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

Abstract

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 α1A-adrenergic receptor-induced rapid contraction of small mesenteric arteries. Here, we tested whether PBR associated with OH affects the α1-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 α1-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 α1-agonist stimulation. The treatment with either Ca2+-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 α1A-adrenoceptors in peripheral arterial constriction, as an end organ of orthostatic blood pressure reflex, is associated with OH in prolonged bed rest patients.

• Authors: Toshio Kitazawa, Kazuyo Kitazawa
• Journal: Pflugers Archiv : European journal of physiology (Pflugers Arch) Vol. 469 Issue 12 Pg. 1651-1662 (Dec 2017) ISSN: 1432-2013 [Electronic] Germany
• PMID: 28717991 (Publication Type: Journal Article)

Chemical References

• Muscle Proteins
• Phosphoproteins
• Ppp1r14a protein, rat

Topics

• Animals
• Arterial Pressure (physiology)
• Bed Rest (adverse effects)
• Female
• Head-Down Tilt (adverse effects, physiology)
• Heart Rate (physiology)
• Hypotension, Orthostatic (etiology, metabolism)
• Male
• Mesenteric Arteries (metabolism)
• Muscle Proteins (metabolism)
• Phosphoproteins (metabolism)
• Phosphorylation
• Rats
• Rats, Sprague-Dawley