1. The effects of sarafotoxin S6c (S6c), a selective endothelin ETB receptor agonist, on renal haemodynamics and urine formation were examined in anaesthetized dogs. 2. Intrarenal arterial infusion of S6c at a rate of 1 or 5 ng/kg per min produced a transient increase in renal blood flow (RBF), with no change in systemic blood pressure and heart rate; RBF then decreased gradually to below the basal value. There were significant and dose-dependent increases in urine flow and free water clearance and decreases in urine osmolality during S6c infusion, whereas urinary excretion of sodium and glomerular filtration rate (GFR) remained unchanged. Simultaneously, S6c administration elicited a marked increase in urinary excretion of nitric oxide (NO) metabolites, NO2- and NO3- (UNOxV). 3. In dogs simultaneously administered S6c (5 ng/kg per min) and NG-nitro-L-arginine (NOARG; 40 micrograms/kg per min), a NO synthase inhibitor, the renal vasodilator effect of S6c was abolished and marked reductions in RBF and GFR were observed. The S6c-induced diuretic action was not affected by NOARG. In the presence of NOARG, there was a small amount of UNOxV at the basal level and the administration of S6c did not increase UNOxV. 4. These results suggest that an intrarenal arterial infusion of S6c enhances the production of NO in the kidney and that this enhancement contributes to the peptide-induced renal vasodilation. In contrast, it is unlikely that S6c-induced water diuresis is related to NO production stimulated by this peptide.

No abstract

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for cardiac safety assessment but have limitations for the evaluation of drug-induced contractility. Threedimensional (3D) cardiac tissues are similar to native tissue and valuable for the assessment of contractility. However, a longer time and specialized equipment are required to generate 3D tissues. We previously developed a simple method to generate 3D tissue in a short period by coating the cell surfaces with extracellular matrix proteins. We hypothesized that this 3D cardiac tissue could be used for simultaneous evaluation of drug-induced repolarization and contractility. In the present work, we examined the effects of several compounds with different mechanisms of action by cell motion imaging. Consequently, human ether-ago-go-related gene (HERG) channel blockers with high arrhythmogenic risk caused prolongation of contraction-relaxation duration and arrhythmia-like waveforms. Positive inotropic drugs, which increase intracellular Ca 2+ levels or myocardial Ca 2+ sensitivity, caused an increase in maximum contraction speed (MCS) or average deformation distance (ADD) (ouabain, 138% for MCS at 300 nM; pimobendane, 132% for ADD at 3 mM). For negative inotropic drugs, verapamil reduced both MCS and ADD (61% at 100 nM). Thus, this 3D cardiac tissue detected the expected effects of various cardiovascular drugs, suggesting its usefulness for cardiotoxicity evaluation.

A series of compounds based on 7-{[4-(2-methylphenyl)piperidin-1-yl]methyl}-6,7,8,9-tetrahydro-5 H-cyclohepta[ b]pyridine-9-ol ( (-)-8b), a potent and selective opioid receptor-like 1 (ORL1) antagonist, was prepared and evaluated using structure-activity relationship studies with the aim of removing its affinity to human ether-a-go-go related gene (hERG) K (+) channel. From these studies, 10l was identified as an optimized structure with respect to ORL1 antagonist activity, and affinity to the hERG K (+)channel. Furthermore, 10l showed good in vivo antagonism with a wide therapeutic index in regards to adverse cardiovascular effects.

To clarify the functional role of endothelin-A/endothelin- B (ETA/ETB) receptors in congestive heart failure (CHF), we examined the effects of a non-selective endothelin receptor agonist, endothelin-1 (ET-1), and a selective ETB receptor agonist, sarafotoxin S6c. CHF was induced in dogs by rapid ventricular pacing and resulted in decreased left ventricular dp/dtmax, decreased cardiac output and increased pulmonary vascular resistance. Sarafotoxin S6c (0.3 nmol/kg) resulted in decreased left ventricular dp/dtmax (-26 +/- 2%), decreased cardiac output (-47 +/- 3%) and increased pulmonary vascular resistance (+48 +/- 10%) in dogs without CHF. The effects of sarafotoxin S6c were attenuated in dogs with CHF (-12 +/- 5% in left ventricular dp/dtmax, -19 +/- 5% in cardiac output and +7 +/- 5% in pulmonary vascular resistance). In contrast, ET-1 (0.5 nmol/kg) had no effect on left ventricular dp/dtmax in dogs without CHF and increased left ventricular dp/dtmax by 16 +/- 3% in dogs with CHF. These data indicate that reduced cardiac contractile and pulmonary vasoconstrictor responses via the ETB receptor are attenuated and that responses mediated by the ETA receptor are more prominent in the context of CHF. This suggests a functional shift of endothelin receptor subtypes in CHF.