Hisato Kitagawa

Endothelium-dependent increases in rat gastric mucosal hemodynamics induced by acetylcholine and vagal stimulation

The role of vascular endothelial cells in the vagal control of hemodynamics was studied in rat gastric mucosa. Vagal stimulation and intra-arterial administration of acetylcholine and of papaverine increased hemoglobin (Hb) and oxygen saturation of hemoglobin (SO2) in the gastric mucosa. The increases induced by vagal stimulation were reduced but not abolished by atropine. The responses to acetylcholine and vagal stimulation were reduced by quinacrine, p-bromophenacyl bromide and nordihydroguaiaretic acid, while indomethacin had no effect. Intra-arterial infusion of collagenase removed the endothelial cells from submucosal vasculatures and depressed the increase in mucosal hemodynamics in response to acetylcholine and vagal stimulation. The response to papaverine was not depressed in rats treated with quinacrine or collagenase. These results suggest that the increase in gastric mucosal blood flow induced by acetylcholine or vagal stimulation is mediated by the endothelium-derived relaxing factor.

Effects of terfenadine, astemizole and epinastine on electrocardiogram in conscious cynomolgus monkeys

We examined the effects of non-sedative histamine H1 receptor antagonists on the electrocardiogram (ECG) in conscious cynomolgus monkeys. Terfenadine (3 mg kg(-1) h(-1), i.v.) and astemizole (0.3 and 1 mg kg(-1) h(-1), i.v.) caused significant time-dependent increases in the QT interval and QTc Bazett (QTc). However, normal ECG forms were found during a 60-min infusion of epinastine (3 mg kg(-1) h(-1) i.v.). A higher dose of epinastine (10 mg kg(-1) h(-1), i.v.) increased the QTc and PR interval only 5 min after the start of the infusion. The minimum plasma concentrations of terfenadine, astemizole and epinastine which caused QTc prolongation were 85, 35 and over than 3600 ng/ml, respectively. These drugs did not alter the PQ and QRS intervals and did not cause arrhythmia or atrioventricular block. Our results are consistent with the clinical observation that prolongation of QTc is caused by terfenadine and astemizole but not by epinastine. Thus, measurement of QTc in cynomolgus monkey appears to be a useful approach for evaluating the potential cardiotoxicity of histamine H1 receptor antagonists.

Epinastine, a nonsedating histamine H1 receptor antagonist, has a negligible effect on HERG channel

Terfenadine and astemizole rarely cause cardiac arrhythmias by suppressing the cardiac rapid delayed rectifier K+ channel encoded by the human ether-a-go-go-related gene (HERG). Epinastine, however, has not been reported to have the adverse effect. We have therefore compared the effects of epinastine, terfenadine and astemizole on HERG channels expressed in Xenopus oocytes. Terfenadine and astemizole suppressed the HERG current with IC50 of 431 nM and 69 nM, respectively. In contrast, 100 microM epinastine inhibited the HERG current by only 11+/-2.1%. These results may provide an explanation for the difference in the cardiotoxicity between different nonsedating histamine H1 receptor antagonists.

Roles of Gastric Acid Secretion and Motility in Gastric Mucosal Lesion Formation Induced by Water-Immersion Stress in Rats

The roles of gastric acid and motility in gastric mucosal lesion formation induced by water-immersion stress were studied pharmacologically in rats. Gastric acid secretion and motility increased markedly during water-immersion, and mucosal lesions were formed. Cimetidine inhibited the increase in gastric acid secretion, but papaverine inhibited the increases in both acid secretion and motility. Both agents prevented the formation of mucosal lesions. In acid perfused rats, the increase in motility and lesion formation induced by water-immersion stress were prevented by papaverine, but not by cimetidine. These results suggest that the increases in both acid secretion and motility play important roles in the formation of mucosal lesions induced by water-immersion stress in rats.

Augmentation of vagal reflex bradycardia by central α1adrenoceptors in the cat

SummaryVagal reflex bradycardia was induced in anaesthetized cats with high level spinal axotomy by electrical stimulation of either the carotid sinus nerves or a depressor nerve. In both preparations reflex bradycardia increased with the rate of stimulation. Injection of 1 μg/kg clonidine into a lateral cerebral ventricle augmented reflex bradycardia in response to carotid sinus nerve stimulation while the same dose of clonidine was ineffective when given intravenously. The antagonistic effect of intracerebroventricular yohimbine (50 μg/kg) indicated that the effect of clonidine was due to its α1agonistic action. In contrast to carotid nerve stimulation the reflex bradycardia in response to depressor nerve stimulation was affected neither by intracerebroventricular injection of clonidine (2 μg/kg) nor by yohimbine (100 μg/kg).It is concluded that in the cat, the function of the central parts of the baroreceptor reflex which originate from the carotid sinus area is augmented by stimulation of α1adrenoceptors while the function of those parts originating from the aortic area is not.

Gastric mucosal protective action of endothelium-derived relaxing factor.

The change in the endothelial function by the application of 0.6 N HCl and the effects of endothelium-derived relaxing factor (EDRF) inhibitors and nitrites on HCl-induced lesions were studied to clarify the effect of EDRF on gastric lesions in rats. The EDRF-induced increase in the gastric mucosal hemodynamics induced by vagal stimulation or intra-arterial administration of acetylcholine was inhibited by the EDRF inhibitors or removal of endothelial cells. Topical application of 0.6 N HCl on the exposed gastric mucosa abolished the response of the mucosal hemodynamics to acetylcholine or vagal stimulation. Gastric lesions induced by 0.45 N HCl were enhanced by EDRF inhibitors or removal of endothelial cells from gastric submucosal arterioles.

Enhancement of contractile responses to partial α-adrenoceptor agonists during warming in rat aorta

SummaryWe examined the effects of warming on the contractile responses to full and partial α-adrenoceptor agonists in rat aorta. The contractions elicited by norepinephrine and methoxamine were not affected during warming (40°C, 42°C), whereas those induced by clonidine and St 587 were significantly enhanced. KCl-induced contractions of rat aorta were not affected by warming. The dissociation constants of clonidine and St 587 at 40°C were not different from those at 37°C. At 40°C, the receptor occupancy-contractile response curve of clonidine was a hyperbolic curve similar to that of methoxamine at 37°C, although at 37°C the curve was almost linear. The responses of St 587 at both 37°C and 40°C were related inversely hyperbolic to the receptor occupancy, but the receptor occupancy-contractile response curve was shifted to the left and upward during warming. Clonidine and St 587 elicited equal responses at lower fractional occupancies at 40°C than at 37°C. The relative efficacies of clonidine and St 587 to methoxamine were significantly augmented during warming. It is suggested that the contractile responses to partial α-adrenoceptor agonists in rat aorta are enhanced during warming, and that this effect is related to the intrinsic efficacy of the agonists rather than to any function of their relative selectivity for α1- or α2-adrenoceptors. Such enhancement is due to augmentation of the efficacy rather than to augmentation of the affinity of the agonists.

Inhibitory effects of various spasmolytics on the vagal afferent gastric excitatory response in cats

The inhibitory effects of atropine, cimetropium, pirenzepine and N-butylscopolamine on the vagal afferent gastric excitatory response in cats under anesthesia with pentobarbital sodium and infusion of gallamine were examined. Electrical stimulation of vagal trunk in left side (10 Hz in frequency, 3 msec in duration, 15 V in intensity and for 10 sec) caused an initial gastric excitatory response during the period of stimulation followed by a late excitatory gastric response after stimulation in normal cats. The initial response was inhibited by atropine (100 microg/kg, i.v.) and hexamethonium (10 mg/kg, i.v.), while the late response was inhibited by atropine but not by hexamethonium (10 mg/kg, i.v.). In chronic supranodose vagotomized cats 11-15 days after the operation, stimulation of the vagal trunk caused a late gastric excitatory response after the stimulation period, which was inhibited by atropine (100 microg/kg, i.v.) but not by hexamethonium (10 mg/kg, i.v.). The two types of gastric responses in normal cats have been defined as follows: the initial gastric excitatory response (atropine- and hexamethonium- sensitive) is due to activation of vagal efferent fibers and the late gastric excitatory response (atropine-sensitive and hexamethonium-resistant) is due to activation of vagal afferent fibers. ED50 values of atropine, cimetropium, pirenzepine and N-butylscopolamine in inhibiting the vagal afferent gastric response were 7.2 microg/kg (n=4), 2.4 microg/kg (n=6), 82.6 microg/kg (n=3) and 93.0 microg/kg (n=4), respectively. The inhibitory effects of atropine and cimetropium on the vagal afferent gastric excitatory response (hexamethonium-resistant) were more potent than those of pirenzepine and N-butylscopolamine. These results suggested that the potent inhibitory effects of cimetropium and atropine on the vagal afferent gastric response may involve a potent spasmolytic effect.