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Dopamine-induced coronary vasoconstriction framed into a spectacular response by adenosine administration in the dog heart
j Mol Cell Cardiol 19 (Supplement III) (1987)
139
DOPAMINE-INDUCED CORONARY VASOCONSTRICTION FRAMED INTO A SPECTACULAR RESPONSE BY AOENOSINE ADMINISTRATION IN THE DOG HEART. A.Koll~r, V.K6kesi, A.Juh~sz-Nagy. Cardiovascular Surgical Clinic, Semmelweis University, Budapest, Hungary. The indifference of adenosine (ADO)-induced coronary vasodilation to beta-blockade was utilized to demonstrate the potency of dopamine (DA), infused into the systemic circulation, to elicit very strong contractile effects in the coronary vessel wall of open chest dogs. Blood supply to the heart was assessed by flowmeter recordings and computer-aided infrared thermography. Pretreatment with oxprenolol (0.5 mg/kg i.v.), a beta-blocker with intrinsic sympathomimetic activity, prevented DA to excite cardiac and coronary beta-adrenoceptors and preserved basic heart activity on a level which was comparable to the control. In this state moderate to large doses of DA (8-32/ug/kg/min i.v.) instead of eliciting vasodilation through hypothetical DA-receptors ingressed consistently coronary vascular resistance. However, the flow effect was comparatively slight, because of the simultaneous increase of blood pressure and the limiting action of metabolic autoregulation. If the same doses of DA were given after the coronary bed had been dilated submaximally by ADO (15-30/ug/kg/min) infused into the left heart, the flow-reducing action of DA became a dramati~ phenomenon. The results clearly show that after eliminating its conventional bets-effects, DA affects the coronary vessels not through the allegedly existing dopaminergic vasodilator but through the preponderant vasoconstrictor mechanisms.
140
THE MODE OF THE C A R D I O P R O T E C T I V E A C T I O N OF G L U C O C O R T I C O I D S . M. Koltai, I. Lepr~n, L. Szekeres. D e p a r t m e n t of Pharmacology, U n i v e r s i t y M e d i c a l School of Szeged, Hungary. Recent progress in g l u c o c o r t i c o i d r e s e a r c h has led to the r e c o g n i t ion that the a n t i - i n f l a m m a t o r y e f f e c t of steroids is i n h i b i t e d by protein synthesis inhibitors, and due to the formation and release of a p h o s p h o l i p a s e A 2 /PLA2/ i n h i b i t o r y second m e s s e n g e r called lipocortin. The activation of PLA 2 is known to be i n v o l v e d in ischemic injuries such as acute m y o c a r d i a l infarction /AMI/. T h e r e f o r e d e x a m e t h a s o n e was a p p l i e d in a conscious rat infarction model. It was found to suppress e a r l y posto c c l u s i o n arrhythmias and i n c r e a s e d survival rate. P r e t r e a t m e n t w i t h act i n o m y c i n D abolished the b e n e f i c i a l effect of desamethasone. These findings suggest that steroid p r o t e c t i o n a g a i n s t fatal c o m p l i c a t i o n s of AMI is b r o u g h t about via indirect m e c h a n i s m . Rat p e r i t o n e a l cells e x p o s e d to d e x a m e t h a s o n e p r o d u c e d lipocortin w h i c h has shown a c a r d i o p r o t e c t i v e e f f e c t when injected i n t r a v e n o u s l y b e f o r e coronary artery ligation. These results support the concept that, similarly to the a n t i - i n f l a m m a tory effect, lipocortin plays a m a j o r role in the m o l e c u l a r m e c h a n i s m of the c a r d i o p r o t e c t i v e effect of g l u c o c o r t i c o i d s .
141
THE ROLE OF PROSTAGLANDINS IN DIABETIC ~ O C A R D I A L VASCULATURE. H.Z. Koltai. National Institute of Cardiology, Budapest, Hungary. Cardiovascular complications in diabetic patients might develop before the manifestation of macro- or microangiopathy, due to the altered reactivity of the arteries. Analysing this phenomenon, results based on "in vivo" haemodynamic, "in vitro" and biochemical investigations in alloxan-diabetic dogs demonstrated that: lo cyclocxygenase inhibition "in vivo" diminish the decrease of coronary conductivity induced by norepinephrine. 2o the vasodilatory effect of exogenous prostacyclin is enhanced ~in rive" in diabetes. 3. the vasoconstrictor effect of PGF2 al~ha on diabetic coronary strips proved to be more expressed compared with the metabolically healthy ones in the presence of indomethacin. 4. phenylephrine did not alter, while hypoxia diminished the vascular prostacyclin production of isolated diabetic coromaries against to its increase in metabolically healthy state, The biochemical differmnces could be prevented by alpha adrenergic blockade. The results tempted us to suppose that the reduced ability of the coronary arteries to vasodilaticn might be the consequence of a diminished endothelial prostacyclin production with a ccncomittant pathological link between the arachidonic cascade and adrenergic vascular innervalion.
S.47
139
DOPAMINE-INDUCED CORONARY VASOCONSTRICTION FRAMED INTO A SPECTACULAR RESPONSE BY AOENOSINE ADMINISTRATION IN THE DOG HEART. A.Koll~r, V.K6kesi, A.Juh~sz-Nagy. Cardiovascular Surgical Clinic, Semmelweis University, Budapest, Hungary. The indifference of adenosine (ADO)-induced coronary vasodilation to beta-blockade was utilized to demonstrate the potency of dopamine (DA), infused into the systemic circulation, to elicit very strong contractile effects in the coronary vessel wall of open chest dogs. Blood supply to the heart was assessed by flowmeter recordings and computer-aided infrared thermography. Pretreatment with oxprenolol (0.5 mg/kg i.v.), a beta-blocker with intrinsic sympathomimetic activity, prevented DA to excite cardiac and coronary beta-adrenoceptors and preserved basic heart activity on a level which was comparable to the control. In this state moderate to large doses of DA (8-32/ug/kg/min i.v.) instead of eliciting vasodilation through hypothetical DA-receptors ingressed consistently coronary vascular resistance. However, the flow effect was comparatively slight, because of the simultaneous increase of blood pressure and the limiting action of metabolic autoregulation. If the same doses of DA were given after the coronary bed had been dilated submaximally by ADO (15-30/ug/kg/min) infused into the left heart, the flow-reducing action of DA became a dramati~ phenomenon. The results clearly show that after eliminating its conventional bets-effects, DA affects the coronary vessels not through the allegedly existing dopaminergic vasodilator but through the preponderant vasoconstrictor mechanisms.
140
THE MODE OF THE C A R D I O P R O T E C T I V E A C T I O N OF G L U C O C O R T I C O I D S . M. Koltai, I. Lepr~n, L. Szekeres. D e p a r t m e n t of Pharmacology, U n i v e r s i t y M e d i c a l School of Szeged, Hungary. Recent progress in g l u c o c o r t i c o i d r e s e a r c h has led to the r e c o g n i t ion that the a n t i - i n f l a m m a t o r y e f f e c t of steroids is i n h i b i t e d by protein synthesis inhibitors, and due to the formation and release of a p h o s p h o l i p a s e A 2 /PLA2/ i n h i b i t o r y second m e s s e n g e r called lipocortin. The activation of PLA 2 is known to be i n v o l v e d in ischemic injuries such as acute m y o c a r d i a l infarction /AMI/. T h e r e f o r e d e x a m e t h a s o n e was a p p l i e d in a conscious rat infarction model. It was found to suppress e a r l y posto c c l u s i o n arrhythmias and i n c r e a s e d survival rate. P r e t r e a t m e n t w i t h act i n o m y c i n D abolished the b e n e f i c i a l effect of desamethasone. These findings suggest that steroid p r o t e c t i o n a g a i n s t fatal c o m p l i c a t i o n s of AMI is b r o u g h t about via indirect m e c h a n i s m . Rat p e r i t o n e a l cells e x p o s e d to d e x a m e t h a s o n e p r o d u c e d lipocortin w h i c h has shown a c a r d i o p r o t e c t i v e e f f e c t when injected i n t r a v e n o u s l y b e f o r e coronary artery ligation. These results support the concept that, similarly to the a n t i - i n f l a m m a tory effect, lipocortin plays a m a j o r role in the m o l e c u l a r m e c h a n i s m of the c a r d i o p r o t e c t i v e effect of g l u c o c o r t i c o i d s .
141
THE ROLE OF PROSTAGLANDINS IN DIABETIC ~ O C A R D I A L VASCULATURE. H.Z. Koltai. National Institute of Cardiology, Budapest, Hungary. Cardiovascular complications in diabetic patients might develop before the manifestation of macro- or microangiopathy, due to the altered reactivity of the arteries. Analysing this phenomenon, results based on "in vivo" haemodynamic, "in vitro" and biochemical investigations in alloxan-diabetic dogs demonstrated that: lo cyclocxygenase inhibition "in vivo" diminish the decrease of coronary conductivity induced by norepinephrine. 2o the vasodilatory effect of exogenous prostacyclin is enhanced ~in rive" in diabetes. 3. the vasoconstrictor effect of PGF2 al~ha on diabetic coronary strips proved to be more expressed compared with the metabolically healthy ones in the presence of indomethacin. 4. phenylephrine did not alter, while hypoxia diminished the vascular prostacyclin production of isolated diabetic coromaries against to its increase in metabolically healthy state, The biochemical differmnces could be prevented by alpha adrenergic blockade. The results tempted us to suppose that the reduced ability of the coronary arteries to vasodilaticn might be the consequence of a diminished endothelial prostacyclin production with a ccncomittant pathological link between the arachidonic cascade and adrenergic vascular innervalion.
S.47