Synthesis and biological properties of 9-deoxo-16,16-dimethyl-9-methylene-PGE2.

The in vivo monkey uterine stimulating potency of 9-deoxy-16,16-dimethyl-9-methylene-PGE2 is similar to that of 16,16-dimethyl-PGE2 and approximately 15 times that of PGE2. Low doses of this compound stimulated uterine contractions when administered vaginally. Pregnancy was terminated prematurely following subcutaneous, intramuscular or vaginal suppository treatment. Estimates of potential for gastrointestinal side effects using the rat enteropooling assay and in vivo monkey effects indicate that diarrhea will be substantially reduced with retention of uterine stimulating potency.     

Synthesis and biological properties of 9-deoxo-16,16-dimethyl-9-methylene-PGE2

The in vivo monkey uterine stimulating potency of 9-deoxo-16,16-dimethyl-9-methylene-PGE₂ is similar to that of 16,16-dimethyl-PGE₂ and approximately 15 times that of PGE₂. Low doses of this compound stimulated uterine contractions when administered vaginally. Pregnancy was terminated prematurely following subcutaneous, intramuscular or vaginal suppository treatment. Estimates of potential for gastrointestinal side effects using the rat enteropooling assay and in vivo monkey effects indicate that diarrhea will be substantially reduced with retention of uterine stimulating potency.     

Termination of early gestation with a vaginal polysiloxane device impregnated with (15S) -15 methyl prostaglandin F2a methylester

An investigation of the abortifacient activity of (15S) -15 methyl prostaglandin F2_a methyl ester released from a vaginal polysiloxane device was performed in eleven pregnant women of 49 days gestation or less. Bleeding and contractions were induced in all women, but only seven aborted their pregnancies. Five subjects received a vaginal device impregnated with 3 mg of drug and two aborted fetal tissue. Six women were given a vaginal device containing 5 mg of drug and five aborted fetal tissue. Ten of the patients had significant side effects, nausea, emesis, diarrhea and chills. Six women expelled the device prior to the termination of therapy. This prostaglandin analogue, when administered from a vaginal polysiloxane device in early gestation was an effective abortifacient but was accompanied by systemic side effects and a high incidence of expulsion of the evidence prior to its scheduled removal.     

Termination of early gestation with a vaginal polysiloxane device impregnated with (15S)-15 methyl prostaglandin F2alpha methylester

An investigation of the abortifacient activity of (15S)-15 methyl prostaglandin F2alpha methyl ester released from a vaginal polysiloxane device was performed in eleven pregnant women of 49 days gestation or less. Bleeding and contractions were induced in all women, but only seven aborted their pregnancies. Five subjects received a vaginal device impregnated with 3 mg of drug and two aborted fetal tissue. Six women were given a vaginal device containing 5 mg of drug and five aborted fetal tissue. Ten of the patients had significant side effects, nausea, emesis, diarrhea and chills. Six women expelled the device prior to the termination of therapy. This prostaglandin analogue, when administered from a vaginal polysiloxane device in early gestation was an effective abortifacient but was accompanied by systemic side effects and a high incidence of expulsion of the device prior to its scheduled removal.     

The effects of crustacean cardioactive peptide on locust oviducts are calcium-dependent

The role of calcium as a second messenger in the crustacean cardioactive peptide (CCAP)-induced contractions of the locust oviducts was investigated. Incubation of the oviducts in a calcium-free saline containing, a preferential calcium cation chelator, or an extracellular calcium channel blocker, abolished CCAP-induced contractions, indicating that the effects of CCAP on the oviducts are calcium-dependent. In contrast, sodium free saline did not affect CCAP-induced contractions. Co-application of CCAP to the oviducts with preferential L-type voltage-dependent calcium channel blockers reduced CCAP-induced contractions by 32-54%. Two preferential T-type voltage-dependent calcium channel blockers both inhibited CCAP-induced oviduct contractions although affecting different components of the contractions. Amiloride decreased the tonic component of CCAP-induced contractions by 40-55% and flunarizine dihydrochloride decreased the frequency of CCAP-induced phasic contractions by as much as 65%, without affecting tonus. Flunarizine dihydrochloride did not alter the proctolin-induced contractions of the oviducts. Results suggest that the actions of CCAP are partially mediated by voltage-dependent calcium channels similar to vertebrate L-type and T-type channels. High-potassium saline does not abolish CCAP-induced contractions indicating the presence of receptor-operated calcium channels that mediate the actions of CCAP on the oviducts. The involvement of calcium from intracellular stores in CCAP-induced contractions of the oviducts is likely since, an intracellular calcium antagonist decreased CCAP-induced contractions by 30-35%.     

Involvement of cyclooxygenase-dependent pathway in contraction of isolated ileum by urotensin II

We previously reported that urotensin II induced biphasic (brief- and long-lasting) contractions and the brief contraction was mediated by acetylcholine release from ganglionic cholinergic neurons in a segment of guinea-pig ileum. In the present work, we studied the mechanism contributing to long-lasting contractions induced by urotensin II. Treatment with 0.1 microM tetrodotoxin, 300 nM omega-conotoxin GVIA (an inhibitor of N-type Ca2+ channels) and 10 microM indomethacin (an inhibitor of cyclooxygenases) markedly inhibited 100 nM urotensin II-induced long-lasting contractions. The addition of 1 microM prostaglandin F2alpha (PGF2alpha) caused a limited brief contraction following long-lasting contraction, while 1 microM PGE2 induced marked biphasic contractions. Treatment with neurotoxins inhibited the long-lasting contractions induced by PGF2alpha and PGE2 without changing the PGE2-induced brief contractions. Treatment with 1 microM atropine markedly inhibited the urotensin II- and PGF2alpha-induced long-lasting contractions, but was less effective on the PGE2 responses. Treatment with a phospholipase A2 inhibitor decreased the urotensin II-induced contractions. These findings suggest that urotensin II induces, at least partially, long-lasting contractions via PG-sensitive cholinergic neurons and muscarinic acetylcholine receptors in the ileum.     

Sperm duct contractions mediate centrally evoked sperm release in goldfish

In order to determine the peripheral mechanisms underlying sperm release (SR) in goldfish, the contractile activity of the sperm ducts (SD) and testes were monitored during SR responses evoked by electrical stimulation of the brain. Electrical stimulation of the brain triggered testicular and SD contractions, and SR, while electrical stimulation of the genital nerve branch to the SD evoked only SD contractions and SR. Centrally activated SD contractions and SR were blocked by sectioning the SD genital nerve, while testicular contractions were unaffected. Testicular contractions do not appear necessary for centrally evoked SR since the response can be elicited from preparations in which the testes were separated from the SD. The results indicate that SR in goldfish is primarily mediated by the SD and not the testes. Testicular contractions may, however, serve to load the SD with milt. The functional significance of the central pathway(s) associated with SD and testicular contractions are discussed.     

The effect of intestinal anaphylaxis on postprandial motility in the rat

We have previously utilized a rat animal model to demonstrate that challenge of fasted sensitized animals with antigenic food protein is associated with diarrhea and altered intestinal myoelectric and motor activities. In this paper we examine the effect of intestinal anaphylaxis on postprandial motility in the same animal model. Hooded Lister rats were sensitized (S) by intraperitoneal injection of 10 micrograms egg albumin (i.e., antigen (Ag) and compared with sham-sensitized controls (C). Seven days later, three bipolar jejunal electrodes and a jejunostomy tube, for motility recording and Ag administration, were implanted. On day 14, intestinal myoelectric and motor activities were measured in fed animals before and after intraluminal challenge with Ag (100 mg egg albumin/0.5 mL saline) or placebo (P; 0.5 mL saline). Specific immunoglobulin E serum titres were greater than or equal to 1:64 in S animals, while C animals showed no response. None of the C animals challenged with P or Ag and none of the S animals challenged with P defecated after challenge, but all the S animals challenged with Ag developed diarrhea (p less than 0.001). There was no disruption or alteration of the fed motility pattern in C animals challenged with P or Ag, or S animals challenged with P. In fed S animals challenged with Ag the fed motility pattern persisted, but there was a significant (p less than 0.05) increase in the number of high-amplitude aborally propagating clustered contractions, where the phasic contractile activity was superimposed on a sustained tonic elevation of intraluminal pressure lasting 5-10 s.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of cholinergic drugs on muscle contraction in Moniliformis moniliformis (Acanthocephala)

In whole Moniliformis moniliformis spontaneous muscle contractions were rhythmic; longitudinal contractions were measured with a force transducer. The cholinergic agonists levamisole and nicotine significantly increased muscle tension in whole worms; these contractions were tonic and were antagonised by the ganglionic blocker pentolinium and by piperazine. In addition, levamisole-induced contractions were inhibited by gallamine, hexamethonium, and norepinephrine. In worm segments, where drugs in solution were injected through the worms, acetylcholine (ACh) and nicotinic agonists were effective in causing contractions, whereas muscarinic agonists in concentrations up to 1 mM had no effect. Although muscle contraction in M. moniliformis was induced by nicotinic agonists, these contractions were effectively antagonised by a range of chemicals that block ganglionic, skeletal, and muscarinic sites in vertebrates. The presence of ACh in M. moniliformis and the effects of nicotinic agonists on muscle contraction suggest that ACh is a putative excitatory neurotransmitter.     

Reduced exercise hyperaemia in claf muscles working at high contraction frequencies.

The effects of muscle contraction frequency on blood flow to the calf muscle (Qcalf) were studied in six female subjects, who performed dynamic plantar flexions at frequencies of 20, 40, 60, 80 and 100 contractions.min-1, in a supine position. The Qcalf measured by a mercury-in-rubber strain gauge plethysmograph, increased as contraction frequency increased and reached a peak at 60-80 contractions.min-1. After 100 plantar flexions at 60 contractions.min-1, the mean Qcalf was 30.95 (SEM 4.52) ml.100 ml-1.min-1. At 100 contractions.min-1, however, it decreased significantly compared with that at 60 contractions.min-1 at a specified time (2 min or exhaustion) or after a fixed amount of work (100 contractions). The contraction frequency at which Qcalf reached a peak depended on the duration of exercise. The heart rate showed its highest mean value at 60 contractions.min-1 and decreased significantly at 100 contractions.min-1. The mean blood pressure was lower at 100 contractions.min-1 than at 60 contractions.min-1. The relaxation period between contractions, measured by recording the electromyogram from the gastrocnemius muscles, shortened markedly as the frequency increased; the mean value at 100 contractions.min-1 was 0.14 (SEM 0.02) s, which corresponded to 35.7% of the contraction time. This shortened relaxation period between contractions should have led to the inhibition of exercise hyperaemia at the higher contraction frequencies.     

Relaxation of the myocardium of the perfused and ischaemic rabbit heart

The decrease in the rate of relaxation of the myocardium during ischaemic impairment of metabolic processes is accompanied by a decrease in the size of contraction. If we stimulate the ischaemic heart with irregularly distributed pulses we can achieve, by an extrasystolic potentiation mechanism, isolated contractions. If we stimulate the ischaemic heart with irregularly distributed pulses we can achieve, by an extrasystolic potentiation mechanism, isolated contractions of the same size as average contractions in normal perfusion. When comparing the relaxation of such contractions in 15 perfused rabbit hearts, we found a linear correlation between the relaxation rate and the size of the contractions. If we relate to relaxation rate to contraction size, the relaxation rate in early ischaemia (1 min after stopping perfusion) is thus in most cases normal, despite the marked decrease in the size of the contractions. The size of the contractions of the ischaemic mammalian myocardium thus seems to diminish before relaxation (which is likewise energy-dependent) is affected.     

Aging does not affect voluntary activation of the ankle dorsiflexors during isometric, concentric, and eccentric contractions.

This study examines the age-related deficit in force of the ankle dorsiflexors during isometric (Iso), concentric (Con), and eccentric (Ecc) contractions. More specifically, the contribution of neural and muscular mechanisms to the loss of voluntary force was investigated in men and women. The torque produced by the dorsiflexors and the surface electromyogram (EMG) from the tibialis anterior and the soleus were recorded during maximal Iso contractions and during Con and Ecc contractions performed at constant angular velocities (5-100 degrees/s). Central activation was tested by the superimposed electrical stimulation method during maximal voluntary contraction and by computing the ratio between voluntary average EMG and compound muscle action potential (M wave) induced by electrical stimulation (average EMG/M wave). Contractile properties of the dorsiflexor muscles were investigated by recording the mechanical responses to single and paired maximal stimuli. The results showed that the age-related deficit in force (collapsed across genders and velocities) was greater for Iso (20.5%; P < 0.05) and Con (38.6%; P < 0.001) contractions compared with Ecc contractions (6.5%; P > 0.05). When the torque produced during Con and Ecc contractions was expressed relative to the maximal Iso torque, it was significantly reduced in Con contractions and increased in Ecc contractions with aging, with the latter effect being more pronounced for women. In both genders, voluntary activation was not significantly impaired in elderly adults and did not differ from young subjects. Similarly, coactivation was not changed with aging. In contrast, the mechanical responses to single and paired stimuli showed a general slowing of the muscle contractile kinetics with a slightly greater effect in women. It is concluded that the force deficit during Con and Iso contractions of the ankle dorsiflexors in advanced age cannot be explained by impaired voluntary activation or changes in coactivation. Instead, this age-related adaptation and the mechanisms that preserve force in Ecc contractions appeared to be located at the muscular level.     

Force depression following muscle shortening in sub-maximal voluntary contractions of human adductor pollicis

Mechanical properties of skeletal muscles are often studied for controlled, electrically induced, maximal, or supra-maximal contractions. However, many mechanical properties, such as the force-length relationship and force enhancement following active muscle stretching, are quite different for maximal and sub-maximal, or electrically induced and voluntary contractions. Force depression, the loss of force observed following active muscle shortening, has been observed and is well documented for electrically induced and maximal voluntary contractions. Since sub-maximal voluntary contractions are arguably the most important for everyday movement analysis and for biomechanical models of skeletal muscle function, it is important to study force depression properties under these conditions. Therefore, the purpose of this study was to examine force depression following sub-maximal, voluntary contractions. Sets of isometric reference and isometric-shortening-isometric test contractions at 30% of maximal voluntary effort were performed with the adductor pollicis muscle. All reference and test contractions were executed by controlling force or activation using a feedback system. Test contractions included adductor pollicis shortening over 10 degrees, 20 degrees, and 30 degrees of thumb adduction. Force depression was assessed by comparing the steady-state isometric forces (activation control) or average electromyograms (EMGs) (force control) following active muscle shortening with those obtained in the corresponding isometric reference contractions. Force was decreased by 20% and average EMG was increased by 18% in the shortening test contractions compared to the isometric reference contractions. Furthermore, force depression was increased with increasing shortening amplitudes, and the relative magnitudes of force depression were similar to those found in electrically stimulated and maximal contractions. We conclude from these results that force depression occurs in sub-maximal voluntary contractions, and that force depression may play a role in the mechanics of everyday movements, and therefore may have to be considered in biomechanical models of human movement.     

Tonic contractions allow metabolic recuperation of the adductor muscle during escape responses of giant scallop Placopecten magellanicus

To escape from starfish predators, giant scallops, Placopecten magellanicus, swim using series of strong phasic contractions interrupted by tonic contractions. To investigate whether these tonic contractions allow metabolic recuperation of the adductor muscle, we sampled scallops at rest (Control), after an initial series of phasic contractions (Phasic) and after 1 min of tonic contraction following their initial phasic contractions (Phasic + Tonic) and compared muscle levels of phosphoarginine, adenylate nucleotides (ATP, ADP and AMP) and adenylate energy charge (AEC). Scallops in the two active groups did not differ in the numbers of phasic contractions or the mean phasic force production. Phosphoarginine concentrations in the adductor muscle decreased with phasic activity and remained low after 1 min of tonic contraction. ATP and ADP and total adenylate levels did not differ between the three groups, but AMP levels were higher in the scallops sampled after phasic contractions than in control scallops. The AEC was reduced by phasic contractions but returned to control levels after 1 min of tonic contraction. A significant negative correlation between AEC and the number of claps in the Phasic group disappeared in the Phasic + Tonic group. Thus, tonic contractions following phasic contractions allow partial metabolic recovery of the adductor muscle by returning AEC to control levels. However, phosphoarginine levels did not recover during tonic contractions, and a negative correlation between the number of claps and phosphoarginine levels remained in the Phasic + Tonic group. By interspersing tonic contractions between series of phasic contractions, scallops improved muscle energetic status, which should help maintain phasic force production during the remainder of the escape response.     

K+ channels involved in contractility of rabbit small intestine

Most excitable cells, including gastrointestinal smooth muscle cells, express several types of K+ channels. The aim of this study was to examine the types of K' channels involved in the contractility of longitudinal smooth muscle of rabbit small intestine in vitro. Spontaneous contractions and KCl-stimulated contractions were reduced by atropine, phentolamine, propranolol, suramin, tetrodotoxin and indomethacin. The amplitude and tone of spontaneous contractions were increased by apamin, charybdotoxin, iberiotoxin, E4031, tetraetylammonium (TEA) and BaCl2. The frequency of contractions was reduced in the presence of apamin and TEA and increased by charybdotoxin. It was found that 4-aminopyridine increased the tone of spontaneous contractions and reduced the amplitude and frequency of contractions. Glibenclamide did not modify the amplitude, frequency or tone of contractions. KCl-stimulated contractions were increased by E4031, were not modified by apamin, glibenclamide, NS1619 or diazoxide, and were reduced by charybdotoxin, TEA, 4-aminopyridine or BaCl2. These results suggest that both Ca2+-activated K+ channels of small and high conductance, and HERG K+ channels and inward rectifier K+ channels participate in spontaneous contractions of small intestine. On the other hand, voltage-dependent K+ channels, HERG K+ channels, inward rectifier K+ channels and high conductance Ca2+-activated K+ channels are involved in KCl-stimulated contractions.     

Membrane mechanisms of the excitatory action of serotonin on the smooth muscles of the rabbit pulmonary artery

Serotonin induced dose-dependent tonic contractions of the rabbit pulmonary artery smooth muscles with KED50, of 2.7 X 10(-7) mol/l. More than 80% of these contractions were found to be dependent on extracellular calcium. Hyperpolarization of cell membrane by inwardly applied electrical current caused nearly 50% reduction in serotonin-induced contractions. The same portion of contractions was inhibited by verapamil and Ca2+. Serotonin-, but not potassium-induced contractions were completely inhibited by sodium nitroprusside which is thought to be selective inhibitor of receptor-operated calcium channels. These findings could indicate that Ca2+ ions, responsible for serotonin-induced contractions enter the cell from the outer surface of the cellular membrane via receptor-operated calcium channels. Nearly half of serotonin-operated Ca2+ channels appear to be also potential-operated.     

Strength training improves the steadiness of slow lengthening contractions performed by old adults.

When old adults participate in a strength-training program with heavy loads, they experience an increase in muscle strength and an improvement in the steadiness of submaximal isometric contractions. The purpose of this study was to determine the effect of light- and heavy-load strength training on the ability of old adults to perform steady submaximal isometric and anisometric contractions. Thirty-two old adults (60-91 yr) participated in a 4-wk training program of a hand muscle. Both the light- and heavy-load groups increased one-repetition maximum and maximal voluntary contraction (MVC) strength and experienced similar improvements in the steadiness of the isometric and shortening and lengthening contractions. The increase in MVC strength was greater for the heavy-load group and could not be explained by changes in muscle activation. Before training, the lengthening contractions were less steady than the shortening contractions with the lightest loads (10% MVC). After training, there was no difference in steadiness between the shortening and lengthening contractions, except with the lightest load. These improvements were associated with a reduced level of muscle activation, especially during the lengthening contractions.     

Effect of galanin and galanin antagonists on peristalsis in esophageal smooth muscle in the opossum

Galanin, a neuropeptide that is widely distributed in the esophageal nerves, is known to exert a neuromodulatory action in the gut. These studies examined the effect of galanin and galanin antagonists on esophageal peristalsis in anesthetized opossums in vivo. Intraluminal esophageal pressures were recorded at 1, 3, 5, 7, and 9 cm above the lower esophageal sphincter. Esophageal peristaltic contractions were induced by swallow and short- (1-s) and long-train (10-s) vagal stimulation (VS). Galanin (1 nmol/kg) inhibited the amplitude of swallow-induced peristaltic contractions and increased peristaltic velocity by enlarging the latency periods in the upper part of the esophagus and reducing them in the lower part. Galinin nearly abolished esophageal contractions caused by short-train VS at 5 Hz and inhibited the contractions at 10 Hz. Galanin increased latency periods induced by short-train VS with little change in the velocity of peristalsis and reduced the amplitude of both A (cholinergic) and B (noncholinergic) contractions due to long-train VS. However, the decrease in amplitude of B contractions was more marked. Galantide (3 nmol/kg) antagonized the inhibitory action of exogenous galanin on esophageal contractions elicited by short-train VS, but by itself galantide had no significant effect on esophageal contractions. In conclusion, exogenous galanin inhibits the amplitude of swallow-induced peristaltic contractions and converts them into nonperistaltic contractions by inhibiting both the cholinergic and noncholinergic components.     

The effect of D600 on tonic tension, Na+ inward current, and Na+-Ca2+ exchange in frog heart

Preparations of frog atrial muscle were stimulated at 0.33 Hz under voltage clamp, and the resulting membrane currents and the twitch contractions (phasic and tonic components) were recorded in presence or absence of D600. It has been suggested earlier that the tonic contractions are regulated by an electrogenic Na+-Ca2+ exchange, while the phasic contractions are closely related to the calcium inward current (Isi). In this study we investigated the effect of D600 on (i) the tonic contractions elicited by long depolarizing pulses of high amplitude and (ii) the tonic contractions increased by veratrine and resulting in a positive inotropic effect (PIE). While 1 microM D600 reduced Isi and the corresponding phasic contractions to less than 30% of their initial values within 5 min, the inhibitory effect of D600 on tonic contractions developed more slowly or higher concentrations of D600 were needed to achieve similar levels of inhibition within the same time. Furthermore, applications of 5-50 microM D600 inhibited the veratrine-induced increase in INa and in tonic contractions, and both of these effects again fully developed within a few minutes of D600 being removed. The results demonstrate that D600 inhibits not only Isi and phasic contractions, but it also decreases the tonic contractions in frog heart. The effect on the tonic component is associated with inhibition of the tetrodotoxin-sensitive Na+ inward current, and the results are interpreted as an effect of D600 on the electrogenic Na+-Ca2+ exchange. These additional effects of D600 should be considered when using this drug as the "specific" calcium channel blocker.     

杨梅果实提取物抗小鼠腹泻作用的研究

目的研究杨梅果实提取物的抗小鼠腹泻作用,包括预防和治疗作用。方法给小鼠腹腔注射甲型副伤寒沙门菌造成急性腹泻模型,经口灌胃杨梅果实提取物溶液,通过腹泻次数研究提取物对小鼠腹泻的预防作用;先灌胃杨梅果实提取物溶液再给小鼠注射菌液致泻,记录腹泻次数以研究提取物对小鼠腹泻的治疗作用。结果灌胃杨梅果实提取物的小鼠的腹泻次数均有明显的下降,且醇提物的作用效果要好于水提物。结论杨梅果实提取物对甲型副伤寒沙门菌引起的小鼠腹泻具有一定的预防和治疗作用。