COMPARISON OF THE POTENCY OF DIBENZYLINE, ILIDAR, PHENTOLAMINE (REGITINE) AND TOLAZOLINE (PRISCOLINE) IN BLOCKING THE VASOCONSTRICTOR RESPONSES IN CANINE MUSCLE TO LUMBAR SYMPATHETIC STIMULATION AND TO INTRA-ARTERIAL INJECTIONS OF L-EPINEPHRINE AND OF L-NOREPINEPHRINE

¹ Department of Physiology and Pharmacology of the Bowman Gray School of Medicine of Wake Forest College, Winston-Salem, N. C.

1. In 30 dogs, anesthetized with sodium pentobarbital, blood flow in the left hind limb skeletal muscle was recorded with an electromagnetic flowmeter while perfusion pressure was recorded simultaneously with a strain gauge.

2. The ipsilateral lumbar sympathetic chain was exposed retroperitoneally and stimulated at L5, L4 and L3 with monophasic 20 per second, 15 millisecond, 2 to 4 volt square wave pulses, and 1, 3, and 10 microgm. injections of epinephrine and norepinephrine were given intraarterially before and again after each injection of one of the blocking drugs.

3. The blocking drugs were given intra-arterially in logarithmically increasing doses of 0.01 , 0.03, 0.1, etc., to 30 mgm./kgm. Only one blocking drug was used in a given experiment. The blocking drugs studied were: Dibenzyline, Ilidar, phentolamine (Regitine), and tolazoline (Priscoline).

4. The control intra-arterial injections of 1 microgm. of either epinephrine or norepinephrine produced equal degrees of vasoconstriction, and the control response to sympathetic nerve stimulation at L5 was a vasoconstriction of slightly greater magnitude. This was followed by a secondary dilation in all instances in response to epinephrine, in 50 per cent of the animals in response to norepinephrine, and in 33 per cent of the animals in response to sympathetic nerve stimulation at L5.

5. The constrictor response to epinephrine was blocked by very low doses of the blocking drugs, and with an increase in this dose level of 3 to 10 times, epinephrine was fully reversed. At this dose level the constrictor response to norepinephrine and to sympathetic stimulation was only slightly reduced.

6. A dose level of the blocking drugs equal to 30 to 300 times that which just blocked the constrictor response to intra-arterial injections of epinephrine, blocked the constrictor response to norepinephrine and to sympathetic nerve stimulation. This would suggest that a norepinephrine-like substance rather than an epinephrine-like substance is released at the sympathetic nerve endings of skeletal muscle.

7. Dibenzyline was the only one of the four blocking drugs which consistently unmasked a maximal dilator response to norepinephrine at the same dose level at which the constrictor response to norepinephrine was blocked although Ilidar occasionally did so.

8. The maximal dilator response to norepinephrine was blocked by an increase of the dose of the blocking drugs to 1.5 to 50 times the amount necessary to block norepinephrine constriction. The dilator effect of epinephrine was not blocked at this level. A dose level of 30 to 1000 times that which was required to block the initial constrictor response to epinephrine was required to block the dilator effect of epinephrine.

9. A cholinergic dilator response to sympathetic nerve stimulation was unmasked by small doses of the blocking drugs, and was blocked by very high doses of the blocking drugs. This response was easily blocked by atropine 0.01 to 0.04 mgm. intra-arterially.

10. Dibenzyline was different from the other drugs in that it consistently produced a norepinephrine reversal, and in that it blocked the constrictor responses of 10 microgm. of norepinephrine at smaller doses than it blocked 1 microgm. of norepinephrine. Also, it was the only drug which consistently elicited a primary constrictor response to the drug per se.

11. Except as noted above no significant qualitative differences were noted between the four blocking drugs. In general the quantitative order of effectiveness of the blocking drugs on a milligram basis was: Dibenzyline phentolamine Ilidar tolazoline. Dibenzyline was the most effective in that it blocked all of the responses at the lowest doses of any of the four blocking drugs.

12. The primary dilator responses (reversal) to epinephrine and to norepinephrine were elicited by the blocking drugs in the following order of decreasing magnitude: Dibenzyline Ilidar phentolamine tolazoline. This suggests that the first two were relatively more effective in their blockade of the a receptors as compared to the receptors of Ahlquist, than were the latter two.

13. The ideal blocking drug for clinical use in treating vasospastic conditions may be one which, by blocking equally well constrictor and dilator responses, would not cause epinephrine reversal, and might therefore, have less tendency to cause hypotension.