Date of Award


Degree Type


Degree Name

Doctor of Philosophy


Since small pulmonary arteries are thought to be the major site of hypoxic pulmonary vasoconstriction (HPV), the response of pulmonary veins to hypoxia has not been thoroughly investigated. Therefore, the response of isolated guinea-pig pulmonary venules to hypoxia (bath Po{dollar}\sb2{dollar}: 25 torr) and anoxia (bath Po{dollar}\sb2{dollar}: 0 torr) was characterized. Pulmonary venules (effective lumen radius (ELR): 119 {dollar}\pm{dollar} 1 {dollar}\mu{dollar}m) responded to hypoxia and anoxia with a graded, sustained, and repeatable contraction (hypoxia: 3 {dollar}\pm{dollar} 1 mg/mm; anoxia: 27 {dollar}\pm{dollar} 3 mg/mm), while paired femoral venules (ELR: 184 {dollar}\pm{dollar} 7 {dollar}\mu{dollar}m) contracted to the initial anoxic challenge only (5 {dollar}\pm{dollar} 2 mg/mm). The pulmonary venular contractions were calcium-dependent, but independent of the parenchyma.;Endothelial injury was induced by perfusion of vessel segments with either a mixture (HX/XO) of hypoxanthine (5 mM) and xanthine oxidase (0.05 U/ml), or with collagenase (2 mg/ml). HX/XO significantly (p {dollar}<{dollar} 0.05) augmented pulmonary venular contractions to hypoxia (HX/XO: 3.2 {dollar}\pm{dollar} 1.0 mg/mm; control: 1.0 {dollar}\pm{dollar} 0.5 mg/mm) and anoxia (HX/XO: 35.1 {dollar}\pm{dollar} 6.6 mg/mm; control: 20.3 {dollar}\pm{dollar} 4.0 mg/mm), while superoxide dismutase (40 {dollar}\mu{dollar}g/ml) and catalase (323 {dollar}\mu{dollar}g/ml) prevented this augmentation. Collagenase also significantly (p {dollar}<{dollar} 0.05) enhanced the anoxic contractions (collagenase: 36.0 {dollar}\pm{dollar} 3.7 mg/mm; control: 20.9 {dollar}\pm{dollar} 6.8 mg/mm). Neither gossypol (5 {dollar}\mu{dollar}M) or methylene blue (10 {dollar}\mu{dollar}M), nor indomethacin (5 {dollar}\mu{dollar}M) or ibuprofen (10 {dollar}\mu{dollar}M) affected pulmonary venular contractions to reduced Po{dollar}\sb2{dollar}.;Hypoxia and anoxia modestly, but significantly (p {dollar}<{dollar} 0.01), enhanced leukotriene (LT) C{dollar}\sb4{dollar}- and LTD{dollar}\sb4{dollar}-induced pulmonary venular contractions. FPL 57231 (3 {dollar}\mu{dollar}M), LY 163443 (1 {dollar}\mu{dollar}M), nordihydroguaiaretic acid (5 {dollar}\mu{dollar}M), and U-60257B (10 {dollar}\mu{dollar}M) has no effect on pulmonary venular contractions induced by decreased Po{dollar}\sb2{dollar}. Anoxia depressed spontaneous LT release from pulmonary venules. SKF-525A (500 {dollar}\mu{dollar}M) depressed contractions elicited by both decreased Po{dollar}\sb2{dollar} and pharmacological agents; metyrapone (1 mM) was without effect. Induction of the cytochrome P-450 monooxygenase system with {dollar}\beta{dollar}-naphthoflavone did not alter pulmonary venular contractions induced by decreased Po{dollar}\sb2{dollar}.;In summary, the isolated pulmonary venule exhibits several characteristics of HPV in vivo. This model was used to show that the endothelium opposes, rather than mediates, the pulmonary venular contractions induced by decreased Po{dollar}\sb2{dollar}. Neither the leukotrienes nor cyclooxygenase metabolites of arachidonic acid mediated these contractions, and there was no evidence of a mediating role for cytochrome P-450 metabolites of endogenous substrates.



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