Desoxycorticosterone Acetate

In DOCA-salt hypertensive rats, sex differences in vascular reactivity are mediated by differential activation of the ERK1/2 signaling pathway. Male rats display elevated blood pressure and enhanced contractile responses to phenylephrine in both aortas and small mesenteric arteries compared to females. This augmented contraction is driven by increased phosphorylation and activation of ERK1/2 in the vasculature of males, leading to downstream activation of target proteins such as STAT-3 and ELK-1. The mechanism involves reduced phosphorylation and activity of mitogen-activated protein kinase phosphatase-1 (MKP-1), a phosphatase that normally dephosphorylates and inactivates ERK1/2. Lower MKP-1 activity in male DOCA-salt rats results in sustained ERK1/2 signaling. Additionally, plasma levels of interleukin-10 (IL-10), an anti-inflammatory cytokine that positively regulates MKP-1, are decreased in males.

Fig. 1 ERK1/2 phosphorylation is increased in aorta from male DOCA-rats. (Giachini F R.; et al. 2009)

Desoxycorticosterone acetate (DOCA) was formulated into 200 mg subcutaneous pellets for sustained release over three weeks to induce mineralocorticoid hypertension in uninephrectomized rats. Male DOCA‑salt rats developed significantly higher mean arterial pressure (191±3 mm Hg) compared to female DOCA‑salt rats (172±7 mm Hg). The hypertensive response was associated with augmented vascular contractility to phenylephrine in aorta and mesenteric arteries from male rats, which was mediated by enhanced ERK1/2 activation and downregulation of MKP‑1. ERK1/2 inhibition with PD‑98059 eliminated the sex difference in vascular reactivity. This study validated the DOCA‑salt pellet implantation as a reliable sustained‑release model for investigating sex‑dependent mechanisms in hypertension.

Fig. 2 MKP-1 phosphorylation is decreased in aorta from male DOCA-rats. (Giachini F R.; et al. 2010)