CGRP mediate the isosorbide-5-mononitrate cardiovascular response in healthy Chinese male volunteers through a XOR-independent pathway.
OBJECTIVE
This study was designed to determine whether xanthine oxidoreductase (XOR) is involved in Isosorbide- 5-mononitrate (IS-5-MN) metabolism, and to elucidate the role of the neuropeptide calcitonin gene-related peptide (CGRP) in the IS-5-MN response.


METHODS
In 15 Chinese volunteers, we observed the relationship between baseline XOR-mRNA expression in peripheral blood mononuclear cells (PBMCs) and the response to 20 mg IS-5-MN. IS-5-MN pharmacokinetics profiles, changes in plasma concentrations of CGRP, and CGRPmRNA expression in PBMCs were assessed in vivo and in vitro.


RESULTS
Individuals with a lower baseline XOR-mRNA expression showed lower plasma XOR activity and significantly greater changes in SBP (ΔSBP) after IS-5-MN administration. Individuals with a lower baseline XOR-mRNA expression also showed significantly greater increases in plasma concentrations of CGRP. There were no differences in IS-5-MN AUC between the two groups. IS-5-MN significantly up-regulated the expression of CGRP α- and CGRP β-mRNA in PBMCs, which were not affected by the XOR inhibitor allopurinol.


CONCLUSIONS
Our study suggests that CGRP may contribute to the response to IS-5 MN in a XOR-independent pathway.
Zuoliang
Z
Liu
Bikui
B
Zhang
Xin
X
Guo
Lei
L
Chen
Dongyang
D
Yi
Junzi
J
Cong
Ren
R
Guo
D000284:Administration, Oral; D000328:Adult; D000493:Allopurinol / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D044466:Asian People; D001794:Blood Pressure / Q000187:drug effects*; D015740:Calcitonin Gene-Related Peptide / Q000097:blood* / Q000235:genetics; D002478:Cells, Cultured; D002681:China; D004791:Enzyme Inhibitors / Q000494:pharmacology; D064368:Healthy Volunteers; D006801:Humans; D007548:Isosorbide Dinitrate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000097:blood; D015398:Signal Transduction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics
D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D014665:Vasodilator Agents; D000493:Allopurinol; D014969:Xanthine Oxidase; D007548:Isosorbide Dinitrate; D015740:Calcitonin Gene-Related Peptide; C030397:isosorbide-5-mononitrate