Pulmonary arterial hypertension (PAH) in neonates is characterized by progressive pulmonary vasoconstriction and vascular remodeling. An elevated intracellular Ca2+ ([Ca2+]i) appears to be involved, but the mechanisms that disrupt Ca2+ handling by the pulmonary vascular smooth muscle cells are poorly understood. Several reports have implicated Ca2+ influx through L-type Ca 2+ (CaL) channels in the pathogenesis of PAH. For example, the progression of PAH can be blunted by calcium channel blocking drugs in some pediatric patients. The development of PAH also has been linked to an increased production of the potent vasoconstrictor substance, thromboxane (TxA2), and elevated urinary levels of TxA2 have been reported.
Based on these findings, we hypothesized that TxA2 upregulates CaL channels in small pulmonary arteries of neonatal piglets during the development of PAH. Using an established piglet model of hypoxia-induced PAH, we observed an increased nifedipine-sensitive tone in the pulmonary circulation of piglets exposed to 21 days of chronic hypoxia (CH) compared to similar animals exposed to normoxia (N). Western blots revealed a profound upregulation of the pore-forming α1C subunit of the CaL channel in pulmonary arteries of CH piglets.
Next, we investigated if furegrelate, a thromboxane synthase inhibitor, blunted the development of PAH. Newborn piglets were exposed to 21 days of N, CH, or CH plus furegrelate (3 mg/kg, p.o., TID). In CH piglets treated with furegrelate, PVRI was significantly lower compared to untreated CH piglets. Furegrelate also blunted the CH-induced CaL channel upregulation and increased muscular thickness in small pulmonary arteries. These findings suggested that pharmacological inhibition of TxA2 synthase attenuated the development of PAH.
In a final set of experiments, adult mice exposed to CH for 3 weeks developed PAH that was associated with an upregulation of CaL channels in the pulmonary circulation. Thus, this defect appears to be shared between different ages and species of animals.
Collectively, our findings establish a rational basis for using calcium channel blockers as prophylactic therapy in patients at risk for PAH. Furthermore, we propose that furegrelate may be an effective therapeutic strategy to prevent the development of CH-induced PAH in neonates.
|Advisor:||Rusch, Nancy J.|
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 71/01, Dissertation Abstracts International|
|Keywords:||Calcium channels, Hypertension, Pulmonary arterial hypertension, Thromboxane, Voltage-dependent calcium channels|
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