The effect of dehydroepiandrosterone on coronary blood flow in prepubertal anaesthetized pigs

Abstract

Extensive research suspecting an association between plasma levels of dehydroepiandrosterone and the risk of coronary heart disease has not been conclusive. The present study was designed to investigate the effect of dehydroepiandrosterone on the coronary circulation and to determine the mechanisms involved. In prepubertal pigs of both sexes anaesthetized with sodium pentobarbitone, changes in left circumflex or anterior descending coronary flow caused by intravenous infusion of dehydroepiandrosterone were assessed using an electromagnetic flowmeter. Changes in heart rate and arterial pressure were prevented by atrial pacing and by connecting the arterial system to a pressurized reservoir containing Ringer solution. In 20 pigs, infusion of 1 mg h-1 of dehydroepiandrosterone caused a decrease in coronary flow without affecting left ventricular dP/dtmax (rate of change of left ventricular systolic pressure) and filling pressures of the heart. In a further eight pigs, a dose-response curve was obtained by graded increases in the infused dose of hormone between 0.03 and 4 mg h-1. The mechanisms of the above response were studied in the 20 pigs by repeating the experiment after haemodynamic variables had returned to the control values observed before infusion. Blockade of muscarinic cholinoceptors with intravenous atropine (five pigs) and of alpha-adrenoceptors with intravenous phentolamine (five pigs) did not affect the dehydroepiandrosterone-induced coronary vasoconstriction. This response was abolished by blockade of beta-adrenoceptors with intravenous propranolol (five pigs) and of coronary nitric oxide synthase with intracoronary injection of Nomega-nitro-L-arginine methyl ester (five pigs) even after reversing the increase in arterial pressure and coronary vascular resistance caused by the two blocking agents with intravenous infusion of papaverine. The present study showed that intravenous infusion of dehydroepiandrosterone primarily caused coronary vasoconstriction. The mechanisms of this response were shown to involve the inhibition of a vasodilatory beta-adrenergic receptor-mediated effect related to the release of nitric oxide.

Figure 2. Example of experimental recordings showing the haemodynamic effects of the intravenous infusion of 1 mg h⁻¹ of dehydroepiandrosterone in one pig

C, control before infusion; T, test. From top to bottom: heart rate (HR), phasic and mean aortic blood pressure (ABP), left ventricular pressure (LVP), mean right atrial pressure (RAP), left ventricular dP/dt_max (dP/dt), mean and phasic coronary blood flow (CBF).

Figure 1. The response of mean coronary blood flow (CBF) to the intravenous infusion of 1 mg h⁻¹ of dehydroepiandrosterone in 20 pigs

The values of CBF obtained during test period of measurement are plotted on the ordinate against the corresponding control values before infusion on the abscissa. The continuous line is the line of equality.

Figure 3. Response of mean CBF to graded increases of the infused dose of dehydroepiandrosterone between 0.03 and 4 mg h⁻¹ in eight pigs

The means of percentage changes in CBF obtained during the test period of measurement are plotted against the logarithm of the doses. C, control value before infusions. The bars indicate s.d.

Figure 4. The response of mean CBF to the intravenous infusion of 1 mg h⁻¹ of dehydroepiandrosterone after blockade of muscarinic cholinoceptors, adrenoceptors and coronary nitric oxide synthase

The values of CBF obtained in each animal during the test period of measurement are plotted on the ordinate against control values before infusion on the abscissa. The continuous line is line of equality. ○, after blockade of muscarinic cholinoceptors; •, after blockade of α-adrenoceptors; □, after blockade of β-adrenoceptors; ▪, after blockade of coronary nitric oxide synthase.