Biomedical subjects

I J Chen

Publications and source records attributed to I J Chen.

At least 19 recordsLinked to original sources

PubMed2005

San-Huang-Xie-Xin-Tang attenuates inflammatory responses in lipopolysaccharide-exposed rat lungs.

In this study, the potential anti-inflammatory effect of San-Huang-Xie-Xin-Tang (SHXT) and its main component baicalin on LPS-induced lung injury were investigated and compared to the profile of dexamethasone (DEXA) in a pre-clinical animal model. Post-treatment with SHXT (75 mg/kg), baicalin (1.5 mg/kg) and DEXA (0.5 mg/kg), significantly inhibited LPS-induced hypotension, lung edema and acute survival rates. Western blotting analysis results indicated that all of them significantly inhibited LPS-induced iNOS, TGF-beta, p38MAPK, and ICAM-1 expressions in the lung tissues. Results from ELISA analysis showed that SHXT, baicalin and DEXA all decreased plasma levels of IL-1beta, TNF-alpha, and MCP-1 caused by LPS. Based on these findings, SHXT and baicalin decreased plasma concentrations of IL-1beta, TNF-alpha, MCP-1, and expressions of TGF-beta, ICAM-1, phosphorylated p38 MAPK, and iNOS, which were associated with lung injury and lethality. These evidences indicated that SHXT and baicalin showed strong anti-inflammatory activity, similar to that observed for DEXA, and therefore implicated that herbal SHXT might be therapeutically useful for the treatment of endotoxic lung injury.

Animals↗

PubMed2003

Age-dependent protection quantities for external neutron irradiation.

Based on the recommendations issued by the International Commission on Radiological Protection (ICRP), equivalent doses and effective doses for different ages are obtained for external neutron sources. The calculations at 28 neutron energies from 1 x 10(-9) MeV to 20 MeV are carried out for six irradiation geometries: AP, PA, RLAT, LLAT, ROT and ISO. An age-dependent anthropomorphic mathematical phantom series of six age groups: newborn, 1, 5, 10, 15 years old and adult is used with the Monte Carlo computer code MCNP for the dose evaluations. The results for adults are compared with those in ICRP Publication 74 and are in good agreement. At low energies the effective doses increase as the phantom age increases, but at high energics they decrease with increasing age for the AP, PA, ROT and ISO irradiation geometries. In the whole energy region the effective doses decrease as the phantom age increases for the RLAT and LLAT irradiation geometries. The age-dependent equivalent doses behave similarly to the effective doses, with some exceptions caused by the influence of the organ position.

Adolescent↗

PubMed2001

Prevention of cerebral vasospasm by a capsaicin derivative, glyceryl nonivamide, in an experimental model of subarachnoid hemorrhage.

BACKGROUND: Cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) remains a major complication in patients suffering from SAH. In our previous study, we reported that stimulating vascular K(+) channel activity prevented the development of cerebral vasospasm. Recent evidence indicates that glyceryl nonivamide (GLNVA), a capsaicin derivative, has a vasorelaxant effect on the aortic vascular smooth muscle due to the release of coronary calcitonin gene-related peptide, which in turn stimulates K(+) channel opening. The purpose of the present study was to examine the preventive effects of GLNVA on vasospasm. METHODS: New Zealand white rabbits were subjected to experimental SAH by injecting autologous blood into the cisterna magna. GLNVA or vehicle was injected intrathecally immediately after the induction of SAH. All animals were killed by perfusion-fixation at 48 hours after SAH. The basilar arteries were removed and sectioned, and their cross-sectional areas were measured. RESULTS: The average cross-sectional areas of basilar arteries were reduced by 69% and 71% in the SAH only and SAH plus vehicle groups, respectively, when compared with the healthy controls. After treatment with 0.35, 1.75, and 3.5 mg/kg GLNVA in rabbits subjected to SAH the average cross-sectional area was decreased by 46%, 12% and 2%, respectively, when compared with the healthy controls. The protective effect of GLNVA achieved statistical significance at all dosages. Morphologically, corrugation of the internal elastic lamina of vessels was often observed in the vehicle-treated group, but was not prominent in the GLNVA-treated groups or healthy controls. CONCLUSION: The findings showed that GLNVA dose-dependently attenuated cerebral vasospasm after SAH in the rabbit. These results suggest that intrathecal administration of GLNVA could be an effective strategy for preventing cerebral vasospasm after SAH.

Animals↗

PubMed2001

A new aspect of view in synthesizing new type beta-adrenoceptor blockers with ancillary antioxidant activities.

A series of vanilloid-type beta-adrenoceptor blockers derived from antioxidant traditional Chinese herbal medicines were synthesized and tested for their antioxidant and adrenoceptor antagonistic activities. They all possessed significant beta-adrenoceptor blocking activities under in vitro experiments and radioligand binding assays. In addition, some compounds were further examined in in vivo tests and produced antagonist effects matching that of propranolol and labetalol by measurements of antagonism toward (-)isoproterenol-induced tachycardia and (-)phenylephrine-induced pressor responses in anesthetized rats. Furthermore, all of the compounds had antioxidant effects inherited from their original structures. In conclusion, compound 11 had the most potent beta-adrenoceptors blocking activity, 12 and 13 possessed high cardioselectivity, whereas 14, 15 and 16 possessed additional alpha-adrenoceptor blocking activity and 15 is the most effective antioxidant of all. The antioxidant activity may be due to their alpha and beta unsaturated side chain at position 1 and ortho-substituted methoxy moiety on 4-phenoxyethylamine.

Adrenergic beta-Antagonists↗

PubMed2001

A xanthine-based KMUP-1 with cyclic GMP enhancing and K(+) channels opening activities in rat aortic smooth muscle.

1. KMUP-1 (1, 3, 5 mg kg(-1), i.v.), a xanthine derivative, produced dose-dependent sustained hypotensive and short-acting bradycardiac effects in anaesthetized rats. This hypotensive effect was inhibited by pretreatment with glibenclamide (5 mg kg(-1), i.v.). 2. In endothelium-intact or denuded aortic rings preconstricted with phenylephrine, KMUP-1 caused a concentration-dependent relaxation. This relaxation was reduced by endothelium removal, the presence of NOS inhibitor L-NAME (100 microM) and sGC inhibitors methylene blue (10 microM) and ODQ (1 microM). 3. The vasorelaxant effects of KMUP-1 was attenuated by pretreatment with various K(+) channel blockers TEA (10 mM), glibenclamide (1 microM), 4-AP (100 microM), apamin (1 microM) and charybdotoxin (ChTX, 0.1 microM). 4. Increased extracellular potassium levels (30 - 80 mM) caused a concentration-related reduction of KMUP-1-induced vasorelaxations. Preincubation with KMUP-1 (1, 10, 100 nM) increased the ACh-induced maximal vasorelaxations mediated by endogenous NO release, and enhanced the potency of exogenous NO-donor SNP. 5. The vasorelaxant responses of KMUP-1 (0.01, 0.05, 0.1 microM) together with a PDE inhibitor IBMX (0.5 microM) had an additive action. Additionally, KMUP-1 (100 microM) affected cyclic GMP metabolism since it inhibited the activity of PDE in human platelets. 6. KMUP-1 induced a dose-related increase in intracellular cyclic GMP levels in rat A10 vascular smooth muscle (VSM) cells, but not cyclic AMP. The increase in cyclic GMP content of KMUP-1 (0.1 - 100 microM) was almost completely abolished in the presence of methylene blue (10 microM), ODQ (10 microM), and L-NAME (100 microM). 7. In conclusion, these results indicate that KMUP-1 possesses the following merits: (1) stimulation of NO/sGC/cyclic GMP pathway and subsequent elevation of cyclic GMP, (2) K(+) channels opening, and (3) inhibition of PDE or cyclic GMP breakdown. Increased cyclic GMP display a prominent role in KMUP-1-induced VSM relaxations.

Acetylcholine↗

PubMed2001

Age-dependent protection quantities for external photon irradiation.

The age-dependent conversion coefficients of the protection quantities, the equivalent dose and the effective dose defined by the International Commission on Radiological Protection (ICRP), are obtained. A Monte Carlo computer code and the age-dependent hermaphrodite mathematical phantoms of six age groups: newborn, 1, 5, 10, 15 years old and adult are used for the evaluation. Twenty-three photon source energies from 10 keV to 10 MeV and six kinds of irradiation geometries: AP, PA, RLAT, LLAT, ROT, and ISO are chosen in the calculation. The evaluated conversion coefficients for the adult are compared with those in ICRP Publication 74 with good agreement. The conversion coefficients of the equivalent dose and the effective dose increase while the age of the phantom decreases, but with some exceptions for the AP irradiation geometry under certain conditions.

Adolescent↗

PubMed2000

Lipid solubility of vasodilatory vanilloid-type beta-blockers on the functional and binding activities of beta-adrenoceptor subtypes.

Various vanilloid-type beta-adrenoceptor blockers were studied on guinea pig right atrium and trachea and rat colon. In addition, we also investigated their beta(1)-, beta(2)-, and beta(3)-adrenoceptor binding affinities. All these beta-adrenergic antagonists inhibited (-)isoproterenol-induced positive chronotropic effects of the right atrium and tracheal relaxation responses in a concentration-dependent manner. Some of these agents prevented the inhibition of rat colon spontaneous motility by (-)isoproterenol. Of the agents tested, we found that ferulidilol, eugenodilol, eugenolol, isoeugenolol, and ferulinolol, as well as propranolol and metoprolol, possessed beta(3)-adrenoceptor blocking activities, others were nearly without effectiveness. Furthermore, the binding characteristics of vanilloid-type beta-adrenergic antagonists were evaluated in [3H]CGP-12177, a beta(1)/beta(2)-adrenoceptor blocker and a beta(3)-adrenoceptor agonist, binding to beta(1)-, beta(2)-, and beta(3)-adrenoceptor sites in rat ventricle, lung, and interscapular brown adipose tissue (IBAT) membranes, respectively. Eugenodilol, eugenolol, metoprolol, isoeugenolol, and ferulinolol were less potent than both propranolol and ferulidilol in competing for the beta(3)-adrenoceptor binding sites. From the results of in vitro functional and binding studies, we suggested that propranolol, ferulidilol, eugenodilol, eugenolol, metoprolol, isoeugenolol, and ferulinolol all possessed beta(3)-adrenoceptor blocking activities. On the other hand, we also found that eugenodilol, eugenolol, metoprolol, isoeugenolol, and ferulinolol had a low lipid solubility in comparison with propranolol and ferulidilol. In conclusion, we proposed that beta(3)-adrenoceptor antagonistic actions of these vanilloid-type beta-blockers were positively correlated with their lipid solubility.

Adrenergic beta-Agonists↗

PubMed2000

Pharmacological effects of an aldehyde type alpha/beta-adrenoceptor blocking agent with vasodilating properties.

KMUP 880723 (0.5, 1.0, and 3.0 mg/kg, iv) produced dose-dependent hypotensive and bradycardia responses in pentobarbital-anesthetized Wistar rats. KMUP 880723 (1.0 mg/kg, iv) also markedly inhibited both the tachycardia effects induced by (-)isoproterenol and arterial pressor responses induced by phenylephrine. In the isolated Wistar rat right atria, left atria, and guinea pig tracheal strips, KMUP 880723 competitively antagonized the (-)isoproterenol-induced positive chronotropic effects, inotropic effects, and tracheal relaxation effects in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)isoproterenol suggested that KMUP 880723 was a beta(1)/beta(2)-adrenoceptor competitive antagonist. The apparent pA(2) values were 6.89+/-0.10 in the right atria, 7.02+/-0.09 in the left atria, and 6.59+/-0.11 in the trachea, indicating that KMUP 880723 was a nonselective beta-adrenoceptor blocker. In thoracic aorta experiments, KMUP 880723 also produced a competitive antagonism of norepinephrine-induced contraction with a pA(2) value of 7.14+/-0.06. In isolated rat thoracic aorta, KMUP 880723 more potently relaxed the contractions induced by norepinephrine (3 x 10(-6) M) than those by high K(+) (75 mM). In the radioligand-binding assay, the pK(i) values of [3H]CGP-12177 binding to rat ventricle and lung membranes were 6.56 and 6.40, respectively, and the value of [3H]prazosin binding to rat brain membranes was 6.66. These results further confirmed the alpha/beta-adrenoceptor blocking activities of KMUP 880723 reported in the functional studies. We conclude that KMUP 880723 is a nonselective beta-adrenoceptor antagonist with alpha-adrenoceptor blocking-associated vasorelaxant activity.

Adrenergic alpha-Antagonists↗

PubMed2000

A unique xanthine derivative KMCP-98 with activation of adenosine receptor subtypes.

KMCP-98 is a newly synthesized adenosine receptor agonist by alkylation at the 7-position of the xanthines nucleus. We first investigated the pharmacological activities of KMCP-98 under in vivo and in vitro conditions. Acute intravenous injection of KMCP-98 (1.0, 2.0 and 3.0 mg/kg) produced a temporary fall in blood pressure and heart rate, followed by a sustained fall in heart rate in pentobarbital-anesthetized Wistar rats. The hypotensive and bradycardiac responses were inhibited by pretreatment with an A(1) adenosine receptor antagonist 8-phenyltheophylline (8-PT, 0.5 mg/kg). Both KMCP-98 and adenosine (0.3-100 microM) produced negative inotropic activity in isolated guinea pig left atria. The negative inotropic activity of KMCP-98 was significantly blocked by pretreatment with A(1) receptor antagonists 8-PT (10 microM) and xanthine amine congener (XAC, 10 microM), a nonselective adenosine antagonist theophylline (10 microM), a K(+) channel blocker tetraethylammonium (TEA, 10 mM) and a K(ATP) channel blocker glibenclamide (1 microM). KMCP-98 (0.03-30 microM) produced concentration-dependent relaxations in carbachol (1 microM) precontracted guinea pig tracheal smooth muscle. The trachea relaxant response of KMCP-98 was markedly inhibited by A(2), A(2a) and A(2b) adenosine receptor antagonists 3,7-dimethyl-1-propargylxanthine (DMPX, 10 microM), 8-(3-chlorostyryl)caffeine (CSC, 10 microM) and alloxazine (10 microM), respectively, the nitric oxide synthase (NOS) inhibitor L-NAME (100 microM) and also by TEA and glibenclamide. In addition, KMCP-98 (0.03-30 microM) elicited relaxant response in norepinephrine (3 microM) precontracted rat thoracic aorta in a concentration-dependent manner. The thoracic aorta relaxant response of KMCP-98 was also significantly inhibited by DMPX, CSC, alloxazine, L-NAME, TEA and glibenclamide. Furthermore, the binding characteristics of KMCP-98, adenosine and 5'-N-ethylcarboxaminoadenosine (NECA) were evaluated in [(3)H]DPCPX and [(3)H]CGS 21680 binding to rat cortex and striatum, respectively. The K(i) values of KMCP-98 for predominate A(1) and A(2) adenosine receptor sites were 3908+/-952 and 158+/-10 nM, respectively. In conclusion, KMCP-98 was found to be a xanthine-based adenosine receptor agonist associated cardiac depression, tracheal and aortic smooth muscle relaxations.

Animals↗

PubMed2000

Identification of HIV-1 integrase inhibitors via three-dimensional database searching using ASV and HIV-1 integrases as targets.

Integration of viral DNA into the host cell genome is a critical step in the life cycle of HIV. This essential reaction is catalyzed by integrase (IN) through two steps, 3'-processing and DNA strand transfer. Integrase is an attractive target for drug design because there is no known cellular analogue and integration is essential for successful replication of HIV. A computational three-dimensional (3-D) database search was used to identify novel HIV-1 integrase inhibitors. Starting from the previously identified Y3 (4-acetylamino-5-hydroxynaphthalene-2,7-disulfonic acid) binding site on the avian sarcoma virus integrase (ASV IN), a preliminary search of all compounds in the nonproprietary, open part of the National Cancer Institute 3-D database yielded a collection of 3100 compounds. A more rigorous scoring method was used to rescreen the 3100 compounds against both ASV IN and HIV-1 IN. Twenty-two of those compounds were selected for inhibition assays against HIV-1 IN. Thirteen of the 22 showed inhibitory activity against HIV-1 IN at concentrations less than 200 microM and three of them showed antiviral activities in HIV-1 infected CEM cells with effective concentrations (EC50) ranging from 0.8 to 200 microM. Analysis of the computer-generated binding modes of the active compounds to HIV-1 IN showed that simultaneous interaction with the Y3 site and the catalytic site is possible. In addition, interactions between the active compounds and the flexible loop involved in the binding of DNA by IN are indicated to occur. The structural details and the unique binding motif between the HIV-1 IN and its inhibitors identified in the present work may contribute to the future development of IN inhibitors.

Avian Sarcoma Viruses↗

PubMed2000

Vanidipinedilol: a vanilloid-based beta-adrenoceptor blocker displaying calcium entry blocking and vasorelaxant activities.

Calcium channel and beta-adrenoceptor blockade have proved highly useful in antihypertensive therapy. Studies of the mechanisms of action of vanidipinedilol that combine these effects within a single molecule are described here. Intravenous injection of vanidipinedilol (0.1, 0.25, 0.5, 1.0, and 2.0 mg/kg) produced dose-dependent hypotensive and bradycardic responses, significantly different from nifedipine-induced (0.5 mg/kg, i.v.) hypotensive and reflex tachycardic effects in pentobarbital-anesthetized Wistar rats. A single oral administration of vanidipinedilol at doses of 10, 25, and 50 mg/kg dose-dependently reduced blood pressure with a decrease in heart rate in conscious spontaneously hypertensive rats (SHRs). In the isolated Wistar rat atrium, vanidipinedilol (10(-7), 10(-6), and 10(-5) M) competitively antagonized the (-)isoproterenol-induced positive chronotropic and inotropic effects and inhibited the increase in heart rate induced by Ca2+ (3.0-9.0 mM) in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)isoproterenol and CaCl2 suggested that vanidipinedilol possessed beta-adrenoceptor-blocking and calcium entry-blocking activities. On tracheal strips of reserpinized guinea pig, cumulative doses of vanidipinedilol (10(-10) to 3x10(-6) M) produced dose-dependent relaxant responses. Preincubating the preparation with ICI 118,551 (10(-10), 10(-9), 10(-8) M), a beta2-adrenoceptor antagonist, shifted the vanidipinedilol concentration-relaxation curve significantly to a region of higher concentrations. These results implied that vanidipinedilol had a partial beta2-agonist activity. In the isolated thoracic aorta of rat, vanidipinedilol had a potent effect inhibiting high-K+-induced contractions. KCI-induced intracellular calcium changes of blood vessel smooth muscle cell (A7r5 cell lines) determined by laser cytometry also was decreased after administration of vanidipinedilol (10(-8), 10(-7), 10(-6) M). Furthermore, the binding characteristics of vanidipinedilol and various antagonists were evaluated in [3H]CGP-12177 binding to ventricle and lung and [3H]nitrendipine binding to cerebral cortex membranes in rats. The order of potency of beta1- and beta2-adrenoceptor antagonist activity against [3H]CGP-12177 binding was (-)propranolol (pKi, 8.59 for beta1 and 8.09 for beta2) > vanidipinedilol (pKi, 7.09 for beta1 and 6.64 for beta2) > atenolol (pKi, 6.58 for beta1 and 5.12 for beta2). The order of potency of calcium channel antagonist activity against [3H]nitrendipine binding was nifedipine (pKi, 9.36) > vanidipinedilol (pKi, 8.07). The ratio of beta1-adrenergic-blocking/calcium entry-blocking selectivity is 0.1 and indicated that vanidipinedilol revealed more in calcium entry-blocking than in beta-adrenergic-blocking activities. It has been suggested that vanidipinedilol-induced smooth muscle relaxation may involve decreased entry of Ca2+ and partial beta2-agonist activities. In conclusion, vanidipinedilol is a nonselective beta-adrenoceptor antagonist with calcium channel blocking and partial beta2-agonist associated vasorelaxant and tracheal relaxant activities. Particularly, the vasodilator effects of vanidipinedilol are attributed to a synergism of its calcium entry blocking and partial beta2-agonist activities in the blood vessel. A sustained bradycardic effect results from beta-adrenoceptor blocking and calcium entry blocking, which blunts the sympathetic activation-associated reflex tachycardia in the heart.

Adrenergic beta-1 Receptor Antagonists↗

PubMed2000

The interference of uptake of thallium-201 in cultured rat myocardial cells with existence of potassium related pharmaceuticals--a preliminary report.

Thallium-201 myocardial perfusion imaging is wildly used to detect and assess the extent of jeopardized myocardial ischemia in the coronary artery disease and the viability of myocardium post infarction. In recent years, there has been a great deal of pharmacological development of blockers and openers of potassium channel. In this study, we will discuss the interference of uptake of thallium-201 ion in cultured neonatal rat myocytes with existence of a variety of pharmacological agents. The cultures of neonatal rat myocardial cells were incubated with different agents such as potassium chloride, sodium-potassium ATPase pump inhibitor (ouabain), cesium compound, variable potassium channel blockers (4 AP, TEA and glibenclamide) and their openers (minoxidil, and cromakalim). The radioactivity of intracellular thallium-201 that could enter rat myocardial cells was detected by gamma counter sixty minutes after thallium-201 was added. In this study we found that thallium and potassium ions behave in an analogous manner in cultured rat myocardial cells. Both 2.5 mM and 5 mM concentration of extracellular potassium ion significantly result in reduction of thallium-201 ion influx in rat myocardial cells. 0.5 mM ouabain, an inhibitor of sodium-potassium ATPase pump, reduced about 40% of influx of thallium-201 ion in cultured rat myocardial cells via active transport. Combination of both potassium ion and ouabain inhibit most of thallium-201 ions influx in myocardial cells, but it is not completely inhibited. Cesium, a potassium antagonist, also interferes with the uptake of thallium-201 in cultured rat myocytes in our study. The most interesting finding in our investigation is that potassium channel blockers such as TEA and glibenclamide, inhibit the influx of thallium-201 in myocytes. However, potassium channel openers have no overt effect on influx of thallium-201 in cultured rat myocytes. We indirectly observe about 60% of influx of thallium-201 ion into cultured rat myocardial cells via active sodium-potassium ATPase pump. Potassium, cesium and potassium channel blockers, such as TEA and glibenclamide, inhibited the different percentage of influx of thallium-201 in cultured rat myocardial cells in this study.

Adenosine Triphosphate↗

PubMed1999

Nitrated nonivamide displaying a drawback of proton's role in capsaicin-associated sensory and neuronal activities.

Nitrated nonivamide (NVANO)-induced triad hypotension, and biphasic bradycardia at 0.25-1.0 mg/kg (IV) was inhibited by capsazepine (1.0 mg/kg, IV), atropine (1.0 mg/kg, IV), and vagotomy in rats. NVANO also elicited a hypotensive spinal reflex at 5.0 mg/kg (IA). In the isolated rat vagus, NVANO (10.0-100.0 microM) revealed a sensory C-spike inhibition and membrane depolarization. NVANO (5.0 microM)-induced calcium influx in the isolated rat dorsal root ganglion cells (DRGs) was diminished by capsazepine (10.0 microM). In the isolated guinea pig atria, NVANO (1.0-50.0 microM)-induced positive inotropic and chronotropic activities were antagonized by capsazepine (1.0-10.0 microM) and human calcitonin gene-related peptide(8-37) (hCGRP(837); 0.1-1.0 microM).

Action Potentials↗

PubMed1999

Eugenodilol: a third-generation beta-adrenoceptor blocker, derived from eugenol, with alpha-adrenoceptor blocking and beta2-adrenoceptor agonist-associated vasorelaxant activities.

Eugenodilol, derived from natural eugenol, was first investigated with in vivo and in vitro models. In our in vivo study, eugenodilol (0.5, 1.0, and 1.5 mg/kg, i.v.) produced dose-dependent hypotensive and bradycardic responses in pentobarbital-anesthetized Wistar rats. Eugenodilol also inhibited the tachycardia and arterial pressor effects induced by (-)isoproterenol and phenylephrine, respectively. In our in vitro study, eugenodilol competitively antagonized (-)isoproterenol-induced positive inotropic and chronotropic effects and tracheal-relaxation responses on isolated guinea pig tissues in a concentration-dependent manner. The apparent pA2 values were 7.88+/-0.12 for right atria, 7.52+/-0.05 for left atria, and 7.33+/-0.15 for trachea, indicating that eugenodilol was a nonselective beta-adrenoceptor blocker. In thoracic aorta experiments, the apparent pA2 values of alpha-adrenoceptor blockade were 7.05+/-0.25 and 6.87+/-0.08 for eugenodilol and labetalol, respectively. In addition, eugenodilol produced cumulative relaxation responses on isolated guinea pig tracheal strips. The effects were competitively antagonized by ICI 118,551 (10(-8)-10(-6) M), a relatively selective beta2-adrenoceptor antagonist. In the radioligand-binding assay, the Ki values of [3H]CGP-12177 binding to rat ventricle and lung membranes were 9.72 and 48.29 nM, respectively, and the value of [3H]prazosin binding to rat brain membrane was 38.72 nM. These results further confirmed the alpha/beta-adrenoceptors-blocking activities of eugenodilol reported in the functional studies. We conclude that eugenodilol is a novel third-generation beta-adrenoceptor blocker with ancillary blocking activity at alpha-adrenoceptors and weak sympathomimetic activity at beta2-adrenoceptors.

Adrenergic beta-Agonists↗

PubMed1999

Isoeugenolol: a selective beta1-adrenergic antagonist with tracheal and vascular smooth muscle relaxant properties.

Isoeugenolol (1.0, 3.0, 5.0 mg/kg, i.v.) produced a dose-dependent bradycardia and a decrease in blood pressure in anesthetized Wistar rats. Isoeugenolol inhibited the tachycardia effects induced by (-)isoproterenol, but had no blocking effect on the arterial pressor responses induced by (-)phenylephrine. In isolated guinea pig tissues, isoeugenolol antagonized (-)isoproterenol-induced positive inotropic and chronotropic effects on the atria and tracheal relaxations in a concentration-dependent manner. The apparent pA2 values for isoeugenolol on right atria, left atria and trachea were 7.63+/-0.03, 7.89+/-0.12 and 6.12+/-0.05, respectively, indicating that isoeugenolol was a highly selective beta1-adrenoceptor blocker. On the other hand, isoeugenolol produced a mild direct cardiac depression at high concentration and was without intrinsic sympathomimetic activity (ISA). In isolated rat thoracic aorta, isoeugenolol relaxed more potently the contractions induced by (-)phenylephrine (10 microM) and 5-HT (10 microM) than those by high K+ (75 mM). In isolated guinea pig trachea, isoeugenolol attenuated the carbachol (1 microM)-con-tracted trachea more significantly than those contracted with high K+. Furthermore, the binding characteristics of isoeugenolol and various beta-adrenoceptor antagonists were evaluated in [3H]CGP-12177 binding to rat ventricle, lung and interscapular brown adipose tissue (IBAT) membranes. The -log IC50 values of isoeugenolol for predominate beta1-, beta2- and beta3-adrenergic receptor sites were 5.82+/-0.09, 4.74+/-0.05 and 4.73+/-0.12, respectively. In conclusion, isoeugenolol was found to be a highly selective beta1-adrenoceptor antagonist with tracheal and vascular smooth muscle relaxant activities, but was devoid of alpha-adrenoceptor-blocking action.

Adrenergic beta-1 Receptor Antagonists↗

PubMed1998

Selective block by glyceryl nonivamide of inwardly rectifying K+ current in rat anterior pituitary GH3 cells.

The effects of glyceryl nonivamide (GLNVA) on ionic currents were compared and examined in rat pituitary GH3 cells. Hyperpolarization-activated K+ currents in GH3 cells bathed in high-K+ Ca2+-free external solution were studied to assess effects of GLNVA on the an inwardly rectifying K+ current (I(K(IR))). GLNVA is very potent in blocking I(K(IR)) in a concentration-dependent manner, with a half maximal concentrations of 0.1 microM. The complete block of I(K(IR)) achieved with concentrations > or = 1 microM revealed the presence of a non-inactivating current. We also found that GLNVA at a concentration above 30 microM inhibited L-type voltage-dependent Ca2+ current and two components of K+ outward currents, while GLNVA (< or = 3 microM) did not have any effect on them. This study shows that GLNVA, in addition to retaining the capability of eliciting peptidergic neurons, is a selective block of I(K(IR)) in GH3 cells and will provide a useful tool for characterizing I(K(IR)) and understanding its physiological function. In addition, the carefulness should be taken about the interpretation of GLNVA-mediated responses in vivo or in vitro.

Animals↗

PubMed1998

An ultra-weak chemiluminescence study on oxidative stress in rabbits following acute thermal injury.

It is not easy to detect oxygen free radicals directly because of their very short half-life. In the present study, a sensitive ultra-weak chemiluminescence detector was used to detect the generation of oxygen free radicals following thermal injury. Twelve New Zealand white rabbits were used in this study. After anesthesia, the bilateral hind-limbs were exposed to 100 degrees C water for 30 s. Six control animals were exposed to 22 degrees C water to act as a control. The chemiluminescence of whole blood and visceral organs were measured with both luminol-amplified t-butyl hydroperoxide-initiated and lucigenin-initiated methods. The results showed that chemiluminescence of blood was affected significantly by acute thermal injury. The chemiluminescence of blood increased significantly at 1 h following acute thermal injury, reached a peak at 2 h, then decreased but still remained above the control level at 4 h following thermal injury. The results for TBHP-initiated chemiluminescence from visceral organs following acute thermal injury were much higher than that of the control rabbits. The effects of lucigenin-initiated tissue chemiluminescence following acute thermal injury were not statistically significant. It is suggested that the decreased vascular antioxidant activity following local thermal injury is partially contributed by the superoxide pathway; while, the remote pathophysiologic events are mediated by the defective scavenging defenses.

Acridines↗

PubMed1998

Ionic effects of capsinolol, a calcitonin gene-related peptide releasing beta-adrenoceptor blocker, on isolated cardiac muscles.

1. Capsinolol (1.0-30.0 microM) in a cumulating manner decreased the maximum upstroke velocity (Vmax), the action potential amplitude and twitch tension in isolated guinea-pig atria and papillary muscle, rabbit papillary muscle, dog Purkinje fibers and human ventricle tissues. 2. In the isolated guinea-pig atrium, perfusing with capsinolol at 3 microM for 3 min temporarily increased the twitch force and decreased spontaneous cycle length; however, the results were reversed after longer exposure of the tissue. 3. Capsinolol prolonged the duration of action potential in the guinea-pig atrium and rabbit papillary muscles. The maximum diastolic potential was shifted to a less-negative level in dog Purkinje fibers and human ventricular muscles.

Action Potentials↗