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

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.