This study was designed to investigate the responses of bradykinin and related peptides in the pulmonary circulation. The pulmonary vascular bed exhibits a great ability to adapt to general and local changes in blood flow, and regulation of the pulmonary circulation is probably localized. The effect of local modulators, such as cyclooxygenase products, nitric oxide and the putative endothelium-dependent hyperolarizing factor on responses to bradykinin and related peptides were investigated. The pharmacologic properties of the new kinin receptor antagonist, HOE-140, were also investigated under conditions of controlled blood flow and constant left atrial pressure in the intact-chest cat These studies demonstrate that bradykinin is a potent vasodilator when lobar arterial pressure is raised to a high steady level with an infusion of U-46619, a thromboxane A$\sp2$ mimetic. Following administration of HOE-140, a kinin B$\sp2$ receptor antagonist, vasodilator responses to bradykinin were reduced in a selective manner. Vasodilator responses to bradykinin were not dependent on activation of muscarinic receptors, K$\sp{+}\sb{\rm ATP}$ channels, the release of vasodilator prostaglandins, or changes in bronchomotor tone. The results suggest that vasodilator responses to bradykinin occur through activation of kinin B$\sp2$ receptors, which mediate nitric oxide release. Nitric oxide subsequently activates soluble guanylate cyclase and increases guanosine 3$\sp\prime, 5\sp\prime$-cyclic monphosphate levels in the pulmonary vascular bed The data investigated the role of K$\sp{+}\sb{\rm ATP}$ channel activation and nitric oxide synthase inhibitors in the pulmonary vascular bed. The results involving inhibition of K$\sp{+}\sb{\rm ATP}$ channels show that U-3788A (nonsulfonylura) and glybenclamide (sulfonylurea), agents which are extensively used in the study of vascular smooth muscle K${+}\sb{\rm APT}$ channnel mechanisms and attenuate vasodilator responses to K$\sp{+}\sb{\rm ATP}$ channel openers, have pronounced effects on thromboxane/prostaglandin receptor-mediated vasoconstrictor responses in the pulmonary vascular bed of the cat. N$\sp\omega$-nitro-L-arginine, N$\sp\omega$-nitro-L-arginine methyl ester, N$\sp\omega$-nitro-L-arginine benzyl ester, and L-N$\sp5$-(1-iminoethyl) ornithine had similar inhibitory effects on bradykinin and substance P. The data suggest that these L-arginine analogs are useful probes for studying nitric oxide mediated responses in the pulmonary vascular bed and the alkyl esters of N$\sp\omega$-nitro-L-arginine do not block muscarinic receptors in the cat. Furthermore, L-N$\sp5$-(1-iminoethyl) ornithine did not increase lobar and systemic arterial pressure in comparison to the other nitric oxide synthase inhibitors, suggesting that basal release and endothelium-dependent agonist-stimulated release of nitric oxide can be differentiated by the adminstration of L-N$\sp5$-(1-iminoethyl) ornithine in the pulmonary vascular bed of the cat The data also demonstrate that des-Arg$\sp9$-bradykinin produces a vasoconstrictor response under low tone conditions and that these responses are mediated by kinin B$\sb1$ receptors, the release of catecholamines within the lung and the activation of alpha adrenergic receptors. While in the same experiments when tone is raised with an infusion of U-46619, des-Arg$\sp9$-bradykinin produces a vasodilator response that is mediated by the activation of kinin B$\sb1$ receptors and the release of nitric oxide from the endothelium. These data provide pharmaclogic evidence for the existence of functionally active kinin B$\sb1$ receptors that mediate tone-dependent vasoconsrictor and vasodilator responses in the pulmonary vascular bed of the cat. (Abstract shortened by UMI.) / acase@tulane.edu
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_27615 |
| Date | January 1996 |
| Contributors | DeWitt, Bracken James (Author), McNamara, Dennis B (Thesis advisor) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Rights | Access requires a license to the Dissertations and Theses (ProQuest) database., Copyright is in accordance with U.S. Copyright law |
Page generated in 0.0035 seconds