Effects of Atrial Natriuretic Peptide After Prolonged Hypothermic Storage of the Isolated Rat Heart

Primary graft failure (PGF) caused by ischemia‐reperfusion injury (IRI) is the strongest determinant of perioperative mortality after heart transplantation. Atrial natriuretic peptide (ANP) has been found to reduce the IRI of cardiomyocytes and may be beneficial in alleviating PGF after heart transplantation, although there is a lack of evidence to support this issue. The purpose of this study was to investigate the cardioprotective effects of ANP after prolonged hypothermic storage. For this purpose, an isolated working‐heart rat model was used. After the preparation, the hearts were arrested with and stored in an extracellular‐based cardioplegic solution at 3–4°C for 6 h and followed by 25 min of reperfusion. The hearts were divided into four groups (n = 7 in each group) according to the timing of ANP administration: Group 1 (in perfusate before storage), Group 2 (in cardioplegia), Group 3 (in reperfusate), and control (no administration of ANP). Left ventricular functional recovery and the incidence of ventricular fibrillation (VF) were compared. ANP administration at the time of reperfusion improved the percent recovery of left ventricular developed pressure (control, 45.5 ± 10.2; Group 1, 47.4 ± 8.8; Group 2, 45.3 ± 12 vs. Group 3, 76.3 ± 7; P < 0.05) and maximum first derivative of the left ventricular pressure (control, 47.9 ± 8.7; Group 1, 46.7 ± 8.8; Group 2, 49.6 ± 10.8 vs. Group 3, 76.6 ± 7.5; P < 0.05). The incidence of VF after reperfusion did not differ significantly among these four groups (71.4, 85.7, 57.1, and 85.7% in Groups 1, 2, 3, and control, respectively). This result suggests that the administration of ANP at the time of reperfusion may have the potential to decrease the incidence of PGF after heart transplantation.     

Human plasma metabolic profiles of benzydamine,a flavin-containing monooxygenase probe substrate,simulated with pharmacokinetic data from control and humanized-liver mice

1.?Benzydamine is used clinically as a nonsteroidal anti-inflammatory drug in oral rinses and is employed in preclinical research as a flavin-containing monooxygenase (FMO) probe substrate. In this study, plasma concentrations of benzydamine and its primary N-oxide and N-demethylated metabolites were investigated in control TK-NOG mice, in humanized-liver mice, and in mice whose liver cells had been ablated with ganciclovir.

2.?Following oral administration of benzydamine (10?mg/kg) in humanized-liver TK-NOG mice, plasma concentrations of benzydamine N-oxide were slightly higher than those of demethyl benzydamine. In contrast, in control and ganciclovir-treated TK-NOG mice, concentrations of demethyl benzydamine were slightly higher than those of benzydamine N-oxide.

3.?Simulations of human plasma concentrations of benzydamine and its N-oxide were achieved using simplified physiologically based pharmacokinetic models based on data from control TK-NOG mice and from reported benzydamine concentrations after low-dose administration in humans. Estimated clearance rates based on data from humanized-liver and ganciclovir-treated TK-NOG mice were two orders magnitude high.

4.?The pharmacokinetic profiles of benzydamine were different for control and humanized-liver TK-NOG mice. Humanized-liver mice are generally accepted human models; however, drug oxidation in mouse kidney might need to be considered when probe substrates undergo FMO-dependent drug oxidation in mouse liver and kidney.     

Metabolism of fatty acids and bile acids in plasma is associated with overactive bladder in males: potential biomarkers and targets for novel treatments in a metabolomics analysis

International Urology and Nephrology - The present study was conducted to identify metabolites using a metabolomics approach and investigate the relationship between these metabolites and urgency...     

Neurohumoral regulation of spontaneous constrictions in suburothelial venules of the rat urinary bladder

Venules of the bladder suburothelium develop spontaneous phasic constrictions that may play a critical role in maintaining venular drainage of tissue metabolites. We aimed to investigate neurohumoral regulation of the spontaneous venular constrictions (SVCs). Changes in venular diameter of the rat bladder suburothelium were monitored using a video tracking system, whilst the effects of electrical field stimulation (EFS) and bath-applied bioactive substances were investigated. The innervation of the suburothelial microvasculature was examined by immunohistochemistry. EFS (10 Hz for 30 s) induced an increase in the frequency of SVCs that was prevented by phentolamine (1 μM). In phentolamine-pretreated venules, EFS suppressed SVCs with a venular dilatation in a manner attenuated by propranolol (1 μM) or l-nitro arginine (LNA, 10 μM). BRL37344 (1 μM), a β₃ adrenoceptor agonist, dilated venules and reduced the frequency of SVCs in an LNA-sensitive manner. ACh (1–10 μM) increased the frequency of SVCs. ATP (1 μM) transiently constricted venules and then caused LNA-sensitive cessation of SVCs associated with a dilatation. Substance P (100 nM) caused a venular constriction, whilst calcitonin gene related peptide (CGRP, 100 nM) caused a dilatation of venules and suppression of SVCs that were not inhibited by LNA. Immunohistochemical staining demonstrated sympathetic as well as substance P- and CGRP-containing nerves running along the venules. Spontaneous constrictions of suburothelial venules are accelerated by sympathetic α-adrenergic stimulation, but suppressed upon β-adrenergic stimulation. In addition, suburothelial venular constrictions appear to be modulated by several bioactive substances that could be released from urothelium or suburothelial sensory nerves.     

Bacteremia due to high-level daptomycin-resistant Corynebacterium striatum: A case report with genetic investigation

Corynebacterium striatum, generally considered an opportunistic organism in humans, has recently been known to develop high-level daptomycin resistance (HLDR) shortly after drug exposure. To date, however, only several such clinical isolates have been described in the literature and clinical background of the resistant pathogen remains to be elucidated. Here, we report a case involving a C. striatum strain with HLDR harboring novel nucleotide mutations, together with a review of the relevant literature. To the best of our knowledge, this is the first well-investigated clinical report from Japan including a genetic investigation. Considering the rapid emergence of HLDR C. striatum in vitro experiment, there could be a number of underreporting cases. Scrupulous attention is required when administering daptomycin for the treatment of C. striatum infections, even if the organism has initially exhibited susceptibility.