Exogenous calmodulin potentiates vasodilation elicited by phospholipid-associated VIP in vivo.
The purpose of this study was to determine whether exogenous calmodulin potentiates vasoactive intestinal peptide (VIP)-induced vasodilation in vivo and, if so, whether this response is amplified by association of VIP with sterically stabilized liposomes. Using intravital microscopy, we found that calmodulin suffused together with aqueous and liposomal VIP did not potentiate vasodilation elicited by VIP in the in situ hamster cheek pouch. However, preincubation of calmodulin with liposomal, but not aqueous, VIP for 1 and 2 h and overnight at 4 degrees C before suffusion significantly potentiated vasodilation (P < 0.05). Calmodulin-induced responses were significantly attenuated by calmidazolium, trifluoperazine, and NG-nitro-L-arginine methyl ester (L-NAME) but not D-NAME. The effects of L-NAME were reversed by L- but not D-arginine. Indomethacin had no significant effects on calmodulin-induced responses. Calmodulin had no significant effects on adenosine-, isoproterenol-, acetylcholine-, and calcium ionophore A-23187-induced vasodilation. Collectively, these data indicate that exogenous calmodulin amplifies vasodilation elicited by phospholipid-associated, but not aqueous, VIP in the in situ peripheral microcirculation in a specific, calmodulin active sites-, and nitric oxide-dependent fashion. We suggest that extracellular calmodulin, phospholipids, and VIP form a novel functionally coordinated class of endogenous vasodilators.
Ikezaki
H
H
Department of Medicine, University of Illinois at Chicago, Illinois 60612, USA.
Patel
M
M
Onyüksel
H
H
Akhter
S R
SR
Gao
X P
XP
Rubinstein
I
I
D000109:Acetylcholine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001160:Arterioles / Q000502:physiology; D000001:Calcimycin / Q000494:pharmacology; D002147:Calmodulin / Q000494:pharmacology*; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008081:Liposomes / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D008833:Microcirculation / Q000502:physiology; D009061:Mouth Mucosa / Q000098:blood supply / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002147:Calmodulin; D004791:Enzyme Inhibitors; D007476:Ionophores; D008081:Liposomes; D010743:Phospholipids; D014665:Vasodilator Agents; D014660:Vasoactive Intestinal Peptide; D000001:Calcimycin; D019001:Nitric Oxide Synthase; D000241:Adenosine; D007545:Isoproterenol; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin