Premium
Mechanisms of PTHrP‐induced inhibition of smooth muscle contractility in the guinea pig gastric antrum
Author(s) -
Ohguchi H.,
Mitsui R.,
Imaeda K.,
Joh T.,
Hashitani H.
Publication year - 2017
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.13142
Subject(s) - endocrinology , medicine , contractility , antrum , chemistry , nitric oxide , smooth muscle tissue , cyclic guanosine monophosphate , parathyroid hormone related protein , soluble guanylyl cyclase , biology , stomach , parathyroid hormone , calcium , smooth muscle , guanylate cyclase
Background Parathyroid hormone‐related protein ( PTH rP) that causes hypercalcemia of malignancy appears to function as an endogenous smooth muscle relaxant. For example, PTH rP released upon bladder wall distension relaxes detrusor smooth muscle to accommodate urine. Here, we explored mechanisms underlying PTH rP‐induced suppression of the smooth muscle contractility in the gastric antrum that also undergoes a passive distension. Methods Effects of PTH rP on phasic contractions and electrical slow waves in the antral smooth muscle of the guinea pig stomach were studied using isometric tension and intracellular microelectrode recordings, respectively. Fluorescent immunohistochemistry was also carried out to identify the distribution of PTH / PTH rP receptors. Key Results Parathyroid hormone‐related protein (1‐100 nM) reduced the amplitude of phasic contractions and the basal tension. N ω ‐nitro‐ l ‐arginine (L‐NA, 100 μM), a nitric oxide ( NO ) synthase inhibitor, or 1H‐[1,2,4]oxadiazolo‐[4, 3‐a]quinoxalin‐1‐one (ODQ, 10 µM), a guanylate cyclase inhibitor, diminished the PTH rP (10 nM)‐induced reduction in the amplitude of phasic contractions. SQ22536 (300 μM), an adenylate cyclase inhibitor, attenuated the PTH rP‐induced reduction in basal tension. The combination of ODQ (10 μM) and SQ22536 (300 μM) inhibited the PTH rP‐induced reductions in both phasic contractions and basal tension. PTH rP (100 nM) had no inhibitory effect on the electrical slow waves in the antral smooth muscle. PTH / PTH rP receptors were expressed in cell bodies of PGP9.5‐positive neurons in the myenteric plexus. Conclusions & Inferences Parathyroid hormone‐related protein exerts its inhibitory actions on the antral smooth muscle via both nitric oxide‐cyclic guanosine monophosphate (NO‐cGMP) and cyclic adenosine monophosphate (AMP) pathways. Thus, PTH rP may act as an endogenous relaxant of the gastric antrum employing the two complementary signaling pathways to ensure the adaptive relaxation of stomach.