Investigation of the photosensitizing activity of 1,4-dihydropyridine compounds in rat smooth muscle

Martin-Caraballo, Miguel (1995) Investigation of the photosensitizing activity of 1,4-dihydropyridine compounds in rat smooth muscle. Masters thesis, Memorial University of Newfoundland.

[English] PDF - Accepted Version Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission. Download (5MB)

Abstract

The general aim of this work was to investigate the photodynamic action of 1,4-dihydropyridines (DHPs) with respect to contractile force generation in rat smooth muscle. The preparations chosen possessed (thoracic aorta) or lacked (oesophageal tunica muscularis mucosae (TMM) and pyloric sphincter) intrinsic photoresponsiveness. Exposure to 3'-NO₂-substituted DHP (3'-NO₂-DHP) photosensitized precontracted TMM preparations in a concentration-dependent fashion and this could be mimicked by photodegradable nitric oxide (NO) donors (streptozotocin, sodium nitroprussidem, sodium nitrite). -- 3'-NO₂-DHP- and NO donor-photoactivated responses in TMM, had at least three different components, consisting of (i) a transient fast relaxation, (ii) a fast "off-contraction", and (iii) a slow, delayed relaxation. Only the latter component persisted in calcium-depleted, calyculin A-precontracted preparations or following inhibition of the fast response by DHP L-type Ca⁺⁺ -channel antagonists, skinning of the plasmalemma and extracellular Ca⁺⁺ chelation. -- Both fast and slow relaxations in the TMM were diminished by NO scavengers (LY 83583, carboxy-PTIO), whereas the fast relaxation was also diminished by pre-irradiation of the 3'-NO₂-DHP solution. The selective cGMP-dependent phosphodiesterase inhibitor, zaprinast, enhanced the photorelaxation. -- Unbuffering of the sarcoplasmic reticulum with either cyclopiazonic acid or ryanodine inhibited the Bay K 8644-photoactivated fast response in TMM. This effect was accelerated in the presence of extracellular Ca⁺⁺ and resembles that seen in tissues exposed to the calcium ionophore A23187. -- In thoracic aorta, the endogenous photorelaxation was enhanced by all 3'-NO₂-DHPs tested. LY 83583 effectively inhibited both the endogenous and 3'-NO₂-DHP-augmented photorelaxation. In pyloric sphincter, photosensitization by the 3'-NO₂-DHP, (+)-PN 202 791, was evident as a transient inhibition of the muscarinic agonist-stimulated phasic contractions, followed by a post-irradiation contraction. -- The present study supports the following conclusions: (1) 3'-NO₂-DHP-photoactivated responses are tissue-specific and mimic the endogenous or NO donor-photoactivated response in smooth muscles, (2) photoactivated release of NO, presumably followed by stimulation of soluble guanylate cyclase mediates both the fast and slow relaxations in the TMM, (3) functional L-type Ca⁺⁺-channels are required for the expression of the fast components of the photoactivated response, (4) the slow relaxation may involve direct regulation of contractile protein phosphorylation by a cGMP-dependent protein kinase. -- Keywords: guanylate cyclase; 3'-NO₂-1,4-dihydropyridines; L-type Ca⁺⁺-channel; nitric oxide; tunica muscularis mucosae; photosensitization; pyloric sphincter; sarcoplasmic reticulum; thoracic aorta.

Actions (login required)

View Item