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Hexyl)-Xanthine (Pentoxifylline)Was Obtained by Alkylation of Theobromine.1) It Has Been Suggested That the Effects of Methylxanthinesmay Be Mediated In

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Hexyl)-Xanthine (Pentoxifylline)Was Obtained by Alkylation of Theobromine.1) It Has Been Suggested That the Effects of Methylxanthinesmay Be Mediated In Cardiovascular Effects of Aminophylline and Pentoxifylline on Intact Dogs and Isolated Dog Atria Hidehiko WATANABE, M.D., Yasuyuki FURUKAWA, M.D., and Shigetoshi CHIBA,M.D. SUMMARY The effects of aminophylline and pentoxifylline were investi- gated on the blood pressure and heart rate in the intact dog and on the atrial rate and contractile force in isolated atrial muscle which was perfused with arterial blood of the donor dog. Firstly, each drug was intravenously administered to the donor dog. Both com- pounds produced a dose-dependent hypotension. Aminophylline frequently caused bradycardia in intact dogs and positive chrono- and inotropic effects in isolated atria. However, pentoxifylline usually produced only tachycardia in the donor dog and positive chrono- and inotropic effects on the isolated atrium. When the compounds were administered into the sinus node artery, positive chrono- and inotropic effects were induced, with aminophylline being approximately 3-10 times more potent than pentoxifylline. Larger doses of aminophylline or pentoxifylline when admin- istered intravenously might cause a release of catecholamine, be- cause increased sinus rate and developed tension in isolated atria which was perfused with donor's blood were partially, but signifi- cantly, suppressed by propranolol treatment. In the isolated atrium, aminophylline, but not pentoxifylline, significantly inhibited the negative chronotropic and inotropic ef- fects of adenosine. Additional Indexing Words: Aminophylline Pentoxifylline Adenosine Intact dog Isolated atrium HE xanthines, caffeine, aminophylline, and theobromine are colsely re- T lated vasoactive alkaloids. The water soluble 3,7-dimethyl-1-(5-oxo- hexyl)-xanthine (pentoxifylline)was obtained by alkylation of theobromine.1) It has been suggested that the effects of methylxanthinesmay be mediated in From the Department of Pharmacology, Faculty of Medicine, Shinshu University, Matsumoto 390, Japan. Received for publication March 25, 1981. 235 Jpn. Heart J. 236 WATANABE, FURUKAWA, AND CHIBA March 1982 part by the augmented release of catecholamines from the sympathoadrenal system.2),3) In 1975, Kalsner et al4) reported that aminophylline enhanced beta-adrenergic receptor-mediated responses via a blockade of catecholamine uptake, in addition to its inhibitory action of phosphodiesterase. It has been also reported that caffeine and aminophylline competitively antagonize the effects of adenosine in the heart.5)-8) Moreover, it is well known that methyl- xanthines stimulate vagal and vasomotor centers in the brain stem.9)-12) However, it is still not clear how methylxanthines exert their effects on the cardiovascular system and little informations are available concerning the action of pentoxifylline. In the present study, we made an attempt to investigate direct and in- direct cardiac effects of aminophylline and pentoxifylline, using the isolated atrial preparation perfused with the donor dog's blood.13),14) MATERIALS AND METHODS Eighteen mongrel dogs, weighing 10-20Kg, were anesthetized with so- dium pentobarbital, 30mg/Kg, i.v. After treatment with 2,000 units of sodium heparin i.v., the right atrium was excised and plunged into a cold Tyrode solution at 4-10•Ž. The sinus node artery was cannulated via the right coronary artery and perfused with blood conducted from the carotid artery of the donor dog by aid of a peristaltic pump (Harvard Apparatus, Model 1210). The perfusion pressure was constantly maintained at 100 mmHg. The flow rate was 4.5-5.0ml/min. The atrium was suspended in a bath filled with blood at a constant temperature of 37•Ž. The upper part of the crista terminalis of the atrium was connected directly to the force dis- placement transducer (Grass FTO3B) by a silk thread. Bipolar platinum electrodes were placed into contact with the atrial epicardium. The atrial rate was measured with a cardiotachograph triggered by the signal from the atrial depolarization of an electrogram. The isometric tension was recorded on an ink-writing rectigraph (Sanei Sokki Instrument) through a carrier preamplifier (Nihon Kohden RP-3), RC circuit and a high gain amplifier (Nihon Kohden RPH-2). The donor dogs, weighing 9-16Kg, were also anesthetized with 30mg/ Kg of sodium pentobarbital i.v. and artificially ventilated with room air by use of a Harvard respirator. Sodium heparin, 500units/Kg, was admin- istered intravenously at the beginning of the perfusion and 200units/Kg was added at 1-h intervals. The systemic blood pressure of the donor dog was measured from the cannulated left femoral artery with a pressure transducer (Nihon Kohden RP-2), and heart rate was measured with a cardiotachograph Vol.23 No.2 CARDIOVASCULAR EFFECTS OF METHYLXANTHINES 237 triggered by the R wave of the lead II. Details of the isolated, blood-perfused canine atrial preparations were described in previous papers.13),14) The drugs used in these experiments were aminophylline (Eisai), pen- toxifylline (Hoechst), adenosine (Boehringer & Sohn), (•})-propranolol hy- drochloride (Sumitomo Chemicals), and (•})-norepinephrine hydrochloride (Sankyo). Each drug was administered into the jugular vein of the donor dog, and into the sinus node artery of the isolated atrium. A continuous infusion was performed by use of an infusion pump (Harvard Apparatus Model 901). RESULTS Effects of aminophylline and pentoxifylline injected into the jugular vein of the donor dog Aminophylline or pentoxifylline was injected into the jugular vein of the donor dog. The systemic blood pressure decreased dose-dependently by each drug. The hypotensive effect of aminophylline was usually more potent than that of pentoxifylline. Pentoxifylline dose-dependently caused an increase in the heart rate. On the other hand, aminophylline caused not only tachy- cardia but also frequently bradycardia with relatively larger doses of 3 and 10mg/Kg (expressed as theophylline base), although it caused slight tachy- cardia at a relatively smaller dose of 1mg/Kg. Fig. 1 shows a typical effect Fig. 1. A comparison of effects of aminophylline and pentoxifylline in- jected into the jugular vein of the donor dog at a dose of 10mg/Kg on the blood pressure and heart rate in the donor dog (A), and the developed tension and atrial rate in the isolated atrium (B). JP n. Heart J. 238 WATANABE, FURUKAWA, AND CHIBA March 1982 of aminophylline and pentoxifylline in the same preparation. In the isolated atrium which was perfused with the donor's arterial blood, the developed tension and atrial rate were increased dose-dependently by each drug. In the isolated atrium, effects on atrial rate and developed tension occurred ap- proximately 2.5min after the onset of the injection, since the time to pass through the circuit was about 2.5min. The positive chronotropic and iso- tropic effects of aminophylline were much more potent than those of pen- toxifylline. The results are summarized in Fig. 2. After the treatment with 100ƒÊg/Kg of propranolol i.v., the effects of aminophylline on the blood pressure and heart rate were not influenced, but pentoxifylline-induced tachycardia was significantly suppressed. On the other hand, the positive chrono- and inotropic responses to both drugs were sig- nificantly suppressed but not completely. The results are summarized in Fig. 3. Effects of aminophylline and pentoxifylline injected into the sinus node artery of the isolated right atrium When aminophylline or pentoxifylline was given into the sinus node artery of the isolated right atrium, the developed tension and atrial rate were dose-dependently increased. Effects of aminophylline were roughly about 10 times more potent than those of pentoxifylline in a dose range of 10-300 Fig. 2. Effects of aminophylline and pentoxifylline injected into the jugular veins of the donor dogs at doses of 1-10mg/Kg in 9 experiments. The control blood pressure was 102•}6mmHg (mean•}S.E.M.), the control heart rate was 142•}10beats/min (mean•}S.E.M.), the control developed tension was 2•}0.1g (mean•}S.E.M.), and the control atrial rate was 110•}6 beats/min (mean•}S.E.M.). Vertical lines represent the standard errors of the mean. Vol.23 No.2 CARDIOVASCULAR EFFECTS OF METHYLXANTHINES 239 Fig. 3. Effects of propranolol injected into the jugular veins of donor dogs at doses of 100ƒÊg/Kg on actions of aminophylline and pentoxifylline when given i.v. (10mg/Kg) to donor dogs in 5 experiments. Vertical lines represent the standard errors of the mean. Fig. 4. Positive chrono- and inotropic effects of aminophylline (10-300 ƒÊ g) and pentoxifylline (10-1000ƒÊg) injected into the sinus node artery of the isolated atrium in 5 experiments. Vertical lines represent the standard errors of the mean. Jpn. Heart J. 240 WATANABE,FURUKAWA, AND CHIBA March 1982 Fig. 5. Effects of propranolol (3ƒÊg) injected into the sinus node arteries of 5 isolated atria on actions of aminophylline (300ƒÊg), pentoxifylline (300 ƒÊ g), and norepinephrine (0.1ƒÊg). Vertical lines represent the standard errors of the mean. Fig. 6. Effects of a continuous infusion of aminophylline (125ƒÊg/min) and pentoxifylline (250ƒÊg/min) into the sinus node artery of the isolated atrium on action of adenosine (1-30ƒÊg) when given into the sinus node artery of the isolated atrium. Vol.23 No.2 CARDIOVASCULAR EFFECTS OF METHYLXANTHINES 241 ƒÊ g. Fig. 4 shows dose-response curves of aminophylline (10-300ƒÊg) and pentoxifylline (10-1000ƒÊg). After the treatment with 3ƒÊg of propranolol, the positive chrono- and inotropic effects of aminophylline and pentoxifylline were not significantly
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