The broad long-term objectives of the proposed research are to improve our current understanding of the regulation of the pulmonary vascular bed by humoral factors, including vasoactive products in the cyclooxygenase pathway. Cyclooxygenase (COX) is the initial step in the formation of prostaglandins (PGs) and thromboxane A2 (prostanoids). The prostanoids have marked effects on the pulmonary vascular bed, and PGI2 is used in the treatment of pulmonary hypertension. It is known that there are two COX isoforms in the lung. COX-1 is believed to be a constitutive enzyme involved in physiologic regulation, whereas COX-2 is an inducible isoform upregulated by inflammatory cytokines. Although it is believed that COX-2 Is not present or expressed in low levels in normal tissue, recent studies in the literature and in our laboratory show that COX-1 and COX-2 are abundantly expressed in the normal healthy rodent lung and have the capacity to generate vasoactive prostanoids from the precursor, arachidonic acid. It is our hypothesis that vasoactive prostanoids that increase pulmonary vascular resistance and decrease systemic vascular resistance are generated by COX-1 and COX-2. The first specific aim is to determine the role of COX-1 and COX-2 in the generation of vasoactive prostanoids in the intact-chest mouse using a recently developed right-heart catheterization procedure to measure pulmonary vascular pressures and blood flow. These studies will involve the use of selective COX-1 and COX-2 inhibitors, a platelet aggregation assay to determine COX-1 selectivity, and enzyme immunoassay to measure prostanoid levels in lung tissue. The second specific aim is to determine the role of COX-1 and COX-2 in the generation of vasoactive prostanoids when arachidonic acid is released from endogenous pools by agents or stimuli reported to release prostaglandins from the lung. In these experiments, the effects of the COX-1 and COX-2 inhibitors on responses to ventilatory hypoxia, angiotensin II, and ionophore A23187 will be investigated in the intact-chest mouse. These experiments will test the hypothesis that responses to ionophore A23187 are mediated by the formation of prostanoids in the COX-1 and COX-2 pathway and that COX-1 and COX-2 modulate pulmonary vasoconstrictor responses to angiotensin II and ventilatory hypoxia. The experiments in specific aims 1 and 2 involve the use of selective COX inhibitors which may be problematic, therefore, specific aim three is to determine the role of COX-1 and COX-2 in the generation of vasoactive prostanoids and in the regulation of the pulmonary vascular bed in COX-1 and COX-2 knockout mice. The results of these experiments will provide new information about the role of COX-1 and COX- 2 in the regulation of the pulmonary vascular bed and may lead to new strategies for the treatment of pulmonary hypertensive disorders.
| Pankey, Edward A; Kassan, Modar; Choi, Soo-Kyoung et al. (2014) Vasodilator responses to acetylcholine are not mediated by the activation of soluble guanylate cyclase or TRPV4 channels in the rat. Am J Physiol Heart Circ Physiol 306:H1495-506 |
| Pankey, Edward A; Lasker, George F; Gur, Serap et al. (2013) Analysis of erectile responses to imatinib in the rat. Urology 82:253.e17-24 |
| Lasker, George F; Pankey, Edward A; Frink, Terrence J et al. (2013) The sGC activator BAY 60-2770 has potent erectile activity in the rat. Am J Physiol Heart Circ Physiol 304:H1670-9 |
| Pankey, Edward A; Thammasiboon, Supat; Lasker, George F et al. (2013) Imatinib attenuates monocrotaline pulmonary hypertension and has potent vasodilator activity in pulmonary and systemic vascular beds in the rat. Am J Physiol Heart Circ Physiol 305:H1288-96 |
| Kahn, Marc J; Maley, Jason H; Lasker, George F et al. (2013) Updated role of nitric oxide in disorders of erythrocyte function. Cardiovasc Hematol Disord Drug Targets 13:83-7 |
| Lasker, George F; Pankey, Edward A; Allain, Alexander V et al. (2013) The selective Rho-kinase inhibitor azaindole-1 has long-lasting erectile activity in the rat. Urology 81:465.e7-14 |
| Lasker, George F; Pankey, Edward A; Allain, Alexander V et al. (2013) Analysis of erectile responses to BAY 41-8543 and muscarinic receptor stimulation in the rat. J Sex Med 10:704-18 |
| Nossaman, Bobby D; Kadowitz, Philip J (2013) Stimulators of soluble guanylyl cyclase: future clinical indications. Ochsner J 13:147-56 |
| Nossaman, Bobby D; Pankey, Edward A; Badejo Jr, Adeleke R et al. (2012) Analysis of responses to glyceryl trinitrate and sodium nitrite in the intact chest rat. Nitric Oxide 26:223-8 |
| Pankey, Edward A; Badejo, Adeleke M; Casey, David B et al. (2012) Effect of chronic sodium nitrite therapy on monocrotaline-induced pulmonary hypertension. Nitric Oxide 27:1-8 |
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