European Journal of Pharmacology, 33 (1975) 107--117 @)North-Holland Publishing Company, Amsterdam -- Printed in The Netherlands
C E N T R A L L Y MEDIATED HYPOTENSION AND B R A D Y C A R D I A BY METHYSERGIDE IN ANESTHETIZED DOGS MICHAEL J. ANTONACCIO, EDWARD KELLY and JEANNE HALLEY
Research Department, Pharmaceuticals Division, Ciba--Geigy Corporation, Summit, New Jersey 07901, U.S.A. Received 19 August 1974, revised MS received 17 April 1975, accepted 25 April 1975
M.J. ANTONACCIO, E. KELLY and J. HALLEY, Centrally mediated hypotension and bradycardia by methysergide in anesthetized dogs, European J. Pharmacol. 33 (1975) 107--117. In anesthetized dogs, methysergide (1 and 3 mg/kg i.v.) caused reductions in systolic and diastolic blood pressure, heart rate, left ventricular pressure and peripheral resistance. Cardiac output was unchanged because of an increase in stroke volume. Methysergide exhibited no a-receptor, ganglion, or adrenergic neuron-blocking properties nor did it have marked direct vasodilator action. The BCO, but not the orthostatic, reflex was severely inhibited by the drug, evidence for a central inhibitory action. Atropine, vagotomy or carotid sinus debuffering had little or no effect on the hypotension and bradycardia produced by methysergide, whereas guanethidine pretreatment essentially abolished these effects. Direct intracerebroventricular administration of small doses of methysergide (0.2 mg/kg) caused significant hypotension and bradycardia. It is concluded that methysergide causes centrally mediated hypotension and bradycardia, the mechanism of which is not clearly understood. Centrally mediated Intracerebroventricular
Methysergide
Hypotension
1. Introduction Methysergide is a highly specific 5-HT receptor antagonist with no a-receptor blocking properties (see Gyermek, 1961; Gorlitz and Frey, 1973). However, in experiments from our laboratory in which methysergide was used as a 5-HT receptor antagonist, an incidental finding was the significant hypotensive and bradycardic effects associated with the i.v. administration of this drug (Antonaccio and Robson, 1973c). In a previous report, Fanchamps et al. (1960) found that a 10 pg/kg/min i.v. infusion of methysergide in cats decreased systemic arterial pressure and reduced the pressor response to bilateral carotid artery occlusion (BCO). However, Saxena (1974), while confirming the inhibitory effects of methysergide on BCO, could demonstrate no significant decreases in blood pressure in dogs in bolus doses ranging from 20 to 640 pg/kg i.v. The
Bradycardia
Reflexes
present study was undertaken to examine more closely the hemodynamic effects of methysergide in anesthetized dogs and to determine the mechanism of these effects.
2. Materials and methods Mongrel dogs of either sex were anesthetized with either sodium pentobarbital (32.5 mg/kg i.v.) or a mixture containing sodium diallylbarbiturate (60 mg/kg), urethane (240 mg/kg) and monoethylurea (240 mg/kg) (Dial--urethane) given i.v. Heart rate was measured with a Beckman cardiotachometer (Type 9857B) triggered from the blood pressure pulse. Systemic blood pressure was measured from the femoral artery with a Statham pressure transducer (Model P23AA) and injections were made into the femoral vein. Dogs were prepared for perfusion of the hind
108
M.J. A N T O N A C C I O ET AL.
limb (Antonaccio et al., 1974) and stimulation of the cardiac nerve as previousl:~ described (Antonaccio and Robson, 1973a). For the hemodynamic studies, dogs were respired artificially with a Harvard respirator. The left side of the chest was entered through the seventh intercostal space and the pericardium opened to cradle the heart. Left ventricular pressure was monitored through a polyethylene catheter sewn into the left ventricle through a puncture at the apex of the heart. A flow probe (Micron Instruments, Model RC 1000) was placed around the ascending aorta for the measurement of cardiac o u t p u t (minus coronary flow). Heart rate and blood pressure were monitored as described above.
Dogs were sinus debuffered by removing the carotid sinuses as previously described (Antonaccio et al., 1975). Intracerebroventricular administration of drugs was made with a 23 gauge stainless steel needle placed in the third ventricle of dogs using a David K o p f stereotaxic instrument according to the coordinates of Dua-Sharma et al. (1970). Drugs. Doses are expressed as salts of the following substances: Methysergide maleate, guanethidine monosulfate, 1,1-dimethyl-4phenylpiperazinium iodide (DMPP), 1-norepinephrine bitartrate monohydrate, atropine sulfate, 1-epinephrine bitartrate and the hydrochloride salts of isoproterenol, tyramine and clonidine.
3. Results ..4-
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C E N T R A L L Y MEDIATED HYPOTENSION AND B R A D Y C A R D I A BY METHYSERGIDE IN ANESTHETIZED DOGS MICHAEL J. ANTONACCIO, EDWARD KELLY and JEANNE HALLEY
Research Department, Pharmaceuticals Division, Ciba--Geigy Corporation, Summit, New Jersey 07901, U.S.A. Received 19 August 1974, revised MS received 17 April 1975, accepted 25 April 1975
M.J. ANTONACCIO, E. KELLY and J. HALLEY, Centrally mediated hypotension and bradycardia by methysergide in anesthetized dogs, European J. Pharmacol. 33 (1975) 107--117. In anesthetized dogs, methysergide (1 and 3 mg/kg i.v.) caused reductions in systolic and diastolic blood pressure, heart rate, left ventricular pressure and peripheral resistance. Cardiac output was unchanged because of an increase in stroke volume. Methysergide exhibited no a-receptor, ganglion, or adrenergic neuron-blocking properties nor did it have marked direct vasodilator action. The BCO, but not the orthostatic, reflex was severely inhibited by the drug, evidence for a central inhibitory action. Atropine, vagotomy or carotid sinus debuffering had little or no effect on the hypotension and bradycardia produced by methysergide, whereas guanethidine pretreatment essentially abolished these effects. Direct intracerebroventricular administration of small doses of methysergide (0.2 mg/kg) caused significant hypotension and bradycardia. It is concluded that methysergide causes centrally mediated hypotension and bradycardia, the mechanism of which is not clearly understood. Centrally mediated Intracerebroventricular
Methysergide
Hypotension
1. Introduction Methysergide is a highly specific 5-HT receptor antagonist with no a-receptor blocking properties (see Gyermek, 1961; Gorlitz and Frey, 1973). However, in experiments from our laboratory in which methysergide was used as a 5-HT receptor antagonist, an incidental finding was the significant hypotensive and bradycardic effects associated with the i.v. administration of this drug (Antonaccio and Robson, 1973c). In a previous report, Fanchamps et al. (1960) found that a 10 pg/kg/min i.v. infusion of methysergide in cats decreased systemic arterial pressure and reduced the pressor response to bilateral carotid artery occlusion (BCO). However, Saxena (1974), while confirming the inhibitory effects of methysergide on BCO, could demonstrate no significant decreases in blood pressure in dogs in bolus doses ranging from 20 to 640 pg/kg i.v. The
Bradycardia
Reflexes
present study was undertaken to examine more closely the hemodynamic effects of methysergide in anesthetized dogs and to determine the mechanism of these effects.
2. Materials and methods Mongrel dogs of either sex were anesthetized with either sodium pentobarbital (32.5 mg/kg i.v.) or a mixture containing sodium diallylbarbiturate (60 mg/kg), urethane (240 mg/kg) and monoethylurea (240 mg/kg) (Dial--urethane) given i.v. Heart rate was measured with a Beckman cardiotachometer (Type 9857B) triggered from the blood pressure pulse. Systemic blood pressure was measured from the femoral artery with a Statham pressure transducer (Model P23AA) and injections were made into the femoral vein. Dogs were prepared for perfusion of the hind
108
M.J. A N T O N A C C I O ET AL.
limb (Antonaccio et al., 1974) and stimulation of the cardiac nerve as previousl:~ described (Antonaccio and Robson, 1973a). For the hemodynamic studies, dogs were respired artificially with a Harvard respirator. The left side of the chest was entered through the seventh intercostal space and the pericardium opened to cradle the heart. Left ventricular pressure was monitored through a polyethylene catheter sewn into the left ventricle through a puncture at the apex of the heart. A flow probe (Micron Instruments, Model RC 1000) was placed around the ascending aorta for the measurement of cardiac o u t p u t (minus coronary flow). Heart rate and blood pressure were monitored as described above.
Dogs were sinus debuffered by removing the carotid sinuses as previously described (Antonaccio et al., 1975). Intracerebroventricular administration of drugs was made with a 23 gauge stainless steel needle placed in the third ventricle of dogs using a David K o p f stereotaxic instrument according to the coordinates of Dua-Sharma et al. (1970). Drugs. Doses are expressed as salts of the following substances: Methysergide maleate, guanethidine monosulfate, 1,1-dimethyl-4phenylpiperazinium iodide (DMPP), 1-norepinephrine bitartrate monohydrate, atropine sulfate, 1-epinephrine bitartrate and the hydrochloride salts of isoproterenol, tyramine and clonidine.
3. Results ..4-
i, ....--~ f
~E | i
~o
,,o
-,..
30
60
90
lao
~ N
so
~-.d
3.1. Hemodynamic effects of methysergide
.....
~o
~
~
12o
-IO
~ ~
90
12o
~ ..... ~
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r2o
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4
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