Browsing by Subject "Angiotensin II"
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Item Effects of aging and exercise training on the mechanisms of Angiotensin II-induced vasoconstriction in rat skeletal muscle arterioles(2009-05-15) Park, YoonjungAging is associated with increases in regional and systemic vascular resistance and impaired ability to increase blood flow to active muscles during exercise. Aging enhances vasoconstrictor responsiveness in both humans and animals, and an increase in Angiotensin II-induced vasoconstriction is one possible mechanism for old age-associated increase in muscle vascular resistance. The purpose of this study was to determine 1) whether aging alters Ang II-induced vasoconstriction, 2) whether exercise training attenuates the age-associated alteration in Ang II-mediated vasoconstriction, and 3) the mechanism(s) through which aging and exercise training alter Ang II-induced vasoconstriction in rat skeletal muscle arterioles. Male Fischer 344 rats were assigned to 4 groups: Young sedentary (YS; 4 months), old sedentary (OS; 24 months), young trained (YT) and old trained (OT). Exercise-trained groups performed treadmill exercises for 60 min/day at 15 m/min, on a 15? incline for 5 days/week for 10-12 weeks. First-order (1A) arterioles were isolated from soleus and gastrocnemius muscles for in vitro experimentation. Intraluminal diameter changes were determined in response to the cumulative addition of Ang II (3?10-11 - 3?10-5 M). Ang II dose responses were then determined following the removal of endothelium and treatment with NG-nitro-L-arginine methyl ester (L-NAME, 10-5 M), a nitric oxide synthase (NOS) inhibitor. Ang II-induced vasoconstriction was augmented in the aged skeletal muscle arterioles, both in soleus and gastrocnemius muscles, and age-associated increases in Ang II-induced vasoconstriction were abolished with the removal of endothelium and with L-NAME. Exercise training ameliorated the age-induced increase in Ang II-vasoconstriction, and this alteration was eliminated by the removal of endothelium and with NOS inhibition. These findings suggest that aging enhances Ang II-induced vasoconstrictor responses in the arterioles from both soleus, high oxidative, and white portion of gastrocnemius, low oxidative glycolytic muscles, and this age-associated change occurs through an endothelium-dependent NOS signaling pathway. These results also demonstrated that exercise training can ameliorate the age-associated increase in Ang II vasoconstriction in the arterioles from both high oxidative and low oxidative glycolytic muscles through an endothelium-mediated NOS mechanism.Item Evidence supporting a dual glucocorticoid and mineralocorticoid role for the elasmobranch steroid 1[alpha]-hydroxycorticosterone(2008-08) Evans, Andrew Neil, 1979-; Nunez, B. ScottIn mammals distinct steroid hormones termed mineralocorticoids (MCs) and glucocorticoids (GCs) regulate hydromineral balance and the stress response, respectively. In contrast, it is thought that a single corticosteroid, 1[alpha]-hydroxycorticosterone (1[alpha]-B) serves as both a GC and MC in elasmobranchs. I investigated the putative dual MC and GC roles of 1[alpha]-B by examining ex vivo regulation of interrenal 1[alpha]-B synthesis by osmoregulatory and stress hormones in the euryhaline stingray Dasyatis sabina. A commercial enzyme-linked immunoassay was adapted for the quantification of 1[alpha]-B. I also isolated cDNA sequences encoding two rate-limiting steroidogenic enzymes, the steroidogenic acute regulatory protein (StAR) and P450 cholesterol side-chain cleavage (P450scc), and characterized the steroidogenic activity of the encoded proteins using a heterologous expression system. Both the stress hormone adrenocorticotropic hormone (ACTH) and the antinatriuretic peptide angiotensin II (ANG II) were potently steroidogenic in ex vivo interrenal cultures, whereas C-type natriuretic peptide (CNP) inhibited 1[alpha]-B synthesis. StAR and P450scc mRNA levels were increased by 24 h incubation with ACTH and decreased by both ANG II and CNP. To examine changes in osmoregulatory hormone systems that impinge upon 1[alpha]-B synthesis, I also isolated the cDNA sequences of the ANG II and CNP receptors, AT and NPR-B. Both AT and NPR-B mRNA levels were significantly elevated in osmoregulatory tissues of freshwater (FW; Lake Monroe, FL) versus saltwater (SW; Corpus Christi Bay, TX) populations of D. sabina. Interrenal StAR and NPR-B mRNA levels were also significantly higher in FW individuals. The physiological roles of 1[alpha]-B were further investigated in vivo by examining the effects of stress and FW transfer on interrenal synthesis of 1[alpha]-B. Plasma 1[alpha]-B and glucose were significantly elevated by hook-and-line capture stress, indicating that 1[alpha]-B acts in classical GC fashion to facilitate the stress response. In contrast, 1[alpha]-B was significantly decreased 24 h after SW-FW transfer. In light of the osmotic strategy of euryhaline elasmobranchs, this result is consistent with a MC role for 1[alpha]-B. Taken together, the results of this research strongly support a dual role for 1[alpha]-B in facilitating both hydromineral balance and the stress response in elasmobranchs.Item ROLE OF AGE-ASSOCIATED OXIDATIVE STRESS IN ALTERED RENAL D1 AND AT1 RECEPTOR FUNCTIONS AND HYPERTENSION(2012-04-19) Chugh, Gaurav; Lokhandwala, Mustafa F.; Asghar, Mohammad; Hussain, Tahir; Prince, Randall A.; Shek, EugeneBlood pressure (BP) and oxidative stress increase with aging. Renal dopamine D1 (D1R) and angiotensin AT1 (AT1R) receptors by maintaining sodium homeostasis regulate blood pressure. Impaired D1R and exaggerated AT1R functions in the kidneys contribute to hypertension in animal models, which also exhibit oxidative stress. However, the role of oxidative stress in age-related hypertension has not been studied. In this study, we hypothesized that age-associated increase in oxidative stress by altering renal D1R and AT1R functions cause high BP in aging. To test this hypothesis, we measured oxidative stress, BP, and D1 and AT1 receptor functions in adult (3-month) and old (21-month) Fischer 344 X Brown Norway F1 (FBN) rats supplemented without/with antioxidant tempol. We found age-related increases in oxidative stress and blood pressure; which were reduced with tempol treatment in old FBN rats. D1R and AT1R functions were determined by measuring diuretic and natriuretic responses to SKF-38393 (D1R agonist) and candesartan (AT1 receptor antagonist) respectively. Natriuresis in response to D1R activation was impaired in old rats, suggesting an age-associated decline in D1R function in old FBN rats. Increase in G protein coupled receptor kinase (GRK) expression/activity is associated with reduced D1R-G protein coupling and function in humans and animal models with hypertension. We found age-associated increase in GRK-4 levels accompanied with D1R-G protein uncoupling in the renal proximal tubules of old FBN rats. Tempol treatment reduced GRK-4 levels and restored D1R-G protein coupling in these old rats. Natriuretic and diuretic responses to candesartan; however, were exaggerated in old rats, suggesting an age-associated increase in renal AT1R function in old FBN rats. Age-related increases in angiotensin II-mediated G protein coupling leading to exaggerated Na,K-ATPase activity may have caused increased renal AT1R function observed in old FBN rats. Tempol treatment restored angiotensin II-mediated G protein coupling and Na,K-ATPase response and thus reduced candesartan-mediated natriuresis and diuresis in old FBN rats. Our results demonstrate that both diminished renal D1R and exaggerated AT1R functions are associated with high BP in old FBN rats. Furthermore, oxidative stress may cause altered renal D1R and AT1R functions and high BP in these old rats.