Beneficial Acute Effects of Rho-Kinase Inhibitor in Patients With Pulmonary Arterial Hypertension

Ishikura, Ken; Yamada, Norikazu; M, Ito; Ota, Satoshi; Nakamura, Mashio; Isaka, Naoki; Nakano, Takeshi

doi:10.1253/circj.70.174

Cited by 191 publications

(150 citation statements)

References 33 publications

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“…34 Antagonizing ROCK using fasudil lowers blood pressure in hypertensive patients. 35,36 Mustafa et al 9 reported that TRPM8-induced gastric fundus contraction is associated with the RhoA/ROCK pathway. Although menthol can inhibit the vasoconstriction by blocking L-type calcium channel-induced calcium influx at several vessel beds, 30 it remains to be determined whether menthol has an effect on calcium release from SR and its underlying mechanism.…”

Section: Discussionmentioning

confidence: 99%

Activation of Cold-Sensing Transient Receptor Potential Melastatin Subtype 8 Antagonizes Vasoconstriction and Hypertension Through Attenuating RhoA/Rho Kinase Pathway

et al. 2014

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Abstract-Environmental cold is a nonmodifiable hypertension risk factor. Transient receptor potential melastatin subtype 8 (TRPM8) is a cold-sensing cation channel that can be activated by menthol, a compound with a naturally cold sensation in mint. Little is known about the effect of TRPM8 activation on vascular function and blood pressure. Here, we report that TRPM8 is abundantly expressed in the vasculature. TRPM8 activation by menthol attenuated vasoconstriction via RhoA/Rho kinase pathway inhibition in wild-type mice, but the effect was absent in TRPM8 −/− mice. Chronic dietary menthol blunted mesenteric arterial constriction and lowered blood pressure in genetic hypertensive rats via inhibition of RhoA/Rho kinase expression and activity in the vivo study. TRPM8 effect was associated with inhibition of intracellular calcium release from the sarcoplasmic reticulum, RhoA/Rho kinase activity, and sustained arterial contraction in the vitro study. Importantly, 8-week chronic menthol capsule treatment moderately lowered systolic blood pressure and diastolic blood pressure in prehypertensive individuals compared with the placebo group. Furthermore, chronic menthol capsule administration also improved flowmediated dilatation in prehypertensive individuals, but not in the placebo group. In conclusion, our study demonstrates that TRPM8 activation by menthol benefits vascular function and blood pressure by inhibiting calcium signaling-mediated RhoA/ Rho kinase activation in the vasculature. These findings add to the evidence that long-term dietary menthol treatment had Materials and Methods Animal TreatmentWe obtained male spontaneously hypertensive rats (SHR) and WistarKyoto rats (WKY) from Charles Rivers Laboratories (Malvern, PA) and obtained TRPM8 −/− mice from the laboratory of Dr Patapoutian. 6To maintain an isogenic strain, heterozygous knockout mice and their wild type (WT) littermates were maintained and used for experiments, as previously described 7 (online-only Data Supplement). Cell CultureVascular smooth muscle cells (VSMCs) were obtained from the thoracic aortas of mice and cultured by the tissue explant method, as previously described 14 (online-only Data Supplement). Intracellular Calcium MeasurementsFluorescence measurements were performed at 510 nm emission, with excitation wavelengths of 340 and 380 nm (Fluoroskan Ascent Fluorometer; Thermo Helsinki, Finland; online-only Data Supplement). Blood Pressure MeasurementAnimals were implanted surgically with telemetric transmitters (Data Sciences International, MN), and 24-hour ambulatory systolic and diastolic pressures were measured by telemetry in conscious unrestrained animals 16 (online-only Data Supplement). Prehypertensive Participant CharacteristicsPrehypertensive participants aged between 45 to 65 years were included in this study. The prehypertension diagnosis was based on systolic blood pressure (SBP) of 120 to 139 mm Hg or diastolic blood pressure of 80 to 89 mm Hg (online-only Data Supplement). Flow-Mediated VasodilationFlow-mediated vasod...

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Section: Discussionmentioning

confidence: 99%

Activation of Cold-Sensing Transient Receptor Potential Melastatin Subtype 8 Antagonizes Vasoconstriction and Hypertension Through Attenuating RhoA/Rho Kinase Pathway

et al. 2014

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“…[115][116][117][118] ROCK inhibitors have been shown to decrease PA pressures and PVR both in experimental models of PH and in PAH patients. [119][120][121] The best-characterized action of ROCK is the phosphorylation of the myosin-binding subunit of myosin light chain phosphatase (MLCP), thereby inhibiting MLCP and thus increasing phosphorylation of myosin light chains, which serves to augment contraction. However, since ROCK inhibition also prevents ET-1-induced activation of NHE in normoxic settings, it is likely that the ET-1/ROCK pathway contributes to remodeling as well.…”

Section: Mechanisms Controlling Nhe1 Activity and Expression In Pasmcmentioning

confidence: 99%

Na⁺/H⁺ Exchange and Hypoxic Pulmonary Hypertension

Huetsch

Shimoda

2015

Pulm. circ.

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Intracellular pH (pH i ) homeostasis is key to the functioning of vascular smooth muscle cells, including pulmonary artery smooth muscle cells (PASMCs). Sodium-hydrogen exchange (NHE) is an important contributor to pH i control in PASMCs. In this review, we examine the role of NHE in PASMC function, in both physiologic and pathologic conditions. In particular, we focus on the contribution of NHE to the PASMC response to hypoxia, considering both acute hypoxic pulmonary vasoconstriction and the development of pulmonary vascular remodeling and pulmonary hypertension in response to chronic hypoxia. Hypoxic pulmonary hypertension remains a disease with limited therapeutic options. Thus, this review explores past efforts at disrupting NHE signaling and discusses the therapeutic potential that such efforts may have in the field of pulmonary hypertension.

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“…Likewise, Ishikura and colleagues administered fasudil via intravenous infusion to 8 adult patients with PAH, and found a decrease in PVR and mean PAP, and increased cardiac output. 228 Finally, Fukumoto and colleagues administered fasudil to 9 adult patients with PH. 229 Some patients were receiving oral or intravenous PGI 2 at the time of study.…”

Section: Novel Vasodilatorsmentioning

confidence: 99%

Advances in the Management of Pediatric Pulmonary Hypertension

2011

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Pulmonary hypertension is a rare disease in neonates, infants, and children, and is associated with substantial morbidity and mortality. An adequate understanding of the controlling pathophysiologic mechanisms is lacking. Moreover, a minority of research is focused specifically on neonatal and pediatric populations. Although therapeutic options have increased over the past several decades, they remain limited. In advanced pulmonary hypertension, progressive pulmonary vascular functional and structural changes ultimately cause increased pulmonary vascular impedance, rightventricular failure, and death. Management includes the prevention and/or treatment of active pulmonary vasoconstriction, the support of right-ventricle function, treatment of the underlying disease (if possible), and the promotion of regressive remodeling of structural pulmonary vascular changes. Most currently available therapies augment or inhibit factors, or mediators of their downstream signaling cascades, that originate in the pulmonary vascular endothelium. These pathways include nitric-oxide/cyclic guanosine monophosphate (cGMP), prostacyclin, and endothelin-1. The ability to reverse advanced structural changes remains an as yet unattained goal. This paper reviews the epidemiology, pathophysiology, current treatments, and emerging therapies related to neonatal and pediatric pulmonary hypertension.

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Beneficial Acute Effects of Rho-Kinase Inhibitor in Patients With Pulmonary Arterial Hypertension

Cited by 191 publications

References 33 publications

Activation of Cold-Sensing Transient Receptor Potential Melastatin Subtype 8 Antagonizes Vasoconstriction and Hypertension Through Attenuating RhoA/Rho Kinase Pathway

Activation of Cold-Sensing Transient Receptor Potential Melastatin Subtype 8 Antagonizes Vasoconstriction and Hypertension Through Attenuating RhoA/Rho Kinase Pathway

Na⁺/H⁺ Exchange and Hypoxic Pulmonary Hypertension

Advances in the Management of Pediatric Pulmonary Hypertension

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Beneficial Acute Effects of Rho-Kinase Inhibitor in Patients With Pulmonary Arterial Hypertension

Cited by 191 publications

References 33 publications

Activation of Cold-Sensing Transient Receptor Potential Melastatin Subtype 8 Antagonizes Vasoconstriction and Hypertension Through Attenuating RhoA/Rho Kinase Pathway

Activation of Cold-Sensing Transient Receptor Potential Melastatin Subtype 8 Antagonizes Vasoconstriction and Hypertension Through Attenuating RhoA/Rho Kinase Pathway

Na+/H+ Exchange and Hypoxic Pulmonary Hypertension

Advances in the Management of Pediatric Pulmonary Hypertension

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Na⁺/H⁺ Exchange and Hypoxic Pulmonary Hypertension