The central and regional cardiovascular responses to intravenous and intracoronary administration of the phenyldihydropyridine elgodipine in anaesthetized pigs

Abstract

1. The central and regional cardiovascular responses to intravenous (0.3, 1.0, 3.0 and 10.0 micrograms kg-1 min-1) and intracoronary (0.3, 0.9, 3.0 and 4.5 micrograms kg-1 min-1) infusions of elgodipine, a phenyldihydropyridine, and its solvent were studied in anaesthetized pigs. 2. Elgodipine (i.v.) caused dose-dependent decreases in arterial blood pressure (up to 44%) and systemic vascular resistance (up to 48%), whereas heart rate, LV dP/dtmax, left ventricular filling pressure, cardiac output and segment length shortening did not change. The absence of a negative inotropic effect with the employed doses was confirmed by the intracoronary infusions; with the lowest dose (0.3 micrograms kg-1 min-1) both LV dP/dtmax and segment length shortening decreased by less than 10%. With 0.9 micrograms kg-1 min-1 (intracoronary) the negative inotropic properties of the drug became apparent as LV dP/dtmax and segment length shortening decreased by 20% and 33%, respectively, whereas heart rate and left ventricular filling pressure were not affected. 3. Transmural myocardial blood flow did not change during intravenous infusion of elgodipine, as vasodilatation, more pronounced in the subepicardial than in the subendocardial layers, compensated for the decrease in arterial perfusion pressure. The intracoronary infusions revealed that the decrease in normalized subendocardial/subepicardial blood flow ratio was not secondary to the fall in arterial blood pressure. 4. Myocardial oxygen consumption decreased during both the i.v. and the intracoronary administration of elgodipine. With the i.v. administration the decrease was secondary to the hypotensive action of the drug, whereas with the intracoronary administration the negative inotropic properties played the dominant role. 5. Elgodipine (i.v.), although not affecting total cardiac output, caused a redistribution in favour of the nutritional blood flow at the expense of the arteriovenous anastomotic (AVA) blood flow. Up to an infusion rate of 3.0upg kg - I min- 1 the decrease in AVA-flow was due to a fall in arterial blood pressure, but at the highest infusion rate both the decrease in arterial perfusion pressure and an increase in their resistance contributed to a further decrease in AVA blood flow. 6. The skeletal muscles benefited most from the elgodipine(i.v.)-induced increase in nutritional blood flow, but vasodilatation was not uniform for all muscle groups. Up to an infusion rate of 3 yg kg - ' min- 1 the vasodilatation in the renal vascular bed was more pronounced in the inner than in the outer cortex, but, at 0 pyg kg-1 min-, vascular resistances of both cortical layers returned to baseline values. In all regions of the brain, blood flow was maintained until the highest infusion rate was given. With 10 yg kg- I min - ' only flow to the vital parts of the brain (diencephalon and brain stem) was maintained. Blood flows to the skin and various abdominal organs were well maintained up to 3 pg kg'- min - 1 but, at the highest dose, a decrease was observed in blood flow to the adrenals and spleen. Vascular resistances of all these organs and tissues decreased dose-dependently. 7. The potent systemic and coronary vasodilator actions of elgodipine during i.v. administration, which were not accompanied by negative inotropic and positive chronotropic properties or decreases in the perfusion of vital organs, warrant further study as this compound could be useful in the treatment of essential hypertension, myocardial ischaemia and, possibly, moderate chronic heart failure.