Vasoactive intestinal polypeptide inhibits pacemaker activity via the nitric oxide-cGMP-protein kinase G pathway in the interstitial cells of Cajal of the murine small intestine.
Interstitial cells of Cajal (ICCs) are pacemaker cells that activate the periodic spontaneous depolarization (pacemaker potentials) responsible for the production of slow waves in gastrointestinal smooth muscle. The effects of vasoactive intestinal polypeptide (VIP) on the pacemaker potentials in cultured ICCs from murine small intestine were investigated by whole-cell patch-clamp techniques. Addition of VIP (50 nM-1 microM) decreased the amplitude of pacemaker potentials and depolarized resting membrane potentials. To examine the type of receptors involved in ICC, we examined the effects of the VIP1 agonist and found that it had no effect on pacemaker potentials. Pretreatment with VIP1 antagonist (1 microM) for 10 min also did not block the VIP (50 nM)-induced effects. On the other hand exposure to 1H-(1,2,4)oxadiazolo(4,3-A)quinoxalin- 1-one (ODQ, 100 microM), an inhibitor of guanylate cyclase, prevented VIP inhibition of pacemaker potentials. Similarly KT-5823 (1 microM) or RP-8-CPT-cGMPS (10 microM), inhibitors of protein kinase G (PKG) blocked the effect of VIP (50 nM) on pacemaker potentials as did N-nitro-L-arginine (L-NA, 100 mM), a non-selective nitric oxide synthase (NOS) inhibitor. These results imply that the inhibition of pacemaker activity by VIP depends on the NO-cGMP-PKG pathway.
Kim
Byung Joo
BJ
Department of Physiology and Biophysics, Seoul National University College of Medicine, Seoul 110-799, Korea.
Lee
Jae Hwa
JH
Jun
Jae Yeoul
JY
Chang
In Youb
IY
So
Insuk
I
Kim
Ki Whan
KW
D000818:Animals; D001683:Biological Clocks / Q000187:drug effects*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015398:Signal Transduction; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D009569:Nitric Oxide; D014660:Vasoactive Intestinal Peptide; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP