Vasodilatory Effects of Nipradilol, an α- and β-adrenergic Blocker with Nitric Oxide Releasing Action, in Rabbit Ciliary Artery

Yoshitomi, Takeshi; Yamaji, Katsuhiko; Ishikawa, Hitoshi; Ohnishi, Yoshitaka

doi:10.1006/exer.2002.2061

Cited by 11 publications

(5 citation statements)

References 19 publications

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“…A shortcoming of these in vivo studies of biliary physiology is that the effect of phenylephrine on secretinstimulated choleresis of BDL rats may be influenced by the in vivo vascular effects of phenylephrine. 31 However, in support of the concept that the effects of phenylephrine are due to a direct interaction with cholangiocytes rather than vascular effects, 31 we demonstrated that phenylephrine increases secretin-stimulated ductal lumen expansion in IBDUs from BDL rats. Phenylephrine Increases the Stimulatory Effect of Secretin on IBDU Lumen Space.…”

Section: Resultssupporting

confidence: 64%

“…These findings demonstrated a direct interaction of phenylephrine with ␣-1 adrenergic receptors on cholangiocytes and allowed us to exclude that the potentiation of secretinstimulated choleresis observed in vivo was a consequence of a systemic vascular effect of phenylephrine. 31 We focused on the mechanisms involved in the potentiation of secretin-stimulated ductal secretion by phenylephrine. Similar to what is shown in other cells, 40 the activation of cholangiocyte ␣-1 adrenergic receptors by phenylephrine increased [Ca 2ϩ ] i and IP 3 levels.…”

Section: Discussionmentioning

confidence: 99%

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α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca²⁺- and PKC-dependent stimulation of cAMP

et al. 2004

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Acetylcholine potentiates secretin-stimulated ductal secretion by Ca 2؉ -calcineurin-mediated modulation of adenylyl cyclase. D2 dopaminergic receptor agonists inhibit secretin-stimulated ductal secretion via activation of protein kinase C (PKC)-␥. No information exists regarding the effect of adrenergic receptor agonists on ductal secretion in a model of cholestasis induced by bile duct ligation (BDL). We evaluated the expression of ␣-1A/1C, -1␤ and ␤-1 adrenergic receptors in liver sections and cholangiocytes from normal and BDL rats. We evaluated the effects of the ␣-1 and ␤-1 adrenergic receptor agonists (phenylephrine and dobutamine, respectively) on bile and bicarbonate secretion and cholangiocyte IP 3 and Ca 2؉ levels in normal and BDL rats. We measured the effect of phenylephrine on lumen expansion in intrahepatic bile duct units (IBDUs) and cyclic adenosine monophosphate (cAMP) levels in cholangiocytes from BDL rats in the absence or presence of BAPTA/AM and Gö6976 (a PKC-␣ inhibitor). We evaluated if the effects of phenylephrine on ductal secretion were associated with translocation of PKC isoforms leading to increased protein kinase A activity. ␣-1 and ␤-1 adrenergic receptors were present mostly in the basolateral domain of cholangiocytes and, following BDL, their expression increased. Phenylephrine, but not dobutamine, increased secretin-stimulated choleresis in BDL rats. Phenylephrine did not alter basal but increased secretin-stimulated IBDU lumen expansion and cAMP levels, which were blocked by BAPTA/AM and Gö6976. S ecretin stimulates ductal HCO 3Ϫ secretion 1-5 by interacting with receptors expressed only by rat cholangiocytes. 6 This interaction induces an increase in intracellular cyclic adenosine 3Ј,5Ј-monophosphate (cAMP) levels, 4,5,7 which leads to the opening of cystic fibrosis transmembrane conductance regulator channels, 8 followed by activation of the apically located Cl Ϫ /HCO 3 Ϫ exchanger 9 with secretion of HCO 3 Ϫ into bile. 1 Acetylcholine increases intracellular Ca 2ϩ ([Ca 2ϩ ] i ) levels and oscillations in rat cholangiocytes due to influx of extracellular Ca 2ϩ and mobilization of thapsigarginsensitive [Ca 2ϩ ] i stores. 10 It also increases secretin-stimulated ductal HCO 3 Ϫ secretion via Ca 2ϩ -calcineurin mediated modulation of adenylyl cyclase. 9 The D2 dopaminergic receptor agonist quinelorane inhibits secretinstimulated ductal secretion via activation of the Ca 2ϩ -dependent protein kinase C (PKC)-␥. 11 Adrenergic nerve stimulation causes a decrease in bile flow in the isolated perfused rat liver via interaction with ␣-1 adrenergic receptors. 12 In isolated perfused rat liver, adrenaline induces

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Section: Resultssupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca²⁺- and PKC-dependent stimulation of cAMP

et al. 2004

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“…Prostaglandin F (PGF) 2a analogs with antiglaucoma effects increase optic-nerve-head blood flow in rabbits and monkeys [30], and NO induces ciliary artery smooth muscle cell relaxation [9]. To determine whether the mechanism of vascular relaxation in response to Y-27632 and Y-39983 was related to PGF 2a or NO metabolism, we first examined whether endothelial-derived vasodilators such as prostacyclin and NO were involved.…”

Section: Discussionmentioning

confidence: 99%

“…However, the underlying pharmacological mechanism is unclear. We therefore investigated the underlying mechanism of these drugs on vascular smooth muscles [6][7][8][9][10][11][12]. We examined whether these drugs relaxed the ciliary arteries by different mechanisms, such as nitric oxide (NO) release and inhibition of voltage-dependent or -independent calcium entry.…”

Section: Introductionmentioning

confidence: 99%

Effects of Rho-associated protein kinase inhibitors Y-27632 and Y-39983 on isolated rabbit ciliary arteries

2011

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“…5(A), (B), (C)). 39,40) Nipradilol has also been shown to dilate canine retinal artery and arteriole, 41) and substantially increase uveoscleral out‰ow. 42) The topical application of nipradilol suppresses the endothelin-1-induced contraction of the retinal artery, 43) and lowers intraocular pressure in ocular hypertensive rabbits.…”

Section: Central Muscarinic Cardiotonic Actions Of Aconitinementioning

confidence: 99%

Medical Benefits of Using Natural Compounds and Their Derivatives Having Multiple Pharmacological Actions

Kimura

2006

YAKUGAKU ZASSHI

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The multiple pharmacological actions of a unique compound are a prerequisite for classifying drugs as highly e‹cacious, because the multiple pharmacological actions oŠer the possibility of treating various symptoms of chronic diseases as described below. 1) Sustained hyperglycemia induces macrovascular and microvascular complications in type 2 diabetes mellitus. Antihyperglycemic medication and the control of postprandial hyperglycemia are essentially important for normalizing plasma glucose level. Gymnemic acid IV isolated from Gymnema sylvestre (Asclepiadaceae) leaves has antisweet, antihyperglycemic, glucose uptake inhibitory, and gut glycosidase inhibitory eŠects. Most of these pharmacological eŠects may synergistically contribute to alleviating type 2 diabetes-related symptoms. 2) Diabetic skeletal and vascular smooth muscles are hypersensitive to chemical transmitters, cytokines and autacoids. The sensitivity of neuromuscular synapses is enhanced in diabetes, which seems to be closely associated with neuropathy as one of the diabetic complications. b-Eudesmol found in Atractylodes lancea rhizome has a desensitizing channel blocking action to nicotinic acetylcholine receptors, anti-angiogenic action in vascular endothelium, and neuronal diŠerentiation actions. These multiple pharmacological actions are favorable for treating angiogenic diseases possibly including the complications of diabetes, namely, retinopathy and nephropathy, and cancer. 3) Nipradilol is clinically utilized as a topical antiglaucoma drug. The ocular hypotensive eŠects of this compound are brought about by its a 1 -and b-adrenergic receptor blocking actions, and nitric oxide (NO) releasing action. NO directly activates cyclooxygenases. All these pharmacologic eŠects are beneˆcial for treating glaucoma. The selectivity and speciˆcity of drug action are required for treating acute diseases, infections or for acting as useful reagents. The pleiotropic actions of natural compounds and their derivatives serve as important clues for developing new drugs for various chronic diseases.

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Vasodilatory Effects of Nipradilol, an α- and β-adrenergic Blocker with Nitric Oxide Releasing Action, in Rabbit Ciliary Artery

Cited by 11 publications

References 19 publications

α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca²⁺- and PKC-dependent stimulation of cAMP

α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca²⁺- and PKC-dependent stimulation of cAMP

Effects of Rho-associated protein kinase inhibitors Y-27632 and Y-39983 on isolated rabbit ciliary arteries

Medical Benefits of Using Natural Compounds and Their Derivatives Having Multiple Pharmacological Actions

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Vasodilatory Effects of Nipradilol, an α- and β-adrenergic Blocker with Nitric Oxide Releasing Action, in Rabbit Ciliary Artery

Cited by 11 publications

References 19 publications

α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca2+- and PKC-dependent stimulation of cAMP

α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca2+- and PKC-dependent stimulation of cAMP

Effects of Rho-associated protein kinase inhibitors Y-27632 and Y-39983 on isolated rabbit ciliary arteries

Medical Benefits of Using Natural Compounds and Their Derivatives Having Multiple Pharmacological Actions

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Product

Resources

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α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca²⁺- and PKC-dependent stimulation of cAMP

α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca²⁺- and PKC-dependent stimulation of cAMP