Prolonged bed rest impairs rapid CPI-17 phosphorylation and contraction in rat mesenteric resistance arteries to cause orthostatic hypotension

Kitazawa, Toshio; Kitazawa, Kazuyo
December 2017
Pflugers Archiv European Journal of Physiology;Dec2017, Vol. 469 Issue 12, p1651
Academic Journal
Prolonged bed rest (PBR) causes orthostatic hypotension (OH). Rapid constriction of splanchnic resistance arteries in response to a sudden increase in sympathetic tone contributes to the recovery of orthostatic arterial pressure upon standing. However, the molecular mechanism of PBR-induced dysfunction in arterial constriction is not fully understood. Previously, we showed that CPI-17, a regulatory protein for myosin phosphatase, mediates α-adrenergic receptor-induced rapid contraction of small mesenteric arteries. Here, we tested whether PBR associated with OH affects the α-adrenergic receptor-induced CPI-17 signaling pathway in mesenteric arteries using rats treated by head-down tail-suspension hindlimb unloading (HDU), an experimental OH model. In normal anesthetized rats, mean arterial pressure (MAP) rapidly reduced upon 90° head-up tilt from supine position and then immediately recovered without change in heart rate, suggesting a rapid arterial constriction. On the other hand, after a 4-week HDU treatment, the fast orthostatic MAP recovery failed for 1 min. Alpha1A subtype-specific antagonist suppressed the orthostatic MAP recovery with a small decrease in basal blood pressure, whereas non-specific α-antagonist prazosin strongly reduced both basal MAP and orthostatic recovery. The HDU treatment resulted in 68% reduction in contraction in parallel with 83% reduction in CPI-17 phosphorylation in denuded mesenteric arteries 10 s after α-agonist stimulation. The treatment with either Ca-release channel opener or PKC inhibitor mimicked the deficiency in HDU arteries. These results suggest that an impairment of the rapid PKC/CPI-17 signaling pathway downstream of α-adrenoceptors in peripheral arterial constriction, as an end organ of orthostatic blood pressure reflex, is associated with OH in prolonged bed rest patients.


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