Cpu0507, An Endothelin Receptor Antagonist, Improves Rat Hypoxic Pulmonary Artery Hypertension And Constriction In Vivo And In Vitro

Abstract

1. 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. 2. 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. 3. 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. 4. 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.

A Critical Role for the Protein Apoptosis Repressor With Caspase Recruitment Domain in Hypoxia-Induced Pulmonary Hypertension

“…We, therefore, investigated whether ARC plays a role in the response of PASMCs to endothelin-1 and serotonin (5-HT), growth factors closely linked to pulmonary hypertension (11,12,16). Endothelin-1 elicited robust incorporation of 3 H-thymidine (DNA synthesis) in mock- and Ad.Neg-transduced cells (Figure 3A), but only a very modest increase in Ad.545-transduced cells.…”

“…Hypoxia also induces endothelin-1 and 5-hydoxytryptamine (serotonin) release, which respectively increase PASMC proliferation and hypertrophy (11–14). Inhibition of each of these pathways attenuates the development of pulmonary hypertension (15,16). …”

Effect of the Endothelin Receptor Antagonist Cpu0213, and Its Modulation by Rifampin, on Cardiac and Vascular Tissue Following Chronic Isoproterenol Treatment

“…This results in increased vascular tone and reduced vascular dilator activity with mild spasm of the vasculature implicated in the progression to cardiac insufficiency. Endothelial damage is at the centre of vascular abnormality, 7,13,18 which correlates with a decline in both NO bioavailability and the vasodilator response to ACh. In contract, the vasodilator response to SNP was unchanged in the present study.…”

“…Thoracic aortic rings (3 mm) were suspended in a tissue bath containing 3 mL Krebs’ solution (pH 7.4) as described previously 13 and a cumulative concentration–response curve for phenylephrine (PEl 10 −9 to 10 −5 mol/L) was constructed. After PE had been washed out and ring tension had returned to baseline, tissues were incubated with N G ‐nitro‐ l ‐arginine ( l ‐NNA; 10 −4 mol/L) for 10 min and a cumulative concentration–response curve again constructed for PE.…”

Hypoxie-induzierte Freisetzung reaktiver Sauerstoffspezies (ROS) in isoliert perfundierten und ventilierten Mauslungen

“…Die erste Phase wird gemeinhin als Akutantwort auf die hypoxische Ventilation angesehen und ist prinzipiell unabhängig vom Endothel (Jin et al, 1992 (Schumacker, 2003;Weissmann et al, 2006d). Die zweite Phase der akuten Antwort tritt bei verlängerter Hypoxie auf, ist abhängig vom Endothel (Jin et al, 1992;Yuan et al, 2006;Yuan et al, 1990) und durch einen langsamen Anstieg des pulmonalarteriellen Druckes charakterisiert. Verantwortlich für die Steigerung des PAP sind insbesondere die Mitochondrien, bei denen anhaltende Hypoxie möglicherweise zu einem Leck in der Elektronentransportkette führt, woraufhin wiederum ROS freigesetzt werden (Schumacker, 2003;Schumacker, 2002, 2006;Weissmann et al, 2006d).…”