Correlation of HO-1 expression with onset and reversal of hypoxia-induced vasoconstrictor hyporeactivity

Rats exposed to chronic hypoxia (CH; 4 wk at 0.5 atm) exhibit attenuated re nal vasoconstrictor reactivity to phenylephrine (PE). Preliminary studies f rom our laboratory suggest that this response is mediated by hypoxic induct ion of heme oxygenase (HO) and subsequent release of the endogenous vasodil ator carbon monoxide. Because vascular HO mRNA is increased within hours of hypoxic exposure, we hypothesized that the onset of reduced reactivity may occur fairly rapidly and correlate with HO expression. Therefore, we exami ned the onset of attenuated vasoconstriction on CH exposure as well as the duration of hyporeactivity on return to a normoxic environment. Renal vascu lar resistance (RVR) responses to graded intravenous infusion of PE were me asured in conscious rats under control conditions and after 24 h, 48 h, and 4 wk of CH exposure. Vasoreactivity responses were also determined in 4-wk CH rats 1, 5, 24, and 96 h after return to normoxia. We found that RVR res ponses to PE were significantly blunted after 48 h and 4 wk but not after 2 4 h of hypoxic exposure. Inhibition of HO with zinc protoporphyrin IX incre ased RVR and decreased renal blood flow in 48-h CH rats but not controls. A lthough reactivity to PE was gradually restored after 4 wk of CH, responsiv eness was still slightly blunted at 96 h after return to normoxia. Western blot analysis demonstrated a correlation between HO-1 protein levels and at tenuated vasoconstrictor response in CH and posthypoxic rats. These data su ggest that the onset and offset of physiologically relevant vascular HO exp ression occur within 2-3 days.