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Methylpentynol Carbamate by E Brit. J. Pharmacol. (1959), 14, 284. PHARMACOLOGY OF METHYLPENTYNOL AND METHYLPENTYNOL CARBAMATE BY E. MARLEY From the Department of Pharmacology, Royal College of Surgeons of England, London (RECEIVED DECEMBER 10, 1958) The pharmacology of methylpentynol and methylpentynol carbamate has been studied. The drugs depressed monosynaptic and polysynaptic reflexes, and exerted weak ganglion and neuro- muscular blocking actions. They also produced transitory hypotension, and increase of aortic blood flow. Perfusion of the coronary arteries with these drugs led to slowing of the heart, diminished systolic amplitude, dysrhythmias, and increased coronary flow. Respiration was stimulated with small and depressed with larger doses of both drugs. The two compounds diminished the response of the isolated guinea-pig ileum to drugs acting directly on muscle or through ganglia. The effect of the two substances was likened to that of other central nervous system depressants, particularly to that of ethanol. The toxicology, hypnotic and anticonvulsive injected into the aortic cannula from a Palmer slow effects of methylpentynol (3-methyl-l-pentyn-3-ol, injector. Coronary outflow was collected in a funnel Oblivon) were described by P'An, Gardocki, draining into a graduated cylinder. Harfenist, and Bavley (1953), Marshall and Frog Rectus.-The isolated rectus abdominis muscle Valiance (1955) and Gross, Tripod and Meier of the frog was suspended in a modified Ringer (1955). Similar studies of these properties of solution (NaCl 6 g.; KC1 0.15 g.; CaCl2.6H20 0.3 g.; methylpentynol carbamate were made by NaHCO3 0.5 g.; water 100 ml.) and bubbled with Halpern 50% C02 and 95% 02. Contractures were recorded (1956), by Halpern and Lehmann (1956) and by using a gimbal lever of magnification x 9 giving an Barnes, McCrea, Marshall, Sheahan, and Walsh effective muscle load of 0.8 g. (1958). Although other pharmacological actions Electrically Stimulated Guinea-pig Ileum.-The of methylpentynol have received less attention, method of Paton (1955) using coaxial electrical some have been described by Margolin, Perlman, stimulation was employed. The tissue was suspended Villani, and McGavack (1951) and by Gialdroni in a 10 ml. bath of Krebs solution bubbled with 950%, and Grassi (1952). Quilliam (1955) studied the 02 and 5% C02 at 35 to 37°. Rectangular pulses of effect of methylpentynol and other hypnotic drugs 1.0 msec. duration and of sufficient strength to on frog skeletal muscle. The present work is produce a maximal response to a single shock were concerned with properties of methylpentynol and applied to the electrodes, the intraluminal electrode its carbamate other than anticonvulsant effects. being the anode. Contractions were recorded with a pendular auxotonic lever (Paton, 1957a) with a METHODS magnification of 8. Isolated Rat Phrenic Nerve Diaphragm Preparation. Isolated Tissues.-In all experiments with isolated -The preparation was set up in the manner described tissues, the animal was killed by a blow on the head by Bulbring (1946) but with minor modifications. The and exsanguination. The tissue was rapidly removed tissue was suspended in 50 ml. of Tyrode solution and the dissection completed in cold 0.9% sodium bubbled with 02 at 36 to 37°. Rectangular supra- chloride solution. maximal pulses of 0.5 msec. duration were applied Kitten Hearts.-The coronary vessels were perfused to the nerve at a frequency of 6/min. The stimulating with oxygenated Locke solution (NaCl, 9 g.; KCI electrode consisted of 2 rings of platinum wire 2 mm 0.42 g.; CaCl2.6H20, 0.472 g.; glucose 2.0 g.; apart embedded in one end of a polythene tube (5 mm. NaHCO3 0.5 g.; water to 1,000 ml.) at 37° and at i.d.). The upper end of the tube was above the a constant pressure head. The Martin-Langendorff surface of the fluid in the bath and the nerve was technique was used with the apparatus described by drawn into the tube (filled with Tyrode solution) by a Baker (1951). Methylpentynol or methylpentynol thread. Muscle contractions were recorded with a carbamate, dissolved in the Locke solution, was semi-isometric lever. METHYLPENTYNOL AND METHYLPENTYNOL CARBAMA TE 285 Other Methods.-The cats were anaesthetized with were made into the right femoral vein and retrograde chloralose (80 mg./kg.) after induction by ethyl arterial injections into the stump of the ipsilateral chloride and ether. In some experiments, spinal cats lingual artery. In another experiment, the responses were prepared by the method of Kosterlitz, Krayer, of both nictitating membranes were recorded. The and Matallana (1955) or by pithing. Rabbits were isotonic levers were adjusted so that equal shortening anaesthetized with urethane (1 g./kg., 25% solution). gave equal movements of the writing point. The Rectal temperatures were maintained at 380. loading weight was 4.0 g. and the magnification When methylpentynol or its carbamate was injected seven-fold. The same parameters of stimulation were intraperitoneally into guinea-pigs, the carotid artery used although the stimulating circuits on the two was usually cannulated during the anaesthesia sides were independent. The animal was artificially produced by the drug, 5 ml. blood was withdrawn ventilated and the chest opened by splitting the and laked with distilled water, and the brain was then sternum. The drugs were injected into the right removed. If, however, the anaesthetic effect of the internal mammary artery with the distal aorta drug was insufficient, the animal was given ethyl occluded during continuous stimulation of the right chloride and ether before carotid cannulation. preganglionic and the left postganglionic cervical Because of the volatility of methylpentynol, blood sympathetic trunks. In this way the effects of arterial and tissue samples were stored in sealed tubes until injection to both nictitating membrane preparations required for estimation. could be studied simultaneously. Blood Pressure.-Recordings were made from the Suprarenal Gland. - The blood pressure of left carotid artery on a kymograph using a mercury eviscerated pithed cats was recorded. The peripheral manometer connected to a siliconed glass cannula end of the sectioned nerve to the left suprarenal gland filled with heparin-saline. was stimulated with rectangular pulses of 0.5 msec. Blood Flow.-The density flowmeter described by duration and of 20 volts at a frequency of 10/sec. for Dawes, Mott, and Vane (1953) was connected in series 30 sec. which resulted in maximum output of with the lower abdominal aorta below the renal sympathetic amines (Marley and Paton 1958, vessels. unpublished observations). Injections of methyl- Respiration.-The apparatus described by Paton pentynol or its carbamate into the right femoral vein (1949) was used for cats and rabbits. In man, the were made 45 sec. prior to the period of stimulation. volume of respiratory expired air was measured by Knee Jerk.-The jerk was elicited by a solenoid an integrating motor pneumotachograph (Wolff, 1958), tapping the quadriceps tendon of a cat every 5 sec. % 02 and C02 composition being determined by the and recorded on a kymograph by a lever attached method of Scholander (1947). to the ankle by a thread. Neuromuscular Transmission.-The tension of the twitch of the tibialis anterior muscle of the cat (and Stomach Contraction Following Vagal Stimulation. in one experiment of both tibialis and soleus muscles) -In cats, the oesophageal and pyloro-duodenal was recorded with an isometric steel myograph, the junctions were tied. The stomach was cannulated on preparation being mounted on the Brown-Schuster the greater curvature, washed out and filled with 60 myograph stand. The sciatic nerve was tied centrally, ml. of saline and movements were recorded on a above the point of stimulation and above the point smoked paper. Both vagi were stimulated in the neck of entry of its blood supply. The muscle was excited by supramaximal rectangular pulses of 0.5 msec. by slightly supramaximal shocks at a frequency of duration at a frequency of 5/sec. for 60 sec. which about 6/min. applied to the sciatic nerve through gave maximal contraction of the stomach (Burge and shielded platinum electrodes. In some experiments, Vane, 1958). the muscle was tetanized with shocks at a rate of Gastric Secretion Induced by Histamine.-Cats 50/sec. for a duration of 1 sec. in every 12 sec. were deprived of food, but not water, from the Intravenous injections were made either into a femoral previous evening as Black, Fisher, and Smith (1958) or jugular cannula. Retrograde arterial injections have shown that histamine-induced secretion may were given into the contralateral common iliac artery decline and even cease in animals fed shortly before which was ligatured just below the cannula. Infusions the experiment. Under chloralose anaesthesia, the were given by a Palmer slow injector. abdomen was opened in the midline, the pyloro- Nictitating Membrane.-Records were made of the duodenal junction occluded (leaving the pancreatico- contracture of the nictitating membrane (after duodenal arteries intact) and a glass cannula tied into enucleation of the eyeball) in response to stimulation the body of the stomach near the greater curvature. of the preganglionic or postganglionic portions of the The abdominal wound was closed around the cannula cervical sympathetic trunk which had been separated and the animal turned on its side. The oesophagus from the vagus and cut centrally. Platinum wire was also tied off to prevent drainage of saliva and electrodes were applied to the nerve to be stimulated mucus into the stomach, the vagi being left intact. by supramaximal rectangular pulses of 0.5 msec. The stomach was then washed out with warm saline duration at a frequency of 10/sec., either continuously and the juice collected in graduated centrifuge tubes. or for 30 sec. periods at regular intervals. Infusions Histamine acid phosphate (15 pg. base/min.) was 286 E. MARLEY infused from a Palmer slow injector connected to the Johnson (1953) as modified by Marley and Vane right femoral vein.
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