Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502277
Title: Zaprinast as a novel therapy arterial hypertension : mechanisms of action and cannabinoids as anti-typertensives
Author: O' Rourke, Carlyn
Awarding Body: The University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2009
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Abstract:
Most pulmonary arterial hypertension therapies are centred around the use of anticoagulants, which risk haemorrhaging, and anti-hypertensive drugs, which risk systemic hypotension. The PDE5 inhibitor, zaprinast, is believed to have vasorelaxant properties specific to the pulmonary arterial bed. In the present study, zaprinast relaxed U46619-induced contractions of rat aortic and pulmonary arterial rings independent of the presence of endothelium. It was noted that, the pulmonary artery relaxed two to three times quicker than the aorta. Pre-treating the aorta with the calcium-activated potassium (Kca) channel blocker, tetraethylammonium chloride (TEA, lOmM) and the sarcoplasmic reticulum Ca²⁺-dependent ATPase pump blocker, thapsigargin (1μM), reduced zaprinast-evoked vasorelaxation. Neither affected the U46619-induced contraction of the pulmonary artery. Thus, in aortic smooth muscle cells (SMC), the key player in the zaprinast-induced vasorelaxation is the Kca channel. Blockade of PDE5 by zaprinast causes cGMP accumulation, activating cGMP-PK. This activates the inositol-1,4,5-triphosphate (IP-3) and ryanodine (RyR) receptors on the sarcoplasmic reticulum membrane. This causes vasorelaxation. As neither of these mediators influence the pulmonary response, it is possible that, due to down-regulation or reduced currents in voltage-gated potassium d channels causing a direct Ca influx constricting the artery. This quicker, more direct mechanism may explain the speedier responses in the pulmonary artery.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.502277  DOI: Not available
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