Glucocorticoids modulate vascular reactivity in the rat.
To clarify the role of endogenous glucocorticoids in the regulation of blood pressure, the cardiovascular effects of RU 486, a steroid derivative with antiglucocorticoid properties, were investigated in Wistar rats. Pressor responses to angiotensin II (Ang II), norepinephrine, and vasopressin were studied in normal conscious rats before and after administration of RU 486. At 20 mg/kg/day, RU 486 significantly blunted pressor responses to Ang II and norepinephrine, whereas those to vasopressin were not greatly affected. At a lower dose, RU 486 did not alter pressor responses; at a higher dose, it augmented them, probably through its agonistic glucocorticoid effect. At 20 mg/kg/day, RU 486 antagonized the enhancing effect of a glucocorticoid agonist on pressor responses to Ang II, norepinephrine, and vasopressin. Cardiac output and renal blood flow were measured in anesthetized rats by the microsphere method. RU 486 at 20 mg/kg/day did not alter basal cardiac output and renal blood flow. RU 486 pretreatment attenuated pressor responses to Ang II and norepinephrine but did not alter cardiac output. It significantly blunted the decrease in renal blood flow and the increase in renal vascular resistance induced by Ang II. In rats fed a low sodium diet (where the pressor systems are stimulated), administration of RU 486 (20 mg/kg/day for 5 days) decreased total peripheral vascular resistance by 29% and mean blood pressure by 20 mm Hg. This effect was unrelated to any antimineralocorticoid activity of the compound, as shown by unchanged urinary sodium excretion, sodium balance, and plasma renin concentration. In contrast, it was due to the antiglucocorticoid activity, as shown by restoration of mean blood pressure by corticosterone, the major glucocorticoid in rats. Renal vascular resistance decreased during RU 486 administration in anesthetized (-25%) and unanesthetized (-19%) rats. Glomerular filtration rate, estimated from inulin clearance in conscious rats, did not change significantly. In conclusion, the present results suggest that endogenous glucocorticoids increase vascular reactivity and therefore contribute to blood pressure regulation. They also participate in the control of renal hemodynamics. This effect is most apparent in salt-restricted rats. The vascular action of glucocorticoids was unmasked by the administration of the antiglucocorticoid compound RU 486.
Department of Nephrology, Institut National de la Santé et de la Recherche Medicale U-90, Necker Hospital, Paris, France.
J P
JP
Grünfeld
L
L
Eloy
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D001794:Blood Pressure; D002302:Cardiac Output / Q000187:drug effects; D004039:Diet, Sodium-Restricted; D004963:Estrenes / Q000494:pharmacology*; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D015735:Mifepristone; D009638:Norepinephrine / Q000494:pharmacology; D011311:Pressoreceptors / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects*
D004963:Estrenes; D005938:Glucocorticoids; D000804:Angiotensin II; D001127:Arginine Vasopressin; D015735:Mifepristone; D009638:Norepinephrine