Although dexamethasone (DEX) is known to cause hypertension in humans and in animals, the hemodynamic characteristics of DEX-induced hypertension (DEX-HT) in the rat remain unclear. This study evaluated central and regional hemodynamics, and the role of total peripheral resistance (TPR) using a vasodilator minoxidil. Rats were divided into four groups, namely saline (n¼20), DEX (n¼21), minoxidil+saline (n¼10) and minoxidil+DEX (n¼10). Tail-cuff systolic blood pressure was recorded every second day. After 10-14 days of treatment, central (saline: n¼9, DEX: n¼10) and regional (saline: n¼11, DEX: n¼11) hemodynamic parameters were measured. Central hemodynamic data were also obtained from minoxidil-treated rats. DEX increased blood pressure (Po0.0005) in association with an increase in TPR (Po0.05). However, individual assessments of renal, mesenteric and hindquarter circulations did not detect any significant increase in resistance in these beds. Minoxidil increased cardiac output (P ¢o0.01) and cardiac index (P ¢o0.005) as well as decreased TPR (P¢o0.05) without affecting DEX-HT. DEX prevented weight gain and decreased thymus weight. The increase in TPR in DEX-HT in rats was not simply explained by isolated alterations to resistance in the renal, mesenteric or hindquarter circulations. Minoxidil effectively prevented the increase in TPR but not the increase in blood pressure, suggesting that an increase in TPR is not essential for DEX-induced blood pressure increase. Keywords: dexamethasone; hemodynamics; minoxidil; total peripheral resistance INTRODUCTION Synthetic glucocorticoid dexamethasone (DEX) is commonly used in clinical settings for the treatment of various medical conditions. It is used in adrenal insufficiency as a glucocorticoid hormone replacement treatment, in multiple myeloma together with other chemotherapeutic agents, to decrease cerebral edema due to intracranial pathology and as an anti-emetic in patients with cancer. When used chronically at a supra-physiological dose, DEX results in hypertension. The underlying mechanism for DEX-induced hypertension (DEX-HT) remains unclear. We have recently reviewed postulated mechanisms of DEX-HT. 1 There is evidence against plasma volume expansion 2 or sympathetic nerve activation 3 as key mechanisms of DEX-HT in humans. The roles of endogenous vasoconstrictors and vasodilators in DEX-HT are variable, with possible associations with nitric oxide, prostanoids, angiotensin II, arginine vasopressin, endothelins, catecholamines, neuropeptide Y and atrial natriuretic peptide. 1 Studies on DEX-HT in rodents have indicated that nitric oxide deficiency 4 and oxidative stress 5 are implicated in this form of hypertension. Nevertheless, the hemodynamic profile has not been fully evaluated in this model.The hemodynamics of DEX-HT has been evaluated in both humans 6 and dogs. 7 DEX-HT in humans (3 mg per day) was associated with increased total peripheral resistance (TPR) without any
Aims. To examine the effect of alpha-lipoic acid, an antioxidant with mitochondrial superoxide inhibitory properties, on adrenocorticotrophic hormone- (ACTH-HT) and dexamethasone-induced hypertensions (DEX-HT) in rats and if any antihypertensive effect is mediated via mitochondrial superoxide inhibition. Methods. In a prevention study, rats received ground food or alpha-lipoic-acid-laced food (10 mg/rat/day) for 15 nights. Saline, adrenocorticotrophic hormone (ACTH, 0.2 mg/kg/day), or dexamethasone (DEX, 10 μg/rat/day) was injected subcutaneously from day 5 to day 11. In a reversal study, rats received alpha-lipoic-acid-laced food 4 days after commencement of saline or DEX. Tail-cuff systolic blood pressure (SBP) was measured second daily. Kidney mitochondrial superoxide was examined using (MitoSOX) Red (MitoSOX) via flow cytometry. Results. SBP was increased by ACTH (P < 0.0005) and DEX (P < 0.0005). Alpha-lipoic acid alone did not alter SBP. With alpha-lipoic acid pretreatment, SBP was increased by ACTH (P′ < 0.005) but not by DEX. Alpha-lipoic partially prevented ACTH-HT (P′ < 0.0005) and fully prevented DEX-HT (P′ < 0.0005) but failed to reverse DEX-HT. ACTH and DEX did not increase MitoSOX signal. In ACTH-hypertensive rats, high-dose alpha-lipoic acid (100 mg/rat/day) did not decrease SBP further but raised MitoSOX signal (P < 0.001), suggesting prooxidant activity. Conclusion. Glucocorticoid-induced hypertension in rats is prevented by alpha-lipoic acid via mechanisms other than mitochondrial superoxide reduction.
When performed in patients > 70 years old, angioplasty and coronary bypass surgery result in similar long-term survival rates but otherwise distinctly different clinical courses.
Sepiapterin did not prevent ACTH- or dexamethasone-induced hypertension. NOLA exacerbated dexamethasone-induced hypertension. These data suggest that eNOS uncoupling does not play a major role in the genesis of glucocorticoid-induced hypertension in the rat.
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