Use this URL to cite or link to this record in EThOS:
Title: The role of calcium sensitisation in hypoxic pulmonary vasoconstriction
Author: Dipp, Michelle
ISNI:       0000 0001 3425 2212
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2001
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Restricted access.
Access from Institution:
This thesis investigates the role of extracellular and intracellular calcium (Ca2+) in hypoxic pulmonary vasoconstriction (HPV), in rat and rabbit small pulmonary arteries and also in the isolated ventilated perfused rat lung in situ. 1. Rat and rabbit pulmonary artery rings responded biphasically to a 30min hypoxic challenge (PO2, 16-21Torr). An initial transient rise in tension (phase 1) was followed by a slow progressive rise (phase 2). Removal of the endothelium had no effect on phase 1 but abolished the rising component of phase 2, leaving a steady 'plateau constriction'. This supports the idea that an endothelial vasoconstrictor mediates the rising component of phase 2 but not phase 1 of HPV. This ramp component, but not phase 1 or the endothelium-independent plateau constriction was abolished by the removal of extracellular Ca2+ suggesting extracellular Ca2+ is required for the release and/or actions of an endotheliumderived vasoconstrictor. 2. Pre-incubation with ryanodine and caffeine to deplete intracellular sarcoplasmic reticulum (SR) Ca2+ stores, abolished the entire hypoxic response regardless of the presence of extracellular Ca2+ or of the endothelium. Pre-incubation with cyclopiazonic acid, which blocks the Ca2+ ATPase of the sarcoplasmic reticulum (SR) abolished phase 1, but not phase 2, regardless of the presence of the endothelium. This suggests a role for SR Ca2+ release. Omitting pretone (1ìM PGF2á) reduced, but did not otherwise modify these responses. 3. Measurements of cyclic ADP ribose (cADPR) levels using, acid extraction from rabbit pulmonary artery rings, showed that cADPR levels rise during hypoxia (16- 21Torr), but are significantly lower during severe hypoxia (5-8Torr) or normoxia (154-160Torr). In isolated arteries, the plateau constriction, but not phase 1 or the rising component of phase 2, was shown to be cADPR-sensitive. 4. When perfusate from the isolated hypoxic rat lung was applied to de-endothelialised artery rings, tension rose with a time course similar to that of phase 2 of HPV. The pharmacology of the vasoconstrictors) in the perfusate differs from that of ET-1. Constriction by the perfusate was inhibited by a Rhoassociated kinase antagonist, suggesting a role for myofilament Ca2+ sensitisation via a Rho-associated kinase. 5. Perfusate taken from the lung after the hypoxic challenge does not constrict the artery to the same degree as perfusate from the hypoxic lung suggesting that the vasoconstrictor is metabolised or removed during normoxia.
Supervisor: Nye, Piers C. G. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Calcium ions ; Physiological effect ; Arteritis