Exercise attenuates the effects of hypercholesterolemia on endothelium-dependent relaxation in coronary arteries from adult female pigs.

We tested the hypothesis that exercise training (Ex) attenuates the effects of hypercholesterolemia on endothelium-dependent relaxation in left anterior descending coronary arteries. Adult female pigs were fed a normal-fat (NF) or high-fat (HF) diet for 20 wk. Four weeks after the diet was initiated, pigs were trained or remained sedentary (Sed) for 16 wk, yielding four groups of pigs: 1) NF-Sed, 2) NF-Ex, 3) HF-Sed, and 4) HF-Ex. Sensitivity (EC(50)) to bradykinin (BK) was impaired in HF-Sed arteries. Ex improved BK-induced relaxation such that the EC(50) and maximal response to BK in HF-Ex arteries was not different from that in NF-Sed and NF-Ex. ACh-induced constriction was less in HF-Ex arteries than in HF-Sed, NF-Sed, and NF-Ex. To determine the mechanism(s) by which HF and Ex affected responses to BK and ACh, vasoactive responses were assessed in the presence of N(G)-nitro-L-arginine methyl ester [L-NAME; to inhibit nitric oxide (NO) synthase], indomethacin (Indo; to inhibit cyclooxygenase), and L-NAME + Indo. L-NAME inhibited BK-induced relaxation in NF (not HF) arteries. Indo did not significantly alter relaxation to BK in NF arteries; however, relaxation was enhanced in HF-Sed arteries. Double blockade with L-NAME + Indo attenuated BK-induced relaxation in NF arteries and eliminated relaxation in HF arteries. Neither L-NAME nor Indo altered constrictor responses to ACh in NF or HF arteries; however, double blockade with L-NAME + Indo attenuated constriction to ACh in NF-Ex arteries. Endothelium-independent relaxation to sodium nitroprusside was enhanced in HF-Sed and HF-Ex arteries. Collectively, these results indicate that HF impaired endothelial function in coronary arteries by impairing production of NO and by enhancing production of a constrictor that was inhibited by Indo. Ex attenuated the effects of hypercholesterolemia by improving NO-mediated, endothelium-dependent relaxation and by reducing the influence of the Indo-sensitive constrictor.     

Exercise training preserves endothelium-dependent relaxation in brachial arteries from hyperlipidemic pigs.

We tested the hypothesis that exercise training (Ex) attenuates the effects of hyperlipidemia on endothelial function by enhancing NO-mediated vasorelaxation in porcine brachial (Br) arteries. Adult female pigs were fed a normal-fat (NF) or high-fat (HF) diet for 20 wk. Four weeks after initiation of the diet, pigs underwent Ex or remained sedentary (Sed) for 16 wk. Relaxation to ACh was impaired by HF (P = 0.03). The combination of HF and Sed impaired ACh-induced relaxation more than HF or Sed alone (P = 0.0002). Relaxation to high doses of bradykinin (BK) was impaired by HF (P = 0.0002). Ex significantly improved ACh-induced relaxation (P = 0.01) and tended to improve relaxation to BK (P = 0.38). To determine the mechanism(s) by which HF and Ex affected relaxation to ACh and BK, relaxation was assessed in the presence of N(G)-nitro-l-arginine methyl ester (l-NAME; to inhibit NO synthase), indomethacin (Indo; to inhibit cyclooxygenase), or l-NAME + Indo. In the presence of l-NAME, Indo, or l-NAME + Indo, ACh-induced relaxation was no longer different between HF and NF arteries; however, relaxation remained greater in Ex than in Sed arteries. In the presence of l-NAME or Indo, BK-induced relaxation was no longer altered by HF but was enhanced by Ex. In the presence of l-NAME + Indo, BK-induced relaxation was enhanced by HF and Ex. These data indicate that hyperlipidemia impairs ACh- and BK-induced relaxation by impairing NO- and PGI(2)-mediated relaxation. Ex attenuates the effects of HF by enhancing a vasodilator mechanism independent of NO and PGI(2).     

Exercise training improves femoral artery blood flow responses to endothelium-dependent dilators in hypercholesterolemic pigs

We tested two hypotheses: 1) that the effects of hypercholesterolemia on endothelial function in femoral arteries exceed those reported in brachial arteries and 2) that exercise (Ex) training enhances endothelium-dependent dilation and improves femoral artery blood flow (FABF) in hypercholesterolemic pigs. Adult male pigs were fed a normal fat (NF) or high-fat/cholesterol (HF) diet for 20 wk. Four weeks after the diet was initiated, pigs were Ex trained or remained sedentary (Sed) for 16 wk, thus yielding four groups: NF-Sed, NF-Ex, HF-Sed, and HF-Ex. Endothelium-dependent vasodilator responses were assessed in vivo by measuring changes in FABF after intra-arterial injections of ADP and bradykinin (BK). Endothelium-dependent and -independent relaxation was assessed in vitro by measuring relaxation responses to BK and sodium nitroprusside (SNP). FABF increased in response to ADP and BK in all groups. FABF responses to ADP and BK were not impaired by HF but were improved by Ex in HF pigs. BK- and SNP-induced relaxation of femoral artery rings was not altered by HF or Ex. To determine whether the mechanism(s) for vasorelaxation of femoral arteries was altered by HF or Ex, BK-induced relaxation was assessed in vitro in the absence or presence of N(G)-nitro-l-arginine methyl ester [l-NAME; to inhibit nitric oxide synthase (NOS)], indomethacin (Indo; to inhibit cyclooxygenase), or l-NAME + Indo. BK-induced relaxation was inhibited by l-NAME and l-NAME + Indo in all groups of femoral arteries. Ex increased the NOS-dependent component of endothelium-dependent relaxation in NF (not HF) arteries. Indo did not inhibit BK-induced relaxation. Collectively, these results indicate that hypercholesterolemia does not alter endothelial function in femoral arteries and that Ex training improves FABF responses to ADP and BK; however, the improvement cannot be attributed to enhanced endothelial function in HF femoral arteries. These data suggest that Ex-induced improvements in FABF in HF arteries are mediated by vascular adaptations in arteries/arterioles downstream from the femoral artery.     

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

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.     

Short-term training enhances endothelium-dependent dilation of coronary arteries, not arterioles.

Our objective was to test the hypothesis that short-term exercise training (STR) of pigs increases endothelium-dependent dilation (EDD) of coronary arteries but not coronary arterioles. Female Yucatan miniature swine ran on a treadmill for 1 h, at 3.5 mph, twice daily for 7 days (STR; n = 28). Skeletal muscle citrate synthase activity was increased in STR compared with sedentary controls (Sed; n = 26). Vasoreactivity was evaluated in isolated segments of conduit arteries (1-2 mm ID, 3-4 mm length) mounted on myographs and in arterioles (50-100 microm ID) isolated and cannulated with micropipettes with intraluminal pressure set at 60 cmH(2)O. EDD was assessed by examining responses to increasing concentrations of bradykinin (BK) (conduit arteries 10(-12)-10(-6) M and arterioles 10(-13)-10(-6) M). There were no differences in maximal EDD or BK sensitivity of coronary arterioles from Sed and STR hearts. In contrast, sensitivity of conduit arteries (precontracted with PGF(2alpha)) to BK was increased significantly (P < 0.05) in STR (EC(50), 2.33 +/- 0.62 nM, n = 12) compared with Sed animals (EC(50), 3.88 +/- 0.62 nM, n = 13). Immunoblot analysis revealed that coronary arteries from STR and Sed animals had similar levels of endothelial nitric oxide synthase (eNOS). In contrast, eNOS protein was increased in STR aortic endothelial cells. Neither protein nor mRNA levels of eNOS were different in coronary arterioles from STR compared with Sed animals. STR did not alter expression of superoxide dismutase (SOD-1) protein in any artery examined. We conclude that pigs exhibit increases in EDD of conduit arteries, but not in coronary arterioles, at the onset of exercise training. These adaptations in pigs do not appear to be mediated by alterations in eNOS or SOD-1 expression.     

Effects of exercise training and hypercholesterolemia on adenosine activation of voltage-dependent K+ channels in coronary arterioles

Coronary arterioles from hypercholesterolemic swine display attenuated adenosine-mediated vasodilatation that is attributable to the elimination of voltage-dependent K(+) (Kv) channel stimulation. For the present study, we tested the hypotheses that exercise training would correct impaired adenosine-induced dilatation in coronary arterioles from hypercholesterolemic pigs through restoration of adenosine activation of Kv channels and that vasodilatation to the receptor-independent adenylyl cyclase activator, forskolin, would also be attenuated in arterioles from hypercholesterolemic pigs. Pigs were randomly assigned to a control (NC) or high-fat, high-cholesterol (HC) diet for 20 wk. Four weeks after the diet was initiated, pigs from both groups were assigned to exercise training (Ex; 5 days/wk for 16 wk) or sedentary (Sed) protocols, resulting in four groups of pigs: NC-Sed, NC-Ex, HC-Sed, and HC-Ex. Arterioles ( approximately 150 mum) from both HC-Sed and HC-Ex pigs displayed impaired adenosine-mediated dilatation that was attributable to the elimination of 4-aminopyridine (4-AP; 1 mM)-sensitive Kv channel activation compared with NC counterparts. Arteriolar smooth muscle whole cell Kv currents were significantly reduced in HC-Sed compared with NC-Sed, although HC-Ex and NC-Ex did not differ. Forskolin-mediated dilatation was attenuated by 4-AP (1 mM) and in a concentration-dependent manner by tetraethylammonium (TEA; 0.1-1 mM) in NC-Sed but not HC-Sed. Further, TEA-sensitive Kv currents were diminished in cells of HC-Sed compared with NC-Sed pigs. Quantitative RT-PCR revealed similar expression levels of Kv3.1 and 3.3 in arterioles of NC-Sed and HC-Sed swine with undetectable expression of Kv1.1, 3.2, and 3.4. Taken together, these results suggest that hypercholesterolemia-mediated attenuation of adenosine-induced vasodilatation in coronary arterioles is not corrected by exercise training and is likely attributable to an impairment in the pathway coupling adenylyl cyclase with a highly TEA-sensitive Kv channel isoform(s).     

Chronic exercise training improves ACh-induced vasorelaxation in pulmonary arteries of pigs.

We hypothesized that exercise training would lead to enhanced endothelium-dependent vasodilation in porcine pulmonary arteries. Pulmonary artery rings (2- to 3-mm OD) were obtained from female Yucatan miniature swine with surgically induced coronary artery occlusion (ameroid occluder). Exercise training was performed for 16 wk, and vasomotor responses were studied by using standard isometric techniques. Contractile responses to 80 mM KCl, isosmotic KCl (10-100 mM), and norepinephrine (10(-8) to 10(-4) M) did not differ between sedentary (Sed) and exercise-trained (Ex) pigs. Relaxation was assessed to endothelium-dependent and endothelium-independent vasodilators after norepinephrine contraction. Pulmonary arteries of Ex pigs exhibited greater maximal relaxation to ACh (61.9 +/- 3.5%) than did those of Sed pigs (52.3 +/- 3.9%; P < 0.05). Endothelium-independent relaxation to sodium nitroprusside did not differ. Inhibition of nitric oxide synthase significantly decreased acetylcholine-induced relaxation, with greater inhibition in arteries from Ex pigs (P < 0.05). Inhibition of cyclooxygenase enhanced relaxation to acetylcholine in arteries from Sed pigs. We conclude that exercise training enhances endothelium-dependent (ACh-mediated) vasorelaxation in pulmonary arteries by mechanisms of increased reliance on nitric oxide and reduced production of a prostanoid constrictor.     

Effect of exercise training on nitric oxide and superoxide/H₂O₂ signaling pathways in collateral-dependent porcine coronary arterioles

Endothelial nitric oxide (NO) synthase (NOS) has been shown to contribute to enhanced vascular function after exercise training. Recent studies have revealed that relatively low concentrations of reactive oxygen species can contribute to endothelium-dependent vasodilation under physiological conditions. We tested the hypothesis that exercise training enhances endothelial function via endothelium-derived vasodilators, NO and superoxide/H(2)O(2), in the underlying setting of chronic coronary artery occlusion. An ameroid constrictor was placed around the proximal left circumflex coronary artery to induce gradual occlusion in Yucatan miniature swine. At 8 wk postoperatively, pigs were randomly assigned to sedentary (pen-confined) or exercise-training (treadmill-run: 5 days/wk for 14 wk) regimens. Exercise training significantly enhanced concentration-dependent, bradykinin-mediated dilation in cannulated collateral-dependent arterioles (～130 μm diameter) compared with sedentary pigs. NOS inhibition reversed training-enhanced dilation at low bradykinin concentrations in collateral-dependent arterioles, although increased dilation persisted at higher bradykinin concentrations. Total and phosphorylated (Ser(1179)) endothelial NOS protein levels were significantly increased in arterioles from collateral-dependent compared with the nonoccluded region, independent of exercise. The H(2)O(2) scavenger polyethylene glycol-catalase abolished the training-enhanced bradykinin-mediated dilation in collateral-dependent arterioles; similar results were observed with the SOD inhibitor diethyldithiocarbamate. Fluorescence measures of bradykinin-stimulated H(2)O(2) levels were significantly increased by exercise training, independent of occlusion. The NADPH inhibitor apocynin significantly attenuated bradykinin-mediated dilation in arterioles of exercise-trained, but not sedentary, pigs and was associated with significantly increased protein levels of the NADPH subunit p67phox. These data provide evidence that, in addition to NO, the superoxide/H(2)O(2) signaling pathway significantly contributes to exercise training-enhanced endothelium-mediated dilation in collateral-dependent coronary arterioles.     

Nonuniform effects of endurance exercise training on vasodilation in rat skeletal muscle.

Endurance exercise training (Ex) has been shown to increase maximal skeletal muscle blood flow. The purpose of this study was to test the hypothesis that increased endothelium-dependent vasodilation is associated with the Ex-induced increase in muscle blood flow. Furthermore, we hypothesized that enhanced endothelium-dependent dilation is confined to vessels in high-oxidative muscles that are recruited during Ex. To test these hypotheses, sedentary (Sed) and rats that underwent Ex (30 m/min x 10% grade, 60 min/day, 5 days/wk, 8-12 wk) were studied using three experimental approaches. Training effectiveness was evidenced by increased citrate synthase activity in soleus and vastus lateralis (red section) muscles (P < 0.05). Vasodilatory responses to the endothelium-dependent agent acetylcholine (ACh) in situ tended to be augmented by training in the red section of gastrocnemius muscle (RG; Sed: control, 0.69 +/- 0.12; ACh, 1.25 +/- 0.15; Ex: control, 0.86 +/- 0.17; ACh, 1.76 +/- 0.27 ml x min(-1) x 100 g(-1) x mmHg(-1); 0.05 < P < 0.10 for Ex vs. Sed during ACh). Responses to ACh in situ did not differ between Sed and Ex for either the soleus muscle or white section of gastrocnemius muscle (WG). Dilatory responses of second-order arterioles from the RG in vitro to flow (4-8 microl/min) and sodium nitroprusside (SNP; 10(-7) through 10(-4) M), but not ACh, were augmented in Ex (vs. Sed; P < 0.05). Dilatory responses to ACh, flow, and SNP of arterioles from soleus and WG muscles did not differ between Sed and Ex. Content of the endothelial isoform of nitric oxide synthase (eNOS) was increased in second-order, fourth-order, and fifth-order arterioles from the RG of Ex; eNOS content was similar between Sed and Ex in vessels from the soleus and WG muscles. These findings indicate that Ex induces endothelial adaptations in fast-twitch, oxidative, glycolytic skeletal muscle. These adaptations may contribute to enhanced skeletal muscle blood flow in endurance-trained individuals.     

Endothelin-1 sensitivity of porcine coronary arteries is reduced by exercise training and is gender dependent.

We tested the hypothesis that exercise training reduces the sensitivity of coronary smooth muscle to endothelin-1 (ET-1), with the adaptation being greater in male than in female miniature swine. The efficacy of training was similar in males and females. Cumulative ET-1 contractile responses of coronary branches and left circumflex artery were significantly shifted to the right in exercise-trained (Ex) males but not in Ex females. Analyses of the excitatory concentration causing a 50% response (EC(50)) showed a 1.7- to 2.2-fold shift in Ex males with no change in maximum tension. Nonselective blockade of K-channel activity with tetraethylammonium (TEA; 30-50 mM) significantly shifted the EC(50) to a lower concentration in both Ex males (1.25-fold) and Ex females (2.2-fold) but not in sedentary (Sed) groups. Females (combined Sed and Ex) exhibited a greater response to TEA than did combined Sed and Ex males. Changes in [(32)P]phosphatidic acid ([(32)P]PA) provided an indicator of ET-1-induced phospholipase activity. The magnitude of the [(32)P]PA response was reduced by Ex in both males and females without affecting the EC(50). It is concluded that the contractile sensitivity of coronary arteries to ET-1 is influenced by physical activity in a gender-dependent manner. It is unclear why the contractile sensitivity in females was not reduced by Ex as in the males, because Ex significantly affected responses to TEA and ET-1 stimulation of [(32)P]PA production in both males and females. A potential gender difference in K-channel function may contribute to this discrepancy.     

Exercise training improves aortic endothelium-dependent vasorelaxation and determinants of nitric oxide bioavailability in spontaneously hypertensive rats.

The present study examined in vitro vasomotor function and expression of enzymes controlling nitric oxide (NO) bioavailability in thoracic aorta of adult male normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) that either remained sedentary (Sed) or performed 6 wk of moderate aerobic exercise training (Ex). Training efficacy was confirmed by elevated maximal activities of both citrate synthase (P = 0.0024) and beta-hydroxyacyl-CoA dehydrogenase (P = 0.0073) in the white gastrocnemius skeletal muscle of Ex vs. Sed rats. Systolic blood pressure was elevated in SHR vs. WKY (P < 0.0001) but was not affected by Ex. Despite enhanced endothelium-dependent relaxation to 10(-8) M ACh in SHR vs. WKY (P = 0.0061), maximal endothelium-dependent relaxation to 10(-4) M ACh was blunted in Sed SHR (48 +/- 12%) vs. Sed WKY (84 +/- 6%, P = 0.0067). Maximal endothelium-dependent relaxation to 10(-4) M ACh was completely restored in Ex SHR (93 +/- 9%) vs. Sed SHR (P = 0.0011). N(omega)-nitro-l-arginine abolished endothelium-dependent relaxation in all groups (P 相似文献   

Chronic exercise training does not alter pulmonary vasorelaxation in normal pigs.

Exercise training increases acetylcholine-induced pulmonary vasorelaxation in pigs with coronary occlusion. The present study tested the hypothesis that chronic exercise training enhances endothelium-mediated vasorelaxation in pulmonary arteries from normal pigs. Yucatan miniswine exercised for 16 wk on a treadmill (Ex); control pigs (Sed) remained in pens. Pulmonary artery rings (2- to 3-mm OD) were studied using standard isometric techniques. Contractile responses to 80 mM KCl and norepinephrine (NE) were determined. Vessels were constricted with levels of NE that resulted in half-maximal contraction to examine endothelium-dependent relaxation to ACh and endothelium-independent relaxation to sodium nitroprusside in the presence and absence of nitric oxide synthase inhibition, cyclooxygenase inhibition, and endothelial denudation. Arteries from Ex pigs developed increased contraction to 80 mM KCl, but the response to NE did not differ between groups. Endothelium-dependent and endothelium-independent responses did not differ between Sed and Ex in the presence or absence of pharmacological inhibitors or denudation. We conclude that chronic exercise training does not alter endothelium-dependent or endothelium-independent vasorelaxation responses of pulmonary arteries from normal pigs.     

Effects of exercise training on the vascular reactivity of the whole kidney circulation in rabbits.

Exercise training is known to improve vasodilating mechanisms mediated by endothelium-dependent relaxing factors in the cardiac and skeletal muscle vascular beds. However, the effects of exercise training on visceral vascular reactivity, including the renal circulation, are still unclear. We used the experimental model of the isolated perfused rabbit kidney, which involves both the renal macro- and microcirculation, to test the hypothesis that exercise training improves vasodilator mechanisms in the entire renal circulation. New Zealand White rabbits were pen confined (Sed; n = 24) or treadmill trained (0% grade) for 5 days/wk at a speed of 18 m/min during 60 min over a 12-wk period (ExT; n = 24). Kidneys isolated from Sed and ExT rabbits were continuously perfused in a nonrecirculating system under conditions of constant flow and precontracted with norepinephrine (NE). We assessed the effects of exercise training on renal vascular reactivity using endothelial-dependent [acetylcholine (ACh) and bradykinin (BK)] and -independent [sodium nitroprusside (SNP)] vasodilators. ACh induced marked and dose-related vasodilator responses in kidneys from Sed rabbits, the reduction in perfusion pressure reaching 41 +/- 8% (n = 6; P < 0.05). In the kidneys from ExT rabbits, vasodilation induced by ACh was significantly enhanced to 54 +/- 6% (n = 6; P < 0.05). In contrast, BK-induced renal vasodilation was not enhanced by training [19 +/- 8 and 13 +/- 4% reduction in perfusion pressure for Sed and ExT rabbits, respectively (n = 6; P > 0.05)]. Continuous perfusion of isolated kidneys from ExT animals with N(omega)-nitro-L-arginine methyl ester (L-NAME; 300 microM), an inhibitor of nitric oxide (NO) biosynthesis, completely blunted the additional vasodilation elicited by ACh [reduction in perfusion pressure of 54 +/- 6 and 38 +/- 5% for ExT and L-NAME + ExT, respectively (n = 6; P < 0.05)]. On the other hand, L-NAME infusion did not affect ACh-induced vasodilation in Sed animals. Exercise training also increased renal vasodilation induced by SNP [36 +/- 7 and 45 +/- 10% reduction in perfusion pressure for Sed and ExT rabbits, respectively (n = 6; P < 0.05)]. It is concluded that exercise training alters the rabbit kidney vascular reactivity, enhancing endothelium-dependent and -independent renal vasodilation. This effect seems to be related not only to an increased bioavailability of NO but also to the enhanced responsiveness of the renal vascular smooth muscle to NO.     

Chronic nitric oxide synthase inhibition blunts endothelium-dependent function of conduit coronary arteries, not arterioles

Current literature suggests that chronic nitric oxide synthase (NOS) inhibition has differential effects on endothelium-dependent dilation (EDD) of conduit arteries vs. arterioles. Therefore, we hypothesized that chronic inhibition of NOS would impair EDD of porcine left anterior descending (LAD) coronary arteries but not coronary arterioles. Thirty-nine female Yucatan miniature swine were included in the study. Animals drank either tap water or water with N(G)-nitro-L-arginine methyl ester (L-NAME; 100 mg/l), resulting in control and chronic NOS inhibition (CNI) groups, respectively. Treatment was continued for 1-3 mo (8.3 +/- 0.6 mg x kg(-1) x day(-1)). In vitro EDD of coronary LADs and arterioles was assessed via responses to ADP (LADs only) and bradykinin (BK), and endothelium-independent function was assessed via responses to sodium nitroprusside (SNP). Chronic NOS inhibition diminished coronary artery EDD to ADP and BK. Incubating LAD rings with L-NAME decreased relaxation responses of LADs from control pigs but not from CNI pigs such that between-group differences were abolished. Neither indomethacin (Indo) nor sulfaphenazole incubation significantly affected relaxation responses of LAD rings to ADP or BK. Coronary arteries from CNI pigs showed enhanced relaxation responses to SNP. In contrast to coronary arteries, coronary arterioles from CNI pigs demonstrated preserved EDD to BK and no increase in dilation responses to SNP. L-NAME, Indo, and L-NAME + Indo incubation did not result in significant between-group differences in arteriole dilation responses to BK. These results suggest that although chronic NOS inhibition diminishes EDD of LAD rings, most likely via a NOS-dependent mechanism, it does not affect EDD of coronary arterioles.     

A high-whey-protein diet does not enhance mechanical and structural remodeling of cardiac muscle in response to aerobic exercise in rats

[Purpose]Aerobic exercise training results in distinct structural and mechanical myocardial adaptations. In skeletal muscle, whey protein supplementation is effective in enhancing muscle adaptation following resistance exercise. However, it is unclear whether cardiac adaptation to aerobic exercise can be enhanced by systematic protein supplementation.[Methods]Twelve-week-old rats were assigned to 12 weeks of either sedentary or aerobic exercise with either a standard (Sed+Standard, Ex+Standard) or high-protein (Sed+Pro, Ex+Pro) diet. Echocardiography was used to measure cardiac structural remodeling and performance. Skinned cardiac fiber bundles were used to determine the active and passive stress properties, maximum shortening velocity, and calcium sensitivity.[Results]Aerobic training was characterized structurally by increases in ventricle volume (Ex+Standard, 19%; Ex+Pro, 29%) and myocardial thickness (Ex+Standard, 26%; Ex+-Pro, 12%) compared to that of baseline. Skinned trabecula r fiber bundles also had a greater unloaded shortening velocity (Sed+Standard, 1.04±0.05; Sed+Pro, 1.07±0.03; Ex-+Standard, 1.16±0.04; Ex+Pro, 1.18±0.05 FL/s) and calcium sensitivity (pCa₅₀: Sed+Standard, 6.04±0.17; Sed+Pro, 6.08±0.19; Ex+Standard, 6.30±0.09; Ex+Pro, 6.36±0.12) in trained hearts compared to that of hearts from sedentary animals. However, the addition of a high-protein diet did not provide additional benefits to either the structural or mechanical adaptations of the myocardium.[Conclusion]Therefore, it seems that a high-whey-protein diet does not significantly enhance adaptations of the heart to aerobic exercise in comparison to that of a standard diet.     

Effects of a high-fat diet and voluntary wheel running on gluconeogenesis and lipolysis in rats.

The purpose of the present study was to determine the effects of diet composition and exercise on glycerol and glucose appearance rate (Ra) and on nonglycerol gluconeogenesis (Gneo) in vivo. Male Wistar rats were fed a high-starch diet (St, 68% of energy as cornstarch, 12% corn oil) for a 2-wk baseline period and then were randomly assigned to one of four experimental groups: St (n = 7), high-fat (HF; 35% cornstarch, 45% corn oil; n = 8), St with free access to exercise wheels (StEx; n = 7), and HF with free access to exercise wheels (HFEx; n = 7). After 8 wk, glucose Ra when using [3-3H]glucose, glycerol Ra when using [2H5]glycerol (estimate of whole body lipolysis), and [3-13C]alanine incorporation into glucose (estimate of alanine Gneo) were determined. Body weight and fat pad mass were significantly (P < 0.05) decreased in exercise vs. sedentary animals only. The average amount of exercise was not significantly different between StEx (3,212 +/- 659 m/day) and HFEx (3,581 +/- 765 m/day). The ratio of glucose to alanine enrichment and absolute glycerol Ra (micromol/min) were higher (P < 0.05) in HF and HFEx compared with St and StEx rats. In separate experiments, the ratio of 3H in C-2 to C-6 of glucose from 3H2O (estimate of Gneo from pyruvate) was also higher (P < 0.05) in HF (n = 5) and HFEx (n = 5), compared with St (n = 5) and StEx (n = 5) rats. Voluntary wheel running did not significantly increase estimated alanine or pyruvate Gneo or absolute glycerol Ra. Voluntary wheel running increased (P < 0.05) glycerol Ra when normalized to fat pad mass. These data suggest that a high-fat diet can increase in vivo Gneo from precursors that pass through pyruvate. They also suggest that changes in the absolute rate of glycerol Ra may contribute to the high-fat diet-induced increase in Gneo.     

Interval sprint training enhances endothelial function and eNOS content in some arteries that perfuse white gastrocnemius muscle.

The purpose of this study was to test the hypothesis that interval sprint training (IST) selectively increases endothelium-dependent dilation (EDD) and endothelial nitric oxide synthase and/or superoxide dismutase-1 protein content in arteries and/or arterioles that perfuse the white portion of rat gastrocnemius muscle (WG). Male Sprague-Dawley rats completed 10 wk of IST (n = 62) or remained sedentary (Sed) (n = 63). IST rats performed six 2.5-min exercise bouts, with 4.5 min of rest between bouts (60 m/min, 15% incline), 5 days/wk. EDD was assessed from acetylcholine (ACh)-induced increases in muscle blood flow measured in situ and by ACh-induced dilation of arteries and arterioles [first to third order (1A-3A)] that perfuse red gastrocnemius muscle (RG) and WG. Artery protein content was determined with immunoblot analysis. ACh-induced increases in blood flow were enhanced in WG of IST rats. eNOS content was increased in conduit arteries, gastrocnemius feed artery, and fourth-order arterioles from WG and fifth-order arterioles of RG but not in 2As from RG. EDD was examined in 2As and 3As from a subset of IST and Sed rats. Arterioles were canulated with micropipettes, and intraluminal pressure was set at 60 cmH2O. Results indicate that passive diameter (measured in 0 calcium PSS) of WG 2As was similar in IST and Sed, whereas diameter of WG 3As was greater in IST (96 +/- 8 microm) than Sed (73 +/- 4 microm). WG 2As and 3As of IST rats exhibited greater spontaneous tone, but sensitivity to stretch, phenylephrine, and sodium nitroprusside was similar to Sed arterioles. ACh-induced dilation was enhanced by IST in WG 2As but not in RG 2As or WG 3As. We conclude that IST induces vascular adaptations nonuniformly among arteries that perfuse WG muscle.     

The Effect of Repeated Episodes of Dietary Restriction and Refeeding on Systolic Blood Pressure and Food Intake in Exercise‐Trained Normotensive Rats

Objective: To explore the effects of weight cycling and exercise on blood pressure and macronutrient intake in Sprague‐Dawley rats. Research Methods and Procedures: Female Sprague‐Dawley rats (n = 62; 5 months old) were assigned to an ad libitum (Con) or weight‐cycled (Cyc) group. They were either sedentary (Con‐Sed and Cyc‐Sed) or exercise‐trained (Con‐Ex and Cyc‐Ex) on a motorized treadmill (20 m/minute; 60 minutes/day; 6 days/week). The Cyc groups underwent 2 cycles of 3 weeks of 60% food restriction followed by 5 weeks of ad libitum refeeding using a macronutrient self‐selection diet. Body mass and food intake were analyzed weekly. Systolic blood pressure (SBP) was measured at baseline and during the first and fifth weeks of each refeeding. Results: For both cycling periods, SBP was elevated in Cyc vs. Con groups at Week 1 of refeeding, but was similar among groups by Week 5 of refeeding. Both Con groups had greater total energy intake than the Cyc groups for both cycling periods (Cycle 1: 2882.2 ± 75.1, Con‐Sed; 2916.1 ± 67.1, Con‐Ex; 2692.2 ± 58.7, Cyc‐Sed; and 2780.5 ± 52.4 kcal, Cyc‐Ex) (Cycle 2: 2815.8 ± 75.1, Con‐Sed; 2938.8 ± 49.4, Con‐Ex; 2577.1 ± 60.5, Cyc‐Sed; and 2643.5 ± 65.9 kcal, Cyc‐Ex). Relative fat intake (percentage of total kcal/week) was significantly less for Con‐Ex and Cyc‐Ex than Con‐Sed and Cyc‐Sed throughout both refeeding periods. Discussion: Weight cycling failed to produce significant sustained effects on SBP, body mass, or food intake. Exercise training, irrespective of diet, lowered dietary fat intake.     

SOD-1 expression in pig coronary arterioles is increased by exercise training

Coronary arterioles of exercise-trained (EX) pigs have enhanced nitric oxide (NO.)-dependent dilation. Evidence suggests that the biological half-life of NO. depends in part on the management of the superoxide anion. The purpose of this study was to test the hypothesis that expression of cytosolic copper/zinc-dependent superoxide dismutase (SOD)-1 is increased in coronary arterioles as a result of exercise training. Male Yucatan pigs either remained sedentary (SED, n = 4) or were EX (n = 4) on a motorized treadmill for 16-20 wk. Individual coronary arterioles ( approximately 100-microm unpressurized internal diameter) were dissected and frozen. Coronary arteriole SOD-1 protein (via immunoblots) increased as a result of exercise training (2.16 +/- 0.35 times SED levels) as did SOD-1 enzyme activity (measured via inhibition of pyrogallol autooxidation; approximately 75% increase vs. SED). In addition, SOD-1 mRNA levels (measured via RT-PCR) were higher in EX arterioles (1.68 +/- 0.16 times the SED levels). There were no effects of exercise training on the levels of SOD-2 (mitochondrial), catalase, or p67(phox) proteins. Thus chronic aerobic exercise training selectively increases the levels of SOD-1 mRNA, protein, and enzymatic activity in porcine coronary arterioles. Increased SOD-1 could contribute to the enhanced NO.-dependent dilation previously observed in EX porcine coronary arterioles by improving management of superoxide in the vascular cell environment, thus prolonging the biological half-life of NO.     

Effects of high-cholesterol diet and parallel exercise training on the vascular function of rabbit aortas: a time course study.

It is plausible to assume that exercise training, when applied early enough, can completely correct atherosclerotic defects. Using rabbit aortic specimens, we examined the effects of chronic exercise and high-cholesterol diet feeding on vascular function for different time periods. Male New Zealand White rabbits were divided into four groups: the normal diet groups with or without exercise training and the high-cholesterol diet groups with or without exercise training. Animals in high-cholesterol diet groups were fed 2% cholesterol rabbit chow for 2, 4, or 6 wk. Those in exercise training groups ran on a treadmill at 0.88 km/h for up to 40 min/day, 5 days/wk for the same period of time as the diet feeding. Thoracic aortas were isolated for functional and immunohistochemical analyses. We found that 1). although high-cholesterol diet feeding (>or=2 wk) elevated serum cholesterol levels and impaired acetylcholine-evoked vasorelaxation, only the latter effect was reversed by exercise training; 2). the effects of diet and exercise on acetylcholine-evoked vasorelaxation were mainly due to altered release of nitric oxide and endothelium-derived hyperpolarizing factor; and 3). diet feeding for 4 or 6 wk caused significant lipid deposition and expression of P-selectin, VCAM-1, monocyte chemoattractant protein-1, and inducible nitric oxide synthase, which were largely reduced by exercise training. In conclusion, parallel exercise training almost completely reverses the early-stage endothelial dysfunction caused by high-cholesterol diet feeding.