Rho-Kinase (ROCK) Inhibitor Prevents Chronic Hypoxic Pulmonary Hypertension (PHT) but Augments Somatic Growth Restriction in the Neonatal Rat.

2009 ◽  
Author(s):  
AJ Ziino ◽  
C Kantores ◽  
J Ivanovska ◽  
EZ Xu ◽  
AK Tanswell ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Rho Kinase ◽  
Somatic Growth ◽  
Growth Restriction ◽  
Neonatal Rat ◽  
Rock Inhibitor ◽  
Hypoxic Pulmonary Hypertension

Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide

2008 ◽  
Vol 294 (2) ◽  
pp. L205-L213 ◽  
Author(s):  
Patrick J. McNamara ◽  
Prashanth Murthy ◽  
Crystal Kantores ◽  
Lilian Teixeira ◽  
Doreen Engelberts ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Kinase Inhibitors ◽  
Pulmonary Arteries ◽  
Rho Kinase ◽  
Neonatal Rat ◽  
Rock Inhibitor ◽  
No Donor ◽  
Rat Models ◽  
Pulmonary Hemodynamic

Pulmonary hypertension (PHT) in neonates is often refractory to the current best therapy, inhaled nitric oxide (NO). The utility of a new class of pulmonary vasodilators, Rho-kinase (ROCK) inhibitors, has not been examined in neonatal animals. Our objective was to examine the activity and expression of RhoA/ROCK in normal and injured pulmonary arteries and to determine the short-term pulmonary hemodynamic (assessed by pulse wave Doppler) effects of ROCK inhibitors (15 mg/kg ip Y-27632 or 30 mg/kg ip fasudil) in two neonatal rat models of chronic PHT with pulmonary vascular remodeling (chronic hypoxia, 0.13 FiO2, or 1 mg·kg−1·day−1 ip chronic bleomycin for 14 days from birth). Activity of the RhoA/ROCK pathway and ROCK expression were increased in hypoxia- and bleomycin-induced PHT. In both models, severe PHT [characterized by raised pulmonary vascular resistance (PVR) and impaired right ventricular (RV) performance] did not respond acutely to inhaled NO (20 ppm for 15 min) or to a single bolus of a NO donor, 3-morpholinosydnonimine hydrochloride (SIN-1; 2 μg/kg ip). In contrast, a single intraperitoneal bolus of either ROCK inhibitor (Y-27632 or fasudil) completely normalized PVR but had no acute effect on RV performance. ROCK-mediated vasoconstriction appears to play a key role in chronic PHT in our two neonatal rat models. Inhibitors of ROCK have potential as a testable therapy in neonates with PHT that is refractory to NO.

scholarly journals Endothelin-1–Rho kinase interactions impair lung structure and cause pulmonary hypertension after bleomycin exposure in neonatal rat pups

2016 ◽  
Vol 311 (6) ◽  
pp. L1090-L1100 ◽  
Author(s):  
Jason Gien ◽  
Nancy Tseng ◽  
Gregory Seedorf ◽  
Katherine Kuhn ◽  
Steven H. Abman
Keyword(s):  
Pulmonary Hypertension ◽  
Cell Function ◽  
Normal Values ◽  
Rho Kinase ◽  
Vessel Density ◽  
Neonatal Rat ◽  
Neonatal Rats ◽  
Rock Inhibitor ◽  
Endothelial Cell Function ◽  
Rock Activity

Bronchopulmonary dysplasia (BPD) is the chronic lung disease associated with premature birth, characterized by impaired vascular and alveolar growth. In neonatal rats bleomycin decreases lung growth and causes pulmonary hypertension (PH), which is poorly responsive to nitric oxide. In the developing lung, through Rho kinase (ROCK) activation, ET-1 impairs endothelial cell function; however, whether ET-1–ROCK interactions contribute to impaired vascular and alveolar growth in experimental BPD is unknown. Neonatal rats were treated daily with intraperitoneal bleomycin with and without selective ETA (BQ123/BQ610) and ETB (BQ788) receptor blockers, nonselective ET receptor blocker (ETRB) (bosentan), or fasudil (ROCK inhibitor). At day 14, lungs were harvested for morphometrics, and measurements of Fulton's index (RV/LV+S), medial wall thickness (MWT), and vessel density. Lung ET-1 protein and ROCK activity (phospho-MYPT-1:total MYPT-1 ratio) were also measured by Western blot analysis. Bleomycin increased lung ET-1 protein expression by 65%, RV/LV+S by 60%, mean linear intercept (MLI) by 212%, and MWT by 140% and decreased radial alveolar count (RAC) and vessel density by 40 and 44%, respectively ( P < 0.01 for each comparison). After bleomycin treatment, fasudil and bosentan partially restored RAC and vessel density and decreased MLI, RV/LV+S, and MWT to normal values. Bleomycin increased ROCK activity by 120%, which was restored to normal values by bosentan but not selective ETRB. We conclude that ET-1–ROCK interactions contribute to decreased alveolar and vascular growth and PH in experimental BPD. We speculate that nonselective ETRB and ROCK inhibitors may be effective in the treatment of infants with BPD and PH.

Somatic growth and the risks of bronchopulmonary dysplasia and pulmonary hypertension: connecting epidemiology and physiology

2019 ◽  
Vol 97 (3) ◽  
pp. 197-205 ◽  
Author(s):  
Mark A. Underwood ◽  
Stephen Wedgwood ◽  
Satyan Lakshminrusimha ◽  
Robin H. Steinhorn
Keyword(s):  
Pulmonary Hypertension ◽  
Bronchopulmonary Dysplasia ◽  
Somatic Growth ◽  
Postnatal Growth ◽  
Pulmonary Complications ◽  
Growth Restriction ◽  
Extreme Prematurity ◽  
Poor Growth ◽  
Increased Risk ◽  
Poor Nutrition

In the premature infant, poor growth in utero (fetal growth restriction) and in the first weeks of life (postnatal growth restriction) are associated with increased risk for bronchopulmonary dysplasia and pulmonary hypertension. In this review, we summarize the epidemiologic data supporting these associations, present a novel rodent model of postnatal growth restriction, and review 5 promising mechanisms by which poor nutrition may affect the developing lung. These observations support the hypothesis that nutritional and (or) pharmacologic interventions early in life may be able to decrease risk of the pulmonary complications of extreme prematurity.

Rho/Rho-kinase Signaling in Hypoxic Pulmonary Hypertension

2006 ◽  
pp. 419-435
Author(s):  
Ivan F. McMurtry ◽  
Natalie R. Bauer ◽  
Sarah A. Gebb ◽  
Karen A. Fagan ◽  
Tetsutaro Nagaoka ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Rho Kinase ◽  
Kinase Signaling ◽  
Hypoxic Pulmonary Hypertension

Regression of chronic hypoxic pulmonary hypertension by simvastatin

2007 ◽  
Vol 292 (5) ◽  
pp. L1105-L1110 ◽  
Author(s):  
Reda E. Girgis ◽  
Shehzin Mozammel ◽  
Hunter C. Champion ◽  
Dechun Li ◽  
Xinqi Peng ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arteries ◽  
Rho Kinase ◽  
Left Ventricular ◽  
Right Ventricular Free Wall ◽  
Hmg Coa Reductase ◽  
Simvastatin Treatment ◽  
Hypoxic Pulmonary Hypertension ◽  
Coa Reductase ◽  
Rock Activity

The 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor, simvastatin, has been shown to attenuate chronic hypoxic pulmonary hypertension (CHPH). Here, we assess whether simvastatin is capable of inducing regression of established CHPH and explore potential mechanisms of statin effect. Rats ( n = 8 in each group) were exposed to chronic hypoxia (10% FiO2) for 2 or 4 wk. Simvastatin treatment (20 mg·kg−1·day−1) commenced after 2 wk of hypoxia, at which time CHPH was fully established, reduced mean pulmonary artery pressure (19 ± 0.5 vs. 27 ± 0.9 mmHg; P < 0.001), the ratio of right ventricular free wall to left ventricular plus septal weight (0.41 ± 0.03 vs. 0.54 ± 0.03; P < 0.001), and medial thickening of small pulmonary arteries (13 ± 0.4 vs. 16 ± 0.4%; P < 0.01) compared with 4-wk hypoxic controls. Supplementation with mevalonate (50 mg·kg−1·day−1) prevented the attenuation of CHPH induced by simvastatin during 2 wk of hypoxia. Because statins are known to inhibit Rho-kinase (ROCK), we determined expression of ROCK-1 and -2 in whole lung by Western blot and ROCK activity by phosphorylation of the myosin-binding subunit of myosin phosphatase. Expression of both ROCK-1 and -2 were markedly diminished in simvastatin-treated animals during normoxia and hypoxia (2- and 4-wk) exposure ( P < 0.01). ROCK activity was increased threefold under hypoxic conditions and normalized with simvastatin treatment ( P < 0.001). We conclude that simvastatin attenuates and induces regression of established CHPH through inhibition of HMG-CoA reductase. Inhibition of ROCK expression and activity may be an important mechanism of statin effect.

scholarly journals Rescue treatment with a Rho-kinase inhibitor normalizes right ventricular function and reverses remodeling in juvenile rats with chronic pulmonary hypertension

2010 ◽  
Vol 299 (6) ◽  
pp. H1854-H1864 ◽  
Author(s):  
Emily Z. Xu ◽  
Crystal Kantores ◽  
Julijana Ivanovska ◽  
Doreen Engelberts ◽  
Brian P. Kavanagh ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Right Ventricular ◽  
Systolic Function ◽  
Rho Kinase ◽  
Rock Inhibitor ◽  
Rescue Treatment ◽  
Right Ventricular Systolic Function ◽  
Chronic Pulmonary Hypertension ◽  
Pulmonary Arterial

Chronic pulmonary hypertension in infancy and childhood is characterized by a fixed and progressive increase in pulmonary arterial pressure and resistance, pulmonary arterial remodeling, and right ventricular hypertrophy and systolic dysfunction. These abnormalities are replicated in neonatal rats chronically exposed to hypoxia from birth in which increased activity of Rho-kinase (ROCK) is critical to injury, as evidenced by preventive effects of ROCK inhibitors. Our objective in the present study was to examine the reversing effects of a late or rescue approach to treatment with a ROCK inhibitor on the pulmonary and cardiac manifestations of established chronic hypoxic pulmonary hypertension. Rat pups were exposed to air or hypoxia (13% O2) from postnatal day 1 and were treated with Y-27632 (15 mg/kg) or saline vehicle by twice daily subcutaneous injection commencing on day 14, for up to 7 days. Treatment with Y-27632 significantly attenuated right ventricular hypertrophy, reversed arterial wall remodeling, and completely normalized right ventricular systolic function in hypoxia-exposed animals. Reversal of arterial wall remodeling was accompanied by increased apoptosis and attenuated content of endothelin (ET)-1 and ETA receptors. Treatment of primary cultured juvenile rat pulmonary artery smooth muscle cells with Y-27632 attenuated serum-stimulated ROCK activity and proliferation and increased apoptosis. Smooth muscle apoptosis was also induced by short interfering RNA-mediated knockdown of ROCK-II, but not of ROCK-I. We conclude that sustained rescue treatment with a ROCK inhibitor reversed both the hemodynamic and structural abnormalities of chronic hypoxic pulmonary hypertension in juvenile rats and normalized right ventricular systolic function. Attenuated expression and activity of ET-1 and its A-type receptor on pulmonary arterial smooth muscle was a likely contributor to the stimulatory effects of ROCK inhibition on apoptosis. In addition, our data suggest that ROCK-II may be dominant in enhancing survival of pulmonary arterial smooth muscle.

scholarly journals Postnatal growth restriction augments oxygen-induced pulmonary hypertension in a neonatal rat model of bronchopulmonary dysplasia

2016 ◽  
Vol 80 (6) ◽  
pp. 894-902 ◽  
Author(s):  
Stephen Wedgwood ◽  
Cris Warford ◽  
Sharleen C. Agvateesiri ◽  
Phung Thai ◽  
Sara K. Berkelhamer ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Bronchopulmonary Dysplasia ◽  
Rat Model ◽  
Postnatal Growth ◽  
Growth Restriction ◽  
Neonatal Rat ◽  
Neonatal Rat Model

Sustained therapeutic hypercapnia attenuates pulmonary arterial Rho-kinase activity and ameliorates chronic hypoxic pulmonary hypertension in juvenile rats

2012 ◽  
Vol 302 (12) ◽  
pp. H2599-H2611 ◽  
Author(s):  
Gary Peng ◽  
Julijana Ivanovska ◽  
Crystal Kantores ◽  
Todd Van Vliet ◽  
Doreen Engelberts ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Right Ventricular ◽  
Rho Kinase ◽  
Juvenile Rats ◽  
Hypoxic Pulmonary Hypertension ◽  
Rescue Treatment ◽  
Pulmonary Arterial ◽  
Rock Activity

Sustained therapeutic hypercapnia prevents pulmonary hypertension in experimental animals, but its rescue effects on established disease have not been studied. Therapies that inhibit Rho-kinase (ROCK) and/or augment nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling can reverse or prevent progression of chronic pulmonary hypertension. Our objective in the present study was to determine whether sustained rescue treatment with inhaled CO2 (therapeutic hypercapnia) would improve structural and functional changes of chronic hypoxic pulmonary hypertension. Spontaneously breathing pups were exposed to normoxia (21% O2) or hypoxia (13% O2) from postnatal days 1–21 with or without 7% CO2 (PaCO2 elevated by ∼25 mmHg) or 10% CO2 (PaCO2 elevated by ∼40 mmHg) from days 14 to 21. Compared with hypoxia alone, animals exposed to hypoxia and 10% CO2 had significantly ( P < 0.05) decreased pulmonary vascular resistance, right-ventricular systolic pressure, right-ventricular hypertrophy, and medial wall thickness of pulmonary resistance arteries as well as decreased lung phosphodiesterase (PDE) V, RhoA, and ROCK activity. Rescue treatment with 10% CO2, or treatment with a ROCK inhibitor (15 mg/kg ip Y-27632 twice daily from days 14 to 21), also increased pulmonary arterial endothelial nitric oxide synthase and lung NO content. In contrast, cGMP content and cGMP-dependent protein kinase (PKG) activity were increased by exposure to 10% CO2, but not by ROCK inhibition with Y-27632. In vitro exposure of pulmonary artery smooth muscle cells to hypercapnia suppressed serum-induced ROCK activity, which was prevented by inhibition of PKG with Rp-8-Br-PET-cGMPS. We conclude that sustained hypercapnia dose-dependently inhibited ROCK activity, augmented NO-cGMP-PKG signaling, and led to partial improvements in the hemodynamic and structural abnormalities of chronic hypoxic PHT in juvenile rats. Increased PKG content and activity appears to play a major upstream role in CO2-induced suppression of ROCK activity in pulmonary arterial smooth muscle.

scholarly journals Advanced therapeutic inhalation aerosols of a Nrf2 activator and RhoA/Rho kinase (ROCK) inhibitor for targeted pulmonary drug delivery in pulmonary hypertension: design, characterization, aerosolization, in vitro 2D/3D human lung cell cultures, and in vivo efficacy

2021 ◽  
Vol 15 ◽  
pp. 175346662199824
Author(s):  
Maria F. Acosta ◽  
Priya Muralidharan ◽  
Carissa L. Grijalva ◽  
Michael D. Abrahamson ◽  
Don Hayes ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Engineering Design ◽  
Rho Kinase ◽  
Residual Water ◽  
Particle Engineering ◽  
Rock Inhibitor ◽  
Molecular Fingerprint ◽  
Nrf2 Activator

Inhalable nanostructured microparticles of simvastatin, a Nrf2 activator and RhoA/Rho kinase (ROCK) inhibitor, were rationally designed for targeted pulmonary delivery as dry powder inhalers (DPIs) for the treatment of pulmonary hypertension (PH). Advanced particle engineering design technology was employed to develop inhalable dry powders using different dilute feed concentrations and spray drying pump rates. Several analytical techniques were used comprehensively to characterize the physicochemical properties of the resulting powders. Scanning electron microscopy (SEM) was used to visualize particle morphology (shape), surface structure, size, and size distribution. Karl Fischer titration (KFT) was employed to quantify the residual water content in the powders. X-ray powder diffraction (XRPD) was used to determine crystallinity. Hot-stage microscopy (HSM) under cross-polarizing lens was used to observe the presence or absence of birefringence characteristic of crystallinity. Differential scanning calorimetry (DSC) was employed to quantify thermotropic phase behavior. Attenuated total reflectance (ATR)-Fourier-transform infrared (FTIR) spectroscopy and Raman spectroscopy were used to determine the molecular fingerprint of simvastatin powders before and after particle engineering design. In vitro aerosol dispersion performance was performed with three different Food and Drug Administration (FDA)-approved human DPI devices. Cell viability and transepithelial electrical resistance (TEER) were demonstrated using different in vitro human pulmonary cell two and three-dimensional models at the air–liquid interface, and in vivo safety in healthy rats by inhalation. Efficacy was demonstrated in the in vivo lamb model of PH. Four different inhalable powders of simvastatin were successfully produced. They possessed nanostructured surfaces and were in the inhalable size range. Simvastatin retained its crystallinity following particle engineering design. The more dilute feed concentration spray dried at the lower pump rate produced the smallest particles. All powders successfully aerosolized with all three DPI human devices. Inhaled simvastatin as an aerosol restored the endothelial function in the shunt lamb model of PH, as demonstrated by the reduction of pulmonary vascular resistance (PVR) in response to the endothelium-dependent vasodilator acetylcholine. The reviews of this paper are available via the supplemental material section.

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