Arrhythmogenic potential of alpha-adrenoceptor stimulation in the rat heart

Simple item page
dc.contributor.advisorThandroyen, Francis Trevoren_ZA
dc.contributor.authorFlint, Nigel Stuarten_ZA
dc.date.accessioned2017-12-11T10:16:18Z
dc.date.available2017-12-11T10:16:18Z
dc.date.issued1985en_ZA
dc.description.abstractA recent proposal is that the alpha₁-adrenoceptor may mediate the arrhythmogenic effect of catecholamines during acute myocardial ischaernia. The purpose of this thesis was to explore the role of alpha₁ and alpha₂-adrenoceptor stimulation on vulnerability to ventricular fibrillation in the norrnoxic rat ventricular myocardium and further to evaluate the possible underlying cellular mechanism. The model used was the isolated perfused rat heart (Langendorff technique) in which ventricular fibrillation was electrically induced. The amount of current required to produce ventricular fibrillation was measured as the ventricular fibrillation threshold. Alpha₁-adrenoceptor stirnμlation with methoxamine to 10⁻⁶M to 10⁻⁵M increased the vulnerability to ventricular fibrillation. The arrhythmogenic effect of methoxamine could not be attributed to beta-adrenoceptor stimulation as it occurred in the setting of the beta-adrenoceptor antagonist agent, atenolol; furthermore no accumulation of cyclic AMP, the proposed arrhythmogenic second messenger of beta-adrenoceptor stimulation, occurred. Similarly no alteration in heart rate, coronary flow rate or myocardial high energy phosphate content accompanied the arrhythrnogenic effect of methoxamine. The QT interval increased with alpha₁-adrenoceptor stimulation, this being an indirect index of prolongation of the action potential duration. The arrhythmogenic action of methoxamine was associated with a positive inotropic effect. Prazosin 10⁻⁸M (an alpha₁-adrenoceptor antagonist agent) produced a tenfold displacement to the right of the log concentration response curve of the positive inotropic effect of methoxamine. Prazosin 10⁻⁸M prevented the methoxamine induced fall in ventricular fibrillation threshold. Alpha₂-adrenoceptor stimulation with B-HT 920 and B-HT 933 (azepexole), in the presence of the beta-adrenoceptor antagonist agent atenolol, did not alter the vulnerability to ventricular fibrillation. Alpha₂-adrenoceptor stimulation produced no alteration in heart rate, coronary flow rate or metabolic status. We next explored the possible mechanism underlying the arrhythmogenic effect of methoxamine. Alpha₁-adrenoceptor stimulation enhances transsarcolemmal calcium ion influx and may induce sarcoplasmic reticulum calcium release. To assess the role of transsarcolemmal calcium movement in alpha₁-adrenoceptor mediated effects experiments were undertaken with nisoldipine and low extracellular calcium. To evaluate the role of sarcoplasmic reticulum calcium release, experiments were undertaken with ryanodine (an agent reputed to inhibit sarcoplasmic reticulum calcium release without effecting the slow inward current). Nisoldipine 10⁻⁸M, reducing extracellular calcium (2.5 mM to 1.25 mM) and ryanodine 10⁻⁹M to 10⁻⁸M, prevented the arrhythmogenic and positive inotropic effect of methoxamine. Heart rate, metabolic status and cyclic AMP levels we're unchanged with these procedures. The mechanism underlying the arrhythmogenic action of alpha₁-adrenoceptor stimulation might be an increase in cytosolic calcium concentration. This increase may be secondary to (i) an enhanced transsarcolemmal calcium influx or (ii) an increase in the phasic release of calcium from the sarcoplasmic reticulum.en_ZA
dc.identifier.apacitationFlint, N. S. (1985). <i>Arrhythmogenic potential of alpha-adrenoceptor stimulation in the rat heart</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,MRC/UCT Cape Heart Centre. Retrieved from http://hdl.handle.net/11427/26526en_ZA
dc.identifier.chicagocitationFlint, Nigel Stuart. <i>"Arrhythmogenic potential of alpha-adrenoceptor stimulation in the rat heart."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,MRC/UCT Cape Heart Centre, 1985. http://hdl.handle.net/11427/26526en_ZA
dc.identifier.citationFlint, N. 1985. Arrhythmogenic potential of alpha-adrenoceptor stimulation in the rat heart. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Flint, Nigel Stuart AB - A recent proposal is that the alpha₁-adrenoceptor may mediate the arrhythmogenic effect of catecholamines during acute myocardial ischaernia. The purpose of this thesis was to explore the role of alpha₁ and alpha₂-adrenoceptor stimulation on vulnerability to ventricular fibrillation in the norrnoxic rat ventricular myocardium and further to evaluate the possible underlying cellular mechanism. The model used was the isolated perfused rat heart (Langendorff technique) in which ventricular fibrillation was electrically induced. The amount of current required to produce ventricular fibrillation was measured as the ventricular fibrillation threshold. Alpha₁-adrenoceptor stirnμlation with methoxamine to 10⁻⁶M to 10⁻⁵M increased the vulnerability to ventricular fibrillation. The arrhythmogenic effect of methoxamine could not be attributed to beta-adrenoceptor stimulation as it occurred in the setting of the beta-adrenoceptor antagonist agent, atenolol; furthermore no accumulation of cyclic AMP, the proposed arrhythmogenic second messenger of beta-adrenoceptor stimulation, occurred. Similarly no alteration in heart rate, coronary flow rate or myocardial high energy phosphate content accompanied the arrhythrnogenic effect of methoxamine. The QT interval increased with alpha₁-adrenoceptor stimulation, this being an indirect index of prolongation of the action potential duration. The arrhythmogenic action of methoxamine was associated with a positive inotropic effect. Prazosin 10⁻⁸M (an alpha₁-adrenoceptor antagonist agent) produced a tenfold displacement to the right of the log concentration response curve of the positive inotropic effect of methoxamine. Prazosin 10⁻⁸M prevented the methoxamine induced fall in ventricular fibrillation threshold. Alpha₂-adrenoceptor stimulation with B-HT 920 and B-HT 933 (azepexole), in the presence of the beta-adrenoceptor antagonist agent atenolol, did not alter the vulnerability to ventricular fibrillation. Alpha₂-adrenoceptor stimulation produced no alteration in heart rate, coronary flow rate or metabolic status. We next explored the possible mechanism underlying the arrhythmogenic effect of methoxamine. Alpha₁-adrenoceptor stimulation enhances transsarcolemmal calcium ion influx and may induce sarcoplasmic reticulum calcium release. To assess the role of transsarcolemmal calcium movement in alpha₁-adrenoceptor mediated effects experiments were undertaken with nisoldipine and low extracellular calcium. To evaluate the role of sarcoplasmic reticulum calcium release, experiments were undertaken with ryanodine (an agent reputed to inhibit sarcoplasmic reticulum calcium release without effecting the slow inward current). Nisoldipine 10⁻⁸M, reducing extracellular calcium (2.5 mM to 1.25 mM) and ryanodine 10⁻⁹M to 10⁻⁸M, prevented the arrhythmogenic and positive inotropic effect of methoxamine. Heart rate, metabolic status and cyclic AMP levels we're unchanged with these procedures. The mechanism underlying the arrhythmogenic action of alpha₁-adrenoceptor stimulation might be an increase in cytosolic calcium concentration. This increase may be secondary to (i) an enhanced transsarcolemmal calcium influx or (ii) an increase in the phasic release of calcium from the sarcoplasmic reticulum. DA - 1985 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 1985 T1 - Arrhythmogenic potential of alpha-adrenoceptor stimulation in the rat heart TI - Arrhythmogenic potential of alpha-adrenoceptor stimulation in the rat heart UR - http://hdl.handle.net/11427/26526 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/26526
dc.identifier.vancouvercitationFlint NS. Arrhythmogenic potential of alpha-adrenoceptor stimulation in the rat heart. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,MRC/UCT Cape Heart Centre, 1985 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/26526en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentMRC/UCT Cape Heart Centreen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherHeart Disease Researchen_ZA
dc.titleArrhythmogenic potential of alpha-adrenoceptor stimulation in the rat hearten_ZA
dc.typeMaster Thesis
dc.type.qualificationlevelMasters
dc.type.qualificationnameMSc (Med)en_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
thesis_hsf_1985_flint_nigel_stuart.pdf
Size:
5.48 MB
Format:
Adobe Portable Document Format
Description:
Download
Collections
Masters