Pulmonary hypertension (PH) is a progressive disorder characterized by increased vascular obstruction and decreased pulmonary blood flow leading to elevated pulmonary vascular resistance, right heart failure, and death. The vascular endothelium has an essential role in the maintenance of low vascular tone and endothelial dysregulation is thought to be the initiating event in the development of PH. The NO-sGC-cGMP pathway is an important therapeutic target for the treatment of pulmonary hypertension. In order to investigate novel therapeutic agents targeting the NO-sGC-cGMP pathway in the pulmonary vascular bed of the intact rat, we hypothesized that responses to agonists of the NO-sGC-cGMP pathway will be tone dependent, independent of endogenous NO, and attenuated when sGC is inhibited with ODQ. The magnitude of pulmonary vasodilator responses to the NO donors was increased when pulmonary vasoconstrictor tone was increased with the thromboxane receptor agonist U46619. Pulmonary and systemic vasodilator responses to the nitrosovasodilators were not altered by treatment with the NOS inhibitor L-NAME but were attenuated by ODQ, an agent which oxidized the heme iron of sGC. These data indicate that decreases in pulmonary and systemic arterial pressures in response to iv injection of nitrosovasodilators are tone dependent, independent of endogenous NO, and require the presence of normally reduced heme iron on sGC. Pulmonary and systemic vasodilator responses to novel agents targeting the sGC-cGMP pathway were investigated. Vasodilator responses to Bay-41-8543 were attenuated by L-NAME or ODQ and responses were enhanced when pulmonary arterial pressure was increased with U46619. Responses to the sGC activator Bay 60-2770 were enhanced by L-NAME or ODQ and when pulmonary arterial pressure was increased with U46619. These results suggest that Bay 41-8543 would be useful in the treatment of pulmonary hypertension in disease states where sGC is in the normally reduced state and low levels of NO are present. These data also indicate that Bay 60-2770 would be useful in disease states where sGC is oxidized and non-responsive to NO or sGC stimulating agents. ODQ has been used in investigations of the NO-sGC-cGMP-cGKi pathway in biochemical and isolated vessel studies. However little is known about the effects of OQD on cardiovascular responses in-vivo studies and we hypothesized that ODQ would be useful in studying responses to agents which act on the NO-sGC-cGMP pathway in-vivo. Moreover, we hypothesized that treatment with ODQ would inhibit responses to NO donors and to the endothelial dependent vasodilators Ach and BK. In these studies, ODQ in a dose that significantly attenuated responses to 6 different nitrosovasodilators did not significantly alter pulmonary and systemic responses to Ach or BK suggesting that they ac by another mechanism which may involve TRPV4 channels. The results of these studies show that inorganic nitrite which is converted to vasoactive NO by xanthine oxidoreductase or aldehyde dehydrogenase and nebivolol a beta adrenergic receptor antagonist that releases NO have a beneficial effect in monocrotaline induced pulmonary hypertension in the rat.
|Advisor:||Kadowitz, Philip J.|
|Commitee:||Beckman, Barbara S., Busija, David W., Clarkson, Craig W., Murthy, Subramanyam, Navar, L. Gabrilel, Nossaman, Bobby D.|
|School Location:||United States -- Louisiana|
|Source:||DAI-B 75/07(E), Dissertation Abstracts International|
|Keywords:||Bioactivation of nitrite, Pulmonary hypertension, Pulmonary vascular bed, Sgc activators and stimluators, Soluble guanylate cyclase, Vascular tone|
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