The innervation of the myometrium Some histochemical observations in man and rat

Autonomic innervation of human and rat myometrium has been investigated using various histochemical methods. With all the methods used, rat myometrium shows a loosely interlacing network of bundles of nerve fibers, whereas in myometrium of the human fundus neither cholinergic nor adrenergic fiber bundles could be demonstrated. These findings are discussed in relation to the influence of the autonomic nerve fiber bundles on peristalsis.     

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Changes in the potential and contractility of smooth muscle cells of guinea-pig taenia caeci were measured (22 degrees C) in order to investigate the effect of mebeverine, a derivative of beta-phenylethylamine, on alpha 1-receptor-operated ion channels in particular. Mebeverine (6 X 10(-6) M) showed atropine-like properties by shifting to the right the concentration-response curve obtained with carbachol. Hyperpolarization and cessation of spike activity of the muscle cells, accompanied by an increased amplitude of the electrotonic potential were observed in the presence of mebeverine (6 X 10(-5] after block of the alpha 2-, beta- and muscarinic receptors. This effect of mebeverine was not observed in low-sodium solution (23.8 mM), suggesting that mebeverine decreased sodium permeability. The alpha 1-receptor-induced hyperpolarization caused by adrenaline (3 X 10(-6) M) in the presence of mebeverine declined after reaching an initial maximum. The hyperpolarization induced by a second addition of adrenaline to the preparation was decreased and sustained in the presence of mebeverine, while the decrease of the electrotonic potential evoked during the alpha 1 response was less pronounced. The transient hyperpolarization representing the alpha 1 response in the absence of extracellular calcium developed more slowly in the presence of mebeverine, the area of the response being constant. When the experiment was continued in calcium-free solution after a short exposure to calcium-containing Krebs solution still in the presence of mebeverine, the alpha 1-receptor-induced hyperpolarization was suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Desensitization of PGE2 and PGI2 induced contractions in different smooth muscles of guinea-pig unmasking relaxing properties of prostanoids

Prostaglandin E2 (PGE2) and 16,16-dimethyl PGE2 (16,16-dm PGE2) caused contraction of guinea-pig taenia caeci, contraction and at higher concentrations relaxation of trachea and relaxation of ureter smooth muscle. The prostacyclin derivative iloprost induced contraction of taenia caecum, while it was inactive in the other preparations. After pretreatment of the smooth muscles with 16,16-dm PGE2, stimulation of the PGE2 receptors in taenia caeci and trachea and of PGI2 receptors in taenia caeci caused relaxation. The results indicate that the prostanoid receptor mediating contraction is selectively vulnerable for desensitization in contrast with the receptor mediating smooth muscle relaxation.     

9-Amino-1,2,3,4-tetrahydroacridine (THA), an alleged drug for the treatment of Alzheimer's disease, inhibits acetylcholinesterase activity and slow outward K+ current

The in vitro release of acetylcholine in rat brain tissue was inhibited by 9-amino-1,2,3,4-tetrahydroacridine (THA). Atropine antagonized this effect of THA. As THA does not display an affinity for muscarinic receptors, we conclude that THA inhibits acetylcholinesterase activity. In electrophysiological studies with neurons of Lymnaea stagnalis, THA inhibited the slow outward K+ current and consequently increased the duration of the action potentials. It is discussed that both effects of THA possibly contribute to its reported effect in the treatment of patients with Alzheimer's disease.     

Excessive grooming induced by somatostatin or its analog SMS 201-995

Intracerebroventricular (i.c.v.) administration of somatostatin or SMS 201-995 induces excessive grooming behavior in rats. The grooming inducing effect of somatostatin is rather weak, as doses of 300 ng or less did not result in increased total grooming scores. In contrast a dose of 10 ng SMS 201-995 already significantly increased the total grooming scores. However, doses of 100 ng and more did not further increase the total grooming scores reached with a 50 ng dose of this peptide. Systemic administration of SMS 201-995 in doses up to 900 micrograms did not result in excessive grooming behavior. The patterns of excessive grooming induced by i.c.v. SMS 201-995 and somatostatin were characterized by a predominant display of scratching. Since peptide-induced scratching is mainly due to activation of opiate receptor systems it is suggested that opiate receptors are involved in the behavioral response to SMS 201-995 and somatostatin administration. This suggestion is further supported by the suppressive effect of naloxone on excessive grooming induced by these peptides. Haloperidol and neurotensin also suppress the excessive grooming induced by somatostatin but not that induced by SMS 201-995. Finally, tolerance developed to the grooming-inducing effect of SMS 201-995 and somatostatin. In addition there was cross tolerance between somatostatin and SMS 201-995.     

Effect of dB-c-AMP and forskolin on the 45Ca influx, net Ca uptake and tension in rabbit aortic smooth muscle

The effects of dibutyril-adenosine-3',5'-cyclic monophosphate (dB-c-AMP) and forskolin on aortic tension and 45Ca influx were measured. dB-c-AMP reduced both the rate of force development and the maximal tension achieved in solutions containing various K+ concentrations. Stimulated 45Ca influx was also reduced, however, to a lesser extent than was the tension. Forskolin showed more marked effects of a similar nature. Thus, both these agents which increase intracellular c-AMP caused a rightward shift in the curve expressing force (ordinate) as a function of Ca2+ influx (abscissa). Consequently, we found that dB-c-AMP stimulated more net Ca to be taken up by sarcoplasmic reticulum (SR) at the same influx rate. The conclusion that c-AMP produced these effects by stimulating Ca uptake into the superficial SR was supported by the finding that dB-c-AMP increased the amount of Ca taken up into a caffeine releasable fraction.     

Effects of perfluorodecanoic acid on thyroid status in rats

Treatment of rats with toxic doses of perfluorodecanoic acid (PFDA) results in reduction in feed intake, body weight, serum thyroxine (T4) and triiodothyronine (T3) concentrations, resting heart rates, and body temperatures. Some of these effects resemble changes characteristic of hypothyroidism. Therefore the effects of PFDA on functional thyroid status were examined to relate changes in thyroid status with signs of PFDA toxicity. In the present study, the dose-related effects of PFDA on plasma thyroid hormone concentrations and a number of indices of thyroid status were investigated and compared with signs of PFDA toxicity. Young adult male Sprague-Dawley rats were given single intraperitoneal doses of PFDA (20, 40, or 80 mg/kg), and subsequent changes were evaluated 7 days after dosing. Decreases in body weight and feed intake were used as measures of PFDA toxicity and ranged from minimal to severe. Plasma T4 concentrations and free thyroxine index were drastically reduced at all doses, and these changes were mimicked by pair feeding only at the high dose of PFDA (80 mg/kg). Plasma T3 concentrations were not affected by PFDA treatment, whereas pair feeding at the high-dose level (80 mg PFDA/kg) resulted in a significant reduction (ca. 50% from unlimited-fed control) in T3. Although PFDA caused a dose-dependent decrease in thyroid gland weight which was not completely paralleled by pair feeding, thyroid histology was unremarkable. PFDA treatment resulted in a small decrease in basal metabolic rate (8% at 80 mg PFDA/kg). A greater reduction (ca. 18%) in basal metabolic rate was observed in vehicle-treated controls pair-fed to rats of the 80 mg PFDA/kg dose group. Thermogenesis, as measured by oxygen consumption and body core temperatures, was not greatly affected by PFDA treatment, and these changes were paralleled by pair feeding. Reductions in plasma T4 concentration and free thyroxine index at a low dose of PFDA (20 mg/kg) indicate that PFDA-induced hypothyroxinemia can be dissociated from its overtly toxic effects (i.e., severe hypophagia and body weight loss) observed at higher doses. The results obtained here suggest that despite alterations in plasma thyroid hormone levels there is no consistent pattern of effects on functional thyroid status which could explain the overt toxicity of PFDA.     

Human liver phenol sulfotransferase: assay conditions, biochemical properties and partial purification of isozymes of the thermostable form

Phenol sulfotransferase (PST) catalyzes the sulfate conjugation of phenolic and catechol drugs and neurotransmitters. Human platelets and brain contain at least two forms of PST. One form is relatively thermolabile (TL) and catalyzes the sulfate conjugation of monoamines such as dopamine. The other is thermostable (TS) and catalyzes the sulfation of "simple" phenols such as phenol and p-nitrophenol. We found that homogenates of human liver also contain two forms of PST that are similar to brain and platelet TL and TS PST with regard to substrate specificities, thermal stabilities and sensitivities to inhibitors. Optimal conditions were determined for the assay of these two activities in human liver homogenates. The apparent Km of liver homogenate TL PST for dopamine was 27 microM. The apparent Km of the TS form of the enzyme for p-nitrophenol was 0.94 microM. Human liver TS PST also catalyzed the sulfate conjugation of dopamine, but with an apparent Km of 5 mM, over two orders of magnitude higher than that of TL PST. Two different peaks of TS PST activity were separated from the TL activity by ion exchange chromatography of human liver preparations. Both peaks of TS PST activity were partially purified and characterized. Both had similar substrate specificities and inhibitor sensitivities. Km values of TS PST peak I for p-nitrophenol and for 3'-phosphoadenosine-5'-phosphosulfate were 0.91 and 0.86 microM, respectively, while the Km values of TS PST peak II for these two cosubstrates for the reaction were 0.43 and 0.64 microM, respectively. However, the TS PST activity in peak II was significantly more thermolabile than was the activity in peak I. These results are compatible with the conclusion that human liver homogenates contain at least two forms of PST, forms with properties similar to those of TS and TL PST in homogenates of human cerebral cortex and platelets. In addition, human liver contains two isozymes of TS PST.