The Effect of Anti‐cholinesterase Agents on the Rat's Blood Pressure

Abstract

In most species, the effect of systemic intoxication with an anti-cholinesterase-for example, HETP (hexaethyltetraphosphate), TEPP (tetraethyl pyrophosphate), dyflos (diisopropylphosphorofluoridate), Tabun (ethyl NN-dimethylphosphoramidocyanidate), or neostigmine-is predominantly the production of a profound fall in blood pressure (Modell, Krop, Hitchcock and Riker, 1946;Heymans and Jacob, 1947;Lundholm, 1949;Burgen, Keele and Slome, 1949;Verbeke and Votava, 1949;Salerno and Coon, 1949;Holmstedt, 1951). We have recently noticed that the intravenous administration of the anti-cholinesterase " Sarin " (isopropyl methylphosphonofluoridate) to intact rats produces a sharp rise in blood pressure, then one or two oscillations about the point of increased pressure, followed by a very gradual fall in pressure over the next several minutes (10-180 min. in different animals) back to the pre-injection level (Fig. 1). The cause of this sustained rise in blood pressure produced by sarin has been investigated. METHODSWhite rats of homogeneous strain and weighing 350-500 g. were used. They were anaesthetized with urethane (1.25 g./kg. subcutaneously), and polythene cannulae were inserted into the carotid artery, to record blood pressure, and into the femoral vein. (Fig. 2). With higher single doses (e.g. 90 Itg./kg.) the animal dies before the sustained rise in blood pressure has become established.Bilateral vagotomy does not affect the results, but if sarin is given to a spinal rat only a relatively slow, small and short-lasting increase in blood pressure is caused (Fig. 3). The failure of sarin to produce a sustained elevation of blood pressure in this experiment is not due to the low blood pressure presented by a spinal rat.

The Sympathetic Postganglionic Fibre and the Block by Bretylium; The Block Prevented by Hexamethonium and Imitated by Mecamylamine

“…Recently Gokhale, Gulati & Joshi (1963) have studied the rise of blood pressure caused by physostigmine when injected into the rat. This rise was described by Dirnhuber & Cullumbine (1955) and independently by Varagi6 in 1955. Gokhale et al (1963) have found that the rise is blocked completely by bretylium, but only partly by hexamethonium.…”

Reversal of haemorrhagic shock in rats by cholinomimetic drugs

“…(4) 8mgkg-' i.p. (Lawson, 1943;1944) In the normotensive, non-bled animal, the hypertensive response to cholinomimetics also occurs through the activation of peripheral sympathetic mechanisms and is blocked by guanethidine (Dirnhuber & Cullumbine, 1955;Varagic, 1955;Medacovic & VaragicL, 1957;Brezenoff & Giuliano, 1982). However, in the normotensive animal, the hypertensive response to cholinomimetics involves central muscarinic mechanisms and is in fact abolished by atropine sulphate and scopolamine but not by atropine methylbromide or methylscopolamine (which do not pass the blood-brain barrier).…”

Effect of Some Blocking Drugs on the Pressor Response to Physostigmine in the Rat

“…The pressor response to physostigmine in the rat probably arises from an activation of central nervous sympathetic mechanisms (Varagic, 1955;Dirnhuber & Cullumbine, 1955;Medakovid & Varagid, 1957;Legid & Varagi6, 1961;Varagid & Vojvodic, 1962). Reduction or abolition of the response by antiadrenaline agents, by large doses of hexamethonium and by bretylium or guanethidine suggests that the central stimulant effect of physostigmine may be mediated by way of the established peripheral sympathetic pathways.…”