Hemodynamics of dexamethasone-induced hypertension in the rat

Abstract

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

Glucocorticoids and the Cardiovascular System

“…Since the increase in total peripheral resistance was prevented while the increase in blood pressure was not, the authors suggest that increased total peripheral resistance is not necessary for the development of glucocorticoid-induced hypertension. They speculate that changes in cardiac output and specifi cally stroke volume and resulting plasma expansion may have offset the vasodilator effects of minoxidil though there were no observed differences in hematocrit between the dexamethasone only treated rats and the minoxidil and dexamethasone treated rats in this study [ 46 ].…”

“…A recent study in rats by Ong et al is one of the only attempts in vivo to try to dissect the underlying mechanism of hypertension by examining regional blood fl ow [ 46 ]. In this study, central and regional blow fl ows of dexamethasone-treated rats were compared to those of rats treated with minoxidil and dexamethasone, saline alone and minoxidil alone.…”

Glucocorticoid-induced hypertension

“…Since the increase in total peripheral resistance was prevented, while the increase in blood pressure was not, the authors suggest that increased total peripheral resistance is not necessary for the development of glucocorticoid-induced hypertension. They speculate that changes in cardiac output and specifically stroke volume and resulting plasma expansion may have offset the vasodilator effects of minoxidil, even though there were no observed differences in hematocrit between the dexamethasone-only-treated rats and the minoxidil-and dexamethasone-treated rats in this study [47].…”

“…A recent study in rats by Ong et al is one of the only attempts in vivo to try to dissect the underlying mechanism of hypertension by examining regional blood flow [47]. In this study, central and regional blood flows of dexamethasone-treated rats were compared with those of rats treated with minoxidil and dexamethasone, saline alone, and minoxidil alone.…”

Dexamethasone Upregulates Nox1 Expression in Vascular Smooth Muscle Cells

“…Dexamethasone is the most potent synthetic glucocorticoid which, unlike the naturally occurring cortisol and corticosterone, has virtually pure glucocorticoid activity with negligible mineralocorticoid effects [3]. The long-term use of glucocorticoids is associated with a number of side effects including hypertension [3].…”