The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations.

OBJECTIVE: The histopathological features of malignant hyperthermia (MH) and non-anaesthetic (mostly exertional) rhabdomyolysis (RM) due to RYR1 mutations have only been reported in a few cases. METHODS: We performed a retrospective multi-centre cohort study focussing on the histopathological features of patients with MH or RM due to RYR1 mutations (1987-2017). All muscle biopsies were reviewed by a neuromuscular pathologist. Additional morphometric and electron microscopic analysis were performed where possible. RESULTS: Through the six participating centres we identified 50 patients from 46 families, including patients with MH (n = 31) and RM (n = 19). Overall, the biopsy of 90% of patients showed one or more myopathic features including: increased fibre size variability (n = 44), increase in the number of fibres with internal nuclei (n = 30), and type I fibre predominance (n = 13). Abnormalities on oxidative staining, generally considered to be more specifically associated with RYR1-related congenital myopathies, were observed in 52%, and included unevenness (n = 24), central cores (n = 7) and multi-minicores (n = 3). Apart from oxidative staining abnormalities more frequently observed in MH patients, the histopathological spectrum was similar between the two groups. There was no correlation between the presence of cores and the occurrence of clinically detectable weakness or presence of (likely) pathogenic variants. CONCLUSIONS: Patients with RYR1-related MH and RM exhibit a similar histopathological spectrum, ranging from mild myopathic changes to cores and other features typical of RYR1-related congenital myopathies. Suggestive histopathological features may support RYR1 involvement, also in cases where the in vitro contracture test is not informative.

Effect of cisapride on myoelectrical and motor responses of antropyloroduodenal region during intraduodenal lipid and antral tachygastria in conscious dog.

The myoelectrical and motor response of the antropyloroduodenal region to intraduodenal nutrient stimulation or antral tachygastria represent useful models for, respectively, physiological and pathophysiological gastric stasis to test the efficacy of prokinetic drugs. We evaluated the effects of an intravenous bolus of cisapride (0.63 mg/kg) on the myoelectrical and motor response of the antropyloroduodenal region to an intraduodenal triglyceride emulsion (10% Intralipid, 0.5 ml/min) or antral tachygastria in conscious dogs. Intraduodenal lipid suppressed antral motility (P < 0.05, compared to intraduodenal saline) and stimulated phasic pyloric contractions (P < 0.01, compared to intraduodenal saline), a motor pattern known to be associated with delayed gastric emptying. During intraduodenal lipid stimulation cisapride virtually abolished all isolated pyloric motor events (P < 0.05) and stimulated antral and duodenal motility (P < 0.05 for both) and antropyloroduodenal coordination (65% versus 15%; P < 0.05). Antral tachygastria was associated with a higher number of isolated pyloric motor events in the fasted state [0.8 (0.7-1.1) per minute versus 0.2 (0-0.3) per minute; P < 0.05], but not during intraduodenal lipid stimulation [1.1 (0.9-1.7) per minute versus 1.2 (1.0-1.9) per minute; NS]. Cisapride decreased the number and duration of spontaneous episodes of antral tachygastria during intraduodenal saline and lipid infusion (P < 0.05 for both) and abolished the tachygastria-associated motor patterns. Cisapride induced a 20% decrease in the antral slow-wave frequency during intraduodenal saline and lipid, irrespective of gastric pacemaker rhythm. We conclude that: (1) cisapride overcomes feedback from small intestinal lipid receptors on myoelectrical and motor activities of the antropyloroduodenal region and decreases antral slow-wave frequency, and (2) cisapride inhibits antral tachygastria and tachygastria-associated motor patterns. These effects may contribute to the effective gastrokinetic properties of cisapride in physiological and certain forms of pathophysiological gastric stasis.

Pyloric motility. Sleeve sensor versus strain gauge transducer.

Intraduodenal infusion of nutrients has been shown by intraluminal sleeve-sidehole manometry to suppress antral contractions and stimulate isolated pyloric pressure waves (IPPWs) in humans. It is still unresolved, whether these pyloric contractions occur within an otherwise quiescent zone of motor and electrical activity and whether the presence of the sleeve sensor itself affects this nutrient-associated response. In four conscious dogs, comparisons were made between paired recordings of myoelectrical and motor activities of the antropyloroduodenal region with serosal strain gauge transducers and extracellular bipolar electrodes in the presence and absence of an intraluminal manometric sleeve-sidehole assembly during intraduodenal infusions of saline and a triglyceride emulsion (Intralipid 10%, 0.5 kcal/min). Of 287 isolated pyloric pressure waves, detected by the manometric sleeve sensor, 75% were detected as isolated pyloric contractions by the strain gauge transducers and 72% occurred in the absence of electrical spike activity in the distal antrum or proximal duodenum. The lower incidence of isolated pyloric contractions (strain gauges) was related to: (1) insensitivity of the pyloric strain gauge transducer in comparison to the manometric sleeve sensor (10%), and (2) inability of the manometric sleeve-sidehole assembly to detect pressure waves in the distal antrum (7%) or proximal duodenum (8%) during antral or duodenal wall motion. The presence of the sleeve sensor itself did not affect the number of lipid-induced isolated pyloric contractions but increased their amplitude [median 9 (7-15) mN vs 4 (2-6) mN; P < 0.05].(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of adrenoceptor agonists on striated muscle strips of the canine oesophagus.

1. Acute psychological stress, which could be related to the release of a large amount of catecholamines, may cause oesophageal motility disorders. Therefore, the aim of our study was to elucidate the influence of adrenoceptor agonists on the striated muscle portion of the oesophagus by use of isolated strips from dogs. 2. Contractions were evoked in isolated striated muscle strips by electrical field stimulation (1 pulse min-1, 1 ms/pulse, submaximal voltage). The effects induced by administration of adrenoceptor agonists alone or in the presence of antagonists were tested to determine the nature of the adrenoceptors on this muscle preparation. 3. The administration of both the natural adrenoceptor agonists, adrenaline and noradrenaline, and the synthetic beta-adrenoceptor agonists, isoprenaline (beta 1 + beta 2), dobutamine (beta 1) or ritodrine (beta 2), enhanced the amplitude of the contractions induced by electrical stimulation in a concentration-dependent manner. The maximum responses were 82.6 (adrenaline), 66.2 (noradrenaline), 86.2 (isoprenaline), 34.6 (dobutamine) and 80.8% (ritodrine). The EC20 values obtained were respectively 2 nM, 0.2 microM, 0.91 nM, 3 microM and 80 nM. The administration of the alpha 1-adrenoceptor agonist, phenylephrine, also enhanced the contractile response in a concentration-dependent manner (EC20 value = 0.3 microM) and the maximum response was 64.6%, but the administration of the alpha 2-adrenoceptor agonist, clonidine, did not influence the contractile response. These data suggest the involvement of beta 2- and possibly alpha 1-adrenoceptors in the responses of these adrenoceptor agonists. 4 The selective P2-adrenoceptor antagonist ICI 118551 (3-100nM) shifted the concentration-effect curves for noradrenaline, phenylephrine and ritodrine to the right in a concentration-dependent manner.ICI 118551 (3 nM) also shifted the concentration-effect curves for adrenaline and isoprenaline to the right, but increasing the concentration of ICI 118551 did not cause any further antagonist activity until a concentration of 100 nM, when a further rightward shift was obtained.5. The selective alpha 1-adrenoceptor antagonist, prazosin (30-300 nM), did not affect the increased contractile responses induced by adrenaline, noradrenaline, phenylephrine, isoprenaline or ritodrine.6. In conclusion, it appears that beta2-adrenoceptors are present in the striated muscle portion of the canine oesophagus, where they mediate an enhancement of contractile responses evoked by electrical stimulation. The alpha l-agonist, phenylephrine, appears to interact with beta2-adrenoceptors on this preparation.beta 3-Adrenoceptors have already been demonstrated in smooth muscle from various parts of the gastrointestinal tract, and our study does not exclude the possibility that there is an additional population of beta 3-receptors in the canine striated muscle part of the oesophagus.

Cisapride and 5-hydroxytryptamine enhance motility in the canine antrum via separate pathways, not involving 5-hydroxytryptamine1,2,3,4 receptors.

Prokinetic benzamides (e.g., cisapride) enhance gastrointestinal motility and transit. In vitro studies on the guinea pig ileum suggest that their effect is mediated via serotonergic 5-hydroxytryptamine (5-HT4) receptors, resulting in a facilitation of cholinergic neurotransmission. However, most in vivo studies have been performed on the canine stomach. Therefore, our aim was to determine whether the findings obtained on the guinea pig ileum can be extrapolated to another species and another organ. Does a benzamide facilitate cholinergic neutrotransmission on strips of the canine stomach in vitro? If so, does the benzamide exert its effect via a serotonergic 5-HT4 mechanism? Longitudinal muscle strips with adhering myenteric plexus were isolated from the canine stomach and were electrically stimulated at submaximal frequencies resulting in a mean contractile response of 16 +/- 7% of the response to methacholine (10(-6) M). Atropine and tetrodotoxin (both 3 x 10(-7) M) abolished the contractile responses, whereas hexamethonium (10(-4) M) had no effect. Cisapride (3 x 10(-7) M) enhanced the contractile responses from 14 to 70% (59 +/- 5% increase). 5-HT (3 x 10(-7) M) similarly enhanced the responses from 12 to 72% (58 +/- 5% increase). Cisapride induced a sustained enhancement throughout the duration of the experiment; in contrast, the effect of 5-HT subsided in about 90 min. Single-concentration administration of cisapride (10(-8)-10(-6) M) and 5-HT (10(-9)-3 x 10(-7) M) resulted in EC50 values of 1.0 (0.8-1.4) x 10(-7) M for cisapride and 1.3 (0.8-2.1) x 10(-8) M for 5-HT. Methiothepin and methysergide (both 3 x 10(-7) M; 5-HT1-receptor antagonists), ketanserin and LY 53857 (both 3 x 10(-7) M; 5-HT2-receptor antagonists), granisetron (3 x 10(-7) M; 5-HT3-receptor antagonist) or ICS 205-930 (3 x 10(-7) M; 5-HT3-receptor antagonist and in addition 5-HT4-receptor antagonist at 3 x 10(-6) M) did not reduce the responses to both cisapride and 5-HT. 1-(1-Naphthalenyl)piperazine (10(-6) M; 5-HT-receptor antagonist in the rat gastric fundus) significantly reduced the increase by 5-HT (24 +/- 7%; 7-31%) but had no effect on the cisapride (3 x 10(-7) M)-induced increase (69 +/- 4%; 8-77%).(ABSTRACT TRUNCATED AT 400 WORDS)

Computer-assisted method for the analysis of postprandial gastrointestinal motility in conscious dogs.

A fully automated system to quantify different parameters of gastrointestinal motility and gastroduodenal co-ordination in conscious dogs was designed and built around a personal technical computer (HP 9816). Online it performs sampling of contractions on four different sites of the digestive tract for two dogs simultaneously, data reduction, drift correction and storage of data on hard disk. Offline it performs baseline determination, peak detection, calculation of motility parameters such as amplitude and interval, plus co-ordination between gastric and duodenal motility and presentation of the results in both tabular and graphic form. To illustrate the possibilities and advantages of the computer analysis the early postprandial motor patterns for antrum, duodenum and jejunum were quantified during the first hour after administration of a small test meal.

Vasoconstrictor expression of human platelet-vessel wall interactions: inhibition by the Ca2+ entry blocker flunarizine.

Human blood platelets, stimulated with thrombin, induced contractions of isolated basilar artery segments of the dog. These platelet-mediated vascular contractions were inhibited in a concentration-dependent way by flunarizine, a Ca2+ entry blocker, selective for vascular tissues (IC50: 5.5 X 10(-7) M). This inhibition increased gradually as a function of the time contact with flunarizine, to reach its maximum after 60-90 min. Biochemical and pharmacological analyses using the S2-serotonin receptor antagonist ritanserin, the thromboxane A2/prostaglandin endoperoxide antagonist BM 13.177 and the fatty acid cyclo-oxygenase inhibitor suprofen showed that 5-hydroxytryptamine and prostanoids (thromboxane A2, prostaglandin endoperoxides) were the main mediators involved. The results further suggested amplification between the vascular effects of 5-hydroxytryptamine and prostanoids. Flunarizine did not affect the release of 5-hydroxytryptamine from platelets and did not interfere with their biosynthesis of thromboxane A2.

Ketanserin and vascular contractions in response to cooling.

Rings of tibial arteries of the rabbit were suspended for isometric tension recording in organ chambers filled with oxygenated physiological salt solution. 5-Hydroxytryptamine caused contractions which were enhanced by cooling from 37 to 29 degrees C. Both the contractions induced by 5-hydroxytryptamine and their augmentation by cooling were inhibited by similar concentrations of the serotonergic 5-HT2 antagonist ketanserin. These experiments demonstrate that cooling augments the responsiveness of peripheral arteries to 5-hydroxytryptamine and that the augmentation is mediated by 5-HT2 serotonergic receptors.

Comparison of the responsiveness of isolated arteries and veins taken from the same dogs 17 days apart.

The present experiments demonstrate that isolated arteries and veins taken from the same dogs before and after an interval of 17 days show comparable responses to adrenergic nerve stimulation, exogenous norepinephrine and depolarizing solution. They provide an acceptable model for the in vitro study of chronic influences on canine vascular responsiveness.