High Frequency Contractions Research Articles

458 Reproducibility of Maximum ATP Production Following Isotonic versus Isometric Exercise

OBJECTIVES/GOALS: This project aimed to investigate differences between isometric and isotonic systems for low and high frequency contractions. Intracellular changes in pH caused by the rate of exercise differ in their effect on PCr. The project assessed the reproducibility between these exercise methods. METHODS/STUDY POPULATION: Four subjects were studied (2F/2M, avg. age 27 years). 31P-MRS spectra were measured in the vastus lateralis (VL) using a 3T MRI scanner using a 31P/1H surface coil. In the isometric studies, the (supine) subjects legs were supported by a wedge pad and restrained by straps over the hips and knee with a resistance strap over one ankle. In the isometric studies, the (prone) subjects legs were fit into machine designed to induce isometric exercise. There were 4 exercise bouts that differed by exercise type and frequency and, consequently, duration. 31P-MR spectra were acquired from a 25mm slab of leg positioned parasagittal along the VL. Analyses were done using jMRUI and R. RESULTS/ANTICIPATED RESULTS: With an increase in sample size, we expect differences between recovery time constants, tau, of PCr between the different exercise frequency groups alluded to by other studies investigating recovery rates in bicep skeletal muscle. From the preliminary data, we obtained large limits of agreement of tau = 0.053 s-1 & tau =-0.074 s-1 from using Bland-Altman analysis. As we increase our sample size, we anticipate that we will see differences of PCr recovery rates between the exercise types as well. DISCUSSION/SIGNIFICANCE: Current studies that investigate the differences in PCr recovery rates between different metabolic states differ in the exercise methods employed on subjects. This study aims to standardize PCr recovery assessment in the VL for more interpretable and applicable assessments of metabolic function.

PWE-158 Is Manometry Fit for Purpose in Predicting Response to Sphincterotomy in Type 2 and 3 Sphincter of Oddi Dysfunction - A Tertiary Centres Experience Including A Novel Use of Botulinum Toxin

Introduction The latest Rome III revision of the Milwaukee classification describes 3 types of Sphincter of Oddi dysfunction (SOD). Type 1 is biliary-type pain, abnormal LFTs (>2 times upper limit of normal on ≥2 occasions) and a dilated bile duct (>8 mm). Type 2 is pain and either laboratory or imaging abnormalities and type 3 is pain alone. Type 1 is usually successfully treated with endoscopic sphincterotomy (ES), while Types 2 and 3 respond less consistently and Sphincter of Oddi manometry (SOM) is used to preselect those likely to benefit. There are however concerns with SOM. It is difficult to interpret, time consuming, expensive and associated with a high risk of pancreatitis - this applies to both the solid state and water perfused system, which we used. From 2007 to 2013, our unit performed SOM on type 2 and 3 patients. In 2014, our practice changed to quadrantic ampullary injections of botulinum toxin (100 U) to paralyse the SOD and allow assessment of the response. If clinical improvement persisted to 3 months, a further injection was given. Following two successful responses, ES was performed. Our aim was to assess the safety and efficacy of the two approaches. Methods 50 patients were studied retrospectively - 34 were evaluated with SOM and 16 with botulinum. Results 94.2% of patients were female and 76.9% had a prior cholecystectomy. 25 patients were Type 2 and 27 Type 3. In the SOM group (n = 34), 20 patients had high baseline or high frequency contractions and underwent ES. In this group 40% (n = 8) developed pancreatitis post procedure. In 5 patients SOM was normal and no ES was performed, with the pancreatitis rate being 40% (n = 2). In 9 patients technical problems prevented SOM being performed. Instead, these patients had ES, with the pancreatitis rate being 22.2%. Overall the intention to treat pancreatitis rate for SOM was 35.3%. Overall, this group required 149 bed days, with a median stay of 1 day (range 0–20). Three months following SOM; 77.3% had an improvement in symptoms compared to 45.5% at 12 months. In the botulinum group (n = 16), there were 25 injections and no cases of pancreatitis were reported, a significantly lower rate than SOM (p = 0.005). One patient developed abdominal pain requiring a four day admission. Four patients had no response and had medical manangement instigated for functional disease. The remaining patients are proceding through the management algorithm. Conclusion SOM, has a high risk of pancreatitis and following ES a modest response rate. The risks and cost do not support this strategy and so new management algorithms are required. Our pilot data suggests twice repeated botulinum injection is a safe investigative procedure and worthy of examination in larger trials. Disclosure of Interest None Declared

Dynamics of inhibitory co-transmission, membrane potential and pacemaker activity determine neuromyogenic function in the rat colon

Interaction of different neuromyogenic mechanisms determines colonic motility. In rats, cyclic depolarizations and slow waves generate myogenic contractions of low frequency (LF) and high frequency (HF), respectively. Interstitial cells of Cajal (ICC) located near the submuscular plexus (SMP) generate slow waves. Inhibitory junction potential (IJP) consists on a purinergic fast (IJPf) followed by a nitrergic slow (IJPs) component leading to relaxation. In the present study, we characterized (1) the dynamics of purinergic-nitrergic inhibitory co-transmission and (2) its contribution on prolonged inhibition of myogenic activity. Different protocols of electrical field stimulation (EFS) under different pharmacological conditions were performed to characterize electrophysiological and mechanical responses. Smooth muscle cells (SMCs) in tissue devoid of ICC-SMP had a resting membrane potential (RMP) of -40.7 ± 0.7 mV. Single pulse protocols increased purinergic and nitrergic IJP amplitude in a voltage-dependent manner (IJPfMAX = -26.4 ± 0.6 mV, IJPsMAX = -6.7 ± 0.3 mV). Trains at increasing frequencies enhanced nitrergic (k = 0.8 ± 0.2 s, IJPs∞ = -15 ± 0.5 mV) whereas they attenuated purinergic responses (k = 3.4 ± 0.6 s,IJPf∞ = -8.9 ± 0.6 mV). In tissues with intact ICC-SMP, the RMP was -50.0 ± 0.9 mV and nifedipine insensitive slow waves (10.1 ± 2.0 mV, 10.3 ± 0.5 cpm) were recorded. In these cells, (1) nitrergic and purinergic responses were reduced and (2) slow waves maintained their intrinsic frequency and increased their amplitude under nerve-mediated hyperpolarization. Based on the co-transmission process and consistent with the expected results on RMP, prolonged EFS caused a progressive reduction of LF contractions whereas HF contractions were partially insensitive. In conclusion, inhibitory neurons modulate colonic spontaneous motility and the principles determining post-junctional responses are (1) the frequency of firing that determines the neurotransmitter/receptor involved, (2) the transwall gradient and (3) the origin and nature of each myogenic activity

Respiratory flutter syndrome in a neonate

Respiratory flutter or diaphragmatic flutter is a rare disorder characterized by involuntary, high frequency contractions of the diaphragm. Only 7 cases are reported in infants till date. The present case presented with life threatening respiratory distress immediately after birth. In view of high respiratory rate of 120-154 per minute, clinical and fluoroscopic evidence of diaphragmatic contraction and absence of any obvious CNS, cardiovascular and respiratory pathology, respiratory flutter was diagnosed. It was also associated with dysphagia and laryngomalacia. The patient was managed with prolonged continuous positive airway pressures (CPAP) with partial success, but symptoms improved with use of chlorpromazine.

Körperliches Training und zelluläre Anpassung des Muskels

Resistance training and to a lesser extent endurance training are capable of enhancing protein synthesis in skeletal muscle via various signaling pathways. Additionally, the expression of muscle fiber types responds to different regimes of training stimuli and immobilization as characterized by changes in myosin heavy chain isoforms (I<-->IIA<-->IIX). Eccentric resistance training has been shown to be highly efficient in inducing sarcomeric protein assembly in the longitudinal orientation of muscle cells. However, concentric contractions lead to a hypertrophic response (increased fiber diameter) in muscle which can still be activated in old age. The central signaling pathway to mediate the elevation of protein synthesis in response to training is the mTOR pathway, which is also stimulated by free amino acids. Moreover, adaptation to endurance training is mediated by the calcium-calcineurin-NFATc1 pathway which is strongly activated by the calcium transients involved in the muscle contraction process. High contraction frequency and long duration of training sessions are essential for activation and maintenance of fiber type I expression as well as for induction of transformation of type II into type I fibers. Endurance training sessions should therefore be longer than 30 min and dominated by periods of high frequency contractions. A further factor in the muscular response to training includes the recruitment and integration of satellite cells into muscle fibers. Satellite cells can respond to muscular stretch, activity and injury with increased proliferation and can later be integrated into muscle fibers. Therefore, new myonuclei are available to enhance mRNA synthesis and protein expression in muscle cells. New understanding of the cellular mechanisms of signal transduction in muscle in response to training, bed rest and ageing will help to optimize training and interventions in an ageing population.

Effect of 4-aminopyridine (4-AP) on the spontaneous activity and neuromuscular junction in the rat colon

Two pacemakers are involved in the generation of the spontaneous electrical activity in the rat colon. Slow waves, originated near the submuscular plexus, elicit high frequency contractions whereas low frequency contractions are related to cyclic depolarizations, which might be originated near the Auerbach's plexus. Inhibitory junction potentials (IJPs) in the rat colon show a fast component followed by a sustained NO-mediated hyperpolarization. We have utilised mechanical recordings and intracellular electrophysiology to characterize the effects of 4-AP on spontaneous electrical activity and inhibitory neurotransmission in isolated preparations of rat colon. 4-AP reduced the repolarization of smooth muscle cells and caused a transient (for 4–5 min) depolarization (9.7 ± 3.1 mV; n = 4) and repetitive spikes. The mechanical activity correlated with these electrical changes consisted of a transient increase in tone without cyclic activity followed by long lasting high amplitude cyclic contractions. To avoid smooth muscle cyclic depolarizations, nifedipine 1 μM was added to the perfusion solution. 4-AP 5 mM hyperpolarized (−11.4 ± 2.1 mV, n = 5) the smooth muscle and induced spontaneous IJPs. This effect was not observed when the tissue was preincubated with TTX 1 μM ( n = 7) and L-NNA 1 mM ( n = 4). We conclude that 4-AP inhibits repolarization of smooth muscle cells and induces release of NO from nerve endings. This effect might be due to inhibition of K + channels both in neurons and smooth muscle cells.

Repeat Sphincter of Oddi Manometry in Patients with Post Cholecystectomy Syndrome and Acute Recurrent Pancreatitis After Initial Normal Study

Sphincter of Oddi dysfunction is believed to be the cause of biliary colic-type pain following cholecystectomy in up to 1% of pts (“Post Cholecystectomy Syndrome”). SOM in these pts during ERCP can establish the diagnosis and provide immediate, effective treatment. Similarly ARP may be caused by sphincter dysfunction and sphincterotomy may be curative in a subset of pts. Accuracy of SOM in establishing a diagnosis in PCS and ARP, particularly specificity is largely unknown. AIM: 1) To determine value of repeat SOM in pts presenting with PCS and ARP after initial normal study. 2) To determine clinical response to endotherapy in these pts. Methods: Over a 16-year period, 2497 pts underwent SOM.1873 pts presented with PCS, while 624 pts presented with ARP. Ninety-seven pts with normal SOM presented for follow-up ERCP and SOM and are the subject of this study. This included 41 pts with PCS and 56 pts with ARP. SOM was performed in standard fashion using a perfusion manometry catheter with 3 ports. SO pressure ≥40 mmHg, high frequency contractions, or high amplitude contractions and/or paradoxical response to CCK was considered an abn study. Sphincterotomy was undertaken by first carrying out biliary sphincterotomy followed by pancreatic sphincterotomy. Over the last 5 years of this study, modified pancreatic stents were left in the PD following pancreatic SO sphincterotomy to prevent for ERCP pancreatitis. Results: Of the 41 pts with PCS presenting for repeat SOM, 16 of 41 (39%) had abn SOM, including 13 with CBD SOD, 1 with PD SOD, and 2 with dual SOD. Following ES, 10 of 16 (63%) had good long-term resolution of symptoms. Thirty-six of 56 pts (64%) in the ARP group had abn SOM, including 12 with PD SOD, 4 with CBD SOD, and 8 with dual SOD. After ES, this group had 26/36 (72%) clinical response. Conclusion: Pts with documented PCS and ARP caused by SOD may occasionally have normal sphincter of Oddi manometry. Repeat SOM may reveal abn studies in up to two-thirds of pts. ES in these pts Results in resolution of pain and/or episodes of acute pancreatitis in the majority of pts.

Task-specific design of skeletal muscle: balancing muscle structural composition

Skeletal muscle fibers are composed of three structural elements, each contributing a unique aspect of muscle function, yet each ‘competing’ in a sense for space inside the cell. The volume occupied by myofibrils determines the force of contraction, the volume of sarcoplasmic reticulum sets the rate of onset and relaxation of a fiber’s contraction and hence contraction frequency, and the volume of mitochondria sets the level of sustained performance. The entirety of functional outcomes in muscle, from sustained isometric to high frequency contractions, and from high power output to high endurance, are all primarily attributable to shifts in the proportions (and relationships) of those three structures. This paper examines and reviews these components of muscle first to identify and summarize structure–function ‘rules’, and second to examine the balance between sometimes competing demands. In particular, we focus on those muscles in which power, endurance and frequency are all simultaneously high (flight muscles), and examine how muscle has ‘solved’ problems of space and energy demand. From these results and observations it would appear that for flight to have evolved in small animals, the double packing of inner mitochondrial membranes may be expected in animals under 50–80 g in mass, and asynchronous muscle is structurally essential for flight in small insects with wing beat frequencies above about 100 Hz.

Local paracrine effects of estradiol are central to parturition in the rhesus monkey.

The central biochemical mechanisms involved in primate parturition are still unclear. Studies in both humans and nonhuman primates such as the baboon and rhesus monkey indicate that many factors play a part in the cascade of interactive positive feedforward loops that progressively promote parturition: changes in maternal endocrinology, a nocturnal switch in myometrial activity from low amplitude, infrequent contractures to high amplitude, high frequency contractions (see Fig. 1), dilation of the cervix and biochemical changes in the fetal membranes that lead to rupture. Here we demonstrate that infusion of the aromatase inhibitor 4-hydroxyandrostenedione (4OHA) inhibits conversion of androgen to estrogen and prevents premature delivery caused by administration of androgen to pregnant rhesus monkeys at 0.8 of pregnancy term. 4OHA also inhibited the androstenedione induced maternal endocrine and fetal membrane biochemical changes, and alteration of myometrial activity patterns. Secondly, peripheral estrogen infusions increased myometrial activity but did not produce preterm delivery or fetal membrane changes. We conclude that paracrine functions of estrogen at its site of production play critical and central roles in delivery in the non-human primate.

Comparison between physiologic and somatostatin-induced high frequency contractions in sphincter of Oddi in humans

Comparison between physiologic and somatostatin-induced high frequency contractions in sphincter of Oddi in humans

Comparison between physiologic and octreotide-induced high frequency contractions in sphincter of oddi in humans

Comparison between physiologic and octreotide-induced high frequency contractions in sphincter of oddi in humans

Nitric oxide affects mammalian distal colonic smooth muscle by tonic neural inhibition.

1 The role of the L-arginine-nitric oxide (NO) pathway in tonic neural inhibition of spontaneous mechanical activity of distal colonic circular smooth muscle (DCCSM) was investigated in male Wistar rats. 2 Muscle strips were mounted in organ baths and spontaneous contractions recorded with isometric force transducers. They were characterized as low frequency (LFCs) 0.41 +/- 0.03 N cm-2 or high frequency contractions (HFCs) 0.22 +/- 0.04 N cm-2. The latter occurred intermittently to produce summation contractions (SCs) range 0.5-12 N cm-2. 3 Tetrodotoxin (100 nM) increased the forces of LFCs and SCs. Increase in force to tetrodotoxin did not occur after incubation of the muscle with NG-monomethyl-L-arginine (L-NMMA) 500 microM, an inhibitor of NO biosynthesis. 4 L-NMMA but not its enantiomer D-NMMA increased the force of LFCs (EC50: 200 microM) and SCS (EC50:175 microM) in a concentration-dependent manner which was reversed by L-arginine but not by D-arginine. 5 Muscle, precontracted by acetylcholine, relaxed to sodium nitroprusside (EC50:1.8 microM) NO gas (EV50:70 microliters) and NO solutions (EC50:4 microM) in a concentration-dependent manner. Guanosine 3':5'-cyclic monophosphate tissue concentrations (pmol mg-1 protein) were elevated in muscle after relaxation by sodium nitroprusside (500 microM) from 0.32 +/- 0.06 to 1.2 +/- 0.37 and by 1 ml of NO gas from 0.49 +/- 0.05 to 1.54 +/- 0.14. 6 These data suggest that DCCSM is under tonic neural inhibition mediated by NO biosynthesis.

Corticotropin Releasing Factor (CRF) increases post‐prandial duodenal motor activity in humans

AbstractThe effects of peripherally administered Corticotropin Releasing Factor (CRF) on post‐prandial gastrointestinal motility were studied in normal subjects. Pressure activity was monitored for 90 min pre‐and 120 min post‐prandially in the antrum and duodenum in 8 healthy male volunteers (mean age 45.5 years). Subjects received, on separate days, ovine CRF (0.6 nmol/kg) or vehicle, infused intravenously over 5 min, 15 min after the beginning of the meal. In all subjects, CRF infusion transiently increased the frequency of contractile events to the frequency of the duodenal slow wave (11.7 ± 0.3 cpm). The postprandial duodenal mobility index (MI) after CRF infusion was significantly greater (7.72 ± 0.29) when compared to vehicle infusion (4.34 ± 0.14) (mean ± SEM; P &lt; 0.001). However, the fraction of propagated contractile events was not altered significantly after CRF when compared to vehicle. In contrast, the antral post‐prandial MI was not affected by the CRF application. Serum cortisol levels increased significantly at 60 and 90 min post‐CRF injection. These data indicate that CRF transiently switches the post‐prandial duodenal motor activity to a band of non‐propagated high frequency contractions, but does not affect antral contractions.

Identification of Spontaneous High and Low Frequency Contractions in Colonic Smooth Muscle under Neural Regulation Mediated by Nitric Oxide

Identification of Spontaneous High and Low Frequency Contractions in Colonic Smooth Muscle under Neural Regulation Mediated by Nitric Oxide

Colonic motility in humans—a growing understanding

As yet, there is limited information about the relationship of colonic motility to colonic flow or transit. The overall flow in the colon is slow and highly variable. The measurement of total and segmental transit time is essential for the differentiation of motor disorders associated with delayed transit. Rapid movements of colonic contents (mass movements) occur only a few times during the day. Their motor equivalent is the giant contraction which migrates in the aborad direction at relatively high velocity. Motor activity in the colon is highly variable, with periods of contraction and motor quiescence. Contractions occur at different frequencies ranging from 2 to 13 cycles per minute. High frequency contractions are stationary. Their myo-electrical equivalent is short spike bursts. Long spike bursts result in sustained, low frequency contractions, which may migrate in both directions. Technological advances now make it possible to obtain ambulant manometric recordings from the colon for 24h. Such studies show a circadian variation in colonic motility with increases of activity after meals and after awakening. Motor disorders of the colon are not associated with specific abnormal motor patterns. Rather, they are due to changes in the occurrence of motor patterns seen in health. In constipated patients with slow colonic transit the suppression of strong peristaltic activity is the most plausible common pathogenetic mechanism. In diarrhoeal states, pro-pulsive activity such as the giant migrating contractions may be a major mechanism which promotes the passage of stools. There is no agreement that there is disordered basal colonic motor activity in IBS. There is, however, increasing evidence that in IBS the colon responds abnormally to eating, certain forms of stress and distension, and that this may relate to symptoms. The psychopathology of IBS patients is apparently the most important factor in the health care-seeking behaviour of the patients. No specific therapy has yet been shown to be convincingly effective.

Basic Studies on Skeletal Muscle for Cardiac Assistance

It is well recognized that skeletal muscle is incapable of maintaining the continuous power output needed for significant circulatory assistance unless it is rendered fatigue resistant by electrical stimulation. Most studies using conditioning patterns related to the pumping rate of the natural heart have suggested that such patterns can produce complete transformation to a slow phenotype. Such a transformation has two undesirable accompaniments: a reduction in the contractile speed of the muscle and an extreme reduction in its power-generating capacity. We have investigated the chronic effect on rabbit muscle of intermittent high frequency contractions either alone or overlaid on a continuous background of 10 Hz. If the amount of stimulation were the overriding stimulus for transformation, then the rate and/or extent of transformation should, if anything, be greater with the additional activation. If, on the other hand, components of the transformation could be modulated independently by the pattern of impulses, then the reduction in power output might be avoided to some extent by a pattern somewhat analogous to a strength-training exercise regime. Our results suggest that high force contractions may indeed preserve power output without compromising the acquisition of fatigue resistance.

Effects of the calcium channel agonist, Bay K 8644, on the mechanical output of skeletal muscle fibers

1. 1. The effects of the calcium agonist, Bay K 8644, on the mechanical output of skeletal muscle were studied in frog semitendinosus fiber bundles and in whole sartorius muscles. 2. 2. Low concentrations of Bay K 8644 (≤ 1 μM) had no significant influence on isometric twitches. Concentrations between 5-20 μM increased peak tension by 28.6 ± 2.9% while higher concentrations (≥ 50 μM) initially increased then depressed twitches by 70 ± 3.5%. 3. 3. 10 μM Bay K 8644 also increased peak tension developed during low frequency stimulation (i.e. ≤40 Hz), slightly depressed high frequency contractions (i.e. ≥ 80 Hz) but did not reduce maximal tetanic tension which occurred at about 60 Hz. 4. 4. Potentiation of twitches and low frequency tetani and depression of high frequency tetani by Bay K 8644 were partially antagonized by nifedipine (10 μM), low extracellular calcium and D-600 (5 μM). These conditions did not, however, block the depressant actions of ≥ 50 μM Bay K 8644. 5. 5. In skinned fibers, 10 μM Bay K 8644 had no effect on resting or maximal Ca 2+ activated tension. Also, 10 μM Bay K 8644 had no effect on caffeine contractures when added to the previous Ca 2+ loading solution. 6. 6. These results suggest that Bay K 8644 has both positive and negative inotropic actions on isolated skeletal muscle, which are dependent on drug concentration and muscle activation pattern.

UTERINE CONTRACTILITY AND ACTIONS OF CATECHOLAMINES IN LONGITUDINAL AND CIRCULAR UTERINE LAYERS FROM OVARIECTOMISED GUINEA‐PIGS: THE EFFECTS OF OVARIAN STEROIDS

The influence of ovarian steroids upon responses to electrical stimulation and to activation of adrenoreceptors in field-stimulated preparations of longitudinal and circular myometrium from ovariectomised guinea-pigs has been investigated. Adult virgin guinea-pigs were bilaterally ovariectomised and were treated two weeks later with thrice-weekly injections of oestradiol cypionate for two weeks, or treated as in then given oestradiol cypionate and progesterone for a further four days. Control groups of bilaterally ovariectomised and sham ovariectomised animals remained untreated. Both myometrial layers from untreated ovariectomised guinea-pigs were atrophied. Responses to field stimulation in the circular myometrium were much smaller than those in the longitudinal layer. Steroid pretreatment, most notably treatment with oestradiol and progesterone, were associated with decreased and increased responsiveness to electrical stimulation in the circular and longitudinal myometrial layers respectively. Adrenaline and noradrenaline were consistently excitatory on preparations of circular myometrium from ovariectomised animals. Responses comprised either enhancement of electrically-evoked contractions, or, with the higher concentrations, the appearance of rapid contractions superimposed upon an increase in basal tone. The latter effects were also evident in preparations of circular myometrium from sham operated animals. In preparations of longitudinal myometrium from untreated ovariectomised animals noradrenaline consistently and adrenaline usually caused a simple enhancement of the magnitude of the evoked contractions. Phentolamine reduced the excitatory effects of both amines in both layers. In circular myometrium from the oestrogen-treated group both catecholamines produced phentolamine-sensitive enhancement of electrically-evoked contractions, but did not cause high frequency contractions or increased tonus. Noradrenaline and adrenaline produced qualitatively similar phentolamine-sensitive effects in preparations of longitudinal myometrium from this group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine and dipyridamole: actions and interactions on the contractile response of guinea-pig ileum to high frequency electrical field stimulation.

The action of adenosine on the myenteric plexus-longitudinal muscle strips from guinea-pig ileum to high frequency electrical field stimulation (10 Hz) was investigated. Electrically induced contractions were reduced markedly by tetrodotoxin (0.2 microM) and atropine (1 microM), and partially by noradrenaline (3 microM) and morphine (3 microM). Adenosine, adenosine 5'-monophosphate (AMP) and adenosine triphosphate (ATP) produced a concentration-dependent inhibition of the high frequency contractions over the range of 0.1-100 microM, the most potent being adenosine. The concentration-response curve for adenosine was significantly shifted to the left by dipyridamole (10 nM), while dipyridamole at higher concentrations (30 nM-10 microM), depressed the contraction markedly by itself. Dipyridamole decreased [3H]-adenosine uptake into strips of ileum in a concentration-dependent manner. There was a significant correlationship between the reduction of adenosine uptake and the inhibition of the contraction induced by dipyridamole (r = 0.970). In strips desensitized to adenosine or treated with adenosine deaminase, the inhibitory effect of dipyridamole was significantly reduced. The present investigation revealed that adenosine depressed responses of guinea-pig ileum to high frequency electrical stimulation and suggested that the inhibitory effect of dipyridamole may be closely associated with the behaviour of endogenous adenosine or related compounds.

Termination of midtrimester pregnancy by serial intramuscular injections of 15(S)-15-methyl-prostaglandin F2α

Midtrimester abortion was successfully induced in 117 of 120 patients with serial intramuscular injections of 15(S)-15-methyl-prostaglandin F2alpha (15-me-PGF2alpha). The mean abortion time was 14.12 hours, and parous patients aborted in a mean of 12.85 hours-significantly faster than nulliparous patients who aborted in a mean of 15.24 hours. Ninety-four per cent of the 117 successfully induced abortions occurred in less than 24 hours and 46 per cent in less than 12 hours. Uterine activity was monitored and analyzed in nine patients. Uterine response to a single intramuscular injection of 100 mug of 15-me-PGF2alpha was characterized by the appearance of low-amplitude, high frequency contractions and a rapid increase in baseline intrauterine tonus. A high level of uterine activity, 900 Montevideo Units, was observed within 30 minutes of the first intramuscular injection of 15-me-PGF2alpha. This activity was not maintained and decreased by approximately 30 per cent at the time of the second injection at 1 hour. It was not until 6 hours of 15-me-PGF2alpha therapy that activity stabilized at approximately 500 Montevideo Units. Even though all patients were premedicated with antiemetic and antidiarrhea agents, 68 of 120 patients experienced gastrointestinal side effects related to the 15-me-PGF2alpha administration. Vomiting was the most prevalent side effect, occuring in 65 patients, but the episodes were not severe, were well tolerated by the patients and did not necessitate the termination of prostaglandin administration in any of the patients. In this study abortion was successfully induced between weeks 9 to 27 of gestation. It was observed that patients with gestations of 16 weeks or less aborted significantly faster than patients with gestations of 17 weeks or more, which indicates that this method is highly effective in the induction of abortion within the "gray zone", 12 to 16 weeks of gestation.