Abstract 534: Increased in vivo Sympathetic Tone in Femoral Arteries of MLCK Biosensor Mice Exposed to Chronic Intermittent Hypoxia

Abstract

Increased sympathetic nerve activity (SNA) has been implicated in hypertension induced by chronic exposure to intermittent hypoxia (CIH) in both human and rodents. We have previously reported that the basal femoral arterial tone in vivo was primarily mediated by α1-adrenergic SNA, and hence was useful for assessing SNA in living animals in disease models, such as hypertension. While SNA hyperactivity is believed to be region specific in certain types of hypertension, such as that induced by angiotensin II plus salt, the aim of this study is to determine whether sympathetic tone is increased in femoral arteries in CIH-induced hypertension and to characterize vascular reactivity in CIH animals. Mice with smooth muscle-specific FRET-based Ca/calmodulin sensitive myosin light chain kinase biosensor were exposed to CIH (5% nadir O 2 for 1 min, followed by 21% O 2 for 1 min) or sham exposure (21% O 2 constantly) 8 hrs/day for 5 weeks. At the end of the exposure, blood pressure, measured with an intra-carotid artery catheter (1.5% isoflurane), was greatly increased in CIH group (91 ± 4 mm Hg, n = 8, vs. 83 ± 2 mm Hg in sham control, n = 6, P < 0.05). Mid-thigh femoral arteries were slightly dissected and superfused with physiological saline solution. Simultaneous arterial diameter and quantitative cytoplasmic [Ca 2+ ] in smooth muscle cells within intact arteries were measured with Intra-Vital FRET microscopy. Under resting condition, femoral arteries from CIH-treated mice exhibited significantly increased basal tone (38 ± 4% vs 29 ± 4% of PD in control group, n = 5/group) and [Ca 2+ ] (280 ± 27 vs 205 ± 27 nM). Local application, to the exposed portion of arteries, of phentolamine (0.01-3 μM) and prazosin (1 μM), caused more relaxation and [Ca 2+ ] reduction in CIH than in handled control group. Dose-dependent vasoconstriction induced by phenylephrine, however, was similar, suggesting that the expression or sensitivity of the adrenoceptor was not altered. Passive outer diameter, an indicator of arterial remodeling, measured in Ca 2+ -free solution, were not different between control and CIH groups. These results indicate that the increased femoral arterial tone in vivo was also neurogenic, primarily due to hyper-(central) SNA in mice that developed hypertension following CIH.