Corticosterone binds α1A-adrenoceptors with high affinity and induces strain-dependent vascular desensitization in female spontaneously hypertensive rats

Glucocorticoids are classically associated with hypertension, but their acute vascular effects remain incompletely understood. Female rats were selected due to their higher basal and stress-induced corticosterone levels, making them a physiologically relevant model. We investigated whether corticosterone directly modulates α1-adrenoceptor-mediated vasoconstriction in a strain- and age-dependent manner in female spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats. Vascular reactivity was evaluated in pithed rats and isolated aortic rings from SHR and WKY rats across different ages (young, aged, senescent). Concentration-response curves to phenylephrine were performed under control conditions, after acute corticosterone, and in the presence of selective α 1A -AR (5-methylurapidil) or α 1D -AR (BMY-7378) antagonists. Molecular docking assessed corticosterone binding affinity to α1-adrenoceptor subtypes. In pithed rats, corticosterone decreased phenylephrine sensitivity (increased ED 50 ) in young and aged SHR, with no effect in WKY. In aortic rings, corticosterone reduced phenylephrine sensitivity (decreased pD₂) exclusively in SHR. Principal component analysis revealed that corticosterone-treated SHR curves clustered with α 1A -AR antagonist treatment, suggesting shared signaling. Deviation from additivity analysis (%ΔAUC) showed antagonism between corticosterone and 5-methylurapidil in SHR. Docking demonstrated high-affinity corticosterone binding to α 1A -AR (ΔG = -9.14 kcal/mol; Ki = 198.13 nM). Pharmacological and docking evidence strongly suggest that corticosterone selectively desensitizes α1-adrenoceptor-mediated vasoconstriction in SHR through high-affinity α 1A -AR binding, although alternative mechanisms may contribute. This effect is preserved in young and aged SHR, but lost in senescent animals. This strain-specific, age-dependent interaction reveals a novel non-genomic glucocorticoid action on the vasculature, with implications for blood pressure regulation in hypertension and aging.