dihydroergotoxine and Hypercapnia

In pharmacological screening tests for activity against the cerebral insults of hypoxia and ischaemia induced by MgCl2 or decapitation in mice, the combination of piracetam and dihydroergocristine has been shown to produce synergistic effects in prolonging the survival time. This was not the case in the model of histiocytic anoxia induced by KCN. Using an optimal combination of piracetam and dihydroergocristine (533:1, Diemil) significant increases in cerebral resistance to hypercapnic anoxia and reductions in the duration of the ensuing electrical silence on the electrocorticogram have been demonstrated in the rat. The same combination was also effective in antagonizing the memory ablating effects of anoxia in rats subjected to electric footshocks during a standard passive avoidance response. The absence of clear effects on gross cerebral blood flow and metabolism, together with considerations of the known pharmacological properties of the two components of the combination and the effects of standard drugs in the models used, lead to the conclusion that the explanation of the observed synergism probably lies in complimentary actions at the level of the cerebral neurones and is independent of simple vasodilation.

Topics: Anesthesia; Animals; Avoidance Learning; Brain Ischemia; Cerebrovascular Circulation; Dihydroergotoxine; Dogs; Drug Synergism; Hemodynamics; Hypercapnia; Hypoxia, Brain; Magnesium; Magnesium Chloride; Male; Mice; Pentobarbital; Piracetam; Pyrrolidinones; Rats; Rats, Inbred Strains; Reflex

50 bastard dogs are anesthetized by chloralose (100 mg/kg) and mebubarbital (5 mg/kg) and then perfused by three-different dosages of dihydroergotoxine (DHET) (1.25; 2.5; 5 micrograms/kg/min). The effect of DHET on cerebral oxygenation is analyzed under two conditions: normoxia and hypercapnic hypoxia. The following biochemical and physiological parameters are studied: mean vertebral flow (MVF), aortic arterial pressure (AP), heart rate (HR); pO2, pCO2, total CO2, pH, haemoglobin saturation ratio, both in arteries and veins. Other parameters are calculated: O2 arterio-venous difference, CMRO2, O2 extraction coefficient, cerebral O2 supply, vertebral resistance. Under normoxia, DHET, whatever the dosage, induces a decrease of the MVF associated with an inconstant decrease of oxygen supply. At 2.5 micrograms/kg/min, a permanent and significant increase of CMRO2 is obtained. At 5 micrograms/kg/min, similar results are obtained although the decrease of HR and AP is more pronounced. Under hypoxia, the arterio-venous oxygen content difference and the CMRO2 are increased by DHET (2.5 micrograms/kg/min) without any repercussions on AP and MVF (hypothetical role of the blood pH decrease). In conclusion, DHET doubles the CMRO2, as a consequence of an increase of the oxygen extraction ratio. A 2.5 micrograms/kg/min dosage is by itself able to give this maximum effect without any major consequences on HR, AP and MVF. This effect is still obtained in hypoxia without any peripheral vascular effect.

Topics: Animals; Blood Pressure; Brain; Dihydroergotoxine; Dogs; Female; Hemodynamics; Hypercapnia; Hypoxia; Lung Diseases, Obstructive; Male; Oxygen; Oxygen Consumption; Respiration; Time Factors