Differential effects of the formin inhibitor SMIFH2 on contractility and Ca2+ handling in frog and mouse cardiomyocytes.

Genetic mutations in actin regulators have been emerging as a cause of cardiomyopathy, although the functional link between actin dynamics and cardiac contraction remains largely unknown. To obtain insight into this issue, we examined the effects of pharmacological inhibition of formins, a major class of actin-assembling proteins. The formin inhibitor SMIFH2 significantly enhanced the cardiac contractility of isolated frog hearts, thereby augmenting cardiac performance. SMIFH2 treatment had no significant effects on the Ca2+ sensitivity of frog muscle fibers. Instead, it unexpectedly increased Ca2+ concentrations of isolated frog cardiomyocytes, suggesting that the inotropic effect is due to enhanced Ca2+ transients. In contrast to frog hearts, the contractility of mouse cardiomyocytes was attenuated by SMIFH2 treatment with decreasing Ca2+ transients. Thus, SMIFH2 has opposing effects on the Ca2+ transient and contractility between frog and mouse cardiomyocytes. We further found that SMIFH2 suppressed Ca2+ -release via type 2 ryanodine receptor (RyR2); this inhibitory effect may explain the species differences, since RyR2 is critical for Ca2+ transients in mouse myocardium but absent in frog myocardium. Although the mechanisms underlying the enhancement of Ca2+ transients in frog cardiomyocytes remain unclear, SMIFH2 differentially affects the cardiac contraction of amphibian and mammalian by differentially modulating their Ca2+ handling.

Endothelium-dependent vasodilation in the cerebral arterioles of rats deteriorates during acute hyperglycemia and then is restored by reducing the glucose level.

PURPOSE: Acute hyperglycemia in patients with traumatic brain injury correlates with a poor neurological outcome. We investigated the endothelium function of rat cerebral arterioles during acute hyperglycemia and after reducing the glucose levels using insulin. We also examined whether or not oxidative stress was involved in the cerebral arteriole response to acute hyperglycemia. METHODS: In isoflurane-anesthetized, mechanically ventilated rats, we used closed cranial window preparation to measure the changes in the pial arteriolar diameter following the topical application of acetylcholine (ACh) or adenosine. We examined the pial arteriolar vasodilator response before hyperglycemia, during hyperglycemia, and after reducing the glucose level using insulin. After intravenous pretreatment with an NADPH oxidase inhibitor (apocynin or diphenylene iodonium), we reexamined the pial arteriolar vasodilator response following the topical application of ACh. RESULTS: Under control conditions, the topical application of ACh dose-dependently dilated the cerebral arterioles. The vasodilatory responses to topical ACh were impaired during hyperglycemia and improved after the administration of insulin. The vasodilatory responses to topical adenosine were not affected by the glucose levels. In the apocynin or diphenylene iodonium pretreatment group, the topical application of ACh dilated the cerebral arterioles during hyperglycemia. CONCLUSION: Acute hyperglycemia induces a dysfunction of the endothelium-dependent vasodilation of rat cerebral arterioles. The dysfunction can be reversed by improving the acute hyperglycemia and it can be prevented entirely by the administration of NADPH oxidase inhibitors. These results could suggest that controlling the glucose levels works protectivity to endothelium function of cerebral arterioles.

Efficacy of alogliptin, a dipeptidyl peptidase-4 inhibitor, on glucose parameters, the activity of the advanced glycation end product (AGE) - receptor for AGE (RAGE) axis and albuminuria in Japanese type 2 diabetes.

BACKGROUND: To examine the effects of alogliptin, a dipeptidyl peptidase-4 inhibitor, on glucose parameters, the advanced glycation end product (AGE)-receptor for AGE (RAGE) axis and albuminuria in Japanese type 2 diabetes patients. METHODS: Sixty-one patients whose HbAlc ≥ 6.1% (mean age 64.7 years; 67% men; mean HbAlc 7.4%; 57% were pharmacologically treated) underwent blood and urine sampling and analysis before and after 12 weeks of treatment with alogliptin (25 mg once daily). RESULTS: Alogliptin treatment significantly reduced fasting glucose (160.3 mg/dL at baseline versus 138.0 mg/dL at 12 weeks), glycoalbumin (21.1% at baseline versus 18.9% at 12 weeks), HbAlc (7.4% at baseline versus 6.9% at 12 weeks), circulating soluble form of RAGE concentrations (847.3 pg/mL at baseline versus 791.4 pg/mL at 12 weeks) and urine albumin to creatinine ratio (31.6 mg/g Cr at baseline versus 26.5 mg/g Cr at 12 weeks), whereas 1,5-anhydroglucitol concentrations were significantly increased (7.5 µg/mL at baseline versus 11.6 µg/mL at 12 weeks; all P < 0.05). Circulating AGEs concentrations were reduced only in patients with baseline AGEs ≥7 U/mL (n = 33, from 8.2 U/mL to 7.2U /mL; p < 0.01) after alogliptin treatment. The treatment-induced change of soluble form of sRAGE concentrations was associated with changes of 1,5-anhydroglucitol and HbAlc concentrations (rho = -0.32 and 0.29, respectively). Meanwhile, the treatment-induced change of urine albumin to creatinine ratio was associated with a change in the fasting glucose concentration (rho = 0.25; all p < 0.05). During the intervention, alogliptin treatment was well tolerated without any hypoglycemia or side effects. CONCLUSION: Alogliptin treatment improved the AGE-RAGE axis and reduced albuminuria in Japanese type 2 diabetes patients.

Propofol But Not Desflurane Maintains Rat Cerebral Arteriolar Responses to Acetylcholine During Acute Hyperglycemia.

BACKGROUND: Acute hyperglycemia causes vascular endothelial dysfunction in various organs including the cerebral vessels. It is associated with increased mortality and morbidity in the perioperative period. The impact of anesthetic agents on cerebral vasodilatory responses during hyperglycemia remains unclear. We investigated endothelial function in rat cerebral arterioles during acute hyperglycemia, under propofol or desflurane anesthesia. MATERIALS AND METHODS: A closed cranial window preparation was used to measure changes in pial arteriole diameter induced by topical application of acetylcholine (ACh), an endothelium-dependent vasodilator, in rats anesthetized with propofol or desflurane. Pial arteriole responses to ACh were measured during normoglycemia and hyperglycemia. We then investigated whether the response of cerebral arterioles to acute hyperglycemia under propofol anesthesia were related to propofol or its vehicle, intralipid. RESULTS: ACh resulted in a dose-dependent dilation of cerebral arterioles during propofol and desflurane anesthesia under normoglycemic conditions. The vasodilatory effects of ACh were also maintained under hyperglycemic conditions during propofol anesthesia, but the vasodilator response to ACh was significantly impaired during hyperglycemia compared with normoglycemia with desflurane anesthesia. The vasodilatory effects of ACh were maintained during normoglycemia and hyperglycemia in rats receiving propofol or intralipid. CONCLUSIONS: Rat pial arteriole responses to ACh are maintained during conditions of acute hyperglycemia with propofol anesthesia but suppressed compared with normoglycemia with desflurane anesthesia.

The Cytokine Expression in Patients with Cardiac Complication after Immune Checkpoint Inhibitor Therapy.

We herein report the cytokine expression at different stages for three patients who developed cardiac complications after immune checkpoint inhibitor (ICI) therapy. Case 1 with biopsy-proven myocarditis showed increased levels of interleukin (IL)-8, monocyte chemotactic and activating factor, and granulocyte macrophage colony-stimulating factor (GM-CSF) when he developed Takotsubo cardiomyopathy. Case 2 with subclinical myocarditis showed predominant activation of IL-8 during the progressive clinical course. Case 3 with cytokine-releasing syndrome showed substantial activations of IL-6, IL-8, GM-CSF, and interferon-γ. Our data suggest the development of unique cytokine activation in individual patients with cardiac complications after ICI therapy.

Cerebrovascular reactivity to hypercapnia during sevoflurane or desflurane anesthesia in rats.

BACKGROUND: Hypercapnia causes dilation of cerebral vessels and increases cerebral blood flow, resulting in increased intracranial pressure. Sevoflurane is reported to preserve cerebrovascular carbon dioxide reactivity. However, the contribution of inhaled anesthetics to vasodilatory responses to hypercapnia has not been clarified. Moreover, the cerebrovascular response to desflurane under hypercapnia has not been reported. We examined the effects of sevoflurane and desflurane on vasodilatory responses to hypercapnia in rats. METHODS: A closed cranial window preparation was used to measure the changes in pial vessel diameters. To evaluate the cerebrovascular response to hypercapnia and/or inhaled anesthetics, the pial vessel diameters were measured in the following states: without inhaled anesthetics at normocapnia (control values) and hypercapnia, with inhaled end-tidal minimal alveolar concentration (MAC) of 0.5 or 1.0 of either sevoflurane or desflurane at normocapnia, and an MAC of 1.0 of sevoflurane or desflurane at hypercapnia. RESULTS: Under normocapnia, 1.0 MAC, but not 0.5 MAC, of sevoflurane or desflurane dilated the pial arterioles and venules. In addition, under both 1.0 MAC of sevoflurane and 1.0 MAC of desflurane, hypercapnia significantly dilated the pial arterioles and venules in comparison to their diameters without inhaled anesthetics. The degrees of vasodilation were similar for desflurane and sevoflurane under both normocapnia and hypercapnia. CONCLUSIONS: Desflurane induces cerebrovascular responses similar to those of sevoflurane. Desflurane can be used as safely as sevoflurane in neurosurgical anesthesia.

Effect of blood pressure elevation on cerebral oxygen desaturation in the beach chair position.

OBJECTIVE: The beach chair position (BCP) during shoulder arthroscopy is a known risk factor for cerebral ischemia. We retrospectively investigated whether maintaining the arterial blood pressure (ABP) prevented the decrease in the regional cerebral tissue oxygen saturation (rSO2). METHODS: We analyzed 20 consecutive patients who underwent elective shoulder surgery in the BCP under general anesthesia. The bilateral rSO2 was monitored continuously throughout the procedure with the help of near-infrared spectroscopy (INVOS 5100 Cerebral Oximeter, Somanetics Corporation, Troy, MI, USA). Anesthesiologists maintained patient blood pressure while they were in the BCP, which was measured using an ABP transducer placed at the level of the external auditory meatus. We compared rSO2 measured in the supine position and in the BCP. RESULTS: Measurement of cortex level mean ABP (mABP) values in the BCP were >50 mmHg and over 60% higher than those noted for the supine position in most patients. Although all bilateral rSO2 values in the BCP were significantly lower than those in the supine position, the reductions was <20%. Further, 35% (7 of 20) patients that were part of the study experienced cerebral desaturation events at any given point during the procedure. None of the patients experienced clinical postoperative neurological complications. CONCLUSIONS: Although cortex level mABP in the BCP was >50 mmHg, a decrease was recorded in the rSO2 values. This rSO2 decrease was proportional to the reduction in the cortex level mABP induced by a postural change to the BCP. Therefore, despite appropriate blood pressure management, shoulder surgery in the BCP might involve certain risks for patients with cerebrovascular diseases.

Association Between Liver Function and Peak Oxygen Uptake in Heart Failure Patients: A Retrospective Observational Study.

OBJECTIVE: With respect to liver function and heart failure, 46% of acute decompensated heart failure patients exhibit abnormal liver function. However, there have been no reports of the association between liver function and functional capacity in these patients. Our aim was to clarify the relationship between liver function and functional capacity using the peak oxygen uptake (VO2). METHODS: We retrospectively identified 36 heart failure patients who were referred to our rehabilitation laboratory. These patients underwent cardiopulmonary exercise testing (CPX). Furthermore, we investigated the correlations between peak VO2, blood measurements [e.g., total bilirubin (T-bil) and brain natriuretic peptide], and echocardiographic parameters. Finally, multivariate regression analysis was performed to investigate the independent variables related to peak VO2. RESULTS: The mean peak VO2 was 10.7±2.9 ml/kg/min. Peak VO2 during CPX correlated inversely with T-bil [r=-0.379, 95% confidence intervals (CI): -0.654 to -0.014, P=0.043], aspartate transaminase (r=-0.426, 95% CI: -0.685 to -0.07, P=0.021), and peak heart rate (r=0.391, 95% CI: 0.029 to 0.663, P=0.036). The significant independent factors associated with peak VO2 were treatment with statin (ß=-3.19, P=0.015) and T-bil levels (ß=-4.27, P=0.002). CONCLUSION: Our findings demonstrated that liver function may contribute to the functional capacity in heart failure patients.

Anaphylactic shock due to intravesical administration of pirarubicin hydrochloride for the fifth time.

We report the first case of anaphylaxis induced by intravesical administration of pirarubicin hydrochloride during spinal anesthesia. The patient was a 64-year-old woman being followed up for transitional cell carcinoma of the bladder. Anaphylaxis occurred the fifth time pirarubicin hydrochloride was administered intravesically. Pirarubicin hydrochloride, an anthracycline antitumor antibiotic that is widely used for intravesical instillation chemotherapy, is administered at the end of surgery. Because this is about the time that the patient is leaving the operating room, attention to patient monitoring tends to be divided. Because anaphylaxis may occur at this time, staff should remain vigilant of the risk of anaphylaxis.

Urinary Angiotensinogen Could Be a Prognostic Marker of Renoprotective Effects of Alogliptin in Patients with Type 2 Diabetes.

BACKGROUND: The aims of this study were (1) to examine the renoprotective effects of alogliptin and (2) to establish urinary angiotensinogen (AGT) as a prognostic marker of renoprotective effects of alogliptin in patients with type 2 diabetes (T2D). METHODS: In 43 patients with T2D (18 women, 66.1 ± 1.71 years), 25 mg/day of alogliptin was added to the traditional hypoglycemic agents and/or nondrug treatments. Urinary concentrations of albumin (Alb) and AGT, normalized by urinary concentrations of creatinine (Cr) (UAlbCR and UAGTCR, respectively), were measured before and after the 12-week alogliptin treatment. RESULTS: Alogliptin treatment tended to decrease UAlbCR (99.6 ± 26.8 versus 114.6 ± 36.0 mg/g Cr, P = 0.198). Based on % change in UAlbCR, patients were divided into two groups, responders (< -25%) and nonresponders (≥ -25%), and a logistic analysis of UAGTCR before treatment showed cutoff value of 20.8 µg/g Cr. When all patients were redivided into two groups, those with higher values of UAGTCR before the treatment (Group H, n = 20) and those with lower values (Group L), Group H showed significantly decreased UAlbCR in response to alogliptin (-14.6 ± 8.6 versus +22.8 ± 16.8%, P = 0.033). CONCLUSION: Urinary AGT could be a prognostic marker of renoprotective effects of alogliptin in patients with T2D.

Basic Performance of a Miniature Intraventricular Axial Pump.

A miniature intraventricular axial pump for left ventricular (LV) support is under development. This pump was designed for placement in the LV cavity by insertion through the LV apex with the outlet located at the ascending aorta via the aortic valve. The basic hydro-dynamic characteristics represented as a relationship between pump head (H) and flow (Q) showed a negative linear relationship under a constant head. This characteristic was generally the same as that obtained by other axial rotation pumps. However, the actual H-Q relationship was represented as anticlockwise "loops" caused by the contraction of the natural LV. The comparative in vitro data on these H-Q loops showed that the shape of the loops was changed drastically by the connecting condition between the pump and natural cardiovascular system.