Ferulidilol: A vasodilatory and antioxidant adrenoceptor and calcium entry blocker, with ancillary ?2-agonist activity

Huang, Yeun Chih; Yeh, Jwu‐Lai; Wu, Bin; Lo, Yi-Ching; Liang, Jhy Chong; Lin, Yu-Cheng; Sheu, Sheng Hsiung; Chen, Ing Jun

doi:10.1002/(sici)1098-2299(199906)47:2<77::aid-ddr3>3.0.co;2-q

Cited by 12 publications

(12 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Rat brain homogenates (1 mL) were incubated at 37 C for 5 min with 10 L of test compound or vehicle. Lipid peroxidation was initiated by the addition of 0.1 mL 0.25 mM FeCl 2 and 1 mM ascorbic acid (Huang et al 1999). After 30-min incubation, the reaction was stopped by the addition of 0.1 mL 0.2% butylated hydroxytoluene (BHT).…”

Section: Inhibition Of Lipid Peroxidation and Peroxyl Radical Scavengmentioning

confidence: 99%

Antioxidant eugenosedin-A protects against lipopolysaccharide-induced hypotension, hyperglycaemia and cytokine immunoreactivity in rats and mice

Shen

Yang

et al. 2005

Journal of Pharmacy and Pharmacology

Self Cite

View full text Add to dashboard Cite

Eugenosedin-A has been demonstrated to possess alpha/beta-adrenoceptor and serotonergic receptor blocking activities. We have investigated by what mechanisms eugenosedin-A prevents lipopolysaccharide (LPS)-induced hypotension, vascular hyporeactivity, hyperglycaemia, oxidative injury or inflammatory cytokines formation in rats. Intravenous administration of eugenosedin-A, trazodone, yohimbine (1 mg kg(-1)), aminoguanidine or ascorbic acid (15 mg kg(-1)) normalized LPS (10 mg kg(-1))-induced hypotension. Pretreatment with eugenosedin-A or the other agents 30 min before LPS injection reduced aortic hyporeactivity. LPS-induced increases in plasma interleukin-1beta (IL-beta), IL-6, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and blood glucose levels were significantly inhibited by eugenosedin-A (1 mg kg(-1), i. v.). The same dose of trazodone, a chloropiperazinylbenzene-type antidepressant, and yohimbine, an alpha(2)-adrenoceptor antagonist, reduced IL-1beta and TNF-alpha, but it could not inhibit hyperglycaemia. Aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, and ascorbic acid, an antioxidant, decreased IL-1beta, TNF-alpha contents and hyperglycaemia. Eugenosedin-A and the other agents inhibited Fe(2+)-ascorbic acid-induced peroxidation in rat cortex, indicating that those agents had antioxidant effects, with the exception of aminoguanidine. In free radical scavenged experiments, eugenosedin-A and ascorbic acid eliminated peroxyl radicals. All test agents inhibited the LPS-induced increase of malondialdehyde (MDA) content in rat brain homogenates. When mice were administered an intraperitoneal injection of LPS alone, mortality occurred from 4 to 16 h, after which time all were dead. However, eugenosedin-A significantly prolonged the survival time after LPS injection, suggesting that eugenosedin-A protected against LPS-induced cardiovascular dysfunction, hyperglycaemia, tissue injury and inflammatory cytokine production. This was attributable mainly to the antioxidant and peroxyl radical scavenged effects of eugenosedin-A, and which may be, at least in part, due to its blockade on alpha/beta-adrenergic and serotonergic receptors.

show abstract

Section: Inhibition Of Lipid Peroxidation and Peroxyl Radical Scavengmentioning

confidence: 99%

Antioxidant eugenosedin-A protects against lipopolysaccharide-induced hypotension, hyperglycaemia and cytokine immunoreactivity in rats and mice

Shen

Yang

et al. 2005

Journal of Pharmacy and Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this field, several 1,4-dihydropyridine derivatives, including our previously reported vanidipinedilol [Yeh et al, 2000], predominantly with calcium channel antagonist activity and additional β-adrenoceptor blocking activities, have been prepared to resolve this problem [Asano et al, 1990;Uchida et al, 1993;Shibasaki et al, 1997aShibasaki et al, , 1997bYeh et al, 2000;Nobuhiro et al, 1999]. In contrast, the third generation β-adrenoceptor blockers such as labetalol, carvedilol, and our previously reported ferulidilol and eugenodilol, with βand α-adrenoceptor blocking activities, have been suggested for treatment of hypertension and heart failure [Ruffolo et al, 1992[Ruffolo et al, , 1998Huang et al, 1999aHuang et al, , 1999b.…”

Section: Introductionmentioning

confidence: 99%

“…This new trend encouraged us to synthesize a combinatorial compound that possessed these properties of 1,4-dihydropyridines and the third generation β-adrenoceptor blockers. During the past decade, various vanilloid-derived vasodilatory β-adrenoceptor blockers have been synthesized and investigated in our laboratory Lin et al, 1996;Wu et al, 1996;Sheu et al, 1997;Huang et al, 1999aHuang et al, , 1999bYeh et al, 2000]. In this research, we further created a unique vanilloid-based β-adrenoceptor blocker, labedipinedilol-A 4-{{N-{4-[2-hydroxy-3-(2-methoxy-1-oxyethylamino benzen)propoxy]-3-methoxy}benzyl}}-2,6-dimethyl-3,5dicarbomethyoxy-1,4-dihydropyridine, Fig.…”

Section: Introductionmentioning

confidence: 99%

Labedipinedilol-A: A vanilloid-based ?/?-adrenoceptor blocker with calcium entry blocking and long-acting antihypertensive properties

et al. 2000

Self Cite

View full text Add to dashboard Cite

The combination of β‐adrenoceptor blockade and vasodilator action have proved highly useful in antihypertensive therapy. Studies of the mechanisms of action of labedipinedilol‐A that combine these effects within a single molecule are described in this report. Intravenous labedipinedilol‐A (0.1–1.0 mg/kg) produced dose‐dependent hypotensive and bradycardia responses for above 1.0 h, significantly different from nifedipine (0.5 mg/kg, i.v.)‐induced hypotensive and reflex tachycardia activities in pentobarbital‐anesthetized Wistar rats. Pretreatment with labedipinedilol‐A also inhibited phenylephrine (20 μg/kg, i.v.)‐induced hypertensive and (‐)isoprenaline (0.5 μg/kg, i.v.)‐induced tachycardia effects. Oral administration of labedipinedilol‐A (5–50 mg/kg) in spontaneously hypertensive rats (SHR) reduced the blood pressure and heart rate for 24 h but did not increase heart rate. Labedipinedilol‐A (10–7–10–5 M) competitively antagonized (‐)isoprenaline (10–10–10–4M)‐induced positive chronotropic and inotropic effects of the isolated rat atria and tracheal relaxation responses of the isolated guinea pig tissues. Labedipinedilol‐A also prevented the rate‐increasing effects of increased extracellular Ca2+ (3.0–9.0 mM) in a concentration‐dependent manner. In the isolated rat aorta, labedipinedilol‐A competitively antagonized CaCl2 and norepinephrine‐induced contractions with pKCa–1 and pA2 values of 8.46 ± 0.05 and 8.28 ± 0.03 and had a potent effect of inhibiting high K+‐induced vasocontraction. Furthermore, labedipinedilol‐A, in an equal antagonist activity, inhibited norepinephrine‐induced phasic and tonic contraction. In the cultured blood vessel smooth muscle cell (A7r5 cell line), KCl, norepinephrine, and Bay K 8644‐induced intracellular calcium changes were decreased after application of labedipinedilol‐A (10–9–10–6 M). The binding characteristics of labedipinedilol‐A were evaluated in [3H]CGP‐12177 binding to ventricle and lung and [3H]nitrendipine and [3H]prazosin binding to brain membranes in rats. The ‐logIC50 values of labedipinedilol‐A for β1‐, β2‐, and α1‐adrenoceptor and calcium channel, were 8.17 × 10–7 M, 8.20 × 10–7 M, 2.20 × 10–8 M, and 2.46 × 10–8 M, respectively. Labedipinedilol‐A‐induced sustained depressor effect was mainly attributed to its calcium entry and α‐adrenoceptor blocking activities in the blood vessel. Sustained bradycardia effect resulted from β‐adrenoceptor and calcium entry blocking, which deleted the sympathetic activation‐associated reflex tachycardia in the heart. Drug Dev. Res. 49:94–108, 2000. © 2000 Wiley‐Liss, Inc.

show abstract

“…Lipid peroxidation was initiated by the addition of 0.1 mL of 0.25 mM FeCl 2 and 1 mM ascorbic acid. 21 After 30 minutes of incubation, the reaction was stopped by adding 0.1 mL of 0.2% butylated hydroxytoluene. Thiobarbituric acid was then added, and the mixture was heated for 30 minutes in a boiling water bath.…”

Section: Lipid Peroxidation and Peroxy Radical Scavenging Activitiesmentioning

confidence: 99%

The Vasorelaxing Action of Labedipinedilol-A Involves Endothelial Cell-Derived NO and eNOS Expression Caused by Calcium Influx

Liou

Wu²,

Lai³

et al. 2005

Journal of Cardiovascular Pharmacology

Self Cite

View full text Add to dashboard Cite

Labedipinedilol-A, a novel dihydropyridine-type calcium antagonist, has been shown to induce hypotension and vasorelaxation. The objective of the present study was to investigate the effect of labedipinedilol-A on vascular function of rat aortic rings and cultured human umbilical vein endothelial cells (HUVECs). Labedipinedilol-A induced vasorelaxation in rat aortic rings that had been precontracted with phenylephrine in a concentration-dependent manner. This labedipinedilol-A-induced relaxation was significantly reduced by endothelium removal and by exposure to L-NG-nitroarginine methyl ester (L-NAME), methylene blue, or 1H-[1,2,4]oxadiazolol[4,3,a]quinoxalin-1-one (ODQ). In addition, the cyclic GMP content was significantly increased by labedipinedilol-A, which was inhibited by L-NAME in aorta. In cultured HUVECs, labedipinedilol-A induced concentration-dependent formation of NO and Ca2+ influx, and it increased the abundance of endothelial NO synthase (eNOS) protein. Furthermore, labedipinedilol-A suppressed basal, 10% FBS- and thrombin-stimulated endothelin-1 production, which were reversed by pretreatment with L-NAME, demonstrating that NO was able to inhibit production of ET-1 in HUVECs. Labedipinedilol-A significantly protected cultured HUVECs against dihydroxyfumarate/iron ion-induced decrease of glutathione and cell death. Moreover, labedipinedilol-A also inhibited iron-induced lipid peroxidation in rat brain homogenate and scavenged 2,2'-azobis (2-amidinopropane) dihydrochloride-derived peroxy radicals. Labedipinedilol-A acts as lacidipine with additional antioxidant effects and can protect endothelial cells against free radical-induced lipid peroxidation and cell injury. Our results indicate that the endothelium-dependent vasorelaxation by labedipinedilol-A is mediated through Ca2+-dependent activation of NO synthase and stimulation of NO/cyclic GMP pathway.

show abstract

Ferulidilol: A vasodilatory and antioxidant adrenoceptor and calcium entry blocker, with ancillary ?2-agonist activity

Cited by 12 publications

References 37 publications

Antioxidant eugenosedin-A protects against lipopolysaccharide-induced hypotension, hyperglycaemia and cytokine immunoreactivity in rats and mice

Antioxidant eugenosedin-A protects against lipopolysaccharide-induced hypotension, hyperglycaemia and cytokine immunoreactivity in rats and mice

Labedipinedilol-A: A vanilloid-based ?/?-adrenoceptor blocker with calcium entry blocking and long-acting antihypertensive properties

The Vasorelaxing Action of Labedipinedilol-A Involves Endothelial Cell-Derived NO and eNOS Expression Caused by Calcium Influx

Contact Info

Product

Resources

About