Exercise attenuates the effects of hypercholesterolemia on endothelium-dependent relaxation in coronary arteries from adult female pigs (original) (raw)
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Journal of Applied Physiology, 2003
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.
Atherosclerosis, 1999
The endothelium contributes to the regulation of vascular tone by producing nitric oxide (NO) and the endothelium-derived hyperpolarising factor (EDHF). In hypercholesterolemia, endothelium-dependent relaxation is impaired but can be restored by treatment with lovastatin (LOVAS). We investigated the effects of LOVAS on NO and EDHF-mediated relaxation. Rabbits were fed 1% cholesterol diet for 4 weeks and 0.5% cholesterol for the following 12 weeks (CHOL-group). The LOVAS group additionally received 10 mg of lovastatin over the last 12-week period. Experiments were performed in carotid artery rings. Relaxant responses to acetylcholine (ACh) were recorded in the presence of indomethacin. Nitro-L-arginine (NOARG, 100 mM) and potassium chloride (KCl, 35 mM) were used to differentiate between NO-and EDHF-mediated relaxations. Cholesterol impaired ACh-induced relaxations and this effect was prevented by LOVAS (control 100 9 1%, CHOL 81 96%, LOVAS 98 91%). In the presence of NOARG, relaxations to ACh were not different between the LOVAS and CHOL groups (control 78 94%, CHOL 64 9 6%, LOVAS 64 95%). When KCl was used, ACh-induced relaxations were similar in the LOVAS and control group (control 75 9 5%, CHOL 49 96%, LOVAS 76 9 2%). In arteries treated with NOARG and KCl together, no relaxations were observed. Relaxations of arteries from the control group were not affected by 18 h preincubation with lovastatin (10mM). Lovastatin selectively maintains nitric oxide-mediated endothelium-dependent relaxation in hypercholesterolemic rabbit carotid arteries.
Microcirculation, 2014
Objective-Test the hypothesis that exercise training enhances sustained relaxation to persistent endothelium-dependent vasodilator exposure via increased nitric oxide contribution in small coronary arteries of control and ischemic hearts. Methods-Yucatan swine were designated to a control group or a group in which an ameroid constrictor was placed around the proximal LCX. Subsequently, pigs from both groups were assigned to exercise (5 days/week; 16 weeks) or sedentary regimens. Coronary arteries (~100-350 μm) were isolated from control pigs and from both nonoccluded and collateral-dependent regions of chronically-occluded hearts. Results-In arteries from control pigs, training significantly enhanced relaxation responses to increasing concentrations of bradykinin (10 −10 to 10 −7 M) and sustained relaxation to a single bradykinin concentration (30 nM), which were abolished by NOS inhibition. Training also significantly prolonged bradykinin-mediated relaxation in collateral-dependent arteries of occluded pigs, which was associated with more persistent increases in endothelial cellular Ca 2+ levels, and reversed with NOS inhibition. Protein levels for eNOS and p-eNOS-(Ser1179), but not caveolin-1, Hsp90, or Akt, were significantly increased with occlusion, independent of training state. Conclusions-Exercise training enhances sustained relaxation to endothelium-dependent agonist stimulation in small arteries of control and ischemic hearts by enhanced nitric oxide contribution and endothelial Ca 2+ responses.
1996
Kinins, which are produced locally in arterial walls, stimulate the release of endothelium-derived vasodilator substances. Therefore, they may participate in the metabolic adaptation to chronic exercise that occurs in the coronary circulation. Experiments were designed to compare the reactivity to bradykinin in coronary arteries isolated from sedentary and exercised-trained dogs (for 8-10 weeks). 2 The organ chambers used in this study were designed for measurement of isometric tension and cell membrane potential with glass microelectrodes. Rings of canine isolated coronary arteries with endothelium were suspended in the organ chambers filled with modified Krebs-Ringer bicarbonate solution (37°C, gassed with 5% CO2 in 95 02), and were all treated with indomethacin to prevent interference from prostaglandins. 3 Bradykinin evoked concentration-dependent relaxations of the coronary arteries. However, the kinin was significantly less potent in relaxing coronary arteries from the sedentary dogs than those from the trained ones. 4 In the presence of N0-nitro-L-arginine (an inhibitor of nitric oxide synthases), concentrationrelaxation curves to bradykinin were shifted to the right in both types of preparations. Nonetheless, the peptide was still significantly more potent in arteries from exercise-trained animals. 5 In the electrophysiological experiments, concentration-hyperpolarization curves to bradykinin obtained in arteries from sedentary dogs were also significantly to the right of those in vessels from exercise-trained animals. Thus, in arteries from exercised animals, bradykinin more potently evoked the release of both nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). 7 The angiotensin converting enzyme (ACE)-inhibitor, perindoprilat, shifted to the left the concentration-relaxation curves to bradykinin obtained under control conditions and in the presence of N0-nitro-L-arginine. The concentration-hyperpolarization curves to bradykinin were also shifted to the left by perindoprilat. The shift induced by the ACE-inhibitor in either type of preparation was not significantly different. 8 These findings demonstrate that exercise-training augments the sensitivity of the coronary artery of the dog to the endothelium-dependent effects of bradykinin. This sensitization to bradykinin may reflect an increased role of both NO and EDHF, and is not the consequence of differences in ACE activity in the receptor compartment.
Atherosclerosis, 1997
Studies were designed to compare the N G-nitro-L-arginine-and indomethacin-resistant, endothelium-dependent relaxation to acetylcholine in isolated renal artery rings from normal and cholesterol-fed rabbits. It was assumed that the resistant part in response to acetylcholine is mediated by the endothelial-derived hyperpolarizing factor (EDHF). Rabbits were fed normal (n=15) or cholesterol enriched chow (n=13, 1% cholesterol for 4 weeks, 0.5% for 12 weeks). In organ chamber experiments, renal artery rings were precontracted with 0.1-1 vM phenylephrine or 35 mM KCl, and relaxed with acetylcholine (0.001-10 vM) in the presence of 10 vM indomethacin. Studies were performed in the presence or absence of: 100 vM N G-nitro-L-arginine (L-NOARG) to inhibit the nitric oxide pathway, 100 nM charybdotoxin (CTX) or 1 mM tetrabutylammonium (TBA) to inhibit Ca 2 +-activated K + channels, and 100 vM SKF 525a to inhibit cytochrome P 450 monoxygenase pathway. In normal arteries, L-NOARG partially inhibited acetylcholine-induced relaxation. The resistant part was almost abolished when the arteries were depolarized with KCl, or when L-NOARG was combined with either CTX, TBA or SKF 525a. In arteries from hypercholesterolemic animals, the relaxation to acetylcholine was only slightly impaired as compared to normal animals. However, in comparison to arteries from normal animals, the L-NOARG-resistant part of acetylcholine-induced endothelium-dependent relaxation was enhanced. It is speculated that differences in the balance between nitric oxide (NO)-and EDHF-mediated control of vascular tone may maintain acetylcholine-induced vasodilatation of the renal artery in hypercholesterolemia.
Journal of Applied Physiology, 2004
Hypercholesterolemia is reported to attenuate endothelial function and exercise training has been reported to augment endothelial function. We hypothesized that exercise training would improve endothelial function of coronary arterioles from pigs in the early stages of cardiovascular disease induced by a high fat/cholesterol diet. Yucatan miniature swine were fed a normal (NF) or high fat (HF, 2% cholesterol) diet for 20wks in which 8% and 46% of their kcal were derived from fat, respectively. Both groups were subdivided into sedentary (SED) or exercise trained (EX) groups. This resulted in four experimental groups: NFSED, NFEX, HFSED and HFEX. Endothelial function was assessed in coronary arterioles 75-100 m in diameter dissected from the left ventricular apex. Responses to endothelial dependent dilation induced by bradykinin (BK), ADP and flow were similar in all four groups while dilation to aggregating platelets in the presence of indomethacin and Ketanserin was attenuated in HFSED arterioles (p = 0.01).
British Journal of Pharmacology, 2009
Background and purpose: Nitroxyl (HNO) is emerging as an important regulator of vascular tone as it is potentially produced endogenously and dilates conduit and resistance arteries. This study investigates the contribution of endogenous HNO to endothelium-dependent relaxation and hyperpolarization in resistance arteries. Experimental approach: Rat and mouse mesenteric arteries were mounted in small vessel myographs for isometric force and smooth muscle membrane potential recording. Key results: Vasorelaxation to the HNO donor, Angeli's salt, was attenuated in both species by the soluble guanylate cyclase inhibitor (ODQ, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one), the voltage-dependent K + channel inhibitor, 4-aminopyridine (4-AP) and the HNO scavenger, L-cysteine. In mouse mesenteric arteries, nitric oxide (NO) synthase inhibition (with L-NAME, N w -Nitro-L-arginine methyl ester) markedly attenuated acetylcholine (ACh)-mediated relaxation. Scavenging the uncharged form of NO (NO • ) with hydroxocobalamin (HXC) or HNO with L-cysteine, or 4-AP decreased the sensitivity to ACh, and a combination of HXC and L-cysteine reduced ACh-mediated relaxation, as did L-NAME alone. ACh-induced hyperpolarizations were significantly attenuated by 4-AP alone and in combination with L-NAME. In rat mesenteric arteries, blocking the effects of endothelium-derived hyperpolarizing factor (EDHF) (charybdotoxin and apamin) decreased ACh-mediated relaxation 10-fold and unmasked a NO-dependent component, mediated equally by HNO and NO • ,a sH X Ca n dL-cysteine in combination now abolished vasorelaxation to ACh. Furthermore, ACh-evoked hyperpolarizations, resistant to EDHF inhibition, were virtually abolished by 4-AP.
AJP: Heart and Circulatory Physiology, 2006
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. Endotheliumdependent vasodilator responses were assessed in vivo by measuring changes in FABF after intraarterial 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.
British Journal of Pharmacology, 1997
Relaxing factors released by the endothelium and their relative contribution to the endotheliumdependent relaxation produced by bradykinin (BK) in comparison with dierent vasodilator agents were investigated in human omental resistance arteries. 2 BK produced an endothelium-dependent relaxation of arteries pre-contracted with the thromboxane A 2 agonist, U46619. The B 2 receptor antagonist, Hoe 140 (0.1, 1 and 10 mM), produced a parallel shift to the right of the concentration-response curve to BK with a pA 2 of 7.75. 3 Neither the cyclo-oxygenase inhibitor, indomethacin (10 mM) alone, the nitric oxide synthase inhibitor, N o-nitro-L-arginine methyl ester (L-NAME, 300 mM) alone, the nitric oxide scavenger, oxyhaemoglobin (Hb, 10 mM) alone, nor the combination of L-NAME plus Hb aected the concentration-response curve to BK. Conversely, the combination of indomethacin with either L-NAME or Hb attenuated but did not abolish the BK-induced relaxation. By contrast, the relaxations produced by the Ca 2+ ionophore, calcimycin (A23187), and by the inhibitor of sarcoplasmic reticulum Ca 2+-ATPase, thapsigargin (THAPS), were abolished in the presence of indomethacin plus L-NAME. Also, the presence of indomethacin plus L-NAME produced contraction of arteries with functional endothelium. 4 The indomethacin plus L-NAME resistant component of BK relaxation was abolished in physiological solution (PSS) containing 40 mM KCl and vice versa. However, in the presence of KCl 40 mM, indomethacin plus L-NAME did not aect the nitric oxide donor, S-N-acetylpenicillamineinduced relaxation. 5 The indomethacin plus L-NAME resistant component of the relaxation to BK was signi®cantly attenuated by the K + channel blocker tetrabutylammonium (TBA, 1 mM). However, it was not aected by other K + channel blockers such as apamin (10 mM), 4-aminopyridine (100 mM), glibenclamide (10 mM), tetraethylammonium (10 mM) and charybdotoxin (50 nM). 6 In the presence of indomethacin plus L-NAME, the relaxation produced by BK was not aected by the phospholipase A 2 inhibitor, quinacrine (10 mM) or by the inhibitor of cytochrome P450, SKF 525a (10 mM). Another cytochrome P450 inhibitor, clotrimazole (10 mM) which also inhibits K + channels, inhibited the relaxation to BK. 7 These results show that BK induces endothelium-dependent relaxation in human small omental arteries via multiple mechanisms involving nitric oxide, cyclo-oxygenase derived prostanoid(s) and another factor (probably an endothelium-derived hyperpolarizing factor). They indicate that nitric oxide and cyclo-oxygenase derivative(s) can substitute for each other in producing relaxation and that the third component is not a metabolite of arachidonic acid, formed through the cytochrome P-450 pathway, in these arteries.