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Two new synthetic coronary dilators
Progress
Notes
Edited by EMANUEL GOLDBERGER, New York,
M.D.,
in Cardiology F.A.C.C.
New York
Two New Synthetic /
Coronarv
J
EAN Sict (Department of Pharmacology, The Chicago Medical School) has summarized experimental observations on two synthetic coronary artery dilators. The jirrst drug, 3,5-diiodo-4-hydroxyphenyl 2ethyl-3-benzofuranyl ketone, or L 2329, has been investigated in a series of acute experiments performed in six animal species (CHARLIER, R. Acta Cardiol., Suppl. 7, 1959). A 5 X 1O-7 concentration of L 2329 approximately doubled the coronary flow of the normal isolated rabbit’s heart perfused under pressure (37 to 44 mm. Hg) with Locke’s solution. The coronary flow was tripled by the same concentration of the drug when the heart was maintained in fibril.lation by electrical stimulation. The L 2329 was able to overcome the coronary constriction which was elicited in the same fibrillating heart by posterior pituitary extracts. The coronary flow measured with an electromagnetic rotameter in the chloralosed dog was increased after the intravenous administration of L 2329 ; the minimal effective dose was approximately 1 mg./kg. A dose of 10 to 20 mg./kg. appreciably improved the collateral circulation of the myocardium after ligation of the anterior descending branch of the left the improvement was illuscoronary artery; trated by simultaneous changes of the electrocardiogram. The same doses did not cause any modification of the electrocardiogram in the normal unanesthetized or chloralosed animal. The vasodilator effect of L 2329 was remarkably selective for the coronary bed. Moderate doses (10 mg./kg.) of L 2329 elicited a powerful bronchodilatation; the respiratory rate of the intact or vagotomized dog was enhanced more than the simultaneous increase in amplitude. The same doses did not completely inhibit the bronchiolar spasm that followed the systemic administration of histamine or acetylcholine. The L 2329 appeared to elicit a fairly unselective relaxation of
/
Dilators
the smooth musculature; served on the isolated and uterus.
this effect was obintestine, gallbladder
Another synthetic agent has been recently proby Bretschneider et al. (ArzneimittelForsch., 9: 39, 1959) as a potent and selective posed
coronary vasodilator. It is known as 2,6-bis (diethylamino)-4,8-bispiperidino pyrimidino (5, 4-d)-pyrimidine, or RA8. This drug appears to be more active (0.05 to 0.15 mg./per kg. administered intravenously) and longer acting (twenty to forty minutes) but it seems to have less selective effect as a coronary dilator than L 2329. The RA8, in the upper range of useful doses, elicited an appreciable dilatation of the femoral bed of the anesthetized dog; hypotension developed and was accompanied by a marked tachycardia. The blood pressure remained unchanged in the femoral vein and in the right atrium. The authors suggest that hypotension and tachycardia indicate an overdosage. These signs should be used, therefore, as a warning rather than as an end-point for the proper administration of the drug. The RA8 appeared to be more selective than L 2329 for the vascular system, and seemed not to affect the smooth musculature of the bronchi or intestine as much. The acute toxicity in mice and the chronic toxicity in dogs appear to be similar with both substances. The results of these studies suggest that L 2329 was a less potent, but vascularly more selective, coronary dilator than RA8. Neither agent appreciably influenced the nervous and muscular function of the heart. No information is yet available on the effects of these drugs on the cerebral and splanchnic circulations. The biochemical properties of these agents were not reported. It should be remembered that the absorption, distribution, catabolism and excretion of a drug can limit or decide its therapeutic applications, without regard to the 862
THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Progress
Notes
value of its specific pharmacodynamic properties. The present data were obtained in acute experiments. Therefore, the therapeutic value of prolonged administration of these drugs How will the patient remains to be established. with coronary thrombosis tolerate the hypo-
JUNE
1960
in Cardiology
863
tensive and tachycardiac effects of RA8? How will the patient with chronic angina pectoris tolerate the respiratory and intestinal effects of L 2329? Despite these questions, a new horizon seems to be opening in the treatment of coronary artery disease.
Notes
Edited by EMANUEL GOLDBERGER, New York,
M.D.,
in Cardiology F.A.C.C.
New York
Two New Synthetic /
Coronarv
J
EAN Sict (Department of Pharmacology, The Chicago Medical School) has summarized experimental observations on two synthetic coronary artery dilators. The jirrst drug, 3,5-diiodo-4-hydroxyphenyl 2ethyl-3-benzofuranyl ketone, or L 2329, has been investigated in a series of acute experiments performed in six animal species (CHARLIER, R. Acta Cardiol., Suppl. 7, 1959). A 5 X 1O-7 concentration of L 2329 approximately doubled the coronary flow of the normal isolated rabbit’s heart perfused under pressure (37 to 44 mm. Hg) with Locke’s solution. The coronary flow was tripled by the same concentration of the drug when the heart was maintained in fibril.lation by electrical stimulation. The L 2329 was able to overcome the coronary constriction which was elicited in the same fibrillating heart by posterior pituitary extracts. The coronary flow measured with an electromagnetic rotameter in the chloralosed dog was increased after the intravenous administration of L 2329 ; the minimal effective dose was approximately 1 mg./kg. A dose of 10 to 20 mg./kg. appreciably improved the collateral circulation of the myocardium after ligation of the anterior descending branch of the left the improvement was illuscoronary artery; trated by simultaneous changes of the electrocardiogram. The same doses did not cause any modification of the electrocardiogram in the normal unanesthetized or chloralosed animal. The vasodilator effect of L 2329 was remarkably selective for the coronary bed. Moderate doses (10 mg./kg.) of L 2329 elicited a powerful bronchodilatation; the respiratory rate of the intact or vagotomized dog was enhanced more than the simultaneous increase in amplitude. The same doses did not completely inhibit the bronchiolar spasm that followed the systemic administration of histamine or acetylcholine. The L 2329 appeared to elicit a fairly unselective relaxation of
/
Dilators
the smooth musculature; served on the isolated and uterus.
this effect was obintestine, gallbladder
Another synthetic agent has been recently proby Bretschneider et al. (ArzneimittelForsch., 9: 39, 1959) as a potent and selective posed
coronary vasodilator. It is known as 2,6-bis (diethylamino)-4,8-bispiperidino pyrimidino (5, 4-d)-pyrimidine, or RA8. This drug appears to be more active (0.05 to 0.15 mg./per kg. administered intravenously) and longer acting (twenty to forty minutes) but it seems to have less selective effect as a coronary dilator than L 2329. The RA8, in the upper range of useful doses, elicited an appreciable dilatation of the femoral bed of the anesthetized dog; hypotension developed and was accompanied by a marked tachycardia. The blood pressure remained unchanged in the femoral vein and in the right atrium. The authors suggest that hypotension and tachycardia indicate an overdosage. These signs should be used, therefore, as a warning rather than as an end-point for the proper administration of the drug. The RA8 appeared to be more selective than L 2329 for the vascular system, and seemed not to affect the smooth musculature of the bronchi or intestine as much. The acute toxicity in mice and the chronic toxicity in dogs appear to be similar with both substances. The results of these studies suggest that L 2329 was a less potent, but vascularly more selective, coronary dilator than RA8. Neither agent appreciably influenced the nervous and muscular function of the heart. No information is yet available on the effects of these drugs on the cerebral and splanchnic circulations. The biochemical properties of these agents were not reported. It should be remembered that the absorption, distribution, catabolism and excretion of a drug can limit or decide its therapeutic applications, without regard to the 862
THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Progress
Notes
value of its specific pharmacodynamic properties. The present data were obtained in acute experiments. Therefore, the therapeutic value of prolonged administration of these drugs How will the patient remains to be established. with coronary thrombosis tolerate the hypo-
JUNE
1960
in Cardiology
863
tensive and tachycardiac effects of RA8? How will the patient with chronic angina pectoris tolerate the respiratory and intestinal effects of L 2329? Despite these questions, a new horizon seems to be opening in the treatment of coronary artery disease.