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451 Cardiovascular responses following injection of picrotoxin into the lateral cerebral ventricle of rabbits
Abstracts of’ Pafiers a et6 cardiaque provoquee par l’iropropyl-art&C”01 d&erminPe SW 100 rats. g la fois du point de vue des modifications histoldgiques et des modifications de l’E.C.G. Dans la plus grande majorit des cas les effets constates sur ces differents paramkters ne sont pas proportionnels A 1’intensitC d’inhibition de la monoamine-osydase in vitro ou in Go; ceci est cxtr&mement net en ce qui concerne le debit coronaire et la consommation en oxygtne du ventricule gauche. Les effets de ccs inhibiteurs sur la pression art&iellr sont dus aux modifications du d&bit cardiaque et de mecanique du ventricule gauche. l’eficacitiL’action la plus nette des inhibiteurs de la monoamine-osydasc est d’Cconomisrr la consommation en oxygene du myocarde; ceci paraEt etrc du g une stimulation vagalc cardiaque et ressemblc aux effcts de la SProtonine. Les auteurs discutent B ce propos de la thCorie cle Raab et insistent sur les effets particuliers d’inhibiteurs dr la mono-amine-oxydase d&rives d’hormones de croissance (PC 603-607-6101 ou d’acides gras en C, (PC: 6111, par opposition au Marsilid et A scs d&i\,&.
610) or fatty acids with C, (PC 614) in contrast those of Marsilid and its derivatives. 450 Pharmacological Myocardial (U.S.S.R.).
Analysis Lesions.
z.
of I.
with
Neurogenic \.EDENEYE\..\
Thr fact that adrenaline and noradrenalinc administered in massive doses to an animal ma) cause myocarditis, or rather myocardial generation. is well known. The question arises, whether these same lesions may not develop under the action of adrenalineand noradrenaline-mediators excretccl at the terminals of the sympathrtic nerve in thr heart aftrr excessive irritation of the sympathetic ncrvc. Accordingly, experiments were undertaken upon albino rats. In one series, the animals received a single dosr of adrenalinr or noradrenalinc, in another, under light ether anacsthesia, one of their ganglia stellata was laid bare and traumatized b) means of haemostatic pincers. It was shown that excessive irritation of a ganglion stellatum caused thr Same kind of lesion in thr myocardium as that observed after massi\.rx doses of adrenaline and noradrenaline, but less inrense and developing more slowly. A pharmacological analysis of the phenomenon induces us to think that the destructive action of adrenaline is due to its sympathomimetic activity upon adrenoreactive systems of the myocardium. The rrsults obtained, together with the data gathered from previously published works, lead to the conclusion that sympathetic nerves, which in normal conditions regulate the trophic processes of the myocardium, may, under the action of extraordinary impulses, impair these same processes, and causr dystrophic and destructive lesions. hfost probably, such impulses are transmitted through the fibrrs of the cardial sympathetic ner\‘cs.
449bMode of Action of Inhibitors of Mono-AmineOxydase on the Cardio-Vascular SystemRelationship to Chemical Structure. J. CAHS. ht. HEROLD, N. B.XRRE, 0. KABACOFFand I. B.WRER~XR (France I. The authors have studied the effects of various inhibitors of mono-amine-oxydase (Harmalinc. hlarsilid. Tersavid, Marplan, RO 4 1038, RO 4 2637, Niamide. PC 603, PC 607, PC 610, PC 614) on the cardio-vascular system; thr pharmacological effects of thrse inhibitors of mono-amine-oxydase on the cardio-vascular system and changes in cardiac metabolism were studied on 60 dogs. The effects of thrsr same drugs on modifications of the ECG. caused bb- vasopressin, ha\re been studied on 100 rabbits. The action of these drugs on cardiac necrosis. provoked by iropropyl-arterenol was determined on 100 rats by means of histological investigations and ECG records. In the great majority of cases, the effects which xverc observed on these different levels were not proportional to the degree of in z~itroor in viva inhibition of mono-amine-oxydase. This is very clear in regard to coronary insufficiency and oxygen consumption by the left ventricle. The effects of these inhibitors on arterial pressure are due to modifications of coronary insufficiency and of the mechanical efficiency of the left ventricle. The most striking effect of the inhibitors of mono-amine-oxydasc is to economize on oxygen consumption by the myocardium; this appears to be due to vague stimulation of the heart and resembles the effects of serotonin. The authors discuss Raab’s theory and stress the special effects of the mono-amine-oxydase inhibitors, de&ccl from growth hormones (PC-603-607-
135
45
I
Cardiovascular Responses following Injection of Picrotoxin into the Lateral Cerebral Ventricle of Rabbits. D. R. VARMA, iK. I\;. SHARE and K. I. hIE:Lvn,LE (Canada). Blood pressure and electrocardiographic (Leads II & \-) changes of anaesthetized (pentobarbitone), vagotomized and curarized (gallamine) rabbits on artificial respiration, were recorded before and after in,jection of 0.1 mg picrotoxin into the lateral cerebral ventricle. \Vithin 3-10 min after picrotoxin, marked cardiac arrhythmias (ventricular extrasystoles, paroxsymal auricular or ventricular and even ventricular fibrillation) tachycardia, ensued, followed (in the absence of fatal ventricular fibrillation) by regular rhythm and pronounced S-T depression (2-8 mm) lasting 30-120 min. Blood pressure increase (40-80 mm Hg) appeared 30 set-3 min after injection and lasted 30-60 min. Glyceryltrinitrate antagonized the S-T depression to varying degrees (6 esps.). Pretreatment with
136
-4bstracts
reserpine or phenoxybenzamine (3 exps. each) abolished the cardiovascular responses to picroAfter LSD-25 (‘LO min earlier) picrotoxintoxin. induced ventricular fibrillation within 5 min in all 3 exps. After iproniazid (1 hr earlier) arrhythmia5 and S-T depression ensued in all 3 exps., although ventricular fibrillation was not observed. Spinal section (T4-5) or bilateral adrenalectomy (2 csps. each) did not abolish the responses. It is concluded that picrotoxin stimulates central sympathetic mechanisms leading to increased sympathetic outflow. These linclings suggest that central nervous system controlling mechanisms might be important in initiating both myocardial ischemic changes as ~~11 as cardiac arrhythmias. This procedure also appears to offer promise as an rxpcrimental method for studying these latter types of changes. (Suppwte~l by a Provincial Health Grant am1 a grant from the Q~wl~ec Hurt
L’mm1atim.j
452 The Influence of Pharmacological Agents on the Evolution of Experimental Myocardial Infarction of the Rabbit. X. A. ~hAZDRIKO\.A (U.S.S.R.). The present paper reports the study of influences exerted by different drugs on the development of the collaterals and on the evolution of myocardial infarcation in rabbits. \‘aso-dilators, possessing different mechanisms of action, were tested (nitroglycerine, papaverine, chloracysine, Hcxonium, pentaminc and mecamine). Three to four days after the ligation of the left coronary artery all these drugs (except introglycerine) were injected intramuscularly as a 1 per cent solution, in doses of 3 mg/kg of body wt., daily for 30 days. In the case of nitroglycerine 0.1 ml was placed on the oral mucosa. The condition of the coronary circulation was judged by changes of blood pressure, electrocardiogram and by devclopment of collarctals in the myocardium. The last was done with the help of roentgcnography. Dataobtained show that chloracyzine, papaverine and pentamine speed up normalization of changes in the ECG and blood pressure and accelerate the development of collaterals in the myocardium. The effect of hcxonium and mecamine xvas less favourNitroglyccrinc failed to produce any able. significant changes in the evolution of experimental infarction as compared to the control group of animals. 453 The Effect of Some Vasoactive Drugs on the Blood Flow in Experimentally Produced Myocardial Infarction and on the Cardiac Output of the Infarcted Heart. G. LANGE (C&many). In open-chest dogs the blood flow of the heart muscle was measured simultaneously in an infarcted and in a non-infarcted area with the calorimetric method of Kiese and Lange.“) An isotopic dilu-
of Papers tion method according to the principle of Stewart and Hamilton’“’ was used for the determination of the cardiac output. In the infarcted areas the blood flow was diminished by 50 per cent or more. The infarction was followed by a decrease in blood pressure and cardiac output, frequently after a short increase of the latter. Vasodilator agents, as aminophylline, increased the blood flow in infarctctl as \*cll as in non-infarcted areas and increased the cardiac output as long as no considerable drop in the blood pressure occurred. The following acted similarly: papaverinc, nitroglycerin, 2 :6-bis (diethanolamino)4:8 - dipiperidino - pyrimido(5:4 - o)pyrimidine, 2 - ethyl - 3(3’:5’ - diiodo - 4’ -hydroxy - benzoyl) benzofurane, N - 3’ - phenyl - propyl - (2’) - 1:1 diphenyl-propyl-(3)-aminetolazoline, adcnine nucleotidcs, rauwolfia alkaloids, khelline, chlorpromazine, tctraethylammoniumbromide, azapetine, atropine. By increasing rates of infusions, a dosage for all drugs could be found which augmented the coronary blood flow without an extensive fall in blood pressure. In doses which increased the blood pressure, norepinephrine augmented the coronary blood flow more than epinephrine and was almost as effective as epinephrine in increasing cardiac output. Hypertension and vasopressin which in large doses decreased the blood flow of the infarcted and non-infarcted muscle and the cardiac output increased either in small doses. None of the drugs affected the blood flow in the infarcted area without changing the blood flow of the rest of the myocardium in the same direction. -_ 1. KIESE
and
LANCE
(1957),
-4rch. E:‘vp. Path.
Pharm., 231, 149. L’. FRIMMER, LANGE and RESAC (1961), Path. Pharm. In press.
ilrJ_lr. &f.
__. 454 Synthetic Oxytocin (Syntocinon) As An Antagonist of Cardiac Ischaemic Changes. K. I. MELVILLE and D. R. VARMA (Canada). Myocardial ischaemic changes (ST-T deviations in ECG) were induced: (a) by inhalation of 10 per cent oxygen in nitrogen in normal and atherosclerotic rabbits (maintained on 6 per cent corn oil and 2 per cent cholesterol for 4 to 9 months); (b) by intravenous injection of vasopressin (1 I.U./ kg) in normal rabbits under pentobarbital anaesthesia; and (c) by intraventricular (right lateral cerebral ventricle) injection of picrotoxin (0.1 mg) in normal rabbits under light pentobarbital anaesthesia with the vagi cut, cm-a&cd and on artificial respiration. Oxytocin (1-5 I.U./kg I.V.) was found temporarily to reverse the ST-T changes induced by hypoxaemia in normal and atherosclerotic rabbits (10 exps.), to reduce or abolish the depressor responses and the ST-T changes induced by vasopressin (8 exps.) and to reduce the ST-T changes induced by intraventricular picrotoxin
610) or fatty acids with C, (PC 614) in contrast those of Marsilid and its derivatives. 450 Pharmacological Myocardial (U.S.S.R.).
Analysis Lesions.
z.
of I.
with
Neurogenic \.EDENEYE\..\
Thr fact that adrenaline and noradrenalinc administered in massive doses to an animal ma) cause myocarditis, or rather myocardial generation. is well known. The question arises, whether these same lesions may not develop under the action of adrenalineand noradrenaline-mediators excretccl at the terminals of the sympathrtic nerve in thr heart aftrr excessive irritation of the sympathetic ncrvc. Accordingly, experiments were undertaken upon albino rats. In one series, the animals received a single dosr of adrenalinr or noradrenalinc, in another, under light ether anacsthesia, one of their ganglia stellata was laid bare and traumatized b) means of haemostatic pincers. It was shown that excessive irritation of a ganglion stellatum caused thr Same kind of lesion in thr myocardium as that observed after massi\.rx doses of adrenaline and noradrenaline, but less inrense and developing more slowly. A pharmacological analysis of the phenomenon induces us to think that the destructive action of adrenaline is due to its sympathomimetic activity upon adrenoreactive systems of the myocardium. The rrsults obtained, together with the data gathered from previously published works, lead to the conclusion that sympathetic nerves, which in normal conditions regulate the trophic processes of the myocardium, may, under the action of extraordinary impulses, impair these same processes, and causr dystrophic and destructive lesions. hfost probably, such impulses are transmitted through the fibrrs of the cardial sympathetic ner\‘cs.
449bMode of Action of Inhibitors of Mono-AmineOxydase on the Cardio-Vascular SystemRelationship to Chemical Structure. J. CAHS. ht. HEROLD, N. B.XRRE, 0. KABACOFFand I. B.WRER~XR (France I. The authors have studied the effects of various inhibitors of mono-amine-oxydase (Harmalinc. hlarsilid. Tersavid, Marplan, RO 4 1038, RO 4 2637, Niamide. PC 603, PC 607, PC 610, PC 614) on the cardio-vascular system; thr pharmacological effects of thrse inhibitors of mono-amine-oxydase on the cardio-vascular system and changes in cardiac metabolism were studied on 60 dogs. The effects of thrsr same drugs on modifications of the ECG. caused bb- vasopressin, ha\re been studied on 100 rabbits. The action of these drugs on cardiac necrosis. provoked by iropropyl-arterenol was determined on 100 rats by means of histological investigations and ECG records. In the great majority of cases, the effects which xverc observed on these different levels were not proportional to the degree of in z~itroor in viva inhibition of mono-amine-oxydase. This is very clear in regard to coronary insufficiency and oxygen consumption by the left ventricle. The effects of these inhibitors on arterial pressure are due to modifications of coronary insufficiency and of the mechanical efficiency of the left ventricle. The most striking effect of the inhibitors of mono-amine-oxydasc is to economize on oxygen consumption by the myocardium; this appears to be due to vague stimulation of the heart and resembles the effects of serotonin. The authors discuss Raab’s theory and stress the special effects of the mono-amine-oxydase inhibitors, de&ccl from growth hormones (PC-603-607-
135
45
I
Cardiovascular Responses following Injection of Picrotoxin into the Lateral Cerebral Ventricle of Rabbits. D. R. VARMA, iK. I\;. SHARE and K. I. hIE:Lvn,LE (Canada). Blood pressure and electrocardiographic (Leads II & \-) changes of anaesthetized (pentobarbitone), vagotomized and curarized (gallamine) rabbits on artificial respiration, were recorded before and after in,jection of 0.1 mg picrotoxin into the lateral cerebral ventricle. \Vithin 3-10 min after picrotoxin, marked cardiac arrhythmias (ventricular extrasystoles, paroxsymal auricular or ventricular and even ventricular fibrillation) tachycardia, ensued, followed (in the absence of fatal ventricular fibrillation) by regular rhythm and pronounced S-T depression (2-8 mm) lasting 30-120 min. Blood pressure increase (40-80 mm Hg) appeared 30 set-3 min after injection and lasted 30-60 min. Glyceryltrinitrate antagonized the S-T depression to varying degrees (6 esps.). Pretreatment with
136
-4bstracts
reserpine or phenoxybenzamine (3 exps. each) abolished the cardiovascular responses to picroAfter LSD-25 (‘LO min earlier) picrotoxintoxin. induced ventricular fibrillation within 5 min in all 3 exps. After iproniazid (1 hr earlier) arrhythmia5 and S-T depression ensued in all 3 exps., although ventricular fibrillation was not observed. Spinal section (T4-5) or bilateral adrenalectomy (2 csps. each) did not abolish the responses. It is concluded that picrotoxin stimulates central sympathetic mechanisms leading to increased sympathetic outflow. These linclings suggest that central nervous system controlling mechanisms might be important in initiating both myocardial ischemic changes as ~~11 as cardiac arrhythmias. This procedure also appears to offer promise as an rxpcrimental method for studying these latter types of changes. (Suppwte~l by a Provincial Health Grant am1 a grant from the Q~wl~ec Hurt
L’mm1atim.j
452 The Influence of Pharmacological Agents on the Evolution of Experimental Myocardial Infarction of the Rabbit. X. A. ~hAZDRIKO\.A (U.S.S.R.). The present paper reports the study of influences exerted by different drugs on the development of the collaterals and on the evolution of myocardial infarcation in rabbits. \‘aso-dilators, possessing different mechanisms of action, were tested (nitroglycerine, papaverine, chloracysine, Hcxonium, pentaminc and mecamine). Three to four days after the ligation of the left coronary artery all these drugs (except introglycerine) were injected intramuscularly as a 1 per cent solution, in doses of 3 mg/kg of body wt., daily for 30 days. In the case of nitroglycerine 0.1 ml was placed on the oral mucosa. The condition of the coronary circulation was judged by changes of blood pressure, electrocardiogram and by devclopment of collarctals in the myocardium. The last was done with the help of roentgcnography. Dataobtained show that chloracyzine, papaverine and pentamine speed up normalization of changes in the ECG and blood pressure and accelerate the development of collaterals in the myocardium. The effect of hcxonium and mecamine xvas less favourNitroglyccrinc failed to produce any able. significant changes in the evolution of experimental infarction as compared to the control group of animals. 453 The Effect of Some Vasoactive Drugs on the Blood Flow in Experimentally Produced Myocardial Infarction and on the Cardiac Output of the Infarcted Heart. G. LANGE (C&many). In open-chest dogs the blood flow of the heart muscle was measured simultaneously in an infarcted and in a non-infarcted area with the calorimetric method of Kiese and Lange.“) An isotopic dilu-
of Papers tion method according to the principle of Stewart and Hamilton’“’ was used for the determination of the cardiac output. In the infarcted areas the blood flow was diminished by 50 per cent or more. The infarction was followed by a decrease in blood pressure and cardiac output, frequently after a short increase of the latter. Vasodilator agents, as aminophylline, increased the blood flow in infarctctl as \*cll as in non-infarcted areas and increased the cardiac output as long as no considerable drop in the blood pressure occurred. The following acted similarly: papaverinc, nitroglycerin, 2 :6-bis (diethanolamino)4:8 - dipiperidino - pyrimido(5:4 - o)pyrimidine, 2 - ethyl - 3(3’:5’ - diiodo - 4’ -hydroxy - benzoyl) benzofurane, N - 3’ - phenyl - propyl - (2’) - 1:1 diphenyl-propyl-(3)-aminetolazoline, adcnine nucleotidcs, rauwolfia alkaloids, khelline, chlorpromazine, tctraethylammoniumbromide, azapetine, atropine. By increasing rates of infusions, a dosage for all drugs could be found which augmented the coronary blood flow without an extensive fall in blood pressure. In doses which increased the blood pressure, norepinephrine augmented the coronary blood flow more than epinephrine and was almost as effective as epinephrine in increasing cardiac output. Hypertension and vasopressin which in large doses decreased the blood flow of the infarcted and non-infarcted muscle and the cardiac output increased either in small doses. None of the drugs affected the blood flow in the infarcted area without changing the blood flow of the rest of the myocardium in the same direction. -_ 1. KIESE
and
LANCE
(1957),
-4rch. E:‘vp. Path.
Pharm., 231, 149. L’. FRIMMER, LANGE and RESAC (1961), Path. Pharm. In press.
ilrJ_lr. &f.
__. 454 Synthetic Oxytocin (Syntocinon) As An Antagonist of Cardiac Ischaemic Changes. K. I. MELVILLE and D. R. VARMA (Canada). Myocardial ischaemic changes (ST-T deviations in ECG) were induced: (a) by inhalation of 10 per cent oxygen in nitrogen in normal and atherosclerotic rabbits (maintained on 6 per cent corn oil and 2 per cent cholesterol for 4 to 9 months); (b) by intravenous injection of vasopressin (1 I.U./ kg) in normal rabbits under pentobarbital anaesthesia; and (c) by intraventricular (right lateral cerebral ventricle) injection of picrotoxin (0.1 mg) in normal rabbits under light pentobarbital anaesthesia with the vagi cut, cm-a&cd and on artificial respiration. Oxytocin (1-5 I.U./kg I.V.) was found temporarily to reverse the ST-T changes induced by hypoxaemia in normal and atherosclerotic rabbits (10 exps.), to reduce or abolish the depressor responses and the ST-T changes induced by vasopressin (8 exps.) and to reduce the ST-T changes induced by intraventricular picrotoxin