Evidence That Rho-Kinase Activity Contributes to Cerebral Vascular Tone In Vivo and Is Enhanced During Chronic Hypertension

Chrissobolis, Sophocles; Sobey, Christopher G.

doi:10.1161/hh0801.090441

Cited by 112 publications

(106 citation statements)

References 39 publications

Supporting

Mentioning

100

Contrasting

Unclassified

Order By: Relevance

“…12 This RhoA signaling pathway, through activation of Rho-kinase leading to inhibition of myosin phosphatase resulting in an increase in myosin light chain (MLC) phosphorylation and force in smooth muscle, has been recognized to play a significant role in several vascular disorders. 29,30 The involvement of Rho-kinase in hypertension was first indicated by Uehata et al 15 in rat models of hypertension. In vivo administration of Y-27632, a specific inhibitor of Rho-kinase, preferentially lowered hypertension in these animal Hypertension and erectile dysfunction N Wilkes et al models.…”

Section: Discussionmentioning

confidence: 98%

“…In vivo administration of Y-27632, a specific inhibitor of Rho-kinase, preferentially lowered hypertension in these animal Hypertension and erectile dysfunction N Wilkes et al models. 15,30 In addition to the findings of these animal studies, the involvement of Rho-kinase in the pathogenesis of human hypertension has also been recently established. Intra-arterial infusion of fasudil in hypertensive patients decreased the peripheral vascular resistance in these patients.…”

Section: Discussionmentioning

confidence: 99%

“…As hypertension is known to be associated with alterations in the NO-cGMP pathway [7][8][9] as well as the Rho-kinase pathway, 15,30 we extended our studies to examine whether a combination of PDE5 inhibition, which would prevent cGMP degradation, and Rho-kinase antagonism, which would reduce the penile smooth muscle tone, could result in a synergistic improvement of erectile response in SHR species. Our results showed a significant potentiation of EFS-induced erectile response following Rho-kinase and PDE5 inhibition.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Phosphodiesterase-5 inhibition synergizes rho-kinase antagonism and enhances erectile response in male hypertensive rats

et al. 2004

View full text Add to dashboard Cite

To evaluate the association between hypertension, male erectile function, Rho-kinase, and cyclic GMP pathways, we monitored neurogenic erectile response in spontaneously hypertensive (SHR) vs normotensive rats. We also evaluated SHR erectile function before and after intracavernosal injection of either the specific Rho-kinase inhibitor Y-27632 or a combination of Y-27632 and the PDE5 inhibitor zaprinast to prevent cGMP degradation. SHR had lower resting baseline corpus cavernosum pressure and a higher threshold for development of tumescence than normotensive rats. In SHR, Y-27632 administration reversed hypertension-related changes in male erectile function; Rho-kinase antagonism and PDE5 inhibition in combination had a synergistic effect in improving the neurogenic erectile response. Our data indicate that hypertension is associated with impairment in the SHR neurogenic erectile response that may involve a derangement in hemodynamic mechanisms in penile erectile tissue. Rho-kinase inhibition alone or combined with PDE5 inhibition may be of value in treating hypertension-related ED.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Phosphodiesterase-5 inhibition synergizes rho-kinase antagonism and enhances erectile response in male hypertensive rats

et al. 2004

View full text Add to dashboard Cite

show abstract

“…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%

Hypertension and RhoA/Rho-Kinase Signaling in the Vasculature

2004

View full text Add to dashboard Cite

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...

show abstract

“…1 Overactivation of this pathway has been suggested to participate to the pathogenesis of hypertension in several experimental models [2][3][4][5] and in humans. 6 RhoA acts as a molecular switch that cycles between an inactive GDPbound form and an active GTP-bound form.…”

mentioning

confidence: 99%

Angiotensin II Activates the RhoA Exchange Factor Arhgef1 in Humans

et al. 2015

View full text Add to dashboard Cite

Although a causative role for RhoA-Rho kinase has been recognized in the development of human hypertension, the molecular mechanism(s) and the RhoA guanine exchange factor(s) responsible for the overactivation of RhoA remain unknown. Arhgef1 was identified as a RhoA guanine exchange factor involved in angiotensin II (Ang II)–mediated regulation of vascular tone and hypertension in mice. The aim of this study was to determine whether Arhgef1 is activated and involved in the activation of RhoA-Rho kinase signaling by Ang II in humans. In vitro stimulation of human coronary artery smooth muscle cells and human peripheral blood mononuclear cells by Ang II (0.1 μmol/L) induced activation of Arhgef1 attested by its increased tyrosine phosphorylation. Silencing of Arhgef1 expression by siRNA inhibited Ang II–induced activation of RhoA-Rho kinase signaling. In normotensive subjects, activation of the renin–angiotensin system by a low-salt diet for 7 days increased RhoA-Rho kinase signaling and stimulated Arhgef1 activity in peripheral blood mononuclear cells. In conclusion, our results strongly suggest that Arhgef1 mediates Ang II–induced RhoA activation in humans. Moreover, they show that measurement of RhoA guanine exchange factor activity in peripheral blood mononuclear cells might be a useful method to evaluate RhoA guanine exchange factor activity in humans.

show abstract

Evidence That Rho-Kinase Activity Contributes to Cerebral Vascular Tone In Vivo and Is Enhanced During Chronic Hypertension

Cited by 112 publications

References 39 publications

Phosphodiesterase-5 inhibition synergizes rho-kinase antagonism and enhances erectile response in male hypertensive rats

Phosphodiesterase-5 inhibition synergizes rho-kinase antagonism and enhances erectile response in male hypertensive rats

Hypertension and RhoA/Rho-Kinase Signaling in the Vasculature

Angiotensin II Activates the RhoA Exchange Factor Arhgef1 in Humans

Contact Info

Product

Resources

About