RT Journal Article
SR Electronic
T1 THE PHARMACOLOGY OF BENZYL-IMIDAZOLINE (PRISCOL)
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 271
OP 288
VO 89
IS 3
A1 RAYMOND P. AHLQUIST
A1 RUSSELL A. HUGGINS
A1 R. A. WOODBURY
YR 1947
UL http://jpet.aspetjournals.org/content/89/3/271.abstract
AB The pharmacodynamic relationships of Priscol are very complex. In some of its actions Priscol resembles the sympathomimetic agents, in others it resembles histamine or acetylcholine, and in still others Priscol resembles the sympatholytic substances such as ergotamine or ergotoxine. Each of Priscol's diverse effects will be considered individually. 1. Peripheral vasodilation. Priscol produces general vasodilation and increased venous return in dogs and cats (and probably humans). This dilation is not prevented by atropine or by sympathomimetic agents and therefore is probably not due to acetylcholine-like or histamine-like action. This peripheral vasodilating effect of Priscol appears to be a sympathomimetic effect in a manner similar to other sympathomimetic substances including 3-4-dioxyephedrine and ethyl epinephrine (23), ethyl-norsuprarenin (22) and 1-(p-hydroxyphenyl) -2- isopropylamino ethanol (24). (Another indication of the essential sympathomimetic nature of Priscol is the fact that certain chemical modifications of the Priscol type structure produce very active sympathomimetic pressor agents such as Privine (3, 20, 25).) 2. Cardiac stimulation. Priscol stimulates the intact or isolated heart of dogs and cats. We have shown that this cardiac stimulation is capable of producing a pressor response in many dogs by increasing the cardiac output; the increase in cardiac output being sufficient to increase the arterial pressure even in the face of general peripheral vasodilation. This cardiac effect of Priscol is probably sympathomimetic in nature and appears to be due both to a direct myocardial effect and to active coronary dilation. 3. Pressor action in rabbits. The arterial pressure of rabbits is usually increased by Priscol. This action is apparently histaminic in nature since there is a correlation between the intensity of the histamine pressor action and the Priscol pressor action in the same animal. Pulse contours show that Priscol (and histamine) increases the total peripheral resistance in rabbits. In dogs and cats the total peripheral resistance is diminished. 4. Cardiac depression in rabbits. On the isolated or intact rabbit heart, Priscol produces two different types of transient depression. One is acetylcholinelike in nature since it is prevented by atropine. The other occurs only with large doses and is apparently histaminic since it occurs in the presence of atropine but is prevented by epinephrine or ephecirine. 5. Castro-intestinal action. The principle action of Priscol on the gastrointestinal musculature is stimulation. In the intact animal the stimulation is prevented by atropine but on the isolated gut atropine does not prevent the stimulation. The stimulant action of Priscol on the isolated gut appears to be histaminic in nature since the histamine sensitive ileum (guinea pig) is also more sensitive to Priscol. Priscol also produces some inhibition of the gastrointestinal musculature. This inhibition precedes the stimulation phase in the isolated gut and follows the stimulant phase in the intact animal. With some segments of isolated ileum only inhibition is noted. During the inhibitory phase in the intact animal, especially following large doses of Priscol, the gut appears to be resistant to further Priscol stimulation. This inhibitory action of Priscol could be sympathomimetic in nature. 6. Stimulation of the uterus. Priscol stimulates the intact uterus (pregnant or non-pregnant) of the dog and the isolated uteri of cats, rabbits and guinea pigs. Atropine does not prevent this stimulation. Although this action of Priscol resembles that of histamine in the intact animal the stimulation is much less marked. 7. Sympatholytic action. Priscol effectively blocks the pressor action of epinephrine in experimental animals. This effect is produced by blocking the peripheral vasoconstricting action of epinephrine since it has been shown that epinephnne following Priscol is an active vasodilator (26) and that Priscol does not prevent the cardiac stimulation produced by epinephrine. Priscol also blocks the excitant action of epinephrine on the uterus. This allows the uterine inhibitory action of epinephrine to become apparent. The sympatholytic action of Priscol is similar to that of the ergot alkaloids, ergotoxine and ergotamine. However, in its cardiovascular effects Priscol is entirely dissimilar in action. The ergot alkaloids produce a pressor effect by vasoconstriction. This usually results in a diminished cardiac output. Priscol, on the other hand, increases cardiac output and thereby produces a pressor effect in many dogs. 8. Sympathomimetic anti-pressor action. Priscol selectively blocks the pressor effects of the sympathomimetic amines. It has no effect on the pressor actions of Pitressin, angiotonin, renin or histamine. The amount of amine which is blocked by Priscol varies with the pressor potency of the amine. Only those amines which possess some masked depressor action (epinephrine and tyramine) show "reversal" after Priscol. The depressor amines lose whatever pressor action they may possess but retain their characteristic depressor action. Priscol has great value as a physiological and pharmacological tool. By blocking the vasoconstricting actions of sympathomimetic substances, their vasodilating effects are unmasked and therefore become apparent. In the past. most of the studies on the correlation of chemical structure with pharmacological activity of the sympathomimetics have been on comparative pressor activities. It is becoming more apparent that the sympathomimetic substances are also potential vasodilators and that this action should also be considered in comparative studies. Because Priscol has so many different pharmacological actions it must be used with care therapeutically. When used as a vasodilator its side actions such as cardiac stimulation, gastro-intestinal and uterine stimulation should be kept in mind. Undesirable increase in blood pressure or gastro-intestinal distress may result. The effectiveness of Priscol as an adrenolytic agent in humans has not yet been demonstrated. 1947 by The American Society for Pharmacology and Experimental Therapeutics