Effects of amosulalol on the electrical responses of guinea‐pig vascular smooth muscle to adrenoceptor activation

Fujioka, Masahiko; Suzuki, Hiroyoshi

doi:10.1111/j.1476-5381.1985.tb12933.x

Cited by 8 publications

(3 citation statements)

References 12 publications

(36 reference statements)

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“…14,37,38 In our experiments, application of isoproterenol to isolated, pressurized SCA resulted in vasodilation and concurrent membrane hyperpolarization of cVSMCs. Pretreatment with CGP20712 significantly blunted isoproterenol-induced vasodilation and ablated membrane hyperpolarization suggesting that both effects are mediated by β1AR.…”

Section: Discussionmentioning

confidence: 95%

Beta1-Adrenergic Receptor-Mediated Dilation of Rat Cerebral Artery Requires Shaker-Type K_V1 Channels on PSD95 Scaffold

Moore

McClenahan

Hanvey

et al. 2015

J Cereb Blood Flow Metab

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Postsynaptic density-95 (PSD95) is a scaffolding protein in cerebral vascular smooth muscle cells (cVSMCs), which binds to Shaker-type K(+) (KV1) channels and facilitates channel opening through phosphorylation by protein kinase A. β1-Adrenergic receptors (β1ARs) also have a binding motif for PSD95. Functional association of β1AR with KV1 channels through PSD95 may represent a novel vasodilator complex in cerebral arteries (CA). We explored whether a β1AR-PSD95-KV1 complex is a determinant of rat CA dilation. RT-PCR and western blots revealed expression of β1AR in CA. Isoproterenol induced a concentration-dependent dilation of isolated, pressurized rat CA that was blocked by the β1AR blocker CGP20712. Cranial window imaging of middle cerebral arterioles in situ showed isoproterenol- and norepinephrine-induced dilation that was blunted by β1AR blockade. Isoproterenol-induced hyperpolarization of cVSMCs in pressurized CA was blocked by CGP20712. Confocal images of cVSMCs immunostained with antibodies against β1AR and PSD95 indicated strong colocalization, and PSD95 co-immunoprecipitated with β1AR in CA lysate. Blockade of KV1 channels, β1AR or disruption of PSD95-KV1 interaction produced similar blunting of isoproterenol-induced dilation in pressurized CA. These findings suggest that PSD95 mediates a vasodilator complex with β1AR and KV1 channels in cVSMCs. This complex may be critical for proper vasodilation in rat CA.

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Section: Discussionmentioning

confidence: 95%

Beta1-Adrenergic Receptor-Mediated Dilation of Rat Cerebral Artery Requires Shaker-Type K_V1 Channels on PSD95 Scaffold

Moore

McClenahan

Hanvey

et al. 2015

J Cereb Blood Flow Metab

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“…As in most arteries, sympathetic nerve stimulation initiates rapidly rising EJPs in the guinea-pig mesenteric artery (Fujioka & Suzuki, 1985; Kreulen, 1986; Hottenstein & Kreulen, 1987) (Fig. 1A), that are presumably mediated by released ATP (Ishikawa, 1985; Onaka et al, 1997) acting on P2X receptors (Evans & Surprenant, 1992).…”

Section: Evidence For Release Of Purine Neurotransmittersmentioning

confidence: 99%

The purinergic neurotransmitter revisited: A single substance or multiple players?

Mutafova‐Yambolieva

Durnin

2014

Pharmacology & Therapeutics

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The past half century has witnessed tremendous advances in our understanding of extracellular purinergic signaling pathways. Purinergic neurotransmission, in particular, has emerged as a key contributor in the efficient control mechanisms in the nervous system. The identity of the purine neurotransmitter, however, remains controversial. Identifying it is difficult because purines are present in all cell types, have a large variety of cell sources, and are released via numerous pathways. Moreover, studies on purinergic neurotransmission have relied heavily on indirect measurements of integrated postjunctional responses that do not provide direct information for neurotransmitter identity. This paper discusses experimental support for adenosine 5′-triphosphate (ATP) as a neurotransmitter and recent evidence for possible contribution of other purines, in addition to or instead of ATP, in chemical neurotransmission in the peripheral, enteric and central nervous systems. Sites of release and action of purines in model systems such as vas deferens, blood vessels, urinary bladder and chromaffin cells are discussed. This is preceded by a brief discussion of studies demonstrating storage of purines in synaptic vesicles. We examine recent evidence for cell type targets (e.g., smooth muscle cells, interstitial cells, neurons and glia) for purine neurotransmitters in different systems. This is followed by brief discussion of mechanisms of terminating the action of purine neurotransmitters, including extracellular nucleotide hydrolysis and possible salvage and reuptake in the cell. The significance of direct neurotransmitter release measurements is highlighted. Possibilities for involvement of multiple purines (e.g., ATP, ADP, NAD+, ADP-ribose, adenosine, and diadenosine polyphosphates) in neurotransmission are considered throughout.

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“…The activity of amosulalol as an antagonist of two subtypes of aor P-adrenoceptors was extensively studied in radioligand binding studies and compared with that of some known adrenoceptor antagonists (3,15,33,34). Extensive pharmacological studies were also performed in isolated tissue preparation (7,11,13,15,34,46, 50,53). In these studies, amosulalol displayed a greater selectivity for a Ithan for a,-adrenoceptors but showed no selectivity for P I -or P2-adrenoceptors.…”

Section: Zn Vitr5 A-and P-adrenoceptor Blocking Erectsmentioning

confidence: 99%

Amosulalol

Takenaka¹

1987

Cardiovascular Drug Reviews

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The most important hemodynamic disturbance in patients with hypertension is an increase in peripheral vascular resistance due to arteriolar constriction (8). Accordingly, the most desirable way to lower blood pressure is to decrease peripheral vascular resistance without adversely affecting cardiac function.Both aand P-adrenoceptor antagonists are effective drugs for the treatment of hypertension. Although or-adrenoceptor antagonists decrease the peripheral resistance through attenuation of the sympathetic vasoconstriction, especially at the arterioles, most of these drugs have limited use because of unacceptable reflexly mediated cardiovascular side effects. On the other hand, P-adrenoceptor antagonists are less effective as hypotensives and have a slower onset of action than cx-antagonists. They may even cause an initial increase in peripheral vascular resistance. A combination of an a-antagonist with a @-antagonist is theoretically beneficial because a-blockade eliminates peripheral vasoconstriction and P-blockade overcomes reflex cardiac acceleration and renin release. In fact, such a cbmbination has resulted in some clinical studies in good control of high blood pressure with few side effects (12,26).Based on the above considerations, the concept of combining the activities of aand P-adrenoceptor blockade in a single molecular entity is logical and should lead to an effective treatment of hypertension. Takenaka et al. (46) and Fujikara et al. (9) found that a series of arylethanolamines derived from benzenesulfonamide possessed both a-and /3-adrenoceptor blocking activities in different ratios. Amosulalol was selected from these derivatives, as it blocked or,-and p,-adrenoceptors almost to the same extent and showed beneficial antihypertensive activity in animals (46). CHEMISTRY Amosulalol hydrochloride (YM-09538) is (*)-5-[ I -hydroxy-2-[[2-(o-methoxyphenoxy)ethyl]amino]ethyl]-2-methylbenzenesulfonamide hydrochloride (Fig. 1). It was synthesized and patented by Imai and co-workers at Central Research Laboratories of Yamanouchi Pharmaceutical Co. Ltd. (19). Synthesis pathways of amosu-AMOS ULA LOL SO2 NH2 CH~-&H-CHZ -NH-CH2 -CHz -0 *HCI OCH3 OH FIG. 1. Structure of amosulalol hydrochloride (YM-09538).lalol and 14C-amosulalol and resolution of its optical isomers were reported (2,lO). Amosulalol is a white, odorless crystalline powder with a bitter taste. It has a molecular weight of 416.93 (C18H24N20SS.HC1) and a melting point of 158-162°C. The substance is soluble in methanol, sparingly soluble in water (1.5 g/ 100 ml) and in absolute ethanol, very slightly soluble in acetone, and practically insoluble in ether, chloroform, and benzene. The pKal for the secondary amine and pKa2 for amosulalol are 7.72 and 10.04, respectively. Its n-octanol-water partition coefficient at pH 7.0 is 2.70, which is lower than the values reported for propranolol or labetalol (54). ANIMAL PHARMACOLOGY Zn Vitr5 a-and P-Adrenoceptor Blocking ERectsThe activity of amosulalol as an antagonist of two subtypes of aor P-adrenoceptors wa...

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Effects of amosulalol on the electrical responses of guinea‐pig vascular smooth muscle to adrenoceptor activation

Cited by 8 publications

References 12 publications

Beta1-Adrenergic Receptor-Mediated Dilation of Rat Cerebral Artery Requires Shaker-Type K_V1 Channels on PSD95 Scaffold

Beta1-Adrenergic Receptor-Mediated Dilation of Rat Cerebral Artery Requires Shaker-Type K_V1 Channels on PSD95 Scaffold

The purinergic neurotransmitter revisited: A single substance or multiple players?

Amosulalol

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Effects of amosulalol on the electrical responses of guinea‐pig vascular smooth muscle to adrenoceptor activation

Cited by 8 publications

References 12 publications

Beta1-Adrenergic Receptor-Mediated Dilation of Rat Cerebral Artery Requires Shaker-Type KV1 Channels on PSD95 Scaffold

Beta1-Adrenergic Receptor-Mediated Dilation of Rat Cerebral Artery Requires Shaker-Type KV1 Channels on PSD95 Scaffold

The purinergic neurotransmitter revisited: A single substance or multiple players?

Amosulalol

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Product

Resources

About

Beta1-Adrenergic Receptor-Mediated Dilation of Rat Cerebral Artery Requires Shaker-Type K_V1 Channels on PSD95 Scaffold

Beta1-Adrenergic Receptor-Mediated Dilation of Rat Cerebral Artery Requires Shaker-Type K_V1 Channels on PSD95 Scaffold