FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2154373485> ?p ?o ?g. }

• W2154373485 endingPage "375" @default.
• W2154373485 startingPage "369" @default.
• W2154373485 abstract "A major limitation in the pharmacological treatment of pulmonary arterial hypertension (PAH) is the lack of pulmonary vascular selectivity. Recent studies have identified a tissue-penetrating homing peptide, CARSKNKDC (CAR), which specifically homes to hypertensive pulmonary arteries but not to normal pulmonary vessels or other tissues. Some tissue-penetrating vascular homing peptides have a unique ability to facilitate transport of co-administered drugs into the targeted cells/tissues without requiring physical conjugation of the drug to the peptide (bystander effect). We tested the hypothesis that co-administered CAR would selectively enhance the pulmonary vascular effects of i.v. vasodilators in Sugen5416/hypoxia/normoxia-exposed PAH rats. Systemically administered CAR was predominantly detected in cells of remodeled pulmonary arteries. Intravenously co-administered CAR enhanced pulmonary, but not systemic, effects of the vasodilators, fasudil and imatinib, in PAH rats. CAR increased lung tissue imatinib concentration in isolated PAH lungs without increasing pulmonary vascular permeability. Sublingual CAR was also effective in selectively enhancing the pulmonary vasodilation by imatinib and sildenafil. Our results suggest a new paradigm in the treatment of PAH, using an i.v./sublingual tissue-penetrating homing peptide to selectively augment pulmonary vascular effects of nonselective drugs without the potentially problematic conjugation process. CAR may be particularly useful as an add-on therapy to selectively enhance the pulmonary vascular efficacy of any ongoing drug treatment in patients with PAH. A major limitation in the pharmacological treatment of pulmonary arterial hypertension (PAH) is the lack of pulmonary vascular selectivity. Recent studies have identified a tissue-penetrating homing peptide, CARSKNKDC (CAR), which specifically homes to hypertensive pulmonary arteries but not to normal pulmonary vessels or other tissues. Some tissue-penetrating vascular homing peptides have a unique ability to facilitate transport of co-administered drugs into the targeted cells/tissues without requiring physical conjugation of the drug to the peptide (bystander effect). We tested the hypothesis that co-administered CAR would selectively enhance the pulmonary vascular effects of i.v. vasodilators in Sugen5416/hypoxia/normoxia-exposed PAH rats. Systemically administered CAR was predominantly detected in cells of remodeled pulmonary arteries. Intravenously co-administered CAR enhanced pulmonary, but not systemic, effects of the vasodilators, fasudil and imatinib, in PAH rats. CAR increased lung tissue imatinib concentration in isolated PAH lungs without increasing pulmonary vascular permeability. Sublingual CAR was also effective in selectively enhancing the pulmonary vasodilation by imatinib and sildenafil. Our results suggest a new paradigm in the treatment of PAH, using an i.v./sublingual tissue-penetrating homing peptide to selectively augment pulmonary vascular effects of nonselective drugs without the potentially problematic conjugation process. CAR may be particularly useful as an add-on therapy to selectively enhance the pulmonary vascular efficacy of any ongoing drug treatment in patients with PAH. Pulmonary arterial hypertension (PAH) remains a highly fatal syndrome, despite recent advancements in its treatment.1Galie N. Manes A. Negro L. Palazzini M. Bacchi-Reggiani M.L. Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension.Eur Heart J. 2009; 30: 394-403Crossref PubMed Scopus (549) Google Scholar, 2McLaughlin V.V. Archer S.L. Badesch D.B. Barst R.J. Farber H.W. Lindner J.R. Mathier M.A. McGoon M.D. Park M.H. Rosenson R.S. Rubin L.J. Tapson V.F. Varga J. Harrington R.A. Anderson J.L. Bates E.R. Bridges C.R. Eisenberg M.J. Ferrari V.A. Grines C.L. Hlatky M.A. Jacobs A.K. Kaul S. Lichtenberg R.C. Lindner J.R. Moliterno D.J. Mukherjee D. Pohost G.M. Rosenson R.S. Schofield R.S. Shubrooks S.J. Stein J.H. Tracy C.M. Weitz H.H. Wesley D.J. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology foundation task force on expert consensus documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association.Circulation. 2009; 119: 2250-2294Crossref PubMed Scopus (898) Google Scholar New candidate drugs, such as Rho kinase inhibitors3Abe K. Shimokawa H. Morikawa K. Uwatoku T. Oi K. Matsumoto Y. Hattori T. Nakashima Y. Kaibuchi K. Sueishi K. Takeshit A. Long-term treatment with a rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats.Circ Res. 2004; 94: 385-393Crossref PubMed Scopus (352) Google Scholar, 4Nagaoka T. Morio Y. Casanova N. Bauer N. Gebb S. McMurtry I. Oka M. Rho/rho kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats.Am J Physiol Lung Cell Mol Physiol. 2004; 287: L665-L672Crossref PubMed Scopus (201) Google Scholar, 5Oka M. Homma N. Taraseviciene-Stewart L. Morris K.G. Kraskauskas D. Burns N. Voelkel N.F. McMurtry I.F. Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats.Circ Res. 2007; 100: 923-929Crossref PubMed Scopus (288) Google Scholar, 6Parikh V.N. Jin R.C. Rabello S. Gulbahce N. White K. Hale A. Cottrill K.A. Shaik R.S. Waxman A.B. Zhang Y.Y. Maron B.A. Hartner J.C. Fujiwara Y. Orkin S.H. Haley K.J. Barabasi A.L. Loscalzo J. Chan S.Y. Microrna-21 integrates pathogenic signaling to control pulmonary hypertension: results of a network bioinformatics approach.Circulation. 2012; 125: 1520-1532Crossref PubMed Scopus (224) Google Scholar and tyrosine kinase inhibitors,7Abe K. Toba M. Alzoubi A. Koubsky K. Ito M. Ota H. Gairhe S. Gerthoffer W.T. Fagan K.A. McMurtry I.F. Oka M. Tyrosine kinase inhibitors are potent acute pulmonary vasodilators in rats.Am J Respir Cell Mol Biol. 2011; 45: 804-808Crossref PubMed Scopus (57) Google Scholar, 8Schermuly R.T. Dony E. Ghofrani H.A. Pullamsetti S. Savai R. Roth M. Sydykov A. Lai Y.J. Weissmann N. Seeger W. Grimminger F. Reversal of experimental pulmonary hypertension by PDGF inhibition.J Clin Invest. 2005; 115: 2811-2821Crossref PubMed Scopus (880) Google Scholar have shown promise in providing improved treatment for PAH. However, the clinical application of these agents has generally been hampered by their systemic toxicity/adverse effects.9Bussemaker E. Pistrosch F. Forster S. Herbrig K. Gross P. Passauer J. Brandes R.P. Rho kinase contributes to basal vascular tone in humans: role of endothelium-derived nitric oxide.Am J Physiol Heart Circ Physiol. 2007; 293: H541-H547Crossref PubMed Scopus (35) Google Scholar, 10Casey D.B. Badejo A.M. Dhaliwal J.S. Sikora J.L. Fokin A. Golwala N.H. Greco A.J. Murthy S.N. Nossaman B.D. Hyman A.L. Kadowitz P.J. Analysis of responses to the rho-kinase inhibitory-27632 in the pulmonary and systemic vascular bed of the rat.Am J Physiol Heart Circ Physiol. 2010; 299: H184-H192Crossref PubMed Scopus (37) Google Scholar, 11Kerkela R. Grazette L. Yacobi R. Iliescu C. Patten R. Beahm C. Walters B. Shevtsov S. Pesant S. Clubb F.J. Rosenzweig A. Salomon R.N. Van Etten R.A. Alroy J. Durand J.B. Force T. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate.Nat Med. 2006; 12: 908-916Crossref PubMed Scopus (979) Google Scholar, 12Murthy S.N. Nossaman B.D. Kadowitz P.J. New approaches to the treatment of pulmonary hypertension: from bench to bedside.Cardiol Rev. 2010; 18: 76-84Crossref PubMed Scopus (12) Google Scholar Inhalation is a relatively selective drug delivery method for the lungs,13Nagaoka T. Fagan K.A. Gebb S.A. Morris K.G. Suzuki T. Shimokawa H. McMurtry I.F. Oka M. Inhaled rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension.Am J Respir Crit Care Med. 2005; 171: 494-499Crossref PubMed Scopus (221) Google Scholar but there are several problems with the clinical use of aerosol inhalation in the treatment of PAH.14Melani A.S. Inhalatory therapy training: a priority challenge for the physician.Acta Biomed. 2007; 78: 233-245PubMed Google Scholar In fact, insufficient inhalation due to technical problems may be a major limitation for the effectiveness of inhaled Rho kinase inhibitor, fasudil, in patients with PAH.15Fujita H. Fukumoto Y. Saji K. Sugimura K. Demachi J. Nawata J. Shimokawa H. Acute vasodilator effects of inhaled fasudil, a specific rho-kinase inhibitor, in patients with pulmonary arterial hypertension.Heart Vessels. 2010; 25: 144-149Crossref PubMed Scopus (145) Google Scholar In numerous diseases, the blood vessels in the affected organ express disease-specific cell surface markers (vascular zip codes).16Ruoslahti E. Vascular zip codes in angiogenesis and metastasis.Biochem Soc Trans. 2004; 32: 397-402Crossref PubMed Scopus (129) Google Scholar For example, tumor blood vessels express distinctive markers not present in vessels of normal tissues.16Ruoslahti E. Vascular zip codes in angiogenesis and metastasis.Biochem Soc Trans. 2004; 32: 397-402Crossref PubMed Scopus (129) Google Scholar These target organ–specific molecular structures are detectable by systemically administered homing peptides,16Ruoslahti E. Vascular zip codes in angiogenesis and metastasis.Biochem Soc Trans. 2004; 32: 397-402Crossref PubMed Scopus (129) Google Scholar, 17Ruoslahti E. Peptides as targeting elements and tissue penetration devices for nanoparticles.Adv Mater. 2012; 24: 3747-3756Crossref PubMed Scopus (339) Google Scholar which find their way to the desired location by binding to their receptor expressed in the blood vessels of the target organ. Promising results are accumulating for the use of homing peptides to deliver drugs selectively to tumors.16Ruoslahti E. Vascular zip codes in angiogenesis and metastasis.Biochem Soc Trans. 2004; 32: 397-402Crossref PubMed Scopus (129) Google Scholar, 17Ruoslahti E. Peptides as targeting elements and tissue penetration devices for nanoparticles.Adv Mater. 2012; 24: 3747-3756Crossref PubMed Scopus (339) Google Scholar, 18Sugahara K.N. Teesalu T. Karmali P.P. Kotamraju V.R. Agemy L. Girard O.M. Hanahan D. Mattrey R.F. Ruoslahti E. Tissue-penetrating delivery of compounds and nanoparticles into tumors.Cancer Cell. 2009; 16: 510-520Abstract Full Text Full Text PDF PubMed Scopus (891) Google Scholar This potentially useful targeting technology has not yet been applied to the treatment of PAH, although vascular selectivity would be desired in PAH. We have recently reported tumor-homing peptides that specifically bind to tumor vessels and then extravasate into the tumor tissue, carrying a payload with them.18Sugahara K.N. Teesalu T. Karmali P.P. Kotamraju V.R. Agemy L. Girard O.M. Hanahan D. Mattrey R.F. Ruoslahti E. Tissue-penetrating delivery of compounds and nanoparticles into tumors.Cancer Cell. 2009; 16: 510-520Abstract Full Text Full Text PDF PubMed Scopus (891) Google Scholar, 19Teesalu T. Sugahara K.N. Kotamraju V.R. Ruoslahti E. C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration.Proc Natl Acad Sci U S A. 2009; 106: 16157-16162Crossref PubMed Scopus (618) Google Scholar Even more important, a tumor-penetrating peptide can transport co-administered drugs into the target tissue without chemically coupling the compound with the peptide (bystander effect).20Sugahara K.N. Teesalu T. Karmali P.P. Kotamraju V.R. Agemy L. Greenwald D.R. Ruoslahti E. Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs.Science. 2010; 328: 1031-1035Crossref PubMed Scopus (859) Google Scholar This novel mechanism involves homing peptide–induced activation of an endocytic trans-tissue transport pathway, named CendR-pathway, in the target tissue of the peptide.18Sugahara K.N. Teesalu T. Karmali P.P. Kotamraju V.R. Agemy L. Girard O.M. Hanahan D. Mattrey R.F. Ruoslahti E. Tissue-penetrating delivery of compounds and nanoparticles into tumors.Cancer Cell. 2009; 16: 510-520Abstract Full Text Full Text PDF PubMed Scopus (891) Google Scholar, 19Teesalu T. Sugahara K.N. Kotamraju V.R. Ruoslahti E. C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration.Proc Natl Acad Sci U S A. 2009; 106: 16157-16162Crossref PubMed Scopus (618) Google Scholar, 20Sugahara K.N. Teesalu T. Karmali P.P. Kotamraju V.R. Agemy L. Greenwald D.R. Ruoslahti E. Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs.Science. 2010; 328: 1031-1035Crossref PubMed Scopus (859) Google Scholar The bystander effect provides the advantage of promoting delivery of a drug to its target tissue without the coupling of the drug to the peptide required in conventional drug targeting.20Sugahara K.N. Teesalu T. Karmali P.P. Kotamraju V.R. Agemy L. Greenwald D.R. Ruoslahti E. Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs.Science. 2010; 328: 1031-1035Crossref PubMed Scopus (859) Google Scholar CARSKNKDC (CAR) is a vascular homing peptide originally identified as being capable of homing to the neovasculature in injured, regenerating tissues.21Järvinen T.A.H. Ruoslahti E. Molecular changes in the vasculature of injured tissues.Am J Pathol. 2007; 171: 702-711Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar CAR requires heparan sulfate on the target cells for cell binding and uptake into cells,21Järvinen T.A.H. Ruoslahti E. Molecular changes in the vasculature of injured tissues.Am J Pathol. 2007; 171: 702-711Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar suggesting that this peptide may recognize a unique sulfation pattern of heparan sulfate proteoglycans on the target cells. When CAR is fused together with the anti-fibrotic protein, decorin, as a recombinant fusion protein, it accumulates in the wound and penetrates deep into wound granulation tissue.22Järvinen T.A.H. Ruoslahti E. Target-seeking antifibrotic compound enhances wound healing and suppresses scar formation in mice.Proc Natl Acad Sci U S A. 2010; 107: 21671-21676Crossref PubMed Scopus (82) Google Scholar, 23Järvinen T.A.H. Ruoslahti E. Targeted antiscarring therapy for tissue injuries.Adv Wound Care. 2013; 2: 50-54Crossref Google Scholar More recently, we have shown that CAR also selectively accumulates in the walls of hypertensive pulmonary arteries in monocrotaline- and Sugen5416/hypoxia/normoxia-induced (SU/Hx/Nx) PAH rats, but not in normotensive pulmonary arteries.24Urakami T. Jarvinen T.A. Toba M. Sawada J. Ambalavanan N. Mann D. McMurtry I. Oka M. Ruoslahti E. Komatsu M. Peptide-directed highly selective targeting of pulmonary arterial hypertension.Am J Pathol. 2011; 178: 2489-2495Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar This study also showed that CAR penetrates beyond the vascular endothelium; it accumulates in the entire wall of hypertensive pulmonary arteries and in the surrounding lung parenchyma.24Urakami T. Jarvinen T.A. Toba M. Sawada J. Ambalavanan N. Mann D. McMurtry I. Oka M. Ruoslahti E. Komatsu M. Peptide-directed highly selective targeting of pulmonary arterial hypertension.Am J Pathol. 2011; 178: 2489-2495Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar The tissue-penetrating activity of CAR prompted us to examine whether CAR might also induce a bystander effect, and if it could be used to selectively transport co-administered drugs to CAR’s homing destination (ie, PAH tissue). We have tested the effect of CAR co-administration on three vasodilators: i) the Rho kinase inhibitor, fasudil; ii) the tyrosine kinase inhibitor, imatinib; and iii) the phosphodiesterase type 5 inhibitor, sildenafil. They were tested on blood pressure in PAH rats. We have also determined whether i.v. administration of CAR could be replaced by sublingual dosing. All experimental procedures were approved by the Institutional Animal Care and Use Committee of the University of South Alabama (Mobile). PAH was experimentally induced in adult male Sprague-Dawley rats (weighing 204 ± 31 and 323 ± 30 g at the time of Sugen5416 injection and the hemodynamic experiments, respectively; n = 49) by s.c. injection of Sugen5416 (20 mg/kg; Cayman, Ann Arbor, MI) and exposure to hypoxia (10% O2) for 3 weeks. The rats were then returned to normoxia (21% O2) for an additional 2 weeks (5 weeks after the SU injection; SU/Hx/Nx PAH rats).5Oka M. Homma N. Taraseviciene-Stewart L. Morris K.G. Kraskauskas D. Burns N. Voelkel N.F. McMurtry I.F. Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats.Circ Res. 2007; 100: 923-929Crossref PubMed Scopus (288) Google Scholar All rats were placed on controlled heating pads after they were anesthetized with i.p. 30 mg/kg pentobarbital sodium. Hemodynamic measurements were performed under normoxic conditions, as previously described, with minor modifications.25Abe K. Toba M. Alzoubi A. Ito M. Fagan K.A. Cool C.D. Voelkel N.F. McMurtry I.F. Oka M. Formation of plexiform lesions in experimental severe pulmonary arterial hypertension.Circulation. 2010; 121: 2747-2754Crossref PubMed Scopus (389) Google Scholar Briefly, polyvinyl catheters (internal diameter, 0.28 mm) were inserted into the right ventricle (RV) via the right jugular vein for measurement of RV systolic pressure (RVSP). RVSP, instead of pulmonary arterial pressure, was measured, because the pulmonary artery cannot be routinely catheterized in these severely pulmonary hypertensive rats that have an altered structure of the RV chamber. In cases when we have successfully catheterized the artery, we confirmed that there was no difference between RVSP and systolic pulmonary arterial pressure (data not shown). A microtipped P-V catheter (1.4 Fr; Millar Instruments, Houston, TX) was inserted into the right carotid artery to measure systolic systemic arterial pressure (SAP). In some cases, the catheter was advanced into the left ventricle to measure cardiac output, which was derived from a pressure-volume curve. The cardiac index (CI) was calculated by dividing cardiac output by body weight. The signals were continuously recorded by an MPVS-300 system with PowerLab/4SP, A/D converter (AD Instruments, Colorado Springs, CO), and a personal computer. An additional polyvinyl catheter was inserted into the left jugular vein for the injection of drugs. Two hours after i.v. injection of 3 mg/kg fluorescein-labeled CAR in SU/Hx/Nx rats, lungs were inflated with formalin-agarose mixture at a constant pressure of 20 cm H2O before the fixation. Immunohistochemical (IHC) staining was performed using rabbit anti-fluorescein isothiocyanate antibody (Invitrogen, Carpenteria, CA), followed by labeled polymer–horseradish peroxidase anti-rabbit IgG secondary antibody (Dako Envison+System-HRP), as described previously.24Urakami T. Jarvinen T.A. Toba M. Sawada J. Ambalavanan N. Mann D. McMurtry I. Oka M. Ruoslahti E. Komatsu M. Peptide-directed highly selective targeting of pulmonary arterial hypertension.Am J Pathol. 2011; 178: 2489-2495Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar The techniques of lung isolation, ventilation, and constant-flow perfusion with physiological salt solution (Earle’s balanced salt solution; Sigma, St. Louis, MO) have been described previously.5Oka M. Homma N. Taraseviciene-Stewart L. Morris K.G. Kraskauskas D. Burns N. Voelkel N.F. McMurtry I.F. Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats.Circ Res. 2007; 100: 923-929Crossref PubMed Scopus (288) Google Scholar After the blood was flushed out of the lungs with 20 mL of physiological salt solution, the lungs were perfused with a recirculated volume of 30 mL. The filtration coefficient (Kf) was measured under zone 3 conditions, as previously described.26Alvarez D.F. King J.A. Weber D. Addison E. Liedtke W. Townsley M.I. Transient receptor potential vanilloid 4-mediated disruption of the alveolar septal barrier: a novel mechanism of acute lung injury.Circ Res. 2006; 99: 988-995Crossref PubMed Scopus (241) Google Scholar Kf was calculated as the rate of weight gain 13 to 15 minutes after a 7 to 10 cm H2O increase in pulmonary venous pressure, normalized per gram of lung dry weight. Kf, the product of specific endothelial permeability and surface area for exchange, is a sensitive measure of lung endothelial permeability when surface area is fully recruited.26Alvarez D.F. King J.A. Weber D. Addison E. Liedtke W. Townsley M.I. Transient receptor potential vanilloid 4-mediated disruption of the alveolar septal barrier: a novel mechanism of acute lung injury.Circ Res. 2006; 99: 988-995Crossref PubMed Scopus (241) Google Scholar Lung tissue imatinib concentrations were measured by MicroConstants, Inc., (San Diego, CA) in isolated salt solution–perfused lungs from SU/Hx/Nx rats. After equilibration for 20 minutes, 3 μmol/L imatinib or 3 μmol/L imatinib and 1 mg/30 mL CAR mixture was added to the perfusate reservoir. The lungs were flushed with 30 mL of Earle’s balanced salt solution 5 minutes after the drug administration to remove any residual drugs and were then snap frozen and kept at −80°C. The lungs were homogenized by placing the tissue into 2-mL Matrix tubes from MP Biomedicals (Solon, OH) and adding PBS, pH 7.4, to the tissue, with a 3:1 ratio (v/w). The samples were processed to a smooth homogenate using a Fastprep-24 (MP Biomedicals). Homogenized tissue samples were diluted at least 10-fold using rat plasma with sodium heparin as the anticoagulant. Samples (50.0 μL) containing imatinib with imatinib-d8 as the internal standard were processed simultaneously with spiked standards in rat plasma by adjusting the pH with a 3% ammonia solution and extracted using a solvent mixture of methyl tert butyl ether/hexane (4 mL; 3:1, v/v) and vortex mixing for 5 minutes. The samples were centrifuged to separate the aqueous and organic layers and subsequently kept at −70°C until the lower aqueous layer was frozen. The organic portions were poured into new tubes containing 25.0 μL of 4% propylene glycol in isopropyl alcohol and dried in a TurboVap set at 40°C under a stream of nitrogen gas. The extracts were reconstituted with 50 mmol/L ammonium formate, 0.1% formic acid in water:0.1% formic acid in acetonitrile (400 μL; 10:90, v/v). Analysis was performed on a system composed of an Agilent 1100 high-performance liquid chromatography system coupled to a Waters Quattro Ultima mass spectrometer. The high-performance liquid chromatography system was fitted with an Allure PFP Propyl column (100 × 2.1 mm in diameter, 5 μm) maintained at 40°C. The mobile phase was 50 mmol/L ammonium formate and 0.1% formic acid in water/0.1% formic acid in acetonitrile (11:89, v/v). Imatinib and the internal standard were monitored using transitions of 494.71 > 394.47 and 503.96 > 395.28, respectively. The cone voltage was 50 V, and the collision energy was 23 eV. We examined short-term hemodynamic effects of the co-administration of CAR and fasudil or imatinib in catheterized SU/Hx/Nx PAH rats. After baseline measurements, a mixture of 3 mg/kg CAR (dose based on previous homing studies21Järvinen T.A.H. Ruoslahti E. Molecular changes in the vasculature of injured tissues.Am J Pathol. 2007; 171: 702-711Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 24Urakami T. Jarvinen T.A. Toba M. Sawada J. Ambalavanan N. Mann D. McMurtry I. Oka M. Ruoslahti E. Komatsu M. Peptide-directed highly selective targeting of pulmonary arterial hypertension.Am J Pathol. 2011; 178: 2489-2495Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar) and 0.1, 1, 3, and 10 mg/kg fasudil at 15-minute intervals or 3 mg/kg CAR and 5 and 20 mg/kg imatinib at 15-minute intervals was administered via left jugular vein, and the parameters were continuously monitored. At the end of measurements, the hearts were dissected for calculation of RV/left ventricle + septum weight ratio. We first determined an infusion rate of 10 mg/mL fasudil that caused minimal reductions in SAP and RVSP in SU/Hx/Nx rats. We then infused fasudil i.v. with and without 3 mg/mL CAR at the determined rate of 5 mL/minute using an infusion pump in SU/Hx/Nx PAH rats and monitored the parameters over 30 minutes. We examined the effects of sublingually administered CAR on imatinib- and sildenafil-induced vasodilation in SU/Hx/Nx rats. Fifteen minutes after sublingual administration of 3 mg/kg fluorescein-conjugated CAR, or the same volume of the saline vehicle, 5 and 20 mg/kg imatinib at 15-minute intervals or 3 and 30 mg/kg sildenafil at 15-minute intervals were given i.v. in anesthetized and catheterized rats. After the hemodynamic measurements, the rats were euthanized, and blood was flushed with 30 mL of PBS. Organs were fixed for subsequent IHC analysis. Pulmonary vascular permeability was estimated by measuring the Kf26Alvarez D.F. King J.A. Weber D. Addison E. Liedtke W. Townsley M.I. Transient receptor potential vanilloid 4-mediated disruption of the alveolar septal barrier: a novel mechanism of acute lung injury.Circ Res. 2006; 99: 988-995Crossref PubMed Scopus (241) Google Scholar in isolated perfused lungs from SU/Hx/Nx rats. After 20 minutes of equilibration, Kf values were measured before and 30 minutes after the addition of 1 mg/30 mL CAR mixture. Values are means ± SEM. Comparisons between groups were made with the Student’s unpaired t-test. Differences were considered significant at P < 0.05. We used the SU/Hx/Nx rat model of PAH to study the effect of CAR co-administration on the activity of vasodilators. The SU/Hx/Nx rats had a high RVSP (102 ± 3 mm Hg; n = 33) compared with control rats (24 ± 1 mm Hg; n = 8). Small pulmonary arteries and arterioles displayed severe, occlusive, neointimal lesions in association with the expression of the endothelial cell marker, von Willebrand factor, as reported previously for the PAH model.25Abe K. Toba M. Alzoubi A. Ito M. Fagan K.A. Cool C.D. Voelkel N.F. McMurtry I.F. Oka M. Formation of plexiform lesions in experimental severe pulmonary arterial hypertension.Circulation. 2010; 121: 2747-2754Crossref PubMed Scopus (389) Google Scholar, 27Taraseviciene-Stewart L. Kasahara Y. Alger L. Hirth P. Mc Mahon G. Waltenberger J. Voelkel N.F. Tuder R.M. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension.FASEB J. 2001; 15: 427-438Crossref PubMed Scopus (637) Google Scholar Consistent with a previous study,24Urakami T. Jarvinen T.A. Toba M. Sawada J. Ambalavanan N. Mann D. McMurtry I. Oka M. Ruoslahti E. Komatsu M. Peptide-directed highly selective targeting of pulmonary arterial hypertension.Am J Pathol. 2011; 178: 2489-2495Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar i.v. administered CAR was detected in remodeled pulmonary arteries of SU/Hx/Nx rats (Figure 1, H and I), but not in normal pulmonary arteries (Figure 1, A and B). CAR was distributed in all layers of the remodeled arteries. CAR produced a much lower signal, if any, in other organs (liver, spleen, and heart), except for the kidney, where the peptide is excreted (Figure 1, C–G and J–N). The intensive CAR signal in the kidney was found only in tubules, but not in other structures, such as arteries and glomeruli (Figure 1, E and L). This supports the previous studies21Järvinen T.A.H. Ruoslahti E. Molecular changes in the vasculature of injured tissues.Am J Pathol. 2007; 171: 702-711Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 24Urakami T. Jarvinen T.A. Toba M. Sawada J. Ambalavanan N. Mann D. McMurtry I. Oka M. Ruoslahti E. Komatsu M. Peptide-directed highly selective targeting of pulmonary arterial hypertension.Am J Pathol. 2011; 178: 2489-2495Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar that the presence of CAR in the kidneys is not the result of homing, but the fact that all proteins/peptides with a molecular weight of <60 kDa are excreted through the kidneys. Short-term bolus i.v. injections of fasudil alone caused marked dose-dependent reductions in both RVSP and SAP in anesthetized PAH rats (Figure 2A). Intravenously injecting 3 mg/kg CAR alone had no effects on RVSP, SAP, or CI in PAH rats (RVSP, from 99 ± 17 to 102 ± 19 mm Hg; SAP, from 160 ± 8 to 159 ± 7 mm Hg; CI, from 123 ± 39 to 129 ± 40 mL/minute per kilogram; n = 3). Co-administered CAR significantly enhanced the short-term pressure-lowering effects of fasudil on RVSP, but not on SAP (Figure 2A). Co-administered CAR with 0.1 mg/kg fasudil had no effect on CI when compared with fasudil alone (Table 1).Table 1Cardiac Index Before and After i.v. Injection of AgentsAgentBefore injectionAfter injectionCAR (n = 5)123 ± 39129 ± 40Fasudil (n = 3)116 ± 7129 ± 7CAR + fasudil (n = 3)90 ± 7103 ± 6Values are means ± SEM mL/minute per kilogram. Open table in a new tab Values are means ± SEM mL/minute per kilogram. We next studied whether CAR would potentiate the activity of vasodilators that act through a different molecular mechanism than the Rho kinase inhibition. Short-term i.v. bolus injections of imatinib alone induced a dose-dependent and pulmonary preferential reduction in blood pressure (Figure 2B), which is in agreement with our previous report,7Abe K. Toba M. Alzoubi A. Koubsky K. Ito M. Ota H. Gairhe S. Gerthoffer W.T. Fagan K.A. McMurtry I.F. Oka M. Tyrosine kinase inhibitors are potent acute pulmonary vasodilators in rats.Am J Respir Cell Mol Biol. 2011; 45: 804-808Crossref PubMed Scopus (57) Google Scholar although this effect may be limited to the hypertensive pulmonary" @default.
• W2154373485 created "2016-06-24" @default.
• W2154373485 creator A5006874258 @default.
• W2154373485 creator A5007631989 @default.
• W2154373485 creator A5011168502 @default.
• W2154373485 creator A5018076381 @default.
• W2154373485 creator A5031350381 @default.
• W2154373485 creator A5033132770 @default.
• W2154373485 creator A5050459313 @default.
• W2154373485 creator A5062073722 @default.
• W2154373485 creator A5067443922 @default.
• W2154373485 creator A5070821755 @default.
• W2154373485 creator A5072972767 @default.
• W2154373485 creator A5088477154 @default.
• W2154373485 date "2014-02-01" @default.
• W2154373485 modified "2023-09-24" @default.
• W2154373485 title "A Novel Vascular Homing Peptide Strategy to Selectively Enhance Pulmonary Drug Efficacy in Pulmonary Arterial Hypertension" @default.
• W2154373485 cites W1972718914 @default.
• W2154373485 cites W1989658253 @default.
• W2154373485 cites W1998990808 @default.
• W2154373485 cites W2011181393 @default.
• W2154373485 cites W2012675069 @default.
• W2154373485 cites W2024825549 @default.
• W2154373485 cites W2037896891 @default.
• W2154373485 cites W2051992458 @default.
• W2154373485 cites W2054564235 @default.
• W2154373485 cites W2059189153 @default.
• W2154373485 cites W2078914082 @default.
• W2154373485 cites W2082575848 @default.
• W2154373485 cites W2090878184 @default.
• W2154373485 cites W2107771085 @default.
• W2154373485 cites W2112137254 @default.
• W2154373485 cites W2123647020 @default.
• W2154373485 cites W2132314214 @default.
• W2154373485 cites W2132324778 @default.
• W2154373485 cites W2134077476 @default.
• W2154373485 cites W2137508241 @default.
• W2154373485 cites W2139954704 @default.
• W2154373485 cites W2140810761 @default.
• W2154373485 cites W2146234408 @default.
• W2154373485 cites W2147944062 @default.
• W2154373485 cites W2159516737 @default.
• W2154373485 cites W2160307430 @default.
• W2154373485 cites W2163326536 @default.
• W2154373485 cites W2165997863 @default.
• W2154373485 cites W2531609094 @default.
• W2154373485 doi "https://doi.org/10.1016/j.ajpath.2013.10.008" @default.
• W2154373485 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3906494" @default.
• W2154373485 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/24401613" @default.
• W2154373485 hasPublicationYear "2014" @default.
• W2154373485 type Work @default.
• W2154373485 sameAs 2154373485 @default.
• W2154373485 citedByCount "43" @default.
• W2154373485 countsByYear W21543734852014 @default.
• W2154373485 countsByYear W21543734852015 @default.
• W2154373485 countsByYear W21543734852016 @default.
• W2154373485 countsByYear W21543734852017 @default.
• W2154373485 countsByYear W21543734852018 @default.
• W2154373485 countsByYear W21543734852019 @default.
• W2154373485 countsByYear W21543734852020 @default.
• W2154373485 countsByYear W21543734852021 @default.
• W2154373485 countsByYear W21543734852022 @default.
• W2154373485 crossrefType "journal-article" @default.
• W2154373485 hasAuthorship W2154373485A5006874258 @default.
• W2154373485 hasAuthorship W2154373485A5007631989 @default.
• W2154373485 hasAuthorship W2154373485A5011168502 @default.
• W2154373485 hasAuthorship W2154373485A5018076381 @default.
• W2154373485 hasAuthorship W2154373485A5031350381 @default.
• W2154373485 hasAuthorship W2154373485A5033132770 @default.
• W2154373485 hasAuthorship W2154373485A5050459313 @default.
• W2154373485 hasAuthorship W2154373485A5062073722 @default.
• W2154373485 hasAuthorship W2154373485A5067443922 @default.
• W2154373485 hasAuthorship W2154373485A5070821755 @default.
• W2154373485 hasAuthorship W2154373485A5072972767 @default.
• W2154373485 hasAuthorship W2154373485A5088477154 @default.
• W2154373485 hasBestOaLocation W21543734851 @default.
• W2154373485 hasConcept C126322002 @default.
• W2154373485 hasConcept C151872237 @default.
• W2154373485 hasConcept C164705383 @default.
• W2154373485 hasConcept C18903297 @default.
• W2154373485 hasConcept C2780035454 @default.
• W2154373485 hasConcept C2780930700 @default.
• W2154373485 hasConcept C2909948108 @default.
• W2154373485 hasConcept C71924100 @default.
• W2154373485 hasConcept C86803240 @default.
• W2154373485 hasConcept C98274493 @default.
• W2154373485 hasConceptScore W2154373485C126322002 @default.
• W2154373485 hasConceptScore W2154373485C151872237 @default.
• W2154373485 hasConceptScore W2154373485C164705383 @default.
• W2154373485 hasConceptScore W2154373485C18903297 @default.
• W2154373485 hasConceptScore W2154373485C2780035454 @default.
• W2154373485 hasConceptScore W2154373485C2780930700 @default.
• W2154373485 hasConceptScore W2154373485C2909948108 @default.
• W2154373485 hasConceptScore W2154373485C71924100 @default.
• W2154373485 hasConceptScore W2154373485C86803240 @default.
• W2154373485 hasConceptScore W2154373485C98274493 @default.
• W2154373485 hasIssue "2" @default.
• W2154373485 hasLocation W21543734851 @default.

• next