterolemic male pigs

Abstract

We tested the hypothesis that exercise training (Ex) attenuates hypercholesterolemia-induced impairment of endothelium-dependent relaxation (EDR) in male porcine coronary arteries [left anterior descending coronary arteries (LAD)] by increasing nitric oxide (NO) release [due to increased endothelial NO synthase (NOS) expression] and/or increased bioactivity of NO. Adult male pigs were fed a normal-fat (NF) or high-fat (HF) diet for 20-24 wk. Pigs were Ex or remained sedentary (Sed) for 16-20 wk, beginning after 4 wk on diet. Four groups of pigs were used: NF-Sed, NF-Ex, HF-Sed, and HF-Ex. HF enhanced LAD contractions induced by KCl, aggregating platelets (AP), and serotonin (5-HT). AP and 5-HT produced EDR after blockade of cyclooxygenase with indomethacin (Indo) and smooth-muscle 5-HT(2) receptors with ketanserin. HF impaired EDR induced by AP, 5-HT, and bradykinin. Results indicate a decreased contribution of NO to EDR in HF-Sed LADs, because the percentage of bradykinin-induced EDR inhibited by N(G)-nitro-L-arginine methyl ester was 27% in NF-Sed and 34% in NF-Ex but only 17% in HF-Sed. Also, N(G)-nitro-L-arginine methyl ester + Indo results indicate that release of an Indo-sensitive vasoconstrictor contributes to blunted EDR in HF-Sed LAD. Immunoblot and immunohistochemistry results indicate the following: 1) LAD endothelial NOS protein content was similar among groups; 2) HF decreased LAD superoxide dismutase (SOD) but increased caveolin-1 content; and 3) Ex increased SOD content of HF LADs. We conclude that HF impairs EDR by impairing the contribution of NO released from NOS (due to decreased SOD and increased caveolin-1 protein content) and by production of an Indo-sensitive vasoconstrictor. Ex preserves EDR in HF LADs by decreasing the production of the constrictor and increasing NO-release by NOS and/or NO bioactivity and bioavailability.

Perivascular Fat Alters Reactivity of Coronary Artery

“…Four weeks after the initiation of either the NF or HF diets, pigs were either exercise trained (EX) or remained sedentary (SED) for 16 wk. Exercised pigs performed endurance running at approximately 75% of max capacity on a motorized treadmill, as reported previously (7)(8)(9)(10)16). Sedentary pigs were restricted to their 2 × 4-m pens.…”

“…This design yielded four experimental groups: NF, sedentary (NF-SED) (N = 9); NF, exercise (NF-EX) (N = 5); HF, sedentary (HF-SED) (N = 5); and HF, exercise (HF-EX) (N = 5). Before and at the conclusion of training/ cage confinement programs, both EX and SED pigs performed a graded-intensity treadmill exercise test to exhaustion (7)(8)(9)(10)16). The efficacy of the training protocol was evaluated from measurements of endurance time (from the treadmill exercise test) and heart weight/body weight ratio, and oxidative capacity of skeletal muscle tissue was estimated from measures of citrate synthase activity, as reported previously (9,13,16).…”

“…Before and at the conclusion of training/ cage confinement programs, both EX and SED pigs performed a graded-intensity treadmill exercise test to exhaustion (7)(8)(9)(10)16). The efficacy of the training protocol was evaluated from measurements of endurance time (from the treadmill exercise test) and heart weight/body weight ratio, and oxidative capacity of skeletal muscle tissue was estimated from measures of citrate synthase activity, as reported previously (9,13,16). The treadmill performance test consists of four stages of exercise: stage 1, pigs run 3.1 mph for 5 min on a 0% grade; stage 2, grade is increased to 10% and pigs run for 10 min at 3.1 mph; stage 3, grade remains at 10% but pigs increase speed to 4.3 mph for 10 min; and stage 4, pigs run on a 10% grade at 6 mph until exhaustion is reached.…”

“…Second, we hypothesized that coronary arteries with perivascular adipose tissue isolated from pigs on a high-fat diet would exhibit greater vasoconstrictor responses and/or blunted vasodilator responses because of a decreased anticontractile effect of perivascular adipose tissue (5,6,12). Third, given our interest in the ability of physical activity/exercise training to have beneficial effects on coronary vasomotor function in health and disease (16), we hypothesized that sustained physical activity through treadmill exercise training for 5 d·wk −1 for 16 wk would increase the anticontractile effect of coronary perivascular adipose tissue in both normal-diet and high-fat-diet-fed pigs. The results reveal that porcine coronary perivascular adipose tissue blunts vasocontraction-stimulated by endothelin-1, but not contraction stimulated by acetylcholine, and that arteries from pigs on the high-fat diet did not exhibit greater vasoconstrictor responses and/or blunted vasodilator responses associated with the presence of perivascular adipose tissue.…”

Effects of exercise training on cellular mechanisms of endothelial nitric oxide synthase regulation in coronary arteries after chronic occlusion

“…Furthermore, in a porcine model of chronic coronary occlusion, endothelium-dependent relaxation to bradykinin and ADP was enhanced following exercise training (10). These improvements in endothelial function have been associated with improvements in nitric oxide bioavailability following exercise training (10,11,13,40). However, cellular and molecular mechanisms responsible for improvements in nitric oxide bioavailability in coronary artery disease subsequent to exercise training have not been fully elucidated.…”