RATIONALE: Obesity leads to high cardiovascular morbidity and mortality via multiple mechanisms including obstructive sleep apnea (OSA) and hypertension. Intermittent hypoxia (IH), a hallmark manifestation of OSA, is an established cause of hypertension. The carotid body (CB) has been implicated in the pathogenesis of hypertension in IH and obesity. We discovered that obesity-induced hypertension is mediated via the transient receptor potential melastatin 7 (TRPM7) channel in the glomus cells of CB. Here, we investigate the relevance of TRPM7 signaling in CB for the pathogenesis of hypertension by IH. We developed a novel technique allowing continuous sustained release of the TRPM7 inhibitor FTY720 into the CB area using a hydrogel formulation with a single injection abolishing hypertension in obesity for 3 weeks. We hypothesize that IH causes hypertension acting on CB TRPM7.
Methods: C57BL/6J male mice (n = 9) were implanted with telemetry in the left femoral artery for continuous blood pressure monitoring and exposed to IH for 5 days. IH was administered by decreasing O2 levels from 21% to 6%, 60 cycles/hr, during the light phase, 9AM -9PM. FTY720 hydrogel (n = 5) or control hydrogel (N = 4) were applied locally to the CB region. Blood pressure was recorded at baseline and during IH and the measurement was repeated 2 weeks after hydrogel application. RESULT: IH increased mean arterial pressure from 103.8±1.2 mmHg to 114.3±1.4 mmHg on Day 1 of IH and to 113.0±0.6 mmHg on Day 5 of IH respectively. FTY720 hydrogel abolished IH-induced hypertension by decreasing blood pressure to 106.6±1.6 mmHg (plt;0.005) on Day 1 of IH and to 101.5±1.6 mmHg (plt;0.001) on Day 5 of IH. In contrast, control hydrogel had no effect on IH-induced hypertension.
Conclusion: Our study has shown that inhibition of TRPM7in the carotid bodies abolished IH-induced hypertension.
