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Comparative cardiac effects of physalaemin, eledoisin and angiotensin
138
Pharmacological Research Comrnunications, VoL 1, No.2, 1969
b) In 5 cases, the kininogen level of intramedullary plasma (method of Diniz et al.,
1961 ),
collected during diagnostic sternal puncture, is equal to that of venous blood. e) In 10 cases, the kininogen level of venous blood, collected from t;he antecubital vein during a local ischemia of 5 rain, was from 50 to 6 0 %
that of baseline values. After removing
the
cuff, i.e., during reactive hyperemia, kininogen levels rise, returning almost to baseline values 5 min after the release of ischemia. d) In acute pretreatment with hydrocortisone (100 mgm), intravenously, the decrease in kininogen during ischemia is blocked in 8 cases while a slight decrease of 10 % is noted in 2 cases. e) In acute intravenous pretreatment with the sulphurated amino acid, taurine, (4 gm), a total block of the decrease of kininogeh during ischemia is noted in 9 cases while in 1 case a fall of 10 °/o is observed. f) In acute intravenous pretreatmerit with the kallikrein inhibitor, Trasylol, (200,000 units), a slight but incomplete block of the fall in kininogen is noted in 3 cases. There is a high significant difference between non-pretreated subjects and those pretreated with cortisone or taurine. Only part';al information can be obtained from this study. The decrease of plasmatic kininogen during ischemia (slowed circulation) is not due to low kininogen levels in blood of bone marrow. The complete inhibition of the decrease of kininogen :during ischemia by cortisone makes one think of a possible pre-kallikrein enzyme activity. The inhibitory action of taur~ne is certainly surprising and difficult to interprete. It may have, however, have correlation with its therapeutic properties recently demonstrated in angina pectoris (Sicuteri e_t _al, in press, 1969). BIBLIOGRAPHY MJ. All~ood and G.P. Lewis,- J. Physiol. (Lend), 166: 47, 1963 D.R. Diniz, L.F. Carvalho, J. Ryan and M. Roeha e Silva - Nature 192:1194, 1961. F. Sicuteri, G. Franchi, P.L. Del Bianco and M Fanciullacci - HypotensivePolypeptides, Springer Verlag, N.Y., 1966 F. Sicuteri, G. Franchi and M. Fanciullacci - ClinicalMedicine, in press, 1969 F. Sicuteri, P. Periti, G. Anselmi and M. Faneiullacci Boll.See. ltai. Bioi. Sper., 39: 314, 1963. COMPARATIVE CARDIAC EFFECTS OF PHYSALAEMIN, ELEDOISIN AND ANGIOTENSIN A. Beaulnes and C. Beebe
Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada Whereas physalaemin (P) and eledoisin (E), on one hand, and angiotensin (A) on the other produce opposite effects on vascular smooth muscle, all three polypeptides produce equally potent cardiac stimulant effects in certain animal species. This report will deal primarily with an analysis of the positiv~ inotropic effect of these three synthetic polypeptides in isolated spontaneously beating rabbit and cat atria.
Pharmacological Research Communications, Vol. 1, No.2, 1969
139
The sigmoid-shaped dose-response curves illustrating the positive inotropte effects of P and E in rabbit atria are almost identical; the minimum effective dose is of tile order of 10"10 g]ml and a 7 0 % maximal increase in force of contraction is produced with 10"6 g/ml. BotkxB and E are devoid of any chronotropic properties. The E dose-response curve is a biphasic sinusoid, the minimum effective dose is of the order of 10-15 g/mi and, with increasing concentrations, a first peak is obtained, followed by a decreased response and a second higher peak at concentrations of 10-7 g/ml. Tachy phylaxis develops to all three polypeptides, being more marked towards A. Tachyphylaxis can be eliminated by lengthening the interval between doses or washing the atria repeatedly. A substance produces a slight reduction in frequency of contractions. Cat atria are more sensitive to A but much less sensitive towards P and E. The negative chronotropic effect of A is more marked in c;d .atria. Alpha-adrenergic blocking agents inhibit the positive inotropic effect of P, whereas beta-blockers or histamine blocking agents prove ineffective. On the other hand, both alpha-adrenergic and histamine blocking agents can inhibit completely the stimulan'¢ effect of E. The positive inotropic effect of A is made of two components: a direct, slowly developing and persistant effect and an indirect effect involving beta-adrep.ergie mechanisms. The stimulant effect of A is not blocked by phenoxybenzamine but partially inhibited by pronethalol, bretylium or cocaine. Reserpine reduces the response to A in rabbit atria but enhances the same response in cat atria. These various findings indicate that, in the species studied, these polypeptides are the most potent cardiac stimulants known. Whereas the response to A appears to involve both a direct effect and an indirect beta-adrenergic stimulant effect, the response to P and E would seem to be mediated through an alpha-adrenergic or an histaminergic mechanism.
CIRCULATING KININS PRODUCED BY BLOOD LOSS IN THE DOG H.E. Berry, J.G. Collier and J.R. Vane Department of Pharnacology, Institute of Basic Medical Sciences, Royal College of Surgeons of England, Lincoln's Inn Fields, London W.C~.-EngLand The concentrations of kinins in the circulation of 14 dogs anaesthetized with chloralose were measured continuously by the blood-bathed organ technique (Vane, 1964). Portal and arterial blood was used to superfuse two separate banks of assay organs, each of which included strips of cat jejunum (Ferreira and Vane, 1967). These strips were sensitive to bradykinin (0.5 - 5 ng]ml). A maintained hypotension down to 35-50 mm Hg was produced by arterial bleeding into a raised reservoir. Within 30-150 rain kinins appeared in portal blood; there was usually a further delay (15-30 min) before they appeared in the arterial blood. The kinin concentration (assayed in terms of bradykinin) gradually increased to 2-4 ng/rrt, in portal blood and 1-2 ng/ml in arterial blood. In those experiments in which the shed blood was retransfused, kinin concentrations fell as the blood pressure rose.
Pharmacological Research Comrnunications, VoL 1, No.2, 1969
b) In 5 cases, the kininogen level of intramedullary plasma (method of Diniz et al.,
1961 ),
collected during diagnostic sternal puncture, is equal to that of venous blood. e) In 10 cases, the kininogen level of venous blood, collected from t;he antecubital vein during a local ischemia of 5 rain, was from 50 to 6 0 %
that of baseline values. After removing
the
cuff, i.e., during reactive hyperemia, kininogen levels rise, returning almost to baseline values 5 min after the release of ischemia. d) In acute pretreatment with hydrocortisone (100 mgm), intravenously, the decrease in kininogen during ischemia is blocked in 8 cases while a slight decrease of 10 % is noted in 2 cases. e) In acute intravenous pretreatment with the sulphurated amino acid, taurine, (4 gm), a total block of the decrease of kininogeh during ischemia is noted in 9 cases while in 1 case a fall of 10 °/o is observed. f) In acute intravenous pretreatmerit with the kallikrein inhibitor, Trasylol, (200,000 units), a slight but incomplete block of the fall in kininogen is noted in 3 cases. There is a high significant difference between non-pretreated subjects and those pretreated with cortisone or taurine. Only part';al information can be obtained from this study. The decrease of plasmatic kininogen during ischemia (slowed circulation) is not due to low kininogen levels in blood of bone marrow. The complete inhibition of the decrease of kininogen :during ischemia by cortisone makes one think of a possible pre-kallikrein enzyme activity. The inhibitory action of taur~ne is certainly surprising and difficult to interprete. It may have, however, have correlation with its therapeutic properties recently demonstrated in angina pectoris (Sicuteri e_t _al, in press, 1969). BIBLIOGRAPHY MJ. All~ood and G.P. Lewis,- J. Physiol. (Lend), 166: 47, 1963 D.R. Diniz, L.F. Carvalho, J. Ryan and M. Roeha e Silva - Nature 192:1194, 1961. F. Sicuteri, G. Franchi, P.L. Del Bianco and M Fanciullacci - HypotensivePolypeptides, Springer Verlag, N.Y., 1966 F. Sicuteri, G. Franchi and M. Fanciullacci - ClinicalMedicine, in press, 1969 F. Sicuteri, P. Periti, G. Anselmi and M. Faneiullacci Boll.See. ltai. Bioi. Sper., 39: 314, 1963. COMPARATIVE CARDIAC EFFECTS OF PHYSALAEMIN, ELEDOISIN AND ANGIOTENSIN A. Beaulnes and C. Beebe
Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada Whereas physalaemin (P) and eledoisin (E), on one hand, and angiotensin (A) on the other produce opposite effects on vascular smooth muscle, all three polypeptides produce equally potent cardiac stimulant effects in certain animal species. This report will deal primarily with an analysis of the positiv~ inotropic effect of these three synthetic polypeptides in isolated spontaneously beating rabbit and cat atria.
Pharmacological Research Communications, Vol. 1, No.2, 1969
139
The sigmoid-shaped dose-response curves illustrating the positive inotropte effects of P and E in rabbit atria are almost identical; the minimum effective dose is of tile order of 10"10 g]ml and a 7 0 % maximal increase in force of contraction is produced with 10"6 g/ml. BotkxB and E are devoid of any chronotropic properties. The E dose-response curve is a biphasic sinusoid, the minimum effective dose is of the order of 10-15 g/mi and, with increasing concentrations, a first peak is obtained, followed by a decreased response and a second higher peak at concentrations of 10-7 g/ml. Tachy phylaxis develops to all three polypeptides, being more marked towards A. Tachyphylaxis can be eliminated by lengthening the interval between doses or washing the atria repeatedly. A substance produces a slight reduction in frequency of contractions. Cat atria are more sensitive to A but much less sensitive towards P and E. The negative chronotropic effect of A is more marked in c;d .atria. Alpha-adrenergic blocking agents inhibit the positive inotropic effect of P, whereas beta-blockers or histamine blocking agents prove ineffective. On the other hand, both alpha-adrenergic and histamine blocking agents can inhibit completely the stimulan'¢ effect of E. The positive inotropic effect of A is made of two components: a direct, slowly developing and persistant effect and an indirect effect involving beta-adrep.ergie mechanisms. The stimulant effect of A is not blocked by phenoxybenzamine but partially inhibited by pronethalol, bretylium or cocaine. Reserpine reduces the response to A in rabbit atria but enhances the same response in cat atria. These various findings indicate that, in the species studied, these polypeptides are the most potent cardiac stimulants known. Whereas the response to A appears to involve both a direct effect and an indirect beta-adrenergic stimulant effect, the response to P and E would seem to be mediated through an alpha-adrenergic or an histaminergic mechanism.
CIRCULATING KININS PRODUCED BY BLOOD LOSS IN THE DOG H.E. Berry, J.G. Collier and J.R. Vane Department of Pharnacology, Institute of Basic Medical Sciences, Royal College of Surgeons of England, Lincoln's Inn Fields, London W.C~.-EngLand The concentrations of kinins in the circulation of 14 dogs anaesthetized with chloralose were measured continuously by the blood-bathed organ technique (Vane, 1964). Portal and arterial blood was used to superfuse two separate banks of assay organs, each of which included strips of cat jejunum (Ferreira and Vane, 1967). These strips were sensitive to bradykinin (0.5 - 5 ng]ml). A maintained hypotension down to 35-50 mm Hg was produced by arterial bleeding into a raised reservoir. Within 30-150 rain kinins appeared in portal blood; there was usually a further delay (15-30 min) before they appeared in the arterial blood. The kinin concentration (assayed in terms of bradykinin) gradually increased to 2-4 ng/rrt, in portal blood and 1-2 ng/ml in arterial blood. In those experiments in which the shed blood was retransfused, kinin concentrations fell as the blood pressure rose.