Comparison of Inhibitory Effects of Y-27632, a Rho Kinase Inhibitor, in Strips of Small and Large Mesenteric Arteries from Spontaneously Hypertensive and Normotensive Wistar-Kyoto Rats.

Asano, Masahisa; Nomura, Yukiko

doi:10.1291/hypres.26.97

Cited by 52 publications

(34 citation statements)

References 32 publications

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“…The role of rho-kinase in mediating contractile responses has been studied extensively (Bolz et al, 2000;Matrougui et al, 2001;Budzyn et al, 2006;Faraci et al, 2006). However, to the best of our knowledge, only one previous study has compared how the contribution of rho-kinase to contractile responses might vary between functionally distinct arteries within a vascular bed (Asano and Nomura, 2003). We found evidence for a role of rho-kinase in contractile responses to phenylephrine in both aorta and SMA, albeit to varying degrees.…”

Section: Discussionmentioning

confidence: 74%

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Segmental Differences in the Roles of Rho-Kinase and Protein Kinase C in Mediating Vasoconstriction

Budzyn

Paull²,

Marley³

et al. 2006

J Pharmacol Exp Ther

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Rho-kinase and protein kinase C (PKC) have each been reported to mediate vasoconstriction via calcium sensitization. However, the relative contributions of these two kinases to vascular contraction, and whether their roles vary between large and small arteries, are largely unknown. We therefore assessed the relative roles of rho-kinase and PKC in mediating vasoconstriction in arteries from three segments of the aortic and mesenteric vasculature. We studied contractile responses of rat isolated thoracic aorta (diameter Ϸ2 mm), superior mesenteric artery (SMA; Ϸ1.5 mm), and second order branches of the superior mesenteric artery (BMA; Ϸ300 m). The roles of rho-kinase and PKC in mediating contractile responses to phenylephrine, 9,11-dideoxy-9,11-methanoepoxy prostaglandin F 2␣ (U46619), and KCl were assessed by using the rhokinase inhibitor R- Cotreatment with Y-27632 and Ro 31-8220 markedly attenuated contractile responses to phenylephrine and KCl in all vessels, but it had only a moderate inhibitory effect on responses to U46619 in aorta and SMA. Thus, contractile responses of the larger arteries can involve both rho-kinase and PKC to varying degrees. Conversely, contractile responses of small mesenteric resistance arteries seem to be mediated exclusively by PKC, with no apparent role for rho-kinase.

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Section: Discussionmentioning

confidence: 74%

“…Importantly, rho-kinase inhibition had no effect on contractile responses of BMA to all three contractile agents. Thus, in general, it seems that rho-kinase has a major role in mediating contractile responses of larger conductance vessels, whereas its contribution is greatly diminished in small resistance vessels (Asano and Nomura, 2003).…”

Section: Discussionmentioning

confidence: 97%

Segmental Differences in the Roles of Rho-Kinase and Protein Kinase C in Mediating Vasoconstriction

Budzyn

Paull²,

Marley³

et al. 2006

J Pharmacol Exp Ther

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“…causes relaxation in large and small vessels (Asano and Nomura, 2003). These two pathways, PI3-kinase and Rho/Rhokinase, may be interconnected and the nature of this interaction in spontaneous tone in aorta from DOCA-salt rats was the goal of the present study.…”

Section: Discussionmentioning

confidence: 97%

Rho/Rho Kinase and Phosphoinositide 3-Kinase Are Parallel Pathways in the Development of Spontaneous Arterial Tone in Deoxycorticosterone Acetate-Salt Hypertension

Wehrwein

Northcott

Loberg

et al. 2004

J Pharmacol Exp Ther

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Hypertension is characterized by abnormal vascular contractility and function. Arteries from deoxycorticosterone acetate (DOCA)-salt hypertensive rats develop spontaneous tone that is not observed in arteries from normotensive rats. Inhibition of phosphoinositide 3-kinase (PI3-kinase) by 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) reduces spontaneous tone development. The Rho/Rho-kinase pathway has been suggested to play a role in hypertension and may be dependent on PI3-kinase activity. We hypothesized that Rhokinase is involved in spontaneous tone development and that Rho/Rho-kinase is a downstream effector of PI3-kinase. Using endothelium-denuded aortic strips in isolated tissue bath, we demonstrated that (ϩ)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) (Y27632) (1 M), a Rho-kinase inhibitor, significantly reduced spontaneous tone in the DOCA aorta but that it did not affect sham aorta basal tone (DOCA 63.5 Ϯ 15.9 versus sham 1.2 Ϯ 0.4 total change in percentage of phenylephrine contraction). We examined the interaction between the PI3-kinase and Rho pathways by observing the effects of LY294002 on a Rhokinase effector, myosin phosphatase (MYPT), and Y27632 on a PI3-kinase effector, Akt, using Western blot analysis. Inhibition of PI3-kinase reduced spontaneous tone, but it had no effect on the phosphorylation status of MYPT, indicating that PI3-kinase is not a downstream effector of Rho/Rho-kinase. These data indicate that there is little interaction between the Rho/Rhokinase and PI3-kinase pathways in the DOCA-salt aorta, and the two pathways seem to operate in parallel in supporting spontaneous arterial tone. These data reflect spontaneous tone only and do not rule out the possibility of interaction between these pathways in agonist-stimulated tone.

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“…14 -24 Using Y-27632 to inhibit Rho-kinase, Uehata et al 14 as well as others [15][16][17][18][19][20][21][22][23] have demonstrated a role for Rho-kinase specific to receptormeditated contraction. Additionally, they were the first to demonstrate a role for RhoA and Rho-kinase in various animal models of hypertension.…”

Section: Increased Vasoconstriction and Rhoa/rho-kinase Signaling In mentioning

confidence: 99%

“…Asano and Nomura 16 compared the inhibitory effects of Y-27632 on contractile responses in small and large mesenteric arteries from SHR and normotensive rats. The arteries were contracted to a plateau phase with norepinephrine and subsequently treated with the Rho-kinase inhibitor.…”

Section: Increased Vasoconstriction and Rhoa/rho-kinase Signaling In mentioning

confidence: 99%

Hypertension and RhoA/Rho-Kinase Signaling in the Vasculature

2004

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Abstract-Under normal conditions, contractile activity in vascular smooth muscle is initiated by either receptor activation (norepinephrine, angiotensin II, etc.) or by a stretch-activated mechanism. After this activation, several signaling pathways can initiate a Ca 2ϩ -calmodulin interaction to stimulate phosphorylation of the light chain of myosin. Ca 2ϩ sensitization of the contractile proteins is signaled by the RhoA/Rho-kinase pathway to inhibit the dephosphorylation of the light chain by myosin phosphatase thereby maintaining force generation. In opposition to force generation, NO is released from endothelial cells and causes vasodilation through inhibition of the RhoA/Rho-kinase signaling pathway. This brief review will highlight recent studies demonstrating a role for the RhoA/Rho-kinase signaling pathway in the increased vasoconstriction characteristic of hypertension. Key Words: vasculature Ⅲ signal transduction Ⅲ muscle, smooth Ⅲ nitric oxide Ⅲ vasoconstriction I ncreased peripheral vascular resistance causes elevated arterial pressure in hypertension. Arterial wall thickening, increased vasoconstriction, and reduced vasodilation contribute to this increased peripheral resistance. Multiple regulatory processes (neural, humoral, etc.) and complex cell signaling pathways modulate vascular smooth muscle cell (VSMC) contraction, relaxation, and growth. Under normal conditions, these regulatory processes maintain vessel wall integrity and do not contribute to pathological increases in blood pressure. Remodeling of the vasculature in hypertension involves rearrangement of cellular and extracellular components and has been reviewed extensively. [1][2][3][4][5][6] The present review highlights recent developments in the understanding of cellular and molecular mechanisms underlying increased vasoconstriction in hypertension with an emphasis on the RhoA/Rhokinase signaling pathway in vascular smooth muscle. Contractile MechanismVascular smooth muscle contraction is principally regulated by receptor and mechanical (stretch) activation of the contractile proteins. 7 Depolarization of the plasma membrane can also trigger contraction. For contraction to occur, myosin light chain (MLC) kinase must phosphorylate the light chain of myosin, enabling the cycling of myosin cross-bridges with actin. 7-9 Thus, contractile activity is determined primarily by the phosphorylation state of the light chain of myosin. 8,9 In VSMCs of some blood vessels, phosphorylation of the light chain of myosin is maintained at a low level in the absence of external stimuli (ie, no receptor or mechanical activation). This activity results in what is known as myogenic tone.Recent work suggests that 20-HETE may play a signaling role in the myogenic response of pig coronary arteries. Randriamboavonjy et al 10 observed that 20-HETE elicited contraction and phosphorylation of the light chain of myosin. Both of these activities were inhibited by Y-27632, a Rhokinase inhibitor (see below for description of signaling pathway). Ca 2؉ -Dependent Con...

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Comparison of Inhibitory Effects of Y-27632, a Rho Kinase Inhibitor, in Strips of Small and Large Mesenteric Arteries from Spontaneously Hypertensive and Normotensive Wistar-Kyoto Rats.

Cited by 52 publications

References 32 publications

Segmental Differences in the Roles of Rho-Kinase and Protein Kinase C in Mediating Vasoconstriction

Segmental Differences in the Roles of Rho-Kinase and Protein Kinase C in Mediating Vasoconstriction

Rho/Rho Kinase and Phosphoinositide 3-Kinase Are Parallel Pathways in the Development of Spontaneous Arterial Tone in Deoxycorticosterone Acetate-Salt Hypertension

Hypertension and RhoA/Rho-Kinase Signaling in the Vasculature

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