Journal
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
Volume 33, Issue 11, Pages 1066-1072Publisher
WILEY
DOI: 10.1111/j.1440-1681.2006.04488.x
Keywords
endothelin receptor antagonists; endothelin-1; hypoxia; pulmonary hypertension; reactive oxygen species
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The Aim Of The Present Study Was To Test The Efficacy Of The Novel Endothelin (Et) Receptor Antagonist Cpu0507 In Treating Rat Hypoxic Pulmonary Hypertension (Ph) In Vivo And In Vitro And To Explore The Role Of The Et-1 System In The Disease. Male Sprague-dawley Rats (220 +/- 20 G) Were Divided Into Four Groups: (I) Control; (Ii) Untreated Hypoxic (28 Days Hypoxia); (Iii) Hypoxic Rats Treated In The Last 5 Days Of Hypoxia With Nifedipine(5 Mg/kg Per Day, P.o.); And (Iv) Hypoxic Rats Treated In The Last 5 Days Of Hypoxia With Cpu0507 (20 Mg/kg Per Day, S.c.). Effects Of Treatments On Haemodynamics And Biochemical Data, As Well As Functional Assessments Of The Isolated Pulmonary Artery, Were Determined In Vivo And In Vitro. It Was Found That Cpu0507 Reduced The Elevated Pulmonary Arterial Pressure And Right Heart Weight Index And Restored Abnormalities In Nitric Oxide (No), Malondialdehyde And No Synthase (Nos) In The Serum And Superoxide Dismutase, Hydroxyproline And Nos In Pulmonary Homogenates. In Addition, Cpu0507 Restored Altered Pulmonary Vasoconstrictor And Vasodilator Responses. Vascular Constriction And Dilatation Of Untreated Pulmonary Arteries Were Reverted Effectively Towards Normal Following Exposure Of Artery Rings To Cpu0507 In Vitro. In Conclusion, The Results Indicate That Hypoxic Ph Is Relieved Significantly By Cpu0507 In Vivo And In Vitro And The Effects Are Presumed To Be Mediated By Suppression Of The Et-reactive Oxygen Species Axis.
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