10 research outputs found
Vitamin D Receptor Activation Mitigates the Impact of Uremia on Endothelial Function in the 5/6 Nephrectomized Rats
Endothelial
dysfunction increases cardiovascular disease
risk in chronic kidney disease (CKD). This study
investigates whether VDR activation affects
endothelial function in CKD. The 5/6
nephrectomized (NX) rats with experimental
chronic renal insufficiency were treated with or
without paricalcitol, a VDR activator. Thoracic
aortic rings were precontracted with
phenylephrine and then treated with
acetylcholine or sodium nitroprusside. Uremia
significantly affected aortic relaxation
(−50.0 ± 7.4% in NX rats versus −96.2 ± 5.3% in SHAM at 30 μM acetylcholine). The endothelial-dependent relaxation was improved to –58.2 ± 6.0%, –77.5 ± 7.3%, and –90.5 ± 4.0% in NX rats treated with paricalcitol at 0.021, 0.042, and 0.083 μg/kg for two weeks, respectively, while paricalcitol at 0.042 μg/kg did not affect blood pressure and heart rate. Parathyroid hormone (PTH) suppression alone did not improve endothelial function since cinacalcet suppressed PTH without affecting endothelial-dependent vasorelaxation. N-omega-nitro-L-arginine methyl ester completely abolished the effect of paricalcitol on improving endothelial function. These results demonstrate that VDR activation improves endothelial function in CKD
Systemic Activation of the Calcium Sensing Receptor Produces Acute Effects on Vascular Tone and Circulatory Function in Uremic and Normal Rats: Focus on Central versus Peripheral Control of Vascular Tone and Blood Pressure by Cinacalcet
Diacylglycerol Acyltransferase 1 Inhibition Lowers Serum Triglycerides in the Zucker Fatty Rat and the Hyperlipidemic Hamster
Identification and Preliminary Characterization of a Potent, Safe, and Orally Efficacious Inhibitor of Acyl-CoA:Diacylglycerol Acyltransferase 1
Synthesis and Pharmacology of (Pyridin-2-yl)methanol Derivatives as Novel and Selective Transient Receptor Potential Vanilloid 3 Antagonists
Transient receptor
potential vanilloid 3 (TRPV3) is a Ca<sup>2+</sup>- and Na<sup>+</sup>-permeable channel with a unique expression pattern.
TRPV3 is found in both neuronal and non-neuronal tissues, including
dorsal root ganglia, spinal cord, and keratinocytes. Recent studies
suggest that TRPV3 may play a role in inflammation, pain sensation,
and skin disorders. TRPV3 studies have been challenging, in part due
to a lack of research tools such as selective antagonists. Herein,
we provide the first detailed report on the development of potent
and selective TRPV3 antagonists featuring a pyridinyl methanol moiety.
Systematic optimization of pharmacological, physicochemical, and ADME
properties of original lead <b>5a</b> resulted in identification
of a novel and selective TRPV3 antagonist <b>74a</b>, which
demonstrated a favorable preclinical profile in two different models
of neuropathic pain as well as in a reserpine model of central pain
Identification and Preliminary Characterization of a Potent, Safe, and Orally Efficacious Inhibitor of Acyl-CoA:Diacylglycerol Acyltransferase 1
A high-throughput screen against human DGAT-1 led to
the identification
of a core structure that was subsequently optimized to afford the
potent, selective, and orally bioavailable compound <b>14</b>. Oral administration at doses ≥0.03 mg/kg significantly reduced
postprandial triglycerides in mice following an oral lipid challenge.
Further assessment in both acute and chronic safety pharmacology and
toxicology studies demonstrated a clean profile up to high plasma
levels, thus culminating in the nomination of <b>14</b> as clinical
candidate ABT-046