October 7, 2009; doi:10.1152/ajpregu.00178.2009.-The risk for cardiovascular disease (CVD) increases with advancing age; however, the age at which CVD risk increases significantly is delayed by more than a decade in women compared with men. This cardioprotection, which women experience until menopause, is presumably due to the presence of ovarian hormones, in particular, estrogen. The purpose of this study was to determine how age and ovarian hormones affect flowinduced vasodilation in the coronary resistance vasculature. Coronary arterioles were isolated from young (6 mo), middle-aged (14 mo), and old (24 mo) intact, ovariectomized (OVX), and ovariectomized ϩ estrogen replaced (OVE) female Fischer-344 rats to assess flowinduced vasodilation. Advancing age impaired flow-induced dilation of coronary arterioles (young: 50 Ϯ 4 vs. old: 34 Ϯ 6; % relaxation). Ovariectomy reduced flow-induced dilation in arterioles from young females, and estrogen replacement restored vasodilation to flow. In aged females, flow-induced vasodilation of arterioles was unaltered by OVX; however, estrogen replacement improved flow-induced dilation by ϳ160%. The contribution of nitric oxide (NO) to flow-induced dilation, assessed by nitric oxide synthase (NOS) inhibition with N G -nitro-L-arginine methyl ester (L-NAME), declined with age. L-NAME did not alter flow-induced vasodilation in arterioles from OVX rats, regardless of age. In contrast, L-NAME reduced flowinduced vasodilation of arterioles from estrogen-replaced rats at all ages. These findings indicate that the age-induced decline of flowinduced, NO-mediated dilation in coronary arterioles of female rats is related, in part, to a loss of ovarian estrogen, and estrogen supplementation can improve flow-induced dilation, even at an advanced age.endothelial nitric oxide synthase; Akt; nitric oxide; ovariectomy THE RISK FOR CARDIOVASCULAR disease (CVD) and heart failure increase with advancing age; however, sexual dimorphism exists in the chronological development of these risks (22,47). Although the chronological rate of aging is independent of sex, mechanisms that regulate the cardiovascular system across the lifespan may differ dramatically between men and women. The risk for CVD in men begins to increase at approximately the same age that flow-mediated vasodilation begins to decline (5). Women also exhibit this age-related impairment of flow-mediated vasodilation; however, significant reduction of flow-mediated dilation becomes apparent at the age of menopause, more than a decade later than in men (5). The cardioprotection that women experience until menopause is presumably due to the presence of ovarian estrogen and results in a sex-related delay of the expression of CVD (49). Chronic estrogen treatment has been shown to enhance endothelial function in a number of vascular beds (27, 31, 39), in part, through a pathway involving activation of Akt/PKB and subsequent phosphorylation of endothelial nitric oxide synthase (eNOS) (3,10,15,43,44). Endothelium-dependent vasodilation to a...
cent studies have shown that asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor, is increased in hypertension and chronic kidney disease. However, little is known about the effects of hypertension per se on ADMA metabolism. The purpose of this study was to test the hypothesis that ANG II-induced hypertension, in the absence of renal injury, is associated with increased oxidative stress and plasma and renal cortex ADMA levels in rats. Male SpragueDawley rats were treated with ANG II at 200 ng·kg Ϫ1 ·min Ϫ1 sc (by minipump) for 1 or 3 wk or at 400 ng·kg Ϫ1 ·min Ϫ1 for 6 wk. Mean arterial pressure was increased after 3 and 6 wk of ANG II; however, renal injury (proteinuria, glomerular sclerosis, and interstitial fibrosis) was only evident after 6 wk of treatment. Plasma thiobarbituric acid reactive substances concentration and renal cortex p22 phox protein abundance were increased early (1 and 3 wk), but urinary excretion of isoprostane and H2O2 was only increased after 6 wk of ANG II. An increased in plasma ADMA after 6 wk of ANG II was associated with increased lung protein arginine methyltransferase-1 abundance and decreased renal cortex dimethylarginine dimethylaminohydrolase activity. No changes in renal cortex ADMA were observed. ANG II hypertension in the absence of renal injury is not associated with increased ADMA; however, when the severity and duration of the treatment were increased, plasma ADMA increased. These data suggest that elevated blood pressure alone, for up to 3 wk, in the absence of renal injury does not play an important role in the regulation of ADMA. However, the presence of renal injury and sustained hypertension for 6 wk increases ADMA levels and contributes to nitric oxide deficiency and cardiovascular disease. kidney; protein arginine methyltransferase-1; dimethylarginine dimethylaminohydrolase; oxidative stress NITRIC OXIDE (NO), an important mediator of vascular tone and renal function, regulates glomerular, vascular, and tubular function in the kidney (20). Regulation of NO biosynthesis is complex, and the endogenous competitive inhibitor of NO synthase (NOS), asymmetric dimethylarginine (ADMA), is one important influence on NO production. ADMA is generated by protein arginine methyltransferase (PRMT) class 1 (PRMT-1) enzymes (1). Some ADMA is excreted in the urine, but the major route of ADMA elimination is via metabolism by dimethylarginine dimethylaminohydrolase (DDAH)-1 and DDAH-2 (28). The kidney plays an important role in the metabolism of ADMA, inasmuch as the highest density of the DDAH enzymes is found in the kidney cortex (30); however, these enzymes are also abundantly expressed in many other organs, including the liver and lung.There is a robust correlation between ADMA levels and severe cardiovascular events and mortality (3). However, little is known about the effects of high blood pressure per se on ADMA levels. Some small clinical studies have shown a relationship between high blood pressure and high plasma ADMA concentrations (31, 39, 49), but oth...
Introduction The principal nutrient artery to the femur demonstrates an increase in nitric oxide mediated vasodilation in rats after treadmill exercise training. The present study sought to determine whether exercise training improves hindlimb bone and marrow blood flow distribution at rest and during exercise. Methods Six-eight month old male Sprague-Dawley rats were exercise trained (ET) with treadmill walking at 15 m/min up a 15° incline for 60 min/d over a 10–12 wk period. Sedentary (SED) control animals were acclimated to treadmill exercise for 5 min/d during the week preceding the blood flow measurements. Blood flow to nine distinct regions of the femur, tibia, and fibula were determined at rest and during low-intensity exercise (15 m/min walking, 0° incline) using the reference sample microsphere method. Results The results demonstrate an augmentation of exercise hyperemia above that observed in SED rats during exercise in only one region of bone, the femoral diaphysis of ET rats. However, while exercise hyperemia occurred in 3 of the 9 hindlimb bone regions measured in SED rats, exercise hyperemia occurred in 7 of 9 regions in ET rats. Conclusion These data indicate an increase in generalized hindlimb bone and marrow blood flow during physical activity following a period of exercise training. Elevations in regional bone and marrow blood flow after training may augment medullary pressure and bone interstitial fluid flow, thus benefiting bone integrity.
Non-technical summary In older people, the function of the kidney deteriorates, and one possible way to slow this process down is through exercise. Exercise increases the abundance of important enzymes that are needed for optimal vessel health and kidney function, for instance the nitric oxide synthase and superoxide dismutase (SOD) enzymes. It also reduces oxidative stress, a type of cellular injury caused by highly reactive molecules. When we compared young and old sedentary rats to young and old exercise-trained (12 weeks treadmill) rats, we found that exercise was not effective in reversing the age-related kidney changes. In old rats, renal function declined as did the abundance of the protective SOD enzymes, and oxidative stress increased; interestingly, exercise did not influence these changes. Our results suggest that the cardiovascular benefits of exercise do not necessarily extend to the kidney. AbstractThe ageing kidney exhibits slowly developing chronic kidney disease (CKD) and is associated with nitric oxide (NO) deficiency and increased oxidative stress. The impact of exercise on the ageing kidney is not well understood. Here, we determined whether 12 weeks of treadmill exercise can influence age-dependent CKD in old (22-24 months) Fisher 344 (F344) male rats by comparing sedentary (SED) and exercise (EX) trained rats; young (3 months) rats were also studied. In addition to renal structure and function, we assessed protein levels of various isoforms of the NO synthases (NOS) and superoxide dismutase (SOD) enzymes as well as markers of oxidative stress, in kidney cortex and medulla. Renal function as determined by plasma creatinine, proteinuria, and glomerular structural injury worsened with age and was unaffected by exercise. Ageing also increased the protein abundance of neuronal NOSβ and p22phox while decreasing extracellular (EC) and copper/zinc (CuZn) SOD, in kidney cortex and medulla. H 2 O 2 content and nitrotyrosine abundance also increased in the kidney with age. None of these age-related changes were altered with exercise. However, exercise did increase renal cortical endothelial (e)NOS and EC SOD in young rats. Data indicate that exercise-induced increases in eNOS and EC SOD seen in young rats are lost with age. We conclude that chronic exercise is ineffective in reversing age-dependent CKD in the male F344 rat.
Recently, we showed that administration of the angiotensin-converting enzyme inhibitor enalapril to aged rats attenuated muscle strength decline and mitigated apoptosis in the gastrocnemius muscle. The aim of the present study was to investigate possible mechanisms underlying the muscle-protective effects of enalapril. We also sought to discern the effects of enalapril mediated by nitric oxide (NO) from those independent of this signaling molecule. Eighty-seven male Fischer 344 × Brown Norway rats were randomly assigned to receive enalapril (n = 23), the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; n = 22), enalapril + L-NAME (n = 19), or placebo (n = 23) from 24 to 27 months of age. Experiments were performed on the tibialis anterior muscle. Total NOS activity and the expression of neuronal, endothelial, and inducible NOS isoforms (nNOS, eNOS, and iNOS) were determined to investigate the effects of enalapril on NO signaling. Transcript levels of tumor necrosis factor-alpha (TNF-α) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) were assessed to explore actions of enalapril on inflammation and mitochondrial biogenesis, respectively. Protein expression of energy-sensing and insulin signaling mediators, including protein kinase B (Akt-1), phosphorylated Akt-1 (pAkt-1), mammalian target of rapamycin (mTOR), AMP-activated protein kinase subunit alpha (AMPKα), phosphorylated AMPKα (pAMPKα), and the glucose transporter GLUT-4, was also determined. Finally, the generation of hydrogen peroxide (H2O2) was quantified in subsarcolemmal (SSM) and intermyofibrillar (IFM) mitochondria. Enalapril increased total NOS activity, which was prevented by L-NAME co-administration. eNOS protein content was enhanced by enalapril, but not by enalapril + L-NAME. Gene expression of iNOS was down-regulated by enalapril either alone or in combination with L-NAME. In contrast, protein levels of nNOS were unaltered by treatments. The mRNA abundance of TNF-α was reduced by enalapril relative to placebo, with no differences among any other group. PCG-1α gene expression was unaffected by enalapril and lowered by enalapril + L-NAME. No differences in protein expression of Akt-1, pAkt-1, AMPKα, pAMPKα, or GLUT-4 were detected among groups. However, mTOR protein levels were increased by enalapril compared with placebo. Finally, all treatment groups displayed reduced SSM, but not IFM H2O2 production relative to placebo. Our data indicate that enalapril induces a number of metabolic adaptations in aged skeletal muscle. These effects result from the concerted modulation of NO and angiotensin II signaling, rather than from a dichotomous action of enalapril on the two pathways. Muscle protection by enalapril administered late in life appears to be primarily mediated by mitigation of oxidative stress and pro-inflammatory signaling.
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