Biomedical subjects

K W Hong

Publications and source records attributed to K W Hong.

At least 19 recordsLinked to original sources

PubMed2001

Involvement of NADH/NADPH oxidase-derived superoxide in experimental vasospasm induced by periarterial blood in rat femoral artery.

To elucidate the mechanism(s) involved in periarterial blood-mediated vasospasm in the rat femoral artery, vascular production of superoxide and related expression of intercellular adhesion molecule-1 (ICAM-1) were assessed with subsequent perivascular mobilization of granulocytes and macrophages. Arterial vasospasm characterized by increased wall thickness and decreased lumen size was observed on the side exposed to blood at 7 to 12 days, and these vascular changes were significantly ameliorated by pretreatment with NADH/NADPH oxidase inhibitor, diphenyleneiodonium (200 microM, locally). Increased mobilization of granulocytes was paralleled with the expression of ICAM-1 in the vessels at 24 hours after periarterial application of blood to the femoral artery, and then both declined. Subsequently, infiltration of macrophage progressively increased at all layers throughout 7 to 12 days. In in vitro study, a large amount of superoxide that was inhibitable by diphenyleneiodonium (20 and 100 microM) was produced at 3 hours upon application of 10% autologous blood to the aortic segments. Furthermore, ICAM-1 expression by autologous blood was well correlated with generation of superoxide anion in the aortic segment (r=0.975, P<0.05). Taken together, it is suggested that NADH/NADPH oxidase-derived superoxide is implicated in periarterial blood-induced vasospasm via increased expression of ICAM-1 with subsequent mobilization of granulocyte/macrophage.

Animals↗

PubMed2001

Rebamipide prevents periarterial blood-induced vasospasm in the rat femoral artery model.

We examined the effect of rebamipide on the vasospasm induced by periarterial blood. In the in vitro study, the significant production of superoxide anion that was identified 3 hours after application of 10% whole blood to the rat aortic segments was inhibited by rebamipide (100 and 300 microM) and these results were correlated with the in vitro intercellular adhesion molecule-1 (ICAM-1) expression on the femoral artery. In the in vivo study, there was an increased mobilization of granulocytes in parallel with a large expression of ICAM-1 in the vessels 24 hours after periarterial blood was applied to the femoral artery which then declined. Subsequently, infiltration of macrophages progressively increased at all layers 7-12 days after application. Pretreatment with rebamipide (100 and 300 mg kg(-1) day(-1), p.o.) significantly inhibited the morphological changes as well as the expression of ICAM-1 with inhibition of granulocyte/macrophage mobilization. In association with these findings, increased wall thickness and decreased lumen area were significantly inhibited by pretreatment with rebamipide. These results provide valuable information for the therapeutic use of rebamipide to relieve vascular remodeling induced by periarterial blood.

Alanine↗

PubMed2001

Translocational inefficiency of intracellular proteins in senescence of human diploid fibroblasts.

In order to investigate signal transduction pathways and related changes of actin cytoskeleton organization in cellular senescence, H-ras double mutants--V12S35, V12G37, and V12C40--were constitutively expressed in human foreskin fibroblast (HDF). Senescent HDF cells as well as the H-ras mutant expressers accumulated p-Erk1/2 in the cytoplasm with increased MEK activity and failed to translocate it to nuclei on EGF stimulation. Senescent HDF cells, V12S35 and V12G37 expressers, revealed a failure to export actin fiber from nucleus to cytoplasm and also to form stress fibers. Perinuclear expression of Rac1 was prominent in the HDF cells and V12C40 expresser; however, in the V12S35 expresser, translocation of Rac1 from perinucleus to nucleus and strong expression of RhoA were obvious. In summary, the H-ras double mutant expressers induced premature senescence through the MEK pathway, accompanied by nuclear accumulation of actin and Rac1 proteins, cytoplasmic retention of p-Erk1/2, and marked induction of RhoA expression, suggesting the translocational inefficiency of the intracellular proteins in the senescent HDF cells.

3T3 Cells↗

PubMed2001

Restoration of vasodilation and CBF autoregulation by genistein in rat pial artery after brain injury.

This study determined whether, after fluid percussion injury (FPI), tyrosine kinase activation is coupled to inhibition of K(+) channels and alteration in cerebral blood flow (CBF) autoregulation in the rat pial artery. Injury of moderate severity (2--2.5 atm) was produced by FPI in anesthetized rats equipped with a closed cranial window. The suppressed vasodilation of the pial arterioles to calcitonin gene-related peptide (CGRP) and levcromakalim (LMK) and altered lower limit of CBF autoregulation after FPI were restored by genistein but not by daidzein, an inactive analog. Vasodilation to S-nitroso-N-acetyl penicillamine (0.1--10 micromol/l) was, however, little influenced after FPI. The restored vasodilation was decreased by sodium orthovanadate, suggesting the reciprocal action of tyrosine phosphorylation and dephosphorylation. After FPI, CGRP-induced vasodilation restored by genistein (10 micromol/l) was strongly antagonized by iberiotoxin but not by glibenclamide, whereas LMK-induced vasodilation was, in contrast, inhibited by glibenclamide but not by iberiotoxin. Taken together, we suggest that, after FPI, activation of tyrosine kinase links the inhibition of K(+) channels to impaired autoregulatory vasodilation in response to acute hypotension and alteration in CBF autoregulation in the rat pial artery.

Animals↗

PubMed2001

Antiangiogenic effect of KR31372 in rat sponge implant model.

A rat sponge implant model was used to examine the antiangiogenic effect of KR31372. Topical administration of angiotensin II (AII, 100 ng, daily) into the sponges enhanced the basal sponge-induced neovascularization, leading to higher clearance of (99m)Tc, increased retention of dye in the vessels, and increased numbers of blood vessels. These AII-induced changes were significantly suppressed by oral administration of KR31372 (1 mg/kg for 7 days). Angiogenic effect of recombinant human VEGF(165) (200 ng) was modestly higher than that of AII, which was also significantly inhibited by KR31372. KR31372-mediated suppression of (99m)Tc clearance was reversed by glibenclamide. Levcromakalim showed a modestly suppressive effect on the AII-induced angiogenesis. In conclusion, KR31372 exerted a strong inhibitory effect on the sponge-induced neovascularization, in part, through mediation of glibenclamide-sensitive K(+) channel activation. It is suggested that it may have therapeutic potential in the treatment of angiogenic disorders.

Angiogenesis Inhibitors↗

PubMed2000

Implication of adenosine A2A receptors in hypotension-induced vasodilation and cerebral blood flow autoregulation in rat pial arteries.

This study aimed to evaluate the role for adenosine A2A receptors in the autoregulatory vasodilation to hypotension in relation with cerebral blood flow (CBF) autoregulation in rat pial arteries. Changes in pial artery diameters were observed directly through a closed cranial window. Vasodilation induced by adenosine was markedly suppressed by ZM 241385 (1 micromol/l, A2A antagonist) and alloxazine (1 micromol/l, A2B antagonist), but not by 8-cyclopentyltheophylline (CPT, 1 micromol/l, A1 antagonist). CGS-21680-induced vasodilation was more strongly inhibited by ZM 241385 (25.3-fold; P<0.05) than by alloxazine. In contrast, 5'-N-ethylcarboxamido-adenosine (NECA)-induced vasodilation was more prominently suppressed by alloxazine (12.0-fold; P<0.001) than by ZM 241385. The autoregulatory vasodilation in response to acute hypotension of the pial arteries was significantly suppressed by ZM 241385, but not by CPT and alloxazine. Consistent with this finding, the lower limit of CBF autoregulation significantly shifted to a higher blood pressure by 1 micromol/l of ZM 241385 (53.0+/-3.9 mm Hg to 69.2+/-2.9 mm Hg, P<0.01) and 10 micromol/l of glibenclamide (54.7+/-6.5 mm Hg to 77.9+/-4.2 mm Hg, P<0.001), but not by CPT and alloxazine. Thus, it is suggested that adenosine-induced vasodilation of the rat pial artery is mediated via activation of adenosine A2A and A2B receptors, but not by A1 subtype, and activation of adenosine A2A receptor preferentially contributes to the autoregulatory vasodilation via activation of ATP-sensitive K+ channels in response to hypotension and maintenance of CBF autoregulation.

Animals↗

PubMed2000

Expression of intracellular adhesion molecule-1 linking superoxide to mobilization of granulocytes and macrophages after periarterial blood in rat femoral artery: effect of rebamipide.

OBJECT: To clarify the mechanism(s) involved in the perivascular mobilization of granulocytes and macrophages by periarterial autologous blood (PAAB) in the vicinity of the femoral artery (FA) in rats, superoxide production as well as expression of intercellular adhesion molecule-1 (ICAM-1) were determined by conducting both in vitro and in vivo experiments. METHODS: In an in vitro study, a significant amount of superoxide inhibited by diphenyleneiodonium (20 microM and 100 microM) was identified at 3 hours after application of 10% whole blood to the aortic segments, and these results were correlated with in vitro ICAM-1 expression. High expression of ICAM-1 was subsequently demonstrated in these segments at 24 hours in in vitro and in vivo studies. In the in vivo study, an increased mobilization of granulocytes paralleled with a high expression of ICAM-1 in the vessels at 24 hours after administration of PAAB to the FA and then declined. Subsequently, macrophage infiltration progressively increased at all layers throughout a period of 7 to 12 days. Pretreatment with rebamipide (100 and 300 mg kg(-1) day(-1), orally) significantly inhibited the expression of ICAM-1 with inhibition of mobilization of granulocyte/macrophage. CONCLUSIONS: These findings suggest that application of PAAB to the rat FA causes superoxide-linked expression of ICAM-1 and mobilization of granulocyte and macrophages. Thus, the potential value in suppressing these variables stimulated by PAAB is indicated in therapeutic strategies for prevention and possible regression of vasospasm after subarachnoid hemorrhage.

Alanine↗

PubMed2000

Role of adenosine A(2B) receptors in vasodilation of rat pial artery and cerebral blood flow autoregulation.

This study was aimed to investigate the underlying mechanism of vasodilation induced by the activation of A(2B) adenosine receptors in relation to cerebral blood flow (CBF) autoregulation. Changes in pial arterial diameters were observed directly through a closed cranial window. N(omega)-nitro-L-arginine methyl ester (L-NAME, nitric oxide synthase inhibitor) significantly suppressed the concentration-dependent vasodilations induced by adenosine and 5'-N-ethylcarboxamido-adenosine (NECA) but not the vasodilation by CGS-21680 (A(2A)-receptor agonist). Moreover, NECA-induced vasodilation was suppressed by alloxazine (1 micromol/l) but not by ZM-241385 (1 micromol/l, A(2A) antagonist), which suggests mediation by A(2B)- receptor activation. Otherwise, the level of nitrite/nitrate was concentration dependently increased in the artificial cerebrospinal fluid (CSF) when adenosine and NECA were suffused over the cortical surface. L-NAME and alloxazine, but not ZM-241385, largely inhibited their releases. The lower limit of CBF autoregulation was little affected following pretreatment with L-NAME or alloxazine. Thus it is suggested that adenosine-induced vasodilation via activation of A(2B)-adenosine receptors of the rat pial artery is coupled to the production of nitric oxide, which contributes little to CBF autoregulation.

Animals↗

PubMed2000

Rebamipide inhibits neutrophil adhesion to hypoxia/reoxygenation-stimulated endothelial cells via nuclear factor-kappaB-dependent pathway.

This study was designed to determine whether rebamipide can inhibit neutrophil adhesion to human umbilical vein endothelial cells (HUVECs) stimulated with 1 h of hypoxia followed by 4 h of reoxygenation (H/R). Furthermore, to define the action mechanisms, we determined the effect of rebamipide on the surface expression of endothelial cell adhesion molecules E-selectin, P-selectin, and intercellular adhesion molecule-1 (ICAM-1) on H/R-stimulated HUVECs. Under resting conditions, both E-selectin and P-selectin were not expressed on the surface of HUVECs in contrast to ICAM-1, which was constitutively expressed. After stimulation with H/R, HUVECs showed an enhanced neutrophil adhesivity in association with an increased surface expression of E-selectin and P-selectin with a marginal increase in ICAM-1 expression. In parallel, the increased nuclear translocation of nuclear factor-kappaB in H/R-stimulated HUVECs was monitored by electrophoretic mobility shift assay (adjusted volume units, 11.9 +/- 2.5 x 10(4) counts x mm(2) in unstimulated cells versus 24.2 +/- 3.0 x 10(4) counts x mm(2) in H/R-stimulated cells). Rebamipide suppressed the surface expression of E-selectin and P-selectin with a subsequent inhibition of neutrophil adhesion to H/R-stimulated HUVECs. In line with these results, rebamipide (100, 300, and 1000 microM) inhibited H/R-induced nuclear translocation of nuclear factor-kappaB in a concentration-dependent manner. Taken together, this study demonstrates that rebamipide inhibits neutrophil adhesion to HUVECs by a mechanism involving inhibition of transcription-dependent surface expression of E-selectin and P-selectin in H/R-stimulated endothelial cells.

Alanine↗

PubMed1999

Cysteinyl-tRNA formation: the last puzzle of aminoacyl-tRNA synthesis.

With the exception of the methanogenic archaea Methanococcus jannaschii and Methanobacterium thermoautotrophicum deltaH, all organisms surveyed contain orthologs of Escherichia coli cysteinyl-tRNA synthetase (CysRS). The characterization of CysRS-encoding (cysS) genes and the demonstration of their ability to complement an E. coli cysSts mutant reveal that Methanococcus maripaludis and Methanosarcina barkeri, two other methanogenic archaea, possess canonical CysRS proteins. A molecular phylogeny inferred from 40 CysRS sequences indicates that the CysRS of M. maripaludis and Methanosarcina spp. are specific relatives of the CysRS of Pyrococcus spp. and Chlamydia, respectively. This result suggests that the CysRS gene was acquired by lateral gene transfer in at least one euryarchaeotic lineage.

Amino Acid Sequence↗

PubMed1999

SKP-450 inhibits migration and DNA synthesis stimulated by oxidized low density lipoprotein in smooth muscle cells.

This study was carried out to examine the inhibitory effects of SKP-450 (2-[2"(1", 3"-dioxolone)-2-methyl]-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro-2H-1-be nzo pyran), a potassium channel opener, on the proliferation and migration stimulated by oxidized low density lipoprotein (LDL) of cultured smooth muscle cells of Wistar Kyoto rat aorta. SKP-450 (10(-7) and 10(-6) M) as well as probucol (10(-7)-10(-5) M) reduced the production of thiobarbituric acid reactive substances from LDL submitted to CuSO(4) (10 microM). The increased [3H]thymidine incorporation and migration (chemotactic and wound-edge) of the cultured smooth muscle cells in association with increased production of platelet-derived growth factor (PDGF)-BB-like immunoreactivity stimulated by oxidized LDL were significantly reduced by SKP-450 (10(-7)-10(-6) M). Inhibition by SKP-450 of the oxidized LDL-stimulated [3H]thymidine incorporation was antagonized by iberiotoxin (10(-7) M), but not by glibenclamide (10(-6) M), suggestive of mediation of Ca(2+)-activated K(+) channel opening in the action of SKP-450. Taken together, SKP-450 inhibited the proliferation and migration of the smooth muscle cells as well as PDGF production stimulated by oxidized LDL, accompanying with its antiperoxidative action.

Animals↗

PubMed1999

Effect of omega-conotoxin GVIA and omega-agatoxin IVA on the capsaicin-sensitive calcitonin gene-related peptide release and autoregulatory vasodilation in rat pial arteries.

This study assesses the effect of neuronal voltage-sensitive Ca2+ channel blockers, omega-conotoxin GVIA (CTX), and omega-agatoxin IVA (AgTX) on the vasodilation and release of calcitonin gene-related peptide (CGRP), both of which were induced by either application of capsaicin or acute stepwise hypotension. Changes in pial arterial diameter were determined directly through a closed cranial window. The vasodilation of pial artery induced by either CGRP (0.1 micromol/L) or capsaicin (0.3 micromol/L) was significantly inhibited by CGRP(8-37) (0.1 micromol/L) (P < 0.05 and P < 0.05, respectively). The autoregulatory vasodilation to acute stepwise hypotension was severely attenuated by pretreatment with either CTX or AgTX. When the hypotension was kept for 2, 4, and 10 minutes, the releasable CGRP-like immunoreactivity (CGRP-LI) level (vehicle, 13.4+/-1.5 fmol/mm2/30 min) by 10 micromol/L capsaicin from the isolated pial arteries was significantly reduced in the 4- and 10-minute hypotension groups (11.3+/-1.2 fmol/mm2/30 min, P < 0.05, and 11.1+/-1.5 fmol/mm2/30 min, P < 0.05, respectively), but not in 2-min group. Moreover, the CGRP-LI level released by 10 micromol/L capsaicin (13.7+/-0.9 fmol/mm2/30 min) also was significantly depressed by pretreatment with 1 micromol/L CTX to 10.4+/-1.0 fmol/mm2/30 min (P < 0.01) and with 0.1 micromol/L AgTX to 8.7(1.7 fmol/mm2/30 min (P < 0.001), as well as by pretreatment with 10 micro-mol/L capsaicin (6.0+/-1.6 fmol/ mm2/30 min, P < 0.001). These results suggest that the neuronal N- and P-type voltage-sensitive Ca2+ channels are implicated in the release of CGRP from capsaicin-sensitive perivascular sensory nerves in response to acute hypotension, and that the released CGRP may contribute to the autoregulatory vasodilation in the cerebral microcirculation.

Animals↗

PubMed1999

Metabolism of cAMP to adenosine: role in vasodilation of rat pial artery in response to hypotension.

The purpose of this experiment was to examine whether the cAMP-adenosine pathway is implicated in the autoregulatory vasodilation in response to hypotension. Suffusion with cAMP (1-100 micromol/l) or adenosine (0.01-10 micromol/l) caused a sustained vasodilation of the resting pial arteries in a concentration-dependent manner. In contrast, N6,2'-O-dibutyryl-cAMP and 8-bromo-cAMP exerted a weak dilation at high concentration (100 micromol/l). The vasodilation to cAMP (1-100 micromol/l), adenosine (0.01-10 micromol/l), and hypotension was significantly reduced by pretreatment with 3,7-dimethyl-1-propargylxanthine (1 micromol/l), an A2 receptor antagonist, as well as 3-isobutyl-1-methylxanthine (3 micromol/l), an inhibitor of endo- and ectophosphodiesterase, 1, 3-dipropyl-8-p-sulfophenylxanthine (100 micromol/l), an inhibitor of ecto-5'-phosphodiesterase, or alpha,beta-methylene-adenosine 5'-diphosphate (100 micromol/l), an inhibitor of ecto-5'-nucleotidase. However, 8-cyclopentyltheophylline (1 micromol/l), an A1 antagonist, did not elicit a similar response. The increased release of adenosine when the cortical surface was suffused with cAMP (100 micromol/l) was significantly reduced by 3-isobutyl-1-methylxanthine, 1,3-dipropyl-8-p-sulfophenylxanthine, and alpha,beta-methylene-adenosine 5'-diphosphate (each 100 micromol/l). These results indicate that the cAMP-adenosine pathway as a viable metabolic mechanism is implicated in the production of adenosine in the rat pial artery and contributes to the regulation of vasodilation in response to hypotension.

Adenosine↗

PubMed1999

Inhibitory effect of rebamipide on the neutrophil adherence stimulated by conditioned media from Helicobacter pylori-infected gastric epithelial cells.

We investigated the mechanism or mechanisms by which rebamipide protects against the gastric mucosal inflammation associated with Helicobacter pylori. The production of interleukin (IL)-8 in association with expression of IL-8 mRNA was greatly increased in the H. pylori-infected Kato III cells in a concentration- and time-dependent manner, whereas the secretion of IL-6 and tumor necrosis factor-alpha was not detectable. The increased production of IL-8 and expression of IL-8 mRNA were significantly inhibited by rebamipide (100-1000 microM) in a concentration-dependent manner. Formyl-methionyl-leucyl-phenylalanine (1 nM), as well as conditioned medium (CM) that was produced from H. pylori-infected Kato III cells, caused an increase in surface expression of CD11b on human neutrophils and an increase in neutrophil adhesion to the human umbilical vein endothelial cells. Rebamipide also suppressed the adherence of neutrophils to endothelial cells as well as the expression of CD11b on neutrophils induced by formyl-methionyl-leucyl-phenylalanine and CM. Furthermore, CM-induced neutrophil adhesion to the endothelial cells was significantly inhibited by IL-8-neutralizing antibody, suggesting that IL-8 is implicated in the CM-induced neutrophil adhesion to the cultured human umbilical vein endothelial cells. It is concluded that rebamipide exerts its preventive effect against H. pylori-evoked gastric mucosal cell inflammation by inhibition of the neutrophil adherence to the endothelial cells as well as by suppressing the surface expression of CD11b on neutrophils and the production of proinflammatory cytokine such as IL-8 from gastric epithelial cells.

Alanine↗

PubMed1998

Retracing the evolution of amino acid specificity in glutaminyl-tRNA synthetase.

Molecular phylogenetic studies of glutaminyl-tRNA synthetase suggest that it has relatively recently evolved from the closely related enzyme glutamyl-tRNA synthetase. We have now attempted to retrace one of the key steps in this process by selecting glutaminyl-tRNA synthetase mutants displaying enhanced glutamic acid recognition. Mutagenesis of two residues proximal to the active site, Phe-90 and Tyr-240, was found to improve glutamic acid recognition 3-5-fold in vitro and resulted in the misacylation of tRNA(Gln) with glutamic acid. In vivo expression of the genes encoding these misacylating variants of glutaminyl-tRNA synthetase reduced cellular growth rates by 40%, probably as a result of an increase in translational error rates. These results provide the first biochemical evidence that glutaminyl-tRNA synthetase originated through duplication and consequent diversification of an ancestral glutamyl-tRNA synthetase-encoding gene.

Amino Acid Sequence↗

PubMed1998

The terminal adenosine of tRNA(Gln) mediates tRNA-dependent amino acid recognition by glutaminyl-tRNA synthetase.

Sequence-specific interactions between Escherichia coli glutaminyl-tRNA synthetase and tRNA(Gln) have been shown to determine the apparent affinity of the enzyme for its cognate amino acid glutamine during aminoacylation. Specifically, structural and biochemical studies suggested that residues Asp66, Tyr211, and Phe233 in glutaminyl-tRNA synthetase could potentially facilitate cognate amino recognition through their specific interactions with both A76 of tRNA(Gln)++ and glutamine. These residues were randomly mutated and the resulting glutaminyl-tRNA synthetase variants were screened in vivo for changes in their ability to recognize noncognate tRNAs and retention of tRNA-glutaminylation activity. When the variants selected in this way were characterized in vitro, they all showed dramatic decreases in apparent affinity (KM) for glutamine but little or no change in cognate tRNA affinity. Conservative replacements such as Y211F, F233L, and D66E resulted in 60-, 19-, and 18-fold increases compared to wild-type in the KM for glutamine, respectively, but had little effect on the turnover number (kcat). Nonconservative replacements affected both KM for glutamine and kcat; Y211S, F233D, and D66F displayed 1700, 3700, and 1200-fold decreases in kcat/KM for glutamine compared to wild-type. Double mutant cycle analysis indicated that Tyr211, and Phe233 interact strongly to enhance glutamine binding. These data now show that Asp66, Tyr211 and Phe233 mediate tRNA-dependent cognate amino acid recognition via the invariant 3'-terminal adenosine of tRNA(Gln).

Adenosine↗

PubMed1998

Pharmacological profiles of SKP-450 and its family, a K+ channel opener, in comparison with levcromakalim.

This study was carried out to characterise the vasodepressor and vasorelaxant actions of a benzopyran derivative, SKP-450 and its family, (+/-)-racemate SKP-411, (+)-enantiomer SKP-451, and the metabolites of SKP-450 (SKP-818 and SKP-310) in comparison with levcromakalim (LCRK) in the canine coronary, rabbit basilar and vertebral arterial segments. SKP-450, its family (SKP-411 and SKP-451) and the metabolite of SKP-450 (SKP-818) caused concentration-dependent relaxations as well as LCRK in the canine coronary artery and rabbit basilar and vertebral arteries. The relaxant potency of SKP-450 was significantly higher than that of LCRK in the three arteries in terms of EC50 values. SKP-450- and LCRK-induced vasorelaxations were competitively antagonised by glibenclamide with pA2 values of 7.60 (slope 1.22) and 7.99 (slope, 1.00), respectively. SKP-450 (0.1 and 1.0 microM) caused a significant stimulation of the 86Rb efflux from canine coronary arteries in a concentration-dependent manner as well as LCRK (1 and 10 microM), and their effects were antagonised by glibenclamide (10 microM). SKP-450 as well as LCRK produced long-lasting decreases in mean arterial pressure in the spontaneously hypertensive rats (SHR). These results suggest that SKP-450 has a significantly higher potency than LCRK in in vitro vasorelaxation, and it exerts potent and long-lasting vasodepressor effects with its active metabolite (SKP-818).

Animals↗

PubMed1998

The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist.

KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol- 5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT1) receptors in rabbit aorta and human recombinant AT1 receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (AII) with decreased maximal response (pD'2 = 10.1 +/- 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [125I]AII binding to rabbit aortic membranes (AT1 receptors) and [125I][Sar1, Ile8]AII binding to human recombinant AT1 receptors in a concentration-dependent manner with IC50 values of 0.84 +/- 0.08 nM and 1.92 +/- 0.15 nM, respectively, but did not inhibit specific [125I]AII binding to bovine cerebellum membranes (AT2 receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT1 receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT1 selective angiotensin receptor antagonist which exerts a competitive antagonism in the [125I]AII binding assay and insurmountable AT1 receptor antagonism in the functional study.

1-Sarcosine-8-Isoleucine Angiotensin II↗