7 results on '"Van Vliet, Todd"'
Search Results
2. Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide
- Author
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McNamara, Patrick J., Murthy, Prashanth, Kantores, Crystal, Teixeira, Lilian, Engelberts, Doreen, van Vliet, Todd, Kavanagh, Brian P., and Jankov, Robert P.
- Subjects
Enzyme inhibitors -- Dosage and administration ,Enzyme inhibitors -- Research ,Pulmonary hypertension -- Drug therapy ,Pulmonary hypertension -- Research ,Biological sciences - Abstract
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 [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] or 1 mg [.kg .sup.-1] [day.sup.-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 [micro]g/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. Y-27632; fasudil; two-dimensional echocardiography; pulse wave Doppler; SIN-1
- Published
- 2008
3. Newborn rat response to single vs. combined cGMP-dependent pulmonary vasodilators
- Author
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Enomoto, Masahiro, primary, Jain, Amish, additional, Pan, Jingyi, additional, Shifrin, Yulia, additional, Van Vliet, Todd, additional, McNamara, Patrick J., additional, Jankov, Robert P., additional, and Belik, Jaques, additional
- Published
- 2014
- Full Text
- View/download PDF
4. Sustained therapeutic hypercapnia attenuates pulmonary arterial Rho-kinase activity and ameliorates chronic hypoxic pulmonary hypertension in juvenile rats
- Author
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Peng, Gary, primary, Ivanovska, Julijana, additional, Kantores, Crystal, additional, Van Vliet, Todd, additional, Engelberts, Doreen, additional, Kavanagh, Brian P., additional, Enomoto, Masahiro, additional, Belik, Jaques, additional, Jain, Amish, additional, McNamara, Patrick J., additional, and Jankov, Robert P., additional
- Published
- 2012
- Full Text
- View/download PDF
5. Sustained therapeutic hypercapnia attenuates pulmonary arterial Rho-kinase activity and ameliorates chronic hypoxic pulmonary hypertension in juvenile rats.
- Author
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Gary Peng, Julijana Ivanovska, Kantores, Crystal, Van Vliet, Todd, Engelberts, Doreen, Kavanagh, Brian P., Masahiro Enomoto, Belik, Jaques, Jain, Amish, McNamara, Patrick J., and Jankov, Robert P.
- Abstract
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 CO
2 (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-PETcGMPS. 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. [ABSTRACT FROM AUTHOR]- Published
- 2012
- Full Text
- View/download PDF
6. Newborn rat response to single vs. combined cGMP-dependent pulmonary vasodilators.
- Author
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Enomoto M, Jain A, Pan J, Shifrin Y, Van Vliet T, McNamara PJ, Jankov RP, and Belik J
- Subjects
- Animals, Animals, Newborn, Chronic Disease, Female, HSP20 Heat-Shock Proteins metabolism, HSP27 Heat-Shock Proteins metabolism, Hypoxia physiopathology, Male, Muscle, Smooth, Vascular cytology, Muscle, Smooth, Vascular drug effects, Nitric Oxide metabolism, Nitric Oxide Donors pharmacology, Phosphorylation physiology, Piperazines pharmacology, Primary Cell Culture, Protein Kinase Inhibitors pharmacology, Purines pharmacology, Rats, Rats, Sprague-Dawley, Sildenafil Citrate, Sulfones pharmacology, Vasodilation drug effects, Vasodilation physiology, Cyclic GMP metabolism, Hypoxia metabolism, Muscle, Smooth, Vascular physiology, Pulmonary Circulation drug effects, Pulmonary Circulation physiology, Vasodilator Agents pharmacology
- Abstract
Inhaled nitric oxide (NO) and other cGMP- or cAMP-dependent pulmonary vasodilators are often used in combination for the treatment of the persistent pulmonary hypertension of the newborn syndrome. There is in vitro evidence to indicate that NO downregulate the pulmonary vascular response to cGMP-dependent agonists raising concern as to whether a synergistic effect is observed when employing a combined strategy in newborns. Hypothesizing that a synergistic effect is absent, we evaluated newborn and juvenile rat pulmonary arteries to determine the individual and combined vasodilatory effect of cGMP- and cAMP-dependent agonists. In precontracted near-resistance pulmonary arteries, the addition of sildenafil reduced vasorelaxation response to NO donor S-nitroso-N-acetyl penicillamine (SNAP). A similar decrease in SNAP-induced vasodilation was observed in arteries pretreated with BAY 41-2272 (10(-9) M), a soluble guanylate cyclase stimulator cGMP, and its downstream protein kinase activator. cGMP also reduced the vasorelaxant response to the cAMP-dependent forskolin. Inhibition of endogenous vascular NO generation enhanced SNAP-induced relaxation. The present data suggest that the mechanism involved in the cGMP desensitization to other relaxant agonists involves downregulation of the small heat shock protein HSP20 and is evident in rat pulmonary and systemic vascular smooth muscle cells. In newborn rats with chronic hypoxia-induced pulmonary hypertension, the combination of sildenafil and inhaled NO resulted in a lesser reduction in pulmonary vascular resistance compared with their individual effect. These data suggest that clinical exposure to one cGMP-dependent pulmonary vasodilator may affect the response to other cGMP- or cAMP-mediated agonists.
- Published
- 2014
- Full Text
- View/download PDF
7. Sustained therapeutic hypercapnia attenuates pulmonary arterial Rho-kinase activity and ameliorates chronic hypoxic pulmonary hypertension in juvenile rats.
- Author
-
Peng G, Ivanovska J, Kantores C, Van Vliet T, Engelberts D, Kavanagh BP, Enomoto M, Belik J, Jain A, McNamara PJ, and Jankov RP
- Subjects
- Animals, Carbon Dioxide administration & dosage, Cyclic GMP-Dependent Protein Kinases metabolism, Cyclic Nucleotide Phosphodiesterases, Type 5 metabolism, Hypertension, Pulmonary enzymology, Hypoxia enzymology, Lung blood supply, Lung drug effects, Lung enzymology, Muscle, Smooth, Vascular drug effects, Muscle, Smooth, Vascular metabolism, Myocytes, Smooth Muscle drug effects, Myocytes, Smooth Muscle enzymology, Nitric Oxide metabolism, Nitric Oxide Synthase Type III metabolism, Pulmonary Artery enzymology, Rats, Signal Transduction drug effects, Vasodilation drug effects, rhoA GTP-Binding Protein metabolism, Carbon Dioxide therapeutic use, Hypertension, Pulmonary drug therapy, Hypoxia drug therapy, Pulmonary Artery drug effects, rho-Associated Kinases metabolism
- Abstract
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 CO(2) (therapeutic hypercapnia) would improve structural and functional changes of chronic hypoxic pulmonary hypertension. Spontaneously breathing pups were exposed to normoxia (21% O(2)) or hypoxia (13% O(2)) from postnatal days 1-21 with or without 7% CO(2) (Pa(CO(2)) elevated by ∼25 mmHg) or 10% CO(2) (Pa(CO(2)) elevated by ∼40 mmHg) from days 14 to 21. Compared with hypoxia alone, animals exposed to hypoxia and 10% CO(2) 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% CO(2), 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% CO(2), 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 CO(2)-induced suppression of ROCK activity in pulmonary arterial smooth muscle.
- Published
- 2012
- Full Text
- View/download PDF
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