Evaluating the relationship between ocular blood flow and systemic organ blood flow in hemorrhagic shock using a rabbit model.

This study aimed to investigate the feasibility of utilizing noninvasive ocular blood flow measurements as potential indicators of systemic circulation in rabbits experiencing hemorrhagic shock. Using Laser speckle flowgraphy, ocular blood flow indices, relative flow volume (RFV), and mean blur rate in the choroidal area (MBR-CH) were assessed in New Zealand White rabbits (n = 10) subjected to controlled blood removal and return. Hemodynamic parameters and biochemical markers were monitored alongside ocular circulation during blood removal and return phases. Additionally, correlations between ocular parameters and systemic indices were examined. The results indicated that RFV and MBR-CH exhibited significant correlations with renal and intestinal blood flows, with stronger correlations observed during blood removal. Additionally, ocular blood flow changes closely mirrored systemic dynamics, suggesting their potential as real-time indicators of shock progression and recovery. These findings indicate that ocular blood flow measurements may serve as real-time indicators of the systemic circulation status during hemorrhagic shock, offering potential insights into shock management and guiding tailored interventions. Thus, noninvasive ocular blood flow evaluation holds promise as an innovative tool for assessing systemic circulation dynamics during hemorrhagic shock.

Role of Rho Kinase in Regulating Arterial Stiffness in Anesthetized Rabbits.

The effects of Rho kinase inhibitors fasudil and ripasudil on arterial stiffness were assessed using anesthetized rabbits, where the aortic ß and femoral ß were measured as a stiffness parameter at each arterial region. Intravenous administration of fasudil and ripasudil dose-dependently decreased blood pressure and femoral vascular resistance and increased femoral arterial blood flow, which appeared according to their in vitro potencies for Rho kinase inhibition. Both drugs increased the aortic ß but decreased the femoral ß at hypotensive doses. These results suggest that the inhibition of Rho kinase contributes to reducing elastic recoil in the aorta and an increase in compliance in the femoral artery. In addition, the Rho kinase-associated Ca2+-independent mechanism of arterial vascular smooth muscle contraction may be essential in the regulation of femoral arterial stiffness.

Differential Effects of Ca2+ Channel Blockers Nifedipine and Cilnidipine on Arterial Elasticity in the Aortic and Femoral Arterial Segments of Anesthetized Rabbits.

Ca2+ channel blockers have potent vasodilatory effects and excellent efficacy in preserving organ blood flow. These hemodynamic actions may be partly controlled by the functional stiffness of conduit arteries. In this study, we assessed the effects of the L-type Ca2+ channel blocker nifedipine on aortic and femoral arterial stiffness (referred to as aortic ß and femoral ß, respectively) in anesthetized rabbits. To further clarify the involvement of the autonomic nervous system, we compared the effects of nifedipine with those of the L/N-type Ca2+ channel blocker cilnidipine. Further, the effect of the α-adrenergic receptor blocker doxazosin on the effects of nifedipine on arterial elasticity was examined. An antihypertensive dose of nifedipine (300 µg/kg, administered intravenously) was found to increase the aortic ß but hardly affected the femoral ß. An antihypertensive dose of cilnidipine (30 µg/kg, administered intravenously) increased the aortic ß but decreased the femoral ß. Interestingly, nifedipine decreased the femoral ß in the presence of the α-adrenoceptor blocker doxazosin (1 mg/kg, administered intravenously). These effects suggest that L-type Ca2+ channel blockers essentially increase vascular elasticity via the decrement in arterial stiffness in the femoral artery segment, which is modified by the presence or absence of the inhibitory effect of each drug on reflex sympathetic nerve activity, while decreasing vascular elasticity via the increment in arterial stiffness in the aortic segment independently of sympathetic nerve activity.

The Antiarrhythmic Action of the Na+/Ca2+ Exchanger Inhibitor SEA0400 on Drug-Induced Long QT Syndrome Depends on the Severity of Proarrhythmic Conditions in Anesthetized Atrioventricular Block Rabbits.

To clarify the pharmacological properties of the Na+/Ca2+ exchanger (NCX) inhibitor SEA0400 as an antiarrhythmic agent, we assessed its effects on rapid component of delayed rectifier K+ current (IKr) blocker-induced torsade de pointes (TdP) in isoflurane-anesthetized rabbits. Atrioventricular block was induced in rabbits using a catheter ablation technique, and the monophasic action potential (MAP) of the right ventricle was measured under electrical pacing at 60 beats/min. In non-treated control animals, intravenous administration of low-dose (0.3 mg/kg) or high-dose nifekalant (3 mg/kg) prolonged the MAP duration (MAP90) by 113 ± 11 ms (n = 5) and 237 ± 39 ms (n = 5), respectively, where TdP was induced in 1/5 animals treated with a low dose and in 3/5 animals treated with a high dose of nifekalant. In SEA0400-treated animals, low- and high-dose nifekalant prolonged the MAP90 by 65 ± 13 ms (n = 5) and 230 ± 20 ms (n = 5), respectively. No TdP was induced by the low dose but 1/5 animals treated with a high dose of nifekalant developed TdP. In verapamil-treated animals, low-dose and high-dose nifekalant prolonged MAP90 by 50 ± 12 ms (n = 5) and 147 ± 30 ms (n = 5), respectively, without inducing TdP. These results suggest that SEA0400 has the potential to inhibit low-dose nifekalant-induced TdP by suppressing the MAP-prolonging action of nifekalant, whereas the drug inhibited high-dose nifekalant-induced TdP without affecting the MAP-prolonging action of nifekalant. This may reveal that, in contrast to verapamil, the antiarrhythmic effects of SEA0400 on IKr blocker-induced TdP may be multifaceted, depending on the severity of the proarrhythmogenic conditions present.

The role of arterial stiffness in the onset of Takotsubo cardiomyopathy observed with noradrenaline administration and intracranial blood injection in rabbits.

Takotsubo cardiomyopathy (TCM) has been reported to occur after subarachnoid hemorrhage, and the involvement of a critical activity of catecholamines has been mentioned, but the details of its onset have not been fully clarified. Recently, proper arterial stiffness could be measured with cardio-ankle vascular index. Therefore, we aimed to clarify the role of arterial stiffness in onset of TCM using rabbits under infusion of noradrenaline and injection of blood into brain ventricle. Rabbits were divided into three groups: infusion of noradrenaline (group A), infusion of noradrenaline + injection of saline into the brain ventricle (group B), infusion of noradrenaline + injection of blood in the brain ventricle (group C). Aortic arterial stiffness beta (Aß) and femoral arterial stiffness beta (Fß) were defined according to definition of the cardio-ankle vascular index. Blood pressure (BP), Aß, Fß, and femoral vessel resistance (FVR) were measured. Left ventricular movement were monitored with echocardiography. BP increased uniformly in all three groups. Fß in the group A, B and C increased from 3.6 ± 3.2, 3.6 ± 3.6 and 3.9_ ± 4.2 to 15 ± 2, 17.9 ± 2.4, 34.8 ± 9.1 due to the ICP enhancements in addition to noradrenaline administration, respectively. Fß in groups B and C was significantly larger than that in group A. On echocardiography, a much higher akinesic area of the apex was observed in group C compared with group A and B. Cardiac movements similar to TCM were observed slightly in group B and definitely in group C. Noradrenaline administration infusion and blood injection into the brain ventricle induced TCM accompanying with enhanced femoral arterial stiffness. These results suggested that elevated arterial stiffness might be involved in the formation of TCM in addition to a critical activity of catecholamines and an increase in intracranial pressure with blood injection.

Role of cardiac α1-adrenoreceptors for the torsadogenic action of IKr blocker nifekalant in the anesthetized atrioventricular block rabbit.

We analyzed role of cardiac α1-adrenoreceptors for the torsadogenic action of IKr blocker nifekalant in isoflurane-anesthetized atrioventricular block rabbits. Bradycardia was induced by atrioventricular node ablation, and the ventricle was electrically driven at a constant rate of 60 beats/min throughout the experiments to prevent rate-dependent modification by the IKr blocker in ventricular repolarization phase. Nifekalant (3 mg/kg per 10 min, n = 5) prolonged the duration of monophasic action potential (MAP90) by +178 ± 43 ms, increased the short-term variability of repolarization (STV) to 4.2 ± 1.2 ms, and induced torsade de pointes (TdP) in 1 animal. In the presence of methoxamine (n = 5), nifekalant prolonged the MAP90 by +328 ± 32 ms, increased the STV to 8.0 ± 1.0 ms, and induced TdP in 2 animals. In the presence of prazosin and methoxamine (n = 5), nifekalant prolonged the MAP90 by +267 ± 22 ms, increased the STV to 9.2 ± 3.6 ms, and induced no TdP. These results suggest that cardiac α1-adrenoreceptor activation by methoxamine essentially sensitizes the rabbit heart to nifekalant-induced QT interval prolongation, leading to the onset of TdP.

Impact of pathological complete response following neoadjuvant chemotherapy (gemcitabine, nab-paclitaxel, S-1) and radiation for borderline resectable pancreatic cancer: a case report and review of literature.

BACKGROUND: Pancreatic cancer (PC) is a highly lethal malignancy, even if surgical resection is possible (median survival: < 30 months). The prognosis of borderline resectable pancreatic cancer (BR-PC) is even worse. There is no clear consensus on the optimal treatment strategy, including pre/postoperative therapy, for BR-PC. We report a patient with BR-PC who achieved clinical partial response with neoadjuvant chemoradiation therapy (NACRT) and underwent curative resection, resulting in pathological complete response (pCR). CASE PRESENTATION: A 71-year-old man with jaundice and liver dysfunction was referred to our department because of a 48-mm hypo-vascular mass in the pancreatic head with obstruction of the pancreatic and bile ducts and infiltration of superior mesenteric vein and portal vein. The lesion was identified as atypical cells which suggested adenocarcinoma by biopsy, and he was administered NACRT: gemcitabine and nab-paclitaxel, following S-1 and intensity modulated radiation therapy. After reduction in the tumor size (clinical partial response), pancreaticoduodenectomy was performed, and pCR achieved. Postoperative adjuvant chemotherapy with S-1 was initially administered and the patient is currently alive with no recurrence as of 2 years after surgery. CONCLUSIONS: NACRT is a potentially useful treatment for BR-PC that may lead to pCR and help improve prognosis.

Chronic Volume Overload Caused by Abdominal Aorto-Venocaval Shunt Provides Arrhythmogenic Substrates in the Rat Atrium.

Atrial enlargement is thought to provide arrhythmogenic substrates, leading to the induction of atrial fibrillation (AF). In this study, we investigated the anatomical, molecular biological, and electrophysiological characteristics of remodeled atria in an animal model with chronic volume overload. We used rats that underwent abdominal aorto-venocaval shunt (AVS) surgery. In the in vivo studies, marked changes in electrocardiogram parameters, such as the P-wave duration, PR interval, and QRS width, as well as prolongation of the atrial effective refractory period were observed 12 weeks after the creation of AVS (AVS-12W), which were undetected at 8 weeks postoperative (AVS-8W) despite obvious atrial and ventricular enlargement. Moreover, the duration of AF induced by burst pacing in the AVS-12W rats was significantly longer than that in the Sham and AVS-8W rats. In the isolated atria, a longer action potential duration at 90% repolarization was detected in the AVS-12W rats compared with that in the Sham group. The mRNA levels of the Kv and Kir channels in the right atrium were mostly upregulated in the AVS-8W rats but were downregulated in the AVS-12W rats. These results show that chronic volume overload caused by abdominal AVS provides arrhythmogenic substrates in the rat atrium. The difference in gene expression in the right atrium between the AVS-8W and AVS-12W rats may partly explain the acquisition of arrhythmogenicity.

Cardiac Electropharmacological Effects of Antidiarrheal Drug Loperamide and Its Antidote Naloxone in Anesthetized Guinea Pigs.

Cardiac electropharmacological effects of an antidiarrheal drug loperamide and its antidote naloxone were assessed in isoflurane-anesthetized guinea pigs. Intravenous administration of loperamide at 0.01-0.1 mg/kg did not affect parameters of electrocardiogram (ECG) or monophasic action potential (MAP) of the right ventricle. Additional administration of loperamide at 1 mg/kg prolonged the QT interval and MAP duration of the ventricle accompanied with increments of the PQ interval and QRS width. The potency of loperamide for QT-interval prolongation was about 100-times lower than that of dofetilide, in spite that similar inhibitory effects on the human Ether-a-go-go Related Gene (hERG) K+ channels have been reported between loperamide and dofetilide, implying lower accessibility of loperamide to the K+ channels. Intravenous administration of naloxone at 0.003-0.3 mg/kg, which effectively inhibits µ-opioid receptors, did not affect ECG parameters including QT interval or MAP duration. Furthermore, the loperamide-induced cardiac electrophysiological changes were not modified in the presence of naloxone at 0.3 mg/kg. These results suggest that loperamide has a potential to delay cardiac conduction and repolarization in the in vivo condition. Since naloxone did not modify ECG parameters and loperamide-induced ECG changes, naloxone is confirmed to possess acceptable cardiac safety when used as an antidote.

Analysis of effects of acute hypovolemia on arterial stiffness in rabbits monitored with cardio-ankle vascular index.

Although elasticity of the conduit arteries is known to be contribute effective peripheral circulation via Windkessel effects, the relationship between changes in intra-aortic blood volume and conduit artery elasticity remains unknown. Here we assessed the effects of change in intra-aortic blood volume induced by blood removal and subsequent blood transfusion on arterial stiffness and the involvement of autonomic nervous activity using our established rabbit model in the presence or absence of the ganglion blocker hexamethonium (100 mg/kg). Blood removal at a rate of 1 mL/min gradually decreased the blood pressure and blood flow of the common carotid artery but increased a stiffness indicator the cardio-ankle vascular index, which was equally observed in the presence of hexamethonium. These results suggest that arterial stiffness acutely responds to changes in intra-aortic blood volume independent of autonomic nervous system modification.

[A Case of Gallbladder Cancer with Long Survival Treated with Resection after Downstaging with GC Therapy].

A 68-year-old woman with a chief complaint of obstructive jaundice was referred to our hospital. She was diagnosed with gallbladder cancer with invasion to the liver, extrahepatic bile duct, right hepatic artery and portal vein. After endoscopic retrograde biliary drainage, she received chemotherapy with gemcitabine and cisplatin. After 9 courses, the size of the tumor and the lymph nodes decreased, and we planned surgery. There were no unresectable factors, and the right hepatic artery and portal vein were detached from the tumor. We performed a subtotal stomach-preserving pancreaticoduodenectomy and gallbladder bed resection. We then performed adjuvant chemotherapy with S-1 for 1 year. The patient remains alive without recurrence, 5 years after the surgery. We report the case of advanced gallbladder cancer with downstaging after GC therapy.

Torsadogenic Potential of HCN Channel Blocker Ivabradine Assessed in the Rabbit Proarrhythmia Model.

Torsadogenic effects of ivabradine, an inhibitor of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, were assessed in an in vivo proarrhythmia model of acute atrioventricular block rabbit. Ivabradine at 0.01, 0.1, and 1 mg/kg was intravenously administered to isoflurane-anesthetized rabbits (n = 5) in the stable idioventricular rhythm. Ivabradine at 0.01 and 0.1 mg/kg hardly affected the atrial and ventricular automaticity, QT interval, or the monophasic action potential duration of the ventricle. Additionally administred ivabradine at 1 mg/kg decreased the atrial and ventricular rate significantly but increased the QT interval and duration of the monophasic action potential. Meanwhile, torsade de pointes arrhythmias were detected in 1 out of 5 animals and in 2 out of 5 animals after the administration of 0.1 and 1 mg/kg, respectively. Importantly, torsade de pointes arrhythmias could be observed only in 2 rabbits showing more potent suppressive effects on ventricular automaticity. These results suggest that the torsadogenic potential of ivabradine may become evident when its expected bradycardic action appears more excessively.

Real-Time Evaluation of Regional Arterial Stiffening, Resistance, and Ocular Circulation During Systemic Administration of Adrenaline in White Rabbits.

Purpose: To evaluate continuous variations of ocular microcirculation by laser speckle flowgraphy and those of regional stiffening by pulse wave velocity (PWV) and vascular resistance under systemic adrenaline administration in rabbits. Methods: Six 16-week-old male rabbits were evaluated. The mean blur rates in the retinal vessel (MBR-RV) and choroid (MBR-CH) were measured. We assessed blood pressure (BP), femoral and carotid vascular resistance, and the heart-ankle (ha)-PWV, heart-femoral (hf)-PWV, and femoral-ankle (fa)-PWV. Adrenaline (100, 300, and 1000 ng/kg) was intravenously administered over a 10-minute period during which the parameters were measured simultaneously every 2 minutes. Results: The MBR-RV and MBR-CH values were dose-dependently increased by the adrenaline in parallel with increased BP. At the load of 100 ng/kg adrenaline, the ΔMBR-RV and ΔMBR-CH showed positive correlations with the variation rate in mean arterial blood pressure. Also, the variation rate in carotid vascular resistance and the Δfa-PWV and Δhf-PWV were significantly positively correlated with both the ΔMBR-RV and ΔMBR-CH. At the 300-ng/kg phase, the correlations between the Δha-PWV and both ΔMBR-RV and ΔMBR-CH were canceled; instead, the Δhf-PWV showed a significant negative correlation with the ΔMBR-RV and ΔMBR-CH. At the 1000-ng/kg phase, Δha-PWV again showed significant positive correlations with the ΔMBR-RV and ΔMBR-CH. Conclusions: These results indicate the possibility that under a systemic administration of adrenaline in rabbits, not only the BP value but also the vascular resistance and arterial function are related to the variation in ocular microcirculation. Translational Relevance: A real-time evaluation system of systemic regional arterial function and ocular microcirculation in rabbits was developed.

Electrophysiological Response to Acehytisine Was Modulated by Aldosterone in Rats with Aorto-Venocaval Shunts.

Aldosterone induces cardiac electrical and structural remodeling, which leads to the development of heart failure and/or atrial fibrillation (AF). However, it remains unknown whether aldosterone-induced remodeling may modulate the efficacy of anti-AF drugs. In this study, we aimed to jeopardize the structural and functional remodeling by aldosterone in rats with aorto-venocaval shunts (AVS rats) and evaluate the effect of acehytisine in this model. An AVS operation was performed on rats (n = 6, male) and it was accompanied by the intraperitoneal infusion of aldosterone (AVS + Ald) at 2.0 µg/h for 28 d. The cardiopathy was characterized by echocardiography, electrophysiologic and hemodynamic testing, and morphometric examination in comparison with sham-operated rats (n = 3), sham + Ald (n = 6), and AVS (n = 5). Aldosterone accelerated the progression from asymptomatic heart failure to overt heart failure and induced sustained AF resistant to electrical fibrillation in one out of six rats. In addition, it prolonged PR, QT interval and Wenckebach cycle length. Acehytisine failed to suppress AF in the AVS + Ald rats. In conclusion, aldosterone jeopardized electrical remodeling and blunted the electrophysiological response to acehytisine on AF.

The influence of hemorrhagic shock on ocular microcirculation by obtained by laser speckle flowgraphy in a white rabbit model.

PURPOSE: To clarify the continuous changes in the retinal vessels' and choroid's microcirculation during hemorrhagic shock and resuscitation in a rabbit model. METHODS: Hemorrhagic shock by the removal of blood (30 mL) and resuscitation by a blood-return technique was induced in anesthetized male New Zealand White rabbits (n = 10). We evaluated the retinal vessel blood flow (relative flow volume: RFV) and choroidal blood flow (mean blur rate in the choroid area: MBR-CH) by laser speckle flowgraphy (LSFG), with simultaneous measurements of systemic hemodynamics and laboratory parameters. RESULTS: RFV and MBR-CH showed significant decreases immediately after the initiation of blood removal and recovered by blood return. The lactate concentration tended to increase from baseline by the blood-removal operation, and it was significantly higher at the end of observation period. The %RFV and %MBR-CH each showed a significant positive correlation with mean arterial blood pressure, cardiac output, carotid blood flow, and central venous pressure. %RFV showed a significant positive correlation with %central venous oxygen saturation and negatively correlated with %lactate. The %hemoglobin did not show a significant correlation with %RFV or %MBR-CH. CONCLUSION: This rabbit hemorrhagic shock model confirmed that ocular microcirculation measurements by LSFG feasibly reflect variations in systemic hemodynamics during hemorrhagic shock and recovery.

Effects of Enhanced Intracranial Pressure on Blood Pressure and the Cardio-Ankle Vascular Index in Rabbits.

AIM: Stroke is well known to lead to hypertension; nevertheless, the role of vascular function in hypertension remains unclear. In this study, we aimed to clarify the mechanism underlying increased arterial stiffness following stroke. METHODS: The cardio-ankle vascular index (CAVI) was measured in five New Zealand White rabbits. Under general anesthesia, intracranial pressure (ICP) was increased by injecting saline (15 mL) into the cisterna magna. ICP was monitored using a catheter inserted into the subarachnoid space via right frontal bone craniotomy. Blood pressure (BP), CAVI, and common carotid flow (CCF) were evaluated, and the responses of these parameters to increased ICP were analyzed. RESULTS: Saline injection into the cisterna magna increased the ICP by over 20 mmHg. Both BP and CAVI increased from 63.2±4.84 to 128.8±14.68 mmHg and from 4.02±0.28 to 4.9±0.53, respectively. Similarly, BP and CCF increased. When hexamethonium was administered before the increase in ICP, the increase in BP (132.2±9.41 mmHg with 10 mg/kg hexamethonium vs. 105.6±11.01 mmHg with 100 mg/kg hexamethonium) and CAVI (5.02±0.64 with 10 mg/kg hexamethonium vs. 4.82±0.42 with 100 mg/kg hexamethonium) were suppressed in a dose-dependent manner. CONCLUSION: Increased ICP causes an increase in BP and CAVI, suggesting that enhanced stiffness of the muscular arteries contributes to high BP. Blocking the autonomic nervous system with hexamethonium suppresses the increase in BP and CAVI, indicating that these increases are mediated by activation of the autonomic nervous system.

Torsadogenic potential of a novel remyelinating drug clemastine for multiple sclerosis assessed in the rabbit proarrhythmia model.

We assessed the torsadogenic effects of a novel remyelinating drug clemastine for multiple sclerosis using an in vivo proarrhythmia model of acute atrioventricular block rabbit, since the drug has been demonstrated to suppress the human ether-á-go-go related gene (hERG) K+ channels. Bradycardia was induced by atrioventricular node ablation in isoflurane-anesthetized New Zealand White rabbits (n = 5), and the ventricle was electrically driven at 60 beats/min throughout the experiment, except when extrasystoles appeared. Intravenous administration of clinically relevant dose of 0.03 mg/kg of clemastine and 10-times higher dose of 0.3 mg/kg hardly affected the QT interval or duration of the monophasic action potential (MAP) of the ventricle. Additional administration of clemastine at 3 mg/kg significantly increased the QT interval, MAP duration and the short-term variability of repolarization. Meanwhile, the premature ventricular contractions with R on T phenomenon were observed in 3 out of 5 animals, and torsades de pointes arrhythmias were detected in 1 out of 5 animals. These results suggest that the torsadogenic potential of clemastine is obviously observed in the acute atrioventricular block rabbit, which will not appear within the prescribed dose for multiple sclerosis.

Sensitivity of inhalation anesthetics isoflurane and sevoflurane for the drug-induced QT-interval prolongation in guinea pigs.

We investigated effects of isoflurane and sevoflurane on sparfloxacin-induced QT-interval prolongation in guinea pigs under the monitoring of electrocardiogram and monophasic action potential (MAP), which was compared with those of halothane or non-inhaled anesthetics ketamine/xylazine. Intravenous administration of sparfloxacin at 3 and 10 mg/kg prolonged the QT interval and MAP duration together with bradycardic action under 4 different anesthetic conditions. The order of extent of prolongation of corrected QT interval after the administration of sparfloxacin was isoflurane ≈ sevoflurane ≈ halothane >> ketamine/xylazine, whereas that of the MAP90 at a pacing cycle length of 300 ms was halothane ≥ isoflurane ≈ sevoflurane >> ketamine/xylazine. These results suggest that isoflurane and sevoflurane as well as halothane could sensitize the heart to sparfloxacin-induced QT interval prolongation in guinea pigs.

Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload.

Atrial dilation is an independent risk factor for the development of atrial fibrillation (AF) and modulates the efficacy of anti-AF drugs, leading to the unsatisfactory control of AF. Pre-clinical studies showed anti-AF effects of acehytisine, a multi-ion channel inhibitor, in atria without structural and/or electrophysiological abnormalities, but information is limited regarding its anti-AF efficacy in dilated atria. We evaluated anti-AF effects of acehytisine at 4 and 10 mg/kg intravenously infused over 10 min using 8-week-old Wistar rats (n = 5; male) with atrial dilation caused by aorto-venocaval shunt (AVS). Echocardiography showed that atria were enlarged by +26.9% after one month of operation in AVS rats compared with sham-operated rats (n = 4; male). Electrophysiological examinations indicated burst pacing-induced AF reached 206 s. Acehytisine at doses of 4 and 10 mg/kg decreased the duration of burst pacing-induced AF with prolongation of Wenckebach cycle length and P wave duration in a dose-dependent manner. Importantly, the drug effectively terminated the persistent AF that was resistant to multiple programmed electrical stimulations in one rat. Therefore, these results provide in vivo evidence that acehytisine may be beneficial for preventing and terminating persistent AF in dilated atria.

Electropharmacological profile of an atrial-selective sodium channel blocker acehytisine assessed in the isoflurane-anesthetized guinea-pig model.

Experimental evidence regarding the risk of proarrhythmic potential of acehytisine is limited. We assessed its electropharmacological effect together with proarrhythmic potential at intravenous doses of 4 and 10 mg/kg (n = 6) using isoflurane-anesthetized guinea pigs in comparison with that of bepridil at 1 and 3 mg/kg, intravenously (n = 6). Acehytisine at therapeutic dose (4 mg/kg) decreased the heart rate, prolonged P wave duration, QRS width, QT interval, QTc, MAP90(sinus), MAP90(CL300) and MAP90(CL250). At supratherapeutic dose (10 mg/kg), it prolonged the PR interval besides enhancing the changes induced by the therapeutic dose. Quantitative assessment showed that peak changes in P wave duration by acehytisine at 10 mg/kg were 1.7 times longer than bepridil, and in MAP90(sinus), MAP90(CL300) and MAP90(CL250) by acehytisine were 1.9, 1.5 and 1.5 times shorter than bepridil, respectively. Importantly, qualitative assessment indicated that bepridil increased beat-to-beat variability and J-Tpeakc in a dose-related manner, confirming a higher proarrhythmic risk, whereas such dose-related responses were not observed in acehytisine, suggesting a lower proarrhythmic risk. These results suggest that acehytisine exhibits favorable pharmacological characters, i.e. potent atrial inhibition and lower proarrhythmic toxicity compared with bepridil, being a promising candidate for the treatment of paroxysmal supraventricular tachycardia.