Abstract
Introduction: We have reported that upregulation of the endothelin (ET) system plays a pivotal role in a mouse model of preeclampsia. Because ETA receptor antagonists are teratogenic, we cannot use them to treat pregnant women. Nicotinamide (Nam) inhibits ADP ribosyl cyclase (ADPRC), diminishes a release of Ca 2+ from intracellular stores, and dilates vessels constricted by ET. We have recently reported that Nam ameliorates the high BP induced by excessive sFlt-1. Nam also shows beneficial effects on pregnancy maintenance and fetal growth. Objective: The aim of the present study is to clarify the depressor mechanisms of Nam. Methods: We measured tail-cuff BP before and 5 days after administering 1x10 9 pfu sFlt-1 in non-pregnant WT mice and mice lacking CD38, the major form of ADPRC. We next measured SBP using radiotelemetry to investigate effects of Nam 500 mg/kg BW by using DAB (2,2’-dihydroxyazobenzene, a specific inhibitor of ADPRC) 0.1 mmol/kg BW, CrMP (chromium mesoporphyrin, a specific inhibitor of heme oxygenase) 2 μmol/kg, or fasudil (a Rho kinase inhibitor) 40 mg/kg. Results: Lack of CD38 prevented sFlt-1 induced hypertension (WT 106.0 ± 2.1 mmHg, CD38-/- 105.0 ± 2.1 mmHg, WT sFlt-1 126.3 ± 2.0 mmHg, CD38-/- sFlt-1 110.2 ± 1.2 mmHg), and diminished the decrease in SBP by Nam. DAB transiently decreased SBP, whereas Nam has a depressor effect lasting more than an hour. Pretreatment with CrMP for 30 min reversed the hypotensive effect of Nam within 60min. Both Nam and fasudil decreased elevated BP by sFlt-1, and the combination of them additively decreased BP (sFlt-1 145.9 ± 3.6 mmHg, sFlt-1+Nam 122.9 ± 7.1 mmHg, sFlt-1+fasudil 93.6 ± 9.7 mmHg, sFlt-1+Nam+fasudil 81.9 ± 8.9 mmHg). Conclusions: Nam decreases BP in mice by inhibiting ADPRC and by increasing the production of HO-1. Fasudil explains why depressor effect of Nam is smaller than that of inhibiting ETAR. However, because fasudil is teratogenic, Nam is a promising drug to treat hypertension in preeclampsia.
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