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C U R R E N T P R O G R E S S IN NO R E S E A R C H RMJ P a l m e r
R e s p o n s e o f C o r o n a r y M i c r o v e s s e l s to E x p e r i m e n t a l Ischemia. Robert J. Bach.e, M.D., University of Minnesota, Minneapolis, Minnesota, U S A Myocardial ischemia has generally been considered to cause intense coronary vasodilation, rendering the microvessels unresponsive to vasoconstrictor stimuli. However, in chronically instrumented dogs in which exercise in the presence of a coronary stenosis resulted in myocardial ischemia, intracoronary administration of adenosine caused an increase in blood flow to the post-stenotic myocardial region, indicating the presence of vasodilator reserve. Furthermore, vasomotor responses to vasoactive agents may actually be more prominent in ischemic regions than in normal myocardium. Thus, inhibition of nitric oxide production with N-nitro-L-arginine had no effect on myocardial blood flow during treadmill exercise in normal hearts, but resulted in vasoconstriction with a further decrease in blood flow to ischemic myocardial regions. Similarly, adenosine receptor blockade with 8-phenyltheophyl-line did not alter coronary blood flow in normal hearts, but produced coronary vasoconstriction in myocardial regions which became ischemic during exercise. Vasoactive agents may have special importance in modulating the transmural distribution of perfusion by causing vasomotor changes of the penetrating coronary arteries which deliver blood to the subendocardium. Thus, in the presence of a coronary stenosis which resulted in subendocardial ischemia during exercise, semtonin, caused worsening of the subendocardial hypopeffusion with no change in blood flow to the superficial myocardial layers. Conversely, the nitro-ester ITF 296 or isosorbide dinitrate enhanced perfusion of the ischemic subendocardium during exercise in the presence of a flowlimiting coronary stenosis. These results suggest that by dilating the penetrating arteries these compounds are able to improve subendocardial perfusion.
The discovery in the late 80's of the s)aatheses of nitric oxide (NO) by mammalian cells and the elucidation of its role in a variety of cells and biological processes, has opened up a new field of research. Since then the biology of NO and the L-arginine: NO pathway in the cardiovascular system, the central nervous system, in immunity and inflammation has attracted increasing numbers of researchers and has continued to progress. Advances in our understanding of the L-arginine: NO pathway in health and disease have been facilitated by increased understanding of the molecular biology and biochemistD' of this important mediator. The goal of exploiting our understanding of the L-arginine: NO pathway in novel therapeutics remains elusive, although considerable effort and investment has been made. This presentation will review novel findings in NO research and consider their relevance to our understanding of physiology, pathophysiology and potential therapeutics.
Novel Nitrovasodilators and non-nitrate agents as new drugs for the management of ischaemic heart disease. Jacques Mizrah b Marco Sard|na, Gianni Gromo. Italfarmaco Research Centre. Milano.Italy.
Unanswered Question's Concerning Nitro-Dilator Tolerance E. Bassenge. Inst. of Applied Physiology, University of Freiburg, Germany
The Nitrovasodilators have long been used in the treatment of myocardial ischaemia and remain the drug of choice in the therapy for acute and chronic myocardial ischaemia. New organic nitrates have been designed in order to possess incremental improvements over classical nitrovasodilators and thus to have - a preferential effect on large conductance arterial vessels, especially in the coronary tree - a reduced potential to develop tolerance on tong-term administration and - only a specific nitric oxide mediated action. Both ITF 296 and ITFl129, have shown in various animal models, either after intravenous o r oral administration, marked anti-ischaemic properties, namely a significant reduction of vasospasm-induced ECG abnormalities, a pronounced increase in perfusion in the ischaemic zone but not in the normal zones in the conscious dog subjected to a coronary stenosis plus treadmill exercise and a clear-cut increase of collateral blood flow in both the inner and the outer layers of the ischaemic border' zone when an acute myocardial infarction is generated by insertion of a copper coil into coronary arteries. Moreover, during the 5-days continuous infusion of ITF 296 or ITF 1129 in the conscious dog, the coronary vasodilating effect is well maintained and no major changes in blood pressure were observed. The increase of venous compliance was rather moderate as compared with SIN-1 or Nitroglycerin which may indicate a more balanced action of ITF 296 on arterial and venous beds. There is thus reason to believe that ITF 296 could be a useful drug to explore the importance of coronary vessel dysfunction in stable angina pectoris. Alternatively to nitrovasodilators, new chemical entities have been proposed to the management of cardiac ischaemic syndromes. The antiischaemic actions of these compounds take place in the absence of measurable changes in the parameters known to affect the supplydemand ratio and have been ascribed to a direct, not nitric-oxide mediated protective effect on myocardium. Such compounds could herald a new class of anti-anginal drugs and provide a valuable model for an innovative approach to the study of the intracellular consequences of ischaemia and its treatment.
Continuous, non-intermittent nitrovasodilator therapy induces drug tolerance. This is a multifactorial phenomenon to which a large spectrum of mechanisms contribute in a changing proportion. In the clinical setting the initiation of various counterregulatory mechanisms such as enhanced sympathetic and renin-AII-activity is a major determinant. When higher concentrations of NO-donors under pharmacological conditions were applied, a limited metabolic conversion into NO (reduced cGMP production) was considered in addition t o a desensitization of guanulyl cyclase or an increase in phosphodiesterase activity. Recently it could be shown that the formation of the NO-radical is accompanied by the simultaneous formation of a number of NOx-radicals and O2-derived radicals wich inhibit (probably by oxidation) the enzymes involved in the formation and release of NO. Consequently it could be demonstrated that the simultaneous administration of various antioxidants (Vit. E and C, DMSO etc) are capable of interfering with this unwanted oxidative interactions thereby completely inhibiting the induction of tolerance to NO-donors. Different NO-donors are obviously associated with different rates of NOx- and O2--radical production, resulting in different rates and time courses of tolerance induction, which is - as a new finding (Fink et al FASEB J. 1995)- reflected by a parallel shift in cGMP-dependent platelet activity.
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R e s p o n s e o f C o r o n a r y M i c r o v e s s e l s to E x p e r i m e n t a l Ischemia. Robert J. Bach.e, M.D., University of Minnesota, Minneapolis, Minnesota, U S A Myocardial ischemia has generally been considered to cause intense coronary vasodilation, rendering the microvessels unresponsive to vasoconstrictor stimuli. However, in chronically instrumented dogs in which exercise in the presence of a coronary stenosis resulted in myocardial ischemia, intracoronary administration of adenosine caused an increase in blood flow to the post-stenotic myocardial region, indicating the presence of vasodilator reserve. Furthermore, vasomotor responses to vasoactive agents may actually be more prominent in ischemic regions than in normal myocardium. Thus, inhibition of nitric oxide production with N-nitro-L-arginine had no effect on myocardial blood flow during treadmill exercise in normal hearts, but resulted in vasoconstriction with a further decrease in blood flow to ischemic myocardial regions. Similarly, adenosine receptor blockade with 8-phenyltheophyl-line did not alter coronary blood flow in normal hearts, but produced coronary vasoconstriction in myocardial regions which became ischemic during exercise. Vasoactive agents may have special importance in modulating the transmural distribution of perfusion by causing vasomotor changes of the penetrating coronary arteries which deliver blood to the subendocardium. Thus, in the presence of a coronary stenosis which resulted in subendocardial ischemia during exercise, semtonin, caused worsening of the subendocardial hypopeffusion with no change in blood flow to the superficial myocardial layers. Conversely, the nitro-ester ITF 296 or isosorbide dinitrate enhanced perfusion of the ischemic subendocardium during exercise in the presence of a flowlimiting coronary stenosis. These results suggest that by dilating the penetrating arteries these compounds are able to improve subendocardial perfusion.
The discovery in the late 80's of the s)aatheses of nitric oxide (NO) by mammalian cells and the elucidation of its role in a variety of cells and biological processes, has opened up a new field of research. Since then the biology of NO and the L-arginine: NO pathway in the cardiovascular system, the central nervous system, in immunity and inflammation has attracted increasing numbers of researchers and has continued to progress. Advances in our understanding of the L-arginine: NO pathway in health and disease have been facilitated by increased understanding of the molecular biology and biochemistD' of this important mediator. The goal of exploiting our understanding of the L-arginine: NO pathway in novel therapeutics remains elusive, although considerable effort and investment has been made. This presentation will review novel findings in NO research and consider their relevance to our understanding of physiology, pathophysiology and potential therapeutics.
Novel Nitrovasodilators and non-nitrate agents as new drugs for the management of ischaemic heart disease. Jacques Mizrah b Marco Sard|na, Gianni Gromo. Italfarmaco Research Centre. Milano.Italy.
Unanswered Question's Concerning Nitro-Dilator Tolerance E. Bassenge. Inst. of Applied Physiology, University of Freiburg, Germany
The Nitrovasodilators have long been used in the treatment of myocardial ischaemia and remain the drug of choice in the therapy for acute and chronic myocardial ischaemia. New organic nitrates have been designed in order to possess incremental improvements over classical nitrovasodilators and thus to have - a preferential effect on large conductance arterial vessels, especially in the coronary tree - a reduced potential to develop tolerance on tong-term administration and - only a specific nitric oxide mediated action. Both ITF 296 and ITFl129, have shown in various animal models, either after intravenous o r oral administration, marked anti-ischaemic properties, namely a significant reduction of vasospasm-induced ECG abnormalities, a pronounced increase in perfusion in the ischaemic zone but not in the normal zones in the conscious dog subjected to a coronary stenosis plus treadmill exercise and a clear-cut increase of collateral blood flow in both the inner and the outer layers of the ischaemic border' zone when an acute myocardial infarction is generated by insertion of a copper coil into coronary arteries. Moreover, during the 5-days continuous infusion of ITF 296 or ITF 1129 in the conscious dog, the coronary vasodilating effect is well maintained and no major changes in blood pressure were observed. The increase of venous compliance was rather moderate as compared with SIN-1 or Nitroglycerin which may indicate a more balanced action of ITF 296 on arterial and venous beds. There is thus reason to believe that ITF 296 could be a useful drug to explore the importance of coronary vessel dysfunction in stable angina pectoris. Alternatively to nitrovasodilators, new chemical entities have been proposed to the management of cardiac ischaemic syndromes. The antiischaemic actions of these compounds take place in the absence of measurable changes in the parameters known to affect the supplydemand ratio and have been ascribed to a direct, not nitric-oxide mediated protective effect on myocardium. Such compounds could herald a new class of anti-anginal drugs and provide a valuable model for an innovative approach to the study of the intracellular consequences of ischaemia and its treatment.
Continuous, non-intermittent nitrovasodilator therapy induces drug tolerance. This is a multifactorial phenomenon to which a large spectrum of mechanisms contribute in a changing proportion. In the clinical setting the initiation of various counterregulatory mechanisms such as enhanced sympathetic and renin-AII-activity is a major determinant. When higher concentrations of NO-donors under pharmacological conditions were applied, a limited metabolic conversion into NO (reduced cGMP production) was considered in addition t o a desensitization of guanulyl cyclase or an increase in phosphodiesterase activity. Recently it could be shown that the formation of the NO-radical is accompanied by the simultaneous formation of a number of NOx-radicals and O2-derived radicals wich inhibit (probably by oxidation) the enzymes involved in the formation and release of NO. Consequently it could be demonstrated that the simultaneous administration of various antioxidants (Vit. E and C, DMSO etc) are capable of interfering with this unwanted oxidative interactions thereby completely inhibiting the induction of tolerance to NO-donors. Different NO-donors are obviously associated with different rates of NOx- and O2--radical production, resulting in different rates and time courses of tolerance induction, which is - as a new finding (Fink et al FASEB J. 1995)- reflected by a parallel shift in cGMP-dependent platelet activity.
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