Phlorizin prevents electrically-induced ventricular tachyarrhythmia during ischemia in langendorff-perfused guinea-pig hearts.

Phlorizin is a type of flavonoids and has a peroxynitrite scavenging effect. This study aimed to elucidate the effects of phlorizin on ischemia-induced ventricular tachyarrhythmia (VT). Optical signals from the epicardial surface of the ventricle or left ventricular end diastolic pressure (LVEDP) were recorded during acute global ischemia in 42 Langendorff-perfused guinea pig hearts.

Design, synthesis, and structure-activity relationships of a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl β-D-glycopyranosides substituted with novel hydrophilic groups as highly potent inhibitors of sodium glucose co-transporter 1 (SGLT1).

Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of therapeutic options for postprandial hyperglycemia. Previously, we reported potent and selective SGLT1 inhibitors 1 and 2 showing efficacy in oral carbohydrate tolerance tests in diabetic rat models. In a pharmacokinetic (PK) study of 2, excessive systemic exposure to metabolites of 2 was observed, presumably due to the high permeability of its aglycone (2a).

Structure-activity relationship studies of 4-benzyl-1H-pyrazol-3-yl β-d-glucopyranoside derivatives as potent and selective sodium glucose co-transporter 1 (SGLT1) inhibitors with therapeutic activity on postprandial hyperglycemia.

Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of treatments for postprandial hyperglycemia. A series of 4-benzyl-1H-pyrazol-3-yl β-d-glucopyranoside derivatives have been synthesized, and its inhibitory activity toward SGLTs has been evaluated. By altering the substitution groups at the 5-position of the pyrazole ring, and every position of the phenyl ring, we studied the structure-activity relationship (SAR) profiles and identified a series of potent and selective SGLT1 inhibitors.

The proximal C-terminus of α(1C) subunits is necessary for junctional membrane targeting of cardiac L-type calcium channels.

In cardiac myocytes, LTCCs (L-type calcium channels) form a functional signalling complex with ryanodine receptors at the JM (junctional membrane). Although the specific localization of LTCCs to the JM is critical for excitation-contraction coupling, their targeting mechanism is unclear. Transient transfection of GFP (green fluorescent protein)-α(1S) or GFP-α(1C), but not P/Q-type calcium channel α(1A), in dysgenic (α(1S)-null) GLT myotubes results in correct targeting of these LTCCs to the JMs and restoration of action-potential-induced Ca2+ transients.

KGA-2727, a novel selective inhibitor of a high-affinity sodium glucose cotransporter (SGLT1), exhibits antidiabetic efficacy in rodent models.

The high-affinity sodium glucose cotransporter (SGLT1) plays a critical role in glucose absorption from the gastrointestinal tract. We have developed 3-(3-{4-[3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)propionamide (KGA-2727), which has a pyrazole-O-glucoside structure, as the first selective SGLT1 inhibitor. KGA-2727 inhibited SGLT1 potently and highly selectively in an in vitro assay using cells transiently expressing recombinant SGLTs.

Chronic receptor-mediated activation of Gi/o proteins alters basal t-tubular and sarcolemmal L-type Ca²⁺ channel activity through phosphatases in heart failure.

L-type Ca(2+) channels (LTCCs) play an essential role in the excitation-contraction coupling of ventricular myocytes. We previously found that t-tubular (TT) LTCC current density was halved by the activation of protein phosphatase (PP)1 and/or PP2A, whereas surface sarcolemmal (SS) LTCC current density was increased by the inhibition of PP1 and/or PP2A activity in failing ventricular myocytes of mice chronically treated with isoproterenol (ISO mice). In the present study, we examined the possible involvement of inhibitory heterotrimeric G proteins (G(i/o)) in these abnormalities by chronically administrating pertussis toxin (PTX) to ISO mice (ISO + PTX mice).

Decrease in the density of t-tubular L-type Ca2+ channel currents in failing ventricular myocytes.

In some forms of cardiac hypertrophy and failure, the gain of Ca(2+)-induced Ca(2+) release [CICR; i.e., the amount of Ca(2+) released from the sarcoplasmic reticulum normalized to Ca(2+) influx through L-type Ca(2+) channels (LTCCs)] decreases despite the normal whole cell LTCC current density, ryanodine receptor number, and sarcoplasmic reticulum Ca(2+) content.