Esophageal muscle physiology and morphogenesis require assembly of a collagen XIX–rich basement membrane zone

Collagen XIX is an extremely rare extracellular matrix component that localizes to basement membrane zones and is transiently expressed by differentiating muscle cells. Characterization of mice harboring null and structural mutations of the collagen XIX (Col19a1) gene has revealed the critical contribution of this matrix protein to muscle physiology and differentiation. The phenotype includes smooth muscle motor dysfunction and hypertensive sphincter resulting from impaired swallowing-induced, nitric oxide–dependent relaxation of the sphincteric muscle. Muscle dysfunction was correlated with a disorganized matrix and a normal complement of enteric neurons and interstitial cells of Cajal. Mice without collagen XIX exhibit an additional defect, namely impaired smooth-to-skeletal muscle cell conversion in the abdominal segment of the esophagus. This developmental abnormality was accounted for by failed activation of myogenic regulatory factors that normally drive esophageal muscle transdifferentiation. Therefore, these findings identify collagen XIX as the first structural determinant of sphincteric muscle function, and as the first extrinsic factor of skeletal myogenesis in the murine esophagus.

A mediator derived from arginine mediates inhibitory junction potentials and relaxations in lower esophageal sphincter: an independent role for vasoactive intestinal peptide

This study provides mechanical and electrophysiological evidence to show that a metabolite of arginine, not vasoactive intestinal peptide (VIP), is the putative nonadrenergic noncholinergic (NANC) inhibitory mediator in canine and opossum lower esophageal sphincters (LES). Relaxations of spontaneous active tension by electrical field stimulation (FS) at parameters that induced tetrodotoxin (TTX)-sensitive responses were abolished by L-Nω-arginine methyl ester (L-NAME) at 10−4 M and restored by L-arginine (10−3 M) but not D-arginine (10−3 M). TTX-insensitive relaxations to 5-ms pulses were unaffected by L-NAME, L- or D-arginine. VIP (10−6 M) caused maximum relaxations of basal tension in both the opossum and canine LES. However these relaxations, unlike those from FS were unaffected by L-NAME. Methylene blue (5 × 10−5 M) increased basal tension of the LES in each species, and did not inhibit the relaxation to FS or VIP, but often increased the amplitudes of these responses due to the increase in basal tension. In parallel experiments NANC inhibition of body circular muscle from opossum esophagus was abolished by methylene blue. Electrophysiological studies using micro-electrodes revealed that NANC inhibition was associated with inhibitory junction potentials in the canine LES. These were inhibited by L-NAME and restored by L-arginine but not D-arginine. In contrast, 10−6 M VIP in canine LES did not induce any change in membrane potential during a 20-min superfusion. Sodium nitroprusside also hyperpolarized sphincteric muscle and its effects were not affected by L-NAME. We conclude that esophageal sphincter NANC nerve initiation of inhibitory junction potentials or relaxations depend on a mediator produced from L-arginine, like those of esophageal body circular muscle. This mediator resembles sodium nitroprusside in its actions. However, either the NANC mediator or the response to it differs in body circular muscle and LES since only the former was clearly sensitive to methylene blue. Moreover, TTX-insensitive relaxations to long pulse durations were not mediated by nitric oxide-related mechanisms because L-NAME had no effect on them.Key words: nitric oxide, vasoactive intestinal peptide, sphincter relaxation, inhibitory junction potentials.

Sympathetic nervous control of cat ileocecal sphincter

A perfusion method was designed in order to investigate that effects of stimulation of the splanchnic and lumbar colonic nerves on the ileocecal sphincter (ICS) of the cat. Splanchnic and lumbar colonic nerve stimulation at physiological frequencies, i.e., below 10-12 impulses/s, elicited a contraction of the sphincter concomitant with an inhibition of the motility of the adjacent parts of the small and large intestines. It is concluded that the splanchinc and lumbar colonic nerves contract the ICS by a direct effect on the sphincter and not via a contraction of the intestine surrounding the sphincter. Guanethidine and phenoxybenzamine but not propranolol blocked the contraction of the ICS. It is suggested that the splanchnic and lumbar colonic nerves control the sphincter via an alpha-adrenergic mechanism. Inhibitory fibers within the splanchnic or lumbar colonic nerves to the ICS were not found. The excitatory in the ICS elicited by adrenaline, nor-adrenaline, or phyenylephrine infusion was completely blocked by phenoxybenzamine. Propranolol did not block the effect on ICS of these drugs. On the contrary, an augmented response could be shown, indicating unmasking of an excitatory alpha-receptor response by blockade of inhibitory beta-receptors. Further support for these inhibitory beta-receptors was provided by the finding that isoprenaline had a relaxing effect on the sphincteric muscle, an effect that was blocked by propranolol. In order to block the inhibitory effect on the small and large intestine elicited by splanchnic and lumbar colonic nerve stimulation, both phenoxybenzamine and propranolol had to be administered.