Effects of the antihypertensive agent, cicletanine, on noradrenaline release and vasoconstriction in perfused mesenteric artery of SHR

Nasa, Yoshihisa; Yoshida, Hiroyuki; Urata, Maki; Uchibayashi, Kumiko; Tsunoda, Y; Kamigata, Keiko; Takeo, Satoshi

doi:10.1038/sj.bjp.0701622

Cited by 4 publications

(2 citation statements)

References 27 publications

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“…The mesenteric arterial beds were prepared to measure the perfusion pressure (Nasa et al, 1998). The superior mesenteric artery of diethyl ether-anesthetized mice was dissected and a stainless steel cannula (27-gauge syringe) was inserted.…”

Section: Methodsmentioning

confidence: 99%

Two α₁-Adrenergic Receptor Subtypes Regulating the Vasopressor Response Have Differential Roles in Blood Pressure Regulation

Hosoda

Koshimizu²,

Tanoue³

et al. 2004

Mol Pharmacol

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To study the functional role of individual ␣ 1 -adrenergic (AR) subtypes in blood pressure (BP) regulation, we used mice lacking the ␣ 1B -AR and/or ␣ 1D -AR with the same genetic background and further studied their hemodynamic and vasoconstrictive responses. Both the ␣ 1D -AR knockout and ␣ 1B -/ ␣ 1D -AR double knockout mice, but not the ␣ 1B -AR knockout mice, had significantly (p Ͻ 0.05) lower levels of basal systolic and mean arterial BP than wild-type mice in nonanesthetized condition, and they showed no significant change in heart rate or in cardiac function, as assessed by echocardiogram. All mutants showed a significantly (p Ͻ 0.05) reduced catecholamine-induced pressor and vasoconstriction responses. It is noteworthy that the infusion of norepinephrine did not elicit any pressor response at all in ␣ 1B -/␣ 1D -AR double knockout mice. In an attempt to further examine ␣ 1 -AR subtype, which is involved in the genesis or maintenance of hypertension, BP after salt loading was monitored by tail-cuff readings and confirmed at the endpoint by direct intra-arterial recording. After salt loading, ␣ 1B -AR knockout mice developed a comparable level of hypertension to wild-type mice, whereas mice lacking ␣ 1D -AR had significantly (p Ͻ 0.05) attenuated BP and lower levels of circulating catecholamines. Our data indicated that ␣ 1B -and ␣ 1D -AR subtypes participate cooperatively in BP regulation; however, the deletion of the functional ␣ 1D -AR, not ␣ 1B -AR, leads to an antihypertensive effect. The study shows differential contributions of ␣ 1B -and ␣ 1D -ARs in BP regulation.Catecholamines released from sympathetic nerve terminals cause vascular smooth muscle contraction primarily by activating ␣ 1 -adrenergic receptors (␣ 1 -ARs) in arteries (Hoffman, 2001). Thus, blockade of ␣ 1 -AR leads to a fall in peripheral vascular resistance. Because of their consistent effect in lowering systemic blood pressure (BP), ␣ 1 -AR blockers have been widely used as an antihypertensive drug. However, a large clinical trial unexpectedly disclosed that doxazosin, a nonselective ␣ 1 -AR antagonist, was associated with an increased incidence of heart failure (ALLHAT Collaborative Research Group, 2000). This raised a serious concern about the long-term use of ␣ 1 -AR antagonists in the treatment of hypertension (HT) (ALLHAT Collaborative Research Group, 2000). On the other hand, clinical efficacy of a subtypeselective inhibition of ␣ 1 -AR has not been fully determined.This work was supported in part by research grants from the Scientific Fund of the Ministry of Education, Science, and Culture of Japan, the Japan Health Science Foundation and Ministry of Human Health and Welfare.C.H. and T.K. contributed equally to this work. Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.104.007500. ABBREVIATIONS: ␣

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Section: Methodsmentioning

confidence: 99%

Two α₁-Adrenergic Receptor Subtypes Regulating the Vasopressor Response Have Differential Roles in Blood Pressure Regulation

Hosoda

Koshimizu²,

Tanoue³

et al. 2004

Mol Pharmacol

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“…The perfused mesenteric arterial bed was prepared according to the methods described previously (30). The superior mesenteric artery of diethylether-anesthetized mice (12-18 weeks old) was dissected, and a stainless-steel cannula (27G syringe) was inserted.…”

Section: Introductionmentioning

confidence: 99%

The α1D-adrenergic receptor directly regulates arterial blood pressure via vasoconstriction

Tanoue¹,

Nasa²,

Koshimizu³

et al. 2002

J. Clin. Invest.

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To investigate the physiological role of the α1D-adrenergic receptor (α1D-AR) subtype, we created mice lacking the α1D-AR (α1D–/–) by gene targeting and characterized their cardiovascular function. In α1D–/– mice, the RT-PCR did not detect any transcript of the α1D-AR in any tissue examined, and there was no apparent upregulation of other α1-AR subtypes. Radioligand binding studies showed that α1-AR binding capacity in the aorta was lost, while that in the heart was unaltered in α1D–/– mice. Non-anesthetized α1D–/– mice maintained significantly lower basal systolic and mean arterial blood pressure conditions, relative to wild-type mice, and they showed no significant change in heart rate or in cardiac function, as assessed by echocardiogram. Besides hypotension, the pressor responses to phenylephrine and norepinephrine were decreased by 30–40% in α1D–/– mice. Furthermore, the contractile response of the aorta and the pressor response of isolated perfused mesenteric arterial beds to α1-AR stimulation were markedly reduced in α1D–/– mice. We conclude that the α1D-AR participates directly in sympathetic regulation of systemic blood pressure by vasoconstriction

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Fine Tuning of Sympathetic Transmitter Release via Ionotropic and Metabotropic Presynaptic Receptors

Boehm

Kubista

2002

Pharmacological Reviews

197

154

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The release of transmitters at sympathoeffector junctions is not constant, but subject to modulation by a plethora of different mechanisms. In this respect, presynaptic receptors located on the sympathetic axon terminals are of utmost importance, because they are activated by exogenous agonists and by endogenous neurotransmitters. In the latter case, the transmitters that activate the presynaptic receptors of a nerve terminal may be released either from the very same nerve ending or from a different axon terminal, and the receptors involved are auto- and heteroreceptors, respectively. In terms of their structural and functional features, receptors of sympathetic axon terminals can be categorized as either ionotropic (transmitter-gated ion channels) or metabotropic (most commonly G protein-coupled) receptors. This review summarizes results on more than 30 different metabotropic and four different ionotropic receptors that have been found to control the amount of transmitter being released from sympathetic neurons. Each of these receptors may not only stimulate, facilitate, and reduce sympathetic transmitter release, respectively, but also interact with the functions of other receptors present on the same axonal varicosity. This provides a multitude of mechanisms that regulate the amount of sympathetic transmitter output. Accordingly, a sophisticated cross-talk within and between extra- and intracellular signals is integrated at axon terminals to adapt the strength of sympathoeffector transmission to a given situation. This will not only determine the function of the sympathetic nervous system in health and disease, but also therapeutic and untoward effects of drugs that bind to the presynaptic receptors in sympathetically innervated tissues.

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Effects of the antihypertensive agent, cicletanine, on noradrenaline release and vasoconstriction in perfused mesenteric artery of SHR

Cited by 4 publications

References 27 publications

Two α₁-Adrenergic Receptor Subtypes Regulating the Vasopressor Response Have Differential Roles in Blood Pressure Regulation

Two α₁-Adrenergic Receptor Subtypes Regulating the Vasopressor Response Have Differential Roles in Blood Pressure Regulation

The α1D-adrenergic receptor directly regulates arterial blood pressure via vasoconstriction

Fine Tuning of Sympathetic Transmitter Release via Ionotropic and Metabotropic Presynaptic Receptors

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Effects of the antihypertensive agent, cicletanine, on noradrenaline release and vasoconstriction in perfused mesenteric artery of SHR

Cited by 4 publications

References 27 publications

Two α1-Adrenergic Receptor Subtypes Regulating the Vasopressor Response Have Differential Roles in Blood Pressure Regulation

Two α1-Adrenergic Receptor Subtypes Regulating the Vasopressor Response Have Differential Roles in Blood Pressure Regulation

The α1D-adrenergic receptor directly regulates arterial blood pressure via vasoconstriction

Fine Tuning of Sympathetic Transmitter Release via Ionotropic and Metabotropic Presynaptic Receptors

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Product

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Two α₁-Adrenergic Receptor Subtypes Regulating the Vasopressor Response Have Differential Roles in Blood Pressure Regulation

Two α₁-Adrenergic Receptor Subtypes Regulating the Vasopressor Response Have Differential Roles in Blood Pressure Regulation