Disease relevance of Lopac-P-0248

• Functional receptors in Xenopus oocytes for U-37883A, a novel ATP-sensitive K+ channel blocker: comparison with rat insulinoma cells [1].
• Chronic ISD plus U-37883A completely blocked NIC-induced hypotension, although NIC-induced tachycardia persisted [2].

High impact information on Lopac-P-0248

• We suggest that the U-37883 binding site represents a functional receptor that mediates the KATP channel antagonism and natriuresis observed with this class of compounds [3].
• In the present study, the binding characteristics of the U-37883 receptor were investigated using pig kidney cortex microsomes [3].
• U-37883 (4-morpholinecarboximidine-N-1-adamantyl-N-cyclohexyl), a known blocker of ATP-sensitive K+ (KATP) channels, produces natriuresis/diuresis in vivo by a direct effect on the kidney [3].
• Studies with analogs of U-37883A showed that U-52090A inhibited KATP current and displaced [3H]U-37883 from its binding site with similar potencies [1].
• The available data collectively suggest that U-37883A is a more selective blocker of the follicular KATP channel, which is very similar to that in smooth muscle, than of the pancreatic beta cell KATP channel [1].

Biological context of Lopac-P-0248

• U-37883A alone produced inhibition in the concentration range of 0.5 to 5 microM, with the U-37883A IC50 ranging from 0.78 to 1.4 microM [4].
• Effects of K+ channel modulation on glomerular filtration rate and electrolyte excretion were studied using the adenosine-triphosphate- (ATP)-sensitive K+ channel blocker 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexylhydr ochloride (U-37883A) in conscious rats previously equipped with catheters for clearance studies [5].
• U-37883A, which does not inhibit P1075 binding, is one of the most potent blockers of P1075-induced 86Rb+ efflux yet described but is relatively weak as an inhibitor of P1075-mediated vasorelaxation [6].
• Guanidine derivative U-37883A, inhibits mitochondrial K+ uniport [7].
• Higher doses of U-37883A (16-32 mg/kg) fatally reduced MAP (-84%), heart rate (HR; -57%) and LV contractility (-72%) [8].

Anatomical context of Lopac-P-0248

• Inhibition of vascular K(ATP) channels by U-37883A: a comparison with cardiac and skeletal muscle [9].
• Furthermore, Ca2+ uptake by endoplasmic reticulum vesicles has been found to increase in the presence of U-37883A [10].
• Higher concentrations of U-37883A (100 microM) caused a modest decrease in K(ATP) currents in skeletal and cardiac muscle [9].
• 10 microM U-37883A substantially inhibited K(ATP) currents in vascular cells, but had little effect in skeletal or cardiac myocytes [9].
• In addition, U-37883A significantly decreased the osmolality of renal papillary interstitial fluid, indicative of an effect in the medullary portion of the diluting segment [5].

Associations of Lopac-P-0248 with other chemical compounds

• The diuretic profile of 1 and its 1-adamantyl analog (U-37883A, 4) was confirmed orally in dogs, when they were less potent than standard diuretics but showed furosemide-like natriuresis at > or = 100 mumol/kg [11].
• This study describes the in vitro and in vivo characteristics of a guanidine 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl-hydroc hloride (U-37883A), as an antagonist of vascular ATP-sensitive K+ channels (KATP) [12].
• These observations suggest that U-37883A enhances phosphatidylserine synthesis indirectly by acting on calcium transport, thus affecting calcium concentration within the lumen of endoplasmic reticulum membranes [10].
• Furthermore, rats were given intravenous injection of ATP-sensitive K+ channel blocker, either PNU-37883A (4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl) at a concentration of 10 mg/kg or glibenclamide at 30 mg/kg [13].
• P1075-stimulated 86Rb+ efflux, a qualitative measure of K(ATP) channel opening, was inhibited by U-37883A and torasemide with IC50 values of 0.06 and 130 microM, respectively; furosemide induced only a small (23%) inhibition [6].

Gene context of Lopac-P-0248

• Vasodilator responses to hCGRP, hAmylin, and hADM were not altered by the vascular selective K+(ATP) channel antagonist U-37883A [14].
• This inward current was significantly inhibited by PNU-37883A and by a specific anti-Kir6.1 antibody [15].
• 4 The concentration of KK in urine was higher in the PNU-37883A group as compared to the osmotic-diuretic or volume-load group [16].
• 3. Channels containing Kir6.1/SUR2B were more sensitive to inhibition by PNU-37883A than those containing Kir6.2/SUR2B (mean fractional inhibition: 0.70, cf. 0.07) [17].
• Different molecular sites of action for the KATP channel inhibitors, PNU-99963 and PNU-37883A [18].

Analytical, diagnostic and therapeutic context of Lopac-P-0248

• The effects of U-37883A, a vascular ATP-sensitive K(+) channel (K(ATP) channel) blocker, on membrane currents were investigated in pig urethral myocytes by use of patch-clamp techniques (conventional whole-cell recordings, nystatin-perforated patches and cell-attached configuration) [19].
• Hindquarter vasodilator responses to TAPP and endomorphin 2 were not altered by the cyclooxygenase inhibitor sodium meclofenamate, the ATP-dependent K+ channel antagonist U-37883A, or the presence of a time-delay coil in the perfusion circuit [20].

References