Dexamethasone Causes Hypertension in Rats Even Under Chemical Blockade of Peripheral Sympathetic Nerves

Abstract

Synthetic glucocorticoids (GCs) are widely used to treat inflammatory conditions. However, chronic use of GCs can lead to hypertension. The cause of this undesired side effect remains unclear. Previously, we developed an in vivo rat model to study the mechanisms underlying hypertension induced by the chronic administration of the potent synthetic GC, dexamethasone (DEX) and found that the catecholamine biosynthetic pathway plays an important role. In the current study, we used this model to investigate the role of the adrenal medulla, renal nerves, and other peripheral sympathetic nerves in DEX-induced hypertension. After 5 days of baseline telemetric recording of mean arterial pressure (MAP) and heart rate (HR), rats were subjected to one of the following treatments: renal denervation (RDNX), adrenal medullectomy (ADMX), 6-hydroxydopamine (6-OHDA, 20 mg/kg, i.p.) to induce chemical sympathectomy, or a combination of ADMX and 6-OHDA. On day 11, the animals received vehicle (VEH) or DEX in drinking water for 7 days, with the latter causing an increase in MAP in control animals. ADMX and RDNX by themselves exacerbated the pressor effect of DEX. In the chemical sympathectomy group, DEX still caused a rise in MAP but the response was lower (ΔMAP of 6-OHDA/DEX < VEH/DEX, p = 0.039). However, when ΔMAP was normalized to day 10, 6-OHDA + DEX did not show any difference from VEH + DEX, certainly not an increase as observed in DEX + ADMX or RDNX groups. This indicates that sympathetic nerves do not modulate the pressor effect of DEX. TH mRNA levels increased in the adrenal medulla in both VEH/DEX (p = 0.009) and 6-OHDA/DEX (p = 0.031) groups. In the 6-OHDA group, DEX also increased plasma levels of norepinephrine (NE) (p = 0.016). Our results suggest that the activation of catecholamine synthetic pathway could be involved in the pressor response to DEX in animals even under chemical sympathectomy with 6-OHDA.

The Use of the Anticoagulant Heparin and Corticosteroid Dexamethasone as Prominent Treatments for COVID-19

“…Besides, hypertensive patients, who are also at risk for COVID-19 severity, should be at constant monitoring during dexamethasone treatment, once GCs-induced hypertension is frequently observed (115). High dexamethasone doses are associated with increased sodium retention, which leads to the elevation of blood pressure, in addition to chemical alteration of peripheral nerves homeostasis (87,116,117). This effect could lead to complications rather than COVID-19 treatment, increasing the associated mortality risks of the affected individuals.…”

Possible value of galectin‐3 on follow‐up of cardiac remodeling during glucocorticoid treatment

“…Although some studies showed the positive effects of glucocorticoids on the contractile performance of the heart, [8,10] these effects might depend on the dose and the treatment duration. [11,12] Glucocorticoid treatment in the short-term with low doses has positive effects such as an increase in cardiac functions, and a decrease in inflammation; however, chronic glucocorticoid treatment causes hypertension, [13] left ventricular atrophy, cardiac fibrosis. [11] Previous studies of chronic treatment of glucocorticoids also contribute to the development of fibrosis, heart failure, and cardiac arrest.…”

“…[11] Previous studies of chronic treatment of glucocorticoids also contribute to the development of fibrosis, heart failure, and cardiac arrest. [4,9,13,37,38] However, the mechanism linking glucocorticoid-induced insulin resistance in cardiovascular disease are not well elucidated.…”

“…[ 3‐5 ] Like a double‐edged sword, glucocorticoids have significant effects on the cardiovascular system and heart functions. [ 6,7 ] The positive effects of glucocorticoids on the contractile performance of the heart [ 8‐10 ] and cardiomyocyte apoptosis in short‐term treatment [ 11,12 ] turn into a risk factor contributing to the formation of several cardiovascular diseases such as insulin resistance induced high blood pressure, [ 13 ] cardiac fibrosis, [ 11 ] atherosclerosis, [ 14,15 ] heart failure, and cardiac arrest. [ 4,16 ]…”

“…[3][4][5] Like a double-edged sword, glucocorticoids have significant effects on the cardiovascular system and heart functions. [6,7] The positive effects of glucocorticoids on the contractile performance of the heart [8][9][10] and cardiomyocyte apoptosis in short-term treatment [11,12] turn into a risk factor contributing to the formation of several cardiovascular diseases such as insulin resistance induced high blood pressure, [13] cardiac fibrosis, [11] atherosclerosis, [14,15] heart failure, and cardiac arrest. [4,16] A β-galactoside-binding lectin, galectin-3 (Gal-3), is expressed in several cells, including epithelial and inflammatory cells, and plays a critical role in cellular processes such as inflammation, apoptosis, and differentiation.…”