Phosphoinositide Dependent Kinase 1 (PDK1) Contributes to Intermittent Hypoxia‐induced Hypertension

Abstract

Obstructive sleep apnea (OSA) is a risk factor for hypertension. Previous studies from our laboratory demonstrate increased blood pressure in rats exposed to the intermittent hypoxia (IH) model of OSA and increased endothelin‐1 (ET‐1)‐mediated constriction in mesenteric arteries from IH‐exposed rats that is dependent on protein kinase C δ (PKCδ). Phosphoinositide dependent kinase 1 (PDK1) is an upstream regulator of PKCδ. We hypothesized that PDK1contributes to increased ET‐1 constriction and increased blood pressure in IH‐exposed rats. Rats were exposed to IH episodes (cycles between 21% O2/0% CO2 and 5% O2/5% CO2) for 7 hours/day for 14 or 21 days and compared to control rats (maintained at 21% O2/0% CO2). Blood pressure was monitored by telemetry. After 21 days of IH or sham exposure, rats were given a PDK1 inhibitor OSU‐03012 or placebo (33 mg/kg/day) for 3 days. Constriction to ET‐1 but not phenylephrine (PE) was greater in pressurized mesenteric arteries from IH rats compared to control. Inhibiting PDK1 or PKCδ diminished ET‐1 but not PE constriction in arteries from IH rats. Blood pressure was increased in IH compared to control rats. Inhibiting PDK1 in vivo decreased blood pressure in IH rats but had no effect in control rats. Our results provide evidence of a novel role for PDK1/PKCδ in blood pressure regulation in a rodent model of OSA and point to this pathway as a target for blood pressure control in OSA patients.