In vivo en in vitro kardiovaskulere effekte van choliensuur met die wistarrot as proefdier

Abstract

English: 4.1 THE CARDIOVASCULAR EFFECTS OF CHOLIC ACID IN THE WISTAR RAT: 4.1.1. Bradycardia associated with obstructive jaundice is a well recognised clinical observation. Although this phenomenon is usually attributed to increased concentrations of circulating bile salts, the literature on the cardiovascular effects of bile salts is sparse, contradictory and confusing. The object of this investigation was therefore to study the effects of a specific bile acid (cholic acid) on the cardiovascular system of a specific species (the Wistar rat) . Three aspects received particular attention, namely i) to ascertain whether cholic acid does in fact elicit negative chronotropism, ii) to ascertain whether negative chronitropism is dose dependent, iii) to study the possible mechanism or mecpanisms responsible for negative chronotropism. 4.1.2. Experimentally produced obstructive jaundice causes a statistically significant decrease in resting heart rate in thê Wistar rat. 4.1.3. Cholic acid administration in vivo elicits a dose-dependent negative chronotropic effect, which at lower doses is the result of an uncomplicated sinus bradycardia. Progressive impairment of conduction occurs with higher doses and extreme toxicity is manifested as cessation of electrical activity In the heart. A dose-dependent hypotensive effect, which probably results from a decreased cardiac output, also occurs. 4.1.4. An investigation into the role of the autonomic nervous system, revealed that cholic acid causes bradycardia by a direct, as well as by a vagotonic mechanism. This results in a moderate degree of reflex sympathetic compensation. The vagotonic effect of cholic acid probably results from an effect on afferent vagal nerve endings in the aortic arch. 4.1.5. A clearcut negative chronotropic effect was elicited in response to cholic acid in vitro, utilizing isolated rat atrium preparations. A concomitant positive inotropism was observed which was r.elated to the decrease in heart rate and which could be eliminated by electrical pacing at a constant rate. 4.1.6. In vitro negative chronotropism is not directly related to the decrease in surface tension and is not substantially influenced by changes in potassium or sodium concentrations. Atropine does not significantly influence in vitro negative chronotropism, but cholic acid shows physiological antagonism of the positive chronotropic effect of isoprenaline. 4.1.7. The in vitro "pharmacological" effect of cholic acid (i.e. negative chronotropism) can not be attributed to any histochemical or electron microscipical changes. The effect of higher concentrations of cholic acid may however be related to mitochondrial swelling and a decrease in glycogen content of the cells. 4.1.8. Although haemolysis occurs in vivo, it does not contribute to negative chronotropism. Haemolysis probably occurs because of a mechanical monolayer effect on the cell membrane. Although this effect is concentrationdependent, the number of red cells in suspension is also a critical factor. This mechanical effect probably also occurs in cardiac pacemaker and conducting tissues inhibiting ionic flow in a non-specific way. 4.1.9. Observations during some of the experiments and the results of a short study, suggest the cholic acid has anti-arrhythmic properties.

Afrikaans: 4.2 KARDIOVASKULERE EFFEKTE VAN CHOLIENSUUR IN DIE WISTARROT 4.2.1. Bradikardie tydens obstruktiewe géelsug is In welbekende kliniese waarneming. Alhoewel hierdie verskynsel gewoonlik aan verhoogde sistemiese galsoutkonsentrasies toegeskryf word, is daar verbasend min literatuur oor die kardiovaskulêre effekte van galsoute beskikbaar en is die bestaande publikasies teenstrydig en verwarrend. Die doel van hierdie verhandeling was dus om die effek van In spesifieke galsuur (choliensuur) op die kardiovaskulêre stelsel van In spesifieke spesie (die Wistarrot) te ondersoek om veral helderheid oor drie aspekte te verkry, nl.: i) om vas te stelof choliensuur wel negatief chronotrope eienskappe openbaar, ii) om vas te stelof In dosis-effek verwantskap vir so In effek bestaan, iii) om die moontlike meganisme of meganismes wat by so 'n effek betrokke is, te ondersoek. 4.2.2. Eksperimentele obstruktiewe geelsug lok 'n duidelike en statisties-betekenisvolle afname in die rustende hartspoed van Wistarrotte uit. 4.2.3. In vivo toediening van choliensuur veroorsaak 'n dosisafhanklike negatief chronotrope effek, wat by lae doserings die gevolg van 'n ongekompliseerde, dosisafhanklike sinusbradikardie is. Met hoër doserings is daar 'n progressiewe vertraging van geleiding en met ekstreme toksisiteit 'n algehele afwesigheid van elektriese aktiwiteit in die hart. 'n Dosisafhanklike bloeddrukdaling, waarskynlik as gevolg van 'n verlaagde kardiale uitwerp, vind ook plaas. 4.2.4. Toe die rol van die outonome senuweestelsel in vivo ondersoek is, is gevind dat choliensuur op grond van 'n direkte, asook 'n vagotoniese meganisme, bradikardie uitlok. As gevolg hiervan vind 'n sekere mate van refleks kompensasie deur die simpatikus plaas. Die vagotoniese effek van choliensuur is waarskynlik te wyte aan 'n effek op afferente vagale senu-eindes in die aortaboog. 4.2.5. Choliensuur lok 'n duidelike negatief chronolrope effek met gepaardgaande positiewe inotropie in geïsoleerde rotatria uil. Laasgenoemde effek is van die afname in hartspoed afhanklik en kan, deur 'n konstante hartspoed mel elektriese stimulasie te handhaaf, opgehef word. 4.2.6. Die negatiewe chronotrope effek wat in vitro waargeneem is, is nie duidelik aan die afname in oppervlaktespanning gekoppel nie en word ook nie betek8nisvol deur veranderinge in ekstrasellulêre kalium- en kalsiumkonsentrasies beïnvloed nie. Atropien het geen duidelike effek op die in vitro negatiewe chronotropie nie, maar choliensuur tree as fisiologiese antagonis van isoprenalien op. 4.2.7. Die "farmakologiese" effek van choliensuur in vitro ('n duidelike negatiewe chronotropie) kan nie aan enige histochemiese of elektronmikroskopiese veranderinge gekoppel word nie, alhoewel die effek van hoër choliensuurkonsentrasies verband kan hou met mitochondriale swelling en I n afname in gl ikogeen-inhoud van die selle. 4.2.8. Alhoewel choliensuur in vivo hemolise veroorsaak, dra dit nie tot die negatiewe chronotropie by nie. Hemolise vind waarskynlik as gevolg van 'n meganiese monolaageffek op die selwand plaas. Hierdie effek is konsentrasieafhanklik, maar die aantal rooiselle in suspensie is ook van uiterste helnng. Hierdie meganiese effek vind waarskynlik ook op kardiale pasaangeër en geleidingsweefsel plaas, waardeur ioonvloei nie-spesifiek gedemp word. 4.2.9. Toevallige waarnemings tydens sommige eksperimente, asook die resultate van 'n kort steekproef, dui daarop dat choliensuur anti-aritmiese eienskappe besit.