Acidic NAADP-sensitive calcium stores in the endothelium: agonist-specific recruitment and role in regulating blood pressure.
Accumulating evidence implicates nicotinic acid adenine dinucleotide phosphate (NAADP) in the control of Ca(2+)-dependent functions. Little, however, is known concerning its role in the vascular endothelium, a major regulator of blood pressure. Here, we show that NAADP acetoxymethyl ester (NAADP-AM), a cell-permeant NAADP analog, increases cytosolic Ca(2+) concentration in aortic endothelial cells. We demonstrate that these signals and those evoked by acetylcholine are blocked by disrupting acidic organelles with bafilomycin A1. In contrast, Ca(2+) signals in response to thrombin are only partially inhibited by bafilomycin A1 treatment, and those to ATP were insensitive, suggesting that recruitment of acidic stores is agonist-specific. We further show that NAADP-evoked Ca(2+) signals hyperpolarize endothelial cells and generate NO. Additionally, we demonstrate that NAADP dilates aortic rings in an endothelium- and NO-dependent manner. Finally, we show that intravenous administration of NAADP-AM into anesthetized rats decreases mean arterial pressure. Our data extend the actions of NAADP to the endothelium both in vitro and in vivo, pointing to a previously unrecognized role for this messenger in controlling blood pressure.
Brailoiu
G Cristina
GC
Departments of Pharmacology, University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Gurzu
Bogdan
B
Gao
Xin
X
Parkesh
Raman
R
Aley
Parvinder K
PK
Trifa
Diana I
DI
Galione
Antony
A
Dun
Nae J
NJ
Madesh
Muniswamy
M
Patel
Sandip
S
Churchill
Grant C
GC
Brailoiu
Eugen
E
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D009249:NADP / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats
D018942:Macrolides; C531084:nicotinic acid adenine dinucleotide phosphate acetoxymethyl ester; D009249:NADP; C040929:bafilomycin A1; D002118:Calcium