Thiol-Containing Agents in the Management of Unstable Angina Pectoris and Acute Myocardial Infarction JOHN D.
HOROWlTZ, M.B., B.S., Ph.D., Woodville, Australia
The development of unstable angina pectoris and acute myocardial infarction is a process of platelet aggregation and thrombus formation associated with local coronary vasoconstriction. Regional deficiencies in endothelial vasodilator function, due to reduced formation of endothelium-derived relaxing factor (EDRF), may predispose to platelet aggregation and coronary vasoconstriction. Nitroglycerin (NTG), frequently utilized in the management of unstable angina pectoris and acute myocardial infarction, undergoes bioconversion, via a sulfhydryl-dependent process, to nitric oxide, which is identical or closely related to EDRF, Other products of the nitrate bioconversion "cascade" are various S-nitrosothiols, which, like nitric oxide, activate soluble guanylate cyclase, inducing increased formation of cyclic guanosine monophosphate. NTG potentially may act to correct a localized deficiency of EDRF effect, at both the vasculature and platelet levels. In patients with unstable angina, hemody, namic effects and therapeutic efficacy of intravenously infused NTG m a y be attenuated within hours. Combined therapy with NTG and intravenously infused N-acetyleysteine (NAC) results in potentiation of hemodynamic responses to NTG, markedly augments the effects of NTG on platelet aggregation, and reduces the incidence of acute myocardial infarction in patients with severe unstable angina pectoris. The combination of NTG with intermittent NAC infusion may increase the risk of hypotensive episodes in such patients, whereas
From the Department of Cardiology,The Queen ElizabethHospital,Woodville, Australia. This work was supported in part by grants from the National Health and Medical Research Council of Australia. Requests for reprints should be addressedto John D. Horowitz, Ph.D., Department of Cardiology,The Queen Elizabeth Hospital, University of Adelaide, Woodville S.A. 5011, Australia. i
continuous coinfusion of the drugs is better tolerated. The combination of NTG with thiolcontaining agents, such as NAC, may be of therapeutic value in unstable angina pectoris and in evolving acute myocardial infarction. This is currently under investigation. nstable angina pectoris, a clinically heterogeneous disorder [1], is linked to platelet aggreU gation and nonocclusive coronary thrombosis, secondary to fissure or rupture of atheromatous plaques [2-4]. It appears that a number of factors lead to increased tone of vascular smooth muscle in patients with unstable angina and may aggravate the extent of resultant ischemia. For example, impaired endothelial function in patients with coronary atheroma [5] is evidenced by a local loss of effects of the dilator materials, endothelium-derived relaxing factor (EDRF) [6] and prostacyclin (PGt2). EDRF and PGI2 inhibit platelet aggregation [7], but the role of EDRF deficiency may be a significant factor predisposing to local vasoconstriction.
ROLE OF NITRATES IN UNSTABLEANGINA PECTORIS Studies have identified EDRF as either the free nitric oxide (NO) radical [8] or a chemically bound form of NO (S=nitrosothiol) [9,10]. This establishes a common mechanism of vasodilator and antiplatelet effects for EDRF and the organic nitrates, which, like EDRF, are activators of soluble guanylate cyclase [11]. Previous studies suggest that bioconversion of nitrates such as nitroglycerin (NTG) involves a "cascade" that includes NO and S-nitrosothiols [12,13] as components. NTG and similar exogenous activators of soluble guanylate cyclase may correct a localized deficiency of EDRF secretion in patients with coronary atheroma. Apart from the functional antagonism between vasodilator agents, such as EDRF (or NTG) and platelet-derived vasoconstrictors such as thromboxane A2 [12] or 5-hydroxytryptamine (serotonin), endogenous or exogenous NO may critically modulate responses to the vasoconstrictor peptide endothelin, synthesized in endothelial cells in re-
September 30, 1991 The American Journal of Medicine Volume 91 (suppl 3C)
3C-113S
SYMPOSIUM ON OXIDANTSAND ANTIOXIDANTS/ HOROWITZ
sponse to thrombin and/or epinephrine exposure. Endothelin-induced vasoconstriction is more readily reversible by nitrovasodilators or NO than by calcium antagonists [14,15]. Endothelin release may be inhibited by NO [16]. Theoretically, it seems practicable to utilize agents such as nitrovasodilators that readily induce vasodilator effects in response to agents released at sites of coronary thrombosis. Another argument in favor of the use of nitrates in unstable ischemic syndromes is the potential for dilation in the region of stenosed coronary artery and collateral vessels. Studies of the effects of nitrates on the coronary circulation indicate a preferential dilation of vessels supplying potentially ischemic regions of myocardium, with little potential for the induction of"coronary steal" [17,18].
CLINICAL EFFICACY OF NITRATE AND OTHER PHARMACOTHERAPY IN UNSTABLE ANGINA PECTORIS TheraPeutic options in patients with unstable angina pectoris must consider the extent of myocardial ischemia and the symptomatic status. The major goals of successful therapy should be suppression of anginal symptoms and minimization of the risk of acute myocardial infarction (MI). Pharmacotherapeutic objectives in individual patients may be either short term (until patients undergo interventions such as coronary angioplasty or coronary artery bypass surgery) or long term. Short-term studies in patients with severe ischemic symptoms and threatened infarction have established that/3-adrenoceptor antagonists are relatively ineffective in decreasing the incidence of recurrent ischemic pain and/or acute MI [19,20]. Studies with calcium antagonists show heterogeneous results, but raise the possibility that dihydropyridines, such as nifedipine, may increase the risk of further ischemic events [19], while verapamil and diltiazem may decrease the incidence of ischemic symptoms [20,21] and coronary artery occlusion. Agents that may limit or reverse thrombus formation have also been investigated. In patients with severe ischemic symptoms, heparin is more effective than aspirin in relieving pain and preventing acute MI [22]. Long-term studies with aspirin (in patients with less severe ischemia) have established its effectiveness in reducing the incidence of infarction and death [23,24]. The biochemical mechanisms and the theoretical rationale for nitrate use in unstable angina pectoris are shown in Figure 1. Nitrates have also been studied in patients with acute ischemic syndromes,
3C-114S
including unstable angina pectoris and acute MI. Although there is evidence that nitrates reduce mortality in acute infarction [25], studies in unstable angina pectoris have not shown clear-cut results, even those concerning the "lesser" end points of symptom relief and prevention of acute infarction. These may be due to the extent of variable contribution of nonnitrate antianginals during multiple drug therapy, and to the uncertainty of the optimal nitrate treatment regimen in such patients. While there is agreement, based on the study of Curfman et al [26], that initial administration of prophylactic nitrates should be intravenous, the issue of optimal infusion rates of NTG in patients with unstable angina is unresolved, other than that the infusion should not induce more that a 15% decrease in mean arterial pressure [27]. It is known that very high NTG infusion rates should be avoided due to the risk of inducing methemoglobihernia [28], drug interactions with heparin [29], or the onset of hemodynamie tolerance to NTG. The induction of tolerance to nitrates is clinically important where intermittent nitrate administration is likely to be suboptimal. A number of studies show that NTG infusion rates of 50 /~g/min or greater induce a reduction in responsiveness to NTG within a few hours [30-32], while changes in vascular tone are induced by far lower infusion rates in nontolerant patients [33]. Optimal utilization of intravenous NTG in such patients involves infusion rates of 5 to 20/~g/min under most circumstances. Therapeutic efficacy is reduced by continuous administration of more than low doses of nitrates.
RATIONALE FOR COMBINED NITRATE-THIOL ADMINISTRATION IN UNSTABLE ANGINA PECTORIS The NitroglycerinBioconversion"Cascade" and Nitrate Tolerance Nitrates such as NTG and isosorbide dinitrate undergo bioconversion to nitric oxide and Snitrosothiols, and activate soluble guanylate cyclase. Nitrate tolerance represents a failure of this bioconversion process at the initial step, which is catalyzed by sulfhydryl (SH)-containing agents such as glutathione [34,35], and is associated with depletion of tissue SH content. While formation of S-nitrosothiols and NO is probably decreased under nitrate tolerance conditions, this has not been studied in detail. However, guanylate cyclase activators such as the S-nitrosothiols, which do not undergo SH-dependent denitration, are less likely to induce tolerance than NTG [36,37].
September 30, I991 The American Journal of Medicine Volume91 (suppl 3C)
SYMPOSIUM ON OXIDANTS AND ANTIOXIDANTS/ HOROWlTZ
SH
SS
NTG
DINITRATES (less active)
) Organic nitrate %) ester reductase NO2-
HOROWlTZ, M.B., B.S., Ph.D., Woodville, Australia
The development of unstable angina pectoris and acute myocardial infarction is a process of platelet aggregation and thrombus formation associated with local coronary vasoconstriction. Regional deficiencies in endothelial vasodilator function, due to reduced formation of endothelium-derived relaxing factor (EDRF), may predispose to platelet aggregation and coronary vasoconstriction. Nitroglycerin (NTG), frequently utilized in the management of unstable angina pectoris and acute myocardial infarction, undergoes bioconversion, via a sulfhydryl-dependent process, to nitric oxide, which is identical or closely related to EDRF, Other products of the nitrate bioconversion "cascade" are various S-nitrosothiols, which, like nitric oxide, activate soluble guanylate cyclase, inducing increased formation of cyclic guanosine monophosphate. NTG potentially may act to correct a localized deficiency of EDRF effect, at both the vasculature and platelet levels. In patients with unstable angina, hemody, namic effects and therapeutic efficacy of intravenously infused NTG m a y be attenuated within hours. Combined therapy with NTG and intravenously infused N-acetyleysteine (NAC) results in potentiation of hemodynamic responses to NTG, markedly augments the effects of NTG on platelet aggregation, and reduces the incidence of acute myocardial infarction in patients with severe unstable angina pectoris. The combination of NTG with intermittent NAC infusion may increase the risk of hypotensive episodes in such patients, whereas
From the Department of Cardiology,The Queen ElizabethHospital,Woodville, Australia. This work was supported in part by grants from the National Health and Medical Research Council of Australia. Requests for reprints should be addressedto John D. Horowitz, Ph.D., Department of Cardiology,The Queen Elizabeth Hospital, University of Adelaide, Woodville S.A. 5011, Australia. i
continuous coinfusion of the drugs is better tolerated. The combination of NTG with thiolcontaining agents, such as NAC, may be of therapeutic value in unstable angina pectoris and in evolving acute myocardial infarction. This is currently under investigation. nstable angina pectoris, a clinically heterogeneous disorder [1], is linked to platelet aggreU gation and nonocclusive coronary thrombosis, secondary to fissure or rupture of atheromatous plaques [2-4]. It appears that a number of factors lead to increased tone of vascular smooth muscle in patients with unstable angina and may aggravate the extent of resultant ischemia. For example, impaired endothelial function in patients with coronary atheroma [5] is evidenced by a local loss of effects of the dilator materials, endothelium-derived relaxing factor (EDRF) [6] and prostacyclin (PGt2). EDRF and PGI2 inhibit platelet aggregation [7], but the role of EDRF deficiency may be a significant factor predisposing to local vasoconstriction.
ROLE OF NITRATES IN UNSTABLEANGINA PECTORIS Studies have identified EDRF as either the free nitric oxide (NO) radical [8] or a chemically bound form of NO (S=nitrosothiol) [9,10]. This establishes a common mechanism of vasodilator and antiplatelet effects for EDRF and the organic nitrates, which, like EDRF, are activators of soluble guanylate cyclase [11]. Previous studies suggest that bioconversion of nitrates such as nitroglycerin (NTG) involves a "cascade" that includes NO and S-nitrosothiols [12,13] as components. NTG and similar exogenous activators of soluble guanylate cyclase may correct a localized deficiency of EDRF secretion in patients with coronary atheroma. Apart from the functional antagonism between vasodilator agents, such as EDRF (or NTG) and platelet-derived vasoconstrictors such as thromboxane A2 [12] or 5-hydroxytryptamine (serotonin), endogenous or exogenous NO may critically modulate responses to the vasoconstrictor peptide endothelin, synthesized in endothelial cells in re-
September 30, 1991 The American Journal of Medicine Volume 91 (suppl 3C)
3C-113S
SYMPOSIUM ON OXIDANTSAND ANTIOXIDANTS/ HOROWITZ
sponse to thrombin and/or epinephrine exposure. Endothelin-induced vasoconstriction is more readily reversible by nitrovasodilators or NO than by calcium antagonists [14,15]. Endothelin release may be inhibited by NO [16]. Theoretically, it seems practicable to utilize agents such as nitrovasodilators that readily induce vasodilator effects in response to agents released at sites of coronary thrombosis. Another argument in favor of the use of nitrates in unstable ischemic syndromes is the potential for dilation in the region of stenosed coronary artery and collateral vessels. Studies of the effects of nitrates on the coronary circulation indicate a preferential dilation of vessels supplying potentially ischemic regions of myocardium, with little potential for the induction of"coronary steal" [17,18].
CLINICAL EFFICACY OF NITRATE AND OTHER PHARMACOTHERAPY IN UNSTABLE ANGINA PECTORIS TheraPeutic options in patients with unstable angina pectoris must consider the extent of myocardial ischemia and the symptomatic status. The major goals of successful therapy should be suppression of anginal symptoms and minimization of the risk of acute myocardial infarction (MI). Pharmacotherapeutic objectives in individual patients may be either short term (until patients undergo interventions such as coronary angioplasty or coronary artery bypass surgery) or long term. Short-term studies in patients with severe ischemic symptoms and threatened infarction have established that/3-adrenoceptor antagonists are relatively ineffective in decreasing the incidence of recurrent ischemic pain and/or acute MI [19,20]. Studies with calcium antagonists show heterogeneous results, but raise the possibility that dihydropyridines, such as nifedipine, may increase the risk of further ischemic events [19], while verapamil and diltiazem may decrease the incidence of ischemic symptoms [20,21] and coronary artery occlusion. Agents that may limit or reverse thrombus formation have also been investigated. In patients with severe ischemic symptoms, heparin is more effective than aspirin in relieving pain and preventing acute MI [22]. Long-term studies with aspirin (in patients with less severe ischemia) have established its effectiveness in reducing the incidence of infarction and death [23,24]. The biochemical mechanisms and the theoretical rationale for nitrate use in unstable angina pectoris are shown in Figure 1. Nitrates have also been studied in patients with acute ischemic syndromes,
3C-114S
including unstable angina pectoris and acute MI. Although there is evidence that nitrates reduce mortality in acute infarction [25], studies in unstable angina pectoris have not shown clear-cut results, even those concerning the "lesser" end points of symptom relief and prevention of acute infarction. These may be due to the extent of variable contribution of nonnitrate antianginals during multiple drug therapy, and to the uncertainty of the optimal nitrate treatment regimen in such patients. While there is agreement, based on the study of Curfman et al [26], that initial administration of prophylactic nitrates should be intravenous, the issue of optimal infusion rates of NTG in patients with unstable angina is unresolved, other than that the infusion should not induce more that a 15% decrease in mean arterial pressure [27]. It is known that very high NTG infusion rates should be avoided due to the risk of inducing methemoglobihernia [28], drug interactions with heparin [29], or the onset of hemodynamie tolerance to NTG. The induction of tolerance to nitrates is clinically important where intermittent nitrate administration is likely to be suboptimal. A number of studies show that NTG infusion rates of 50 /~g/min or greater induce a reduction in responsiveness to NTG within a few hours [30-32], while changes in vascular tone are induced by far lower infusion rates in nontolerant patients [33]. Optimal utilization of intravenous NTG in such patients involves infusion rates of 5 to 20/~g/min under most circumstances. Therapeutic efficacy is reduced by continuous administration of more than low doses of nitrates.
RATIONALE FOR COMBINED NITRATE-THIOL ADMINISTRATION IN UNSTABLE ANGINA PECTORIS The NitroglycerinBioconversion"Cascade" and Nitrate Tolerance Nitrates such as NTG and isosorbide dinitrate undergo bioconversion to nitric oxide and Snitrosothiols, and activate soluble guanylate cyclase. Nitrate tolerance represents a failure of this bioconversion process at the initial step, which is catalyzed by sulfhydryl (SH)-containing agents such as glutathione [34,35], and is associated with depletion of tissue SH content. While formation of S-nitrosothiols and NO is probably decreased under nitrate tolerance conditions, this has not been studied in detail. However, guanylate cyclase activators such as the S-nitrosothiols, which do not undergo SH-dependent denitration, are less likely to induce tolerance than NTG [36,37].
September 30, I991 The American Journal of Medicine Volume91 (suppl 3C)
SYMPOSIUM ON OXIDANTS AND ANTIOXIDANTS/ HOROWlTZ
SH
SS
NTG
DINITRATES (less active)
) Organic nitrate %) ester reductase NO2-
