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The therapeutic role of drugs acting on cardiovascular dopamine receptors
The Therapeutic
Role of Drugs Acting on Cardiovascular Dopamine Receptors Michael B. Murphy, MD
F
ROM ITS SYNTHESIS in 1910 until the early 1940s dopamine was considered to be similar to norepinephrine and epinephrine in its pharmacological effects because of the pressor response it induced in several animal models.’ However, in 1942, Holtz and Credner* demonstrated that in contrast to the other two sympathomimetic amines, low doses of dopamine could induce a hypotensive effect in the guinea pig. This observation was confirmed in 1959 by Goldberg and Sjoerdsma,3 who demonstrated that low infusion rates of dopamine lowered diastolic blood pressure in the anesthetized dog while increasing cardiac contractile force and heart rate. At higher doses, it increased systemic vascular resistance. Thus ended the long search for a sympathomimetic agent that could increase cardiac output without enhancing peripheral vasoconstriction, which might be useful in the treatment of congestive heart failure. In subsequent human experiments, Goldberg4 made an unexpected observation that dopamine infusion also enhanced diuresis and natriuresis in patients with heart failure. Although he attributed this initially to improved cardiac output, he learned quickly from experiments in the anesthetized dog that dopamine had particularly marked effects in the kidney, combining large increases in renal blood flow and enhanced sodium excretion.5 Further experiments over the past 20 years have elucidated the receptors mediating these effects and have facilitated the clinical use of dopamine in many conditions. In addition, they have allowed the development of newer compounds targeted at individual receptors activated by dopamine, permitting more specific therapy.
ceptors are also found on renal tubular cells where their activation inhibits sodium reabsorption, facilitating natriuresis. DA2 receptors are found on sympathetic neuronal terminals, are also linked to adenylate cyclase, but inhibit its activity and diminish norepinephrine release. They are also found on ganglia where their stimulation inhibits impulse transmission. Accordingly, activation of DA2 receptors also leads to reduction in vascular resistance. Thus, vasodilation through activation of DAi and DA2 receptors is the primary response to the infusion of low-dose dopamine (approximately 0.5 to 2 pg/kg/min) in humans. Infusion at these low doses is frequently referred to as “renal dopamine” because the primary effect is enhanced renal blood flow with diuresis. As the infusion rate is increased (approximately 2 to 4 pg/kg/min) and the circulating concentration of dopamine increases, fi-adrenoceptors are activated. This leads to increased heart rate and cardiac contractility with enhanced cardiac output. This dose range is most appropriate for the treatment of congestive heart failure because it combines improvement in cardiac output with enhanced renal blood flow and diuresis. As the infusion rate of dopamine is increased further, a-adrenoceptor stimulation occurs, leading to arterial vasoconstriction with increased peripheral resistance. This infusion rate is most appropriate for the treatment of circulatory shock. However, it should be noted that although vasoconstriction is noted at infusion rates as low as 5 pg/kg/min in normal volunteers, doses exceeding 20 pglkglmin may be required to achieve this effect in patients with shock.
RECEPTORS ACTED ON BY DOPAMINE
The introduction of dopamine by Goldberg and his colleagues for the treatment of heart fail-
Dopamine is an agonist at several different receptors6 among which two are unique, DAi and DA*. DA1 receptors are located on vascular smooth muscle cells, are linked to adenylate cyclase, and mediate smooth muscle relaxation. They are found in the skeletal, coronary, cerebral, and cutaneous arteries, but are most numerous in the renal and mesenteric vasculature. DA, rehma/
ofCardiorhomcic Anesthesia, Vol4,
No 4,
Suppl 1
MODERN USE OF DOPAMINE IN CRITICAL CARE MEDICINE
From the Committee on Clinical Pharmacology, University of Chicago, Chicago, IL. Address reprint requests to Michael B. Murphy, MD, Committee on Clinical Pharmacology, University of Chicago, 947 E 58th St, Abbott Hall 504, Chicago, IL 60637. 0 1990 by W.B. Saunders Company. 0888-6296/90/0404-1004$03.00/O
(August), 1990: pp 23-26
23
MICHAEL B. MURPHY
24
ure and circulatory shock was a milestone in the treatment of these conditions. The mosaic of pharmacological effects of the drug was perfectly matched to the hemodynamic abnormalities. For example, in the treatment of shock, dopamine exhibits complementary effects in increasing cardiac output by &receptor stimulation to increase systemic blood pressure; simultaneously through DA,-receptor stimulation, it protects perfusion of vital organs such as the brain, heart, and kidney by selectively enhancing flow to these areas. On the other hand, the wide interindividual variability in the dose or concentration-effect relationships has led to a reevaluation of its role in modem practice. Accordingly, dopamine may be used as an adjunct to other therapy, combining its renal effects at low dose with the hemodynamic effects of a second drug chosen to specifically counteract the hemodynamic abnormality. In the treatment of heart failure, dopamine is now frequently combined with the /3-adrenergic agonist dobutamine. For example, El Allaf et al’ have investigated the effects of low-dose dopamine (2.5 pg/kg/min) or dobutamine (approximately 7 pg/kg/min) alone and in combination. In 12 patients experiencing heart failure following acute myocardial infarction, combining dopamine with dobutamine led to a doubling of urine flow rate without altering the hemodynamic benefits of dobutamine. The combination increased cardiac output, but the addition of dopamine enhanced renal function to an extent not achievable with dobutamine alone. Comparable results have been achieved when low-dose dopamine has been added to nitroglycerin8 A similar approach has also been applied in the treatment of shock where enhanced cardiac output, vasoconstriction of some vascular beds, and concomitant preservation of flow to vital organs are simultaneous objectives. In this case, inotropy and vasoconstriction can be achieved by incremental norepinephrine infusions, whereas renal function can be preserved by combining it with a low-dose dopamine infusion.9 DOPAMINE PRO-DRUGS
The clinical use of dopamine has been limited by two factors: the complicated nature of its pharmacology resulting from stimulation of several different receptors, and its poor oral bioavailability resulting from oxidation and conju-
gation in the gut and liver. Attempts to circumvent limited oral bioavailability have largely focused on the development of pro-drugs that reach the systemic circulation following oral administration, with subsequent biotransformation to dopamine or other entities active at dopamine receptors. Levodopa, which is converted to dopamine by the enzyme dopadecarboxylase, has been the most widely studied pro-drug. Used for many decades in the treatment of Parkinson’s disease, where it is coadministered with the peripheral decarboxylase inhibitor carbidopa, it permits the achievement of therapeutic concentrations of dopamine within the central nervous system. On the other hand, administration of levodopa alone leads to the generation of significant amounts of dopamine in the circulation with predictable hemodynamic effects. In recent years, Rajfer et al”,” have demonstrated the beneficial hemodynamic effects of oral levodopa in patients with congestive heart failure. Although its use may be limited by nausea, dysrhythmias, or orthostatic hypotension, it has proved highly efficacious. Further evaluation of its effects on exercise tolerance, sense of well-being, and long-term prognosis remains to be completed. Ibopamine, the diisobuteric ester of nmethyl dopamine (epinine), is already marketed in several countries for the long-term oral treatment of heart failure. Following oral absorption, it is deesterified releasing epinine, an agonist at DA1 , a-, and P-adrenoceptors. Although there is controversy about the long-term efficacy of ibopamine, several short-term studies have confirmed its inotropic effects.‘2,‘3 SELECTIVE DOPAMINE-RECEPTOR AGONISTS
A major goal of research in dopamine pharmacology during the past three decades has been the development of drugs that might act specifically at dopamine receptors. Recently a novel compound, a benzazepine derivative, fenoldopam, has been investigated.‘4s’5 Although subject to extensive presystemic metabolism and requiring parenteral administration, it is devoid of activity at DA2, fi- and a-adrenoceptors at therapeutic concentrations. Its plasma half-life is approximately 9 minutes. l 5 Several studies in patients with hypertension have demonstrated the hypotensive efficacy
CARDIOVASCULAR
DOPAMINE
RESPONSES
25
of fenoldopam. i6,” It lowers blood pressure in mild hypertensives in a dose-dependent fashion and the blood pressure reduction is accompanied by slight tachycardia. Like low-dose dopamine, fenoldopam increases renal blood flow and sodium and water excretion.” In a recent study comparing fenoldopam with nitroprusside in the treatment of severe hypertension, both drugs were equally effective in lowering pressure, but fenoldopam increased creatinine clearance and sodium excretion, whereas nitroprusside either had no effect or reduced these indices. l9 Accordingly, it seems that fenoldopam might be a particularly useful drug in the treatment of patients with severe hypertension and renal impairment with the potential of avoiding the need for the short-term dialysis sometimes required following acute blood pressure reduction in these patients. Studies in anesthetized dogs have also suggested that fenoldopam may offer an advantage over nitroprusside in the achievement of controlled intraoperative hypotension. 2o Whereas nitroprusside reduced renal blood flow as systemic blood pressure was reduced, fenoldopam increased flow in the face of similar blood pressure reduction. However, this application has not yet been studied in humans. SELECTIVE DA,-RECEPTOR AGONISTS
The DA2-receptor agonist bromocriptine has been used for many years in the treatment of Parkinson’s disease and in suppressing prolac-
tin secretion from pituitary tumors. By activating peripheral DA2 receptors, bromocriptine has also been shown to lower blood pressure. Administration of bromocriptine, 5 to 15 mg twice daily, lowered blood pressure by about 20 mm Hg in patients with mild to moderate essential hypertension. These data were confirmed in several studies of both normotensive and hypertensive patients. 2’322However, DA2-receptor agonism has the distinct disadvantage of inducing nausea and vomiting, and this adverse reaction, coupled with the expense of bromocriptine, has prevented its widespread use in the treatment of hypertension. Hydergine, a mixture of several ergot alkaloids that are selective for DA2 receptors, has also been examined in clinical studies in hypertension.23 They confirm its ability to lower blood pressure, but the side-effect profile was similar to that of bromocriptine. SUMMARY
The introduction of dopamine heralded a new era in cardiovascular pharmacology and critical care. With the advent of new selective adrenergic-receptor agonists, its role has been modified to that of adjunctive therapy, although it is still widely used as primary therapy. Efforts continue to circumvent its poor bioavailability by the use of pro-drugs or the development of orally bioavailable selective agonists. The recent development of fenoldopam is a significant advance in the role of the dopaminergic system in the treatment of cardiovascular disease.
REFERENCES I. Goldberg Ll: Cardiovascular and renal actions of dopamine: Potential clinical applications. Pharmacol Rev 24: l-29, 1972 2. Holtz P, Credner K: Die enzymatische Entstehung von Oxytyramin im Organismus und die physiologische Bedeutung der dopadecarboxylase. Arch Pharmacol Exp Path01 200~356-388, 1942 3. Goldberg LI, Sjoerdsma A: Effects of several monoamine oxidase inhibitors on the cardiovascular actions of naturally occurring amines in the dog. J Pharmacol Exp Ther 127:212-218, 1959 4. Goldberg LI: The pharmacological basis of the clinical use of dopamine. Proc R Sot Med 70:7-15, 1977 5. McDonald RH, Goldberg LI: Analysis of the cardiovascular effects of dopamine in the dog. J Pharmacol Exp Ther 140:60-66, I963 6. Lokhandwala MF, Barrett RJ: Cardiovascular dopamine receptors: Physiological, pharmacological and therapeutic implications. J Autonom Pharmacol3: 189-2 15, 1982 7. El Allaf D, Cremers S, D’Orio V, et al: Combined
hemodynamic effects of low doses of dopamine and dobutamine in patients with acute infarction and cardiac failure. Arch Int Physiol Biochim 92:S49-S55, 1986 (suppl) 8. Loeb HS, Ostrenga JP, Gaul W, et al: Beneficial effects of dopamine combined with intravenous nitroglycerin on hemodynamics in patients with severe left ventricular failure. Circulation 68:s 13-820, 1982 9. Schaer GL, Fink MP, Parrillo JE: Norepinephrine alone versus norepinephrine plus low-dose dopamine: Enhanced renal blood flow with combination pressor therapy. Crit Care Med 13:492-496, 1985 10. Rajfer Sl, Anton AH, Rossen JD, et al: Beneficial hemodynamic effects of oral levodopa in heart failure: Relation to the generation of dopamine. N Engl J Med 3 10: 1357- 1362, 1984 11. Rajfer SI, Rossen JD, Nemanich JW, et al: Sustained hemodynamic improvement during long-term therapy with levodopa in heart failure: Role of plasma catecholamines. J Am Coll Cardiol l&1286-1293, 1987 12. Itoh H, Kohli JD, Rajfer SI, et al: Comparison of
26 the cardiovascular actions of dopamine and epinine in the dog. J Pharmacol Exp Ther 23387-93, 1985 13. Dei Cass L, Bolognesi R, Cucchini F, et al: Hemodynamic effects of ibopamine in patients with idiopathic congestive cardiomyopathy. J Cardiovasc Pharmacol 5:249253, 1983 14. Hahn RA, Wardell JR Jr, Sarau HM, et al: Characterization of the peripheral and central effects of SK&F 82526, a novel dopamine receptor agonist. J Pharmacol Exp Ther 223:305-311, 1982 15. Weber RR, McCoy CE, Ziemniak JA, et al: Pharmacokinetic and pharmacodynamic properties of intravenous fenoldopam, a dopamine,-receptor agonist, in hypertensive patients. Br J Clin Pharmacol 25: 17-2 1, 1988 16. White WB, Radford MJ, Gonzalez FM, et al: Selective dopamine, agonist therapy in severe hypertension: Effects of intravenous fenoldopam. J Am Co11Cardiol 11: 11181123, 1988 17. Carey RM, Stote RM, Dubb JW, et al: Selective peripheral dopaminei-receptor stimulation with fenoldopam in human essential hypertension. J Clin Invest 74:2 198-2207, 1984 18. Murphy MB, McCoy CE, Weber RR, et al: Augmentation of renal blood flow and sodium excretion in hy-
MICHAEL B. MURPHY
pertensive patients during blood pressure reduction by intravenous administration of the dopamine, agonist fenoldopam. Circulation 76:1312-1318, 1987 19. Elliott WJ, Weber RR, Nelson KS, et al: Renal and cardiovascular effects of intravenous fenoldopam or nitroprusside in severe hypertension. Circulation 8 1:970-977, 1990 20. Aronson S, Roth S, Glock D, et al: Preservation of renal blood flow during controlled hypotension with fenoldopam. Clin Res 35:88 1A, 1987 2 1. Mercuro G, Rossetti ZL, Tocco L, et al: Bromocriptine reduces plasma noradrenaline and 3,4-dihydroxyphenylacetic acid in normal and hypertensive subjects. Eur J Pharmacol 27:671-675, 1985 22. Whitworth JA, MacDonald I, Kincaid-Smith P: Bromocriptine in mild-to-moderate hypertension. Aust N Z J Med 17:457-458, 1987 23. Mercuro G, Rivano AC, Ruscazio M, et al: Effects of long-term treatment with dihydroergotoxine (hydergine) on blood pressure and plasma norepinephrine in essential hypertensive patients, in Biggie A (ed): Modulation of Central and Peripheral Transmitter Function, Fidia Research Series, Symposia in Neuroscience III. Padua, Italy, Liviana, 1986, pp 189-193
Role of Drugs Acting on Cardiovascular Dopamine Receptors Michael B. Murphy, MD
F
ROM ITS SYNTHESIS in 1910 until the early 1940s dopamine was considered to be similar to norepinephrine and epinephrine in its pharmacological effects because of the pressor response it induced in several animal models.’ However, in 1942, Holtz and Credner* demonstrated that in contrast to the other two sympathomimetic amines, low doses of dopamine could induce a hypotensive effect in the guinea pig. This observation was confirmed in 1959 by Goldberg and Sjoerdsma,3 who demonstrated that low infusion rates of dopamine lowered diastolic blood pressure in the anesthetized dog while increasing cardiac contractile force and heart rate. At higher doses, it increased systemic vascular resistance. Thus ended the long search for a sympathomimetic agent that could increase cardiac output without enhancing peripheral vasoconstriction, which might be useful in the treatment of congestive heart failure. In subsequent human experiments, Goldberg4 made an unexpected observation that dopamine infusion also enhanced diuresis and natriuresis in patients with heart failure. Although he attributed this initially to improved cardiac output, he learned quickly from experiments in the anesthetized dog that dopamine had particularly marked effects in the kidney, combining large increases in renal blood flow and enhanced sodium excretion.5 Further experiments over the past 20 years have elucidated the receptors mediating these effects and have facilitated the clinical use of dopamine in many conditions. In addition, they have allowed the development of newer compounds targeted at individual receptors activated by dopamine, permitting more specific therapy.
ceptors are also found on renal tubular cells where their activation inhibits sodium reabsorption, facilitating natriuresis. DA2 receptors are found on sympathetic neuronal terminals, are also linked to adenylate cyclase, but inhibit its activity and diminish norepinephrine release. They are also found on ganglia where their stimulation inhibits impulse transmission. Accordingly, activation of DA2 receptors also leads to reduction in vascular resistance. Thus, vasodilation through activation of DAi and DA2 receptors is the primary response to the infusion of low-dose dopamine (approximately 0.5 to 2 pg/kg/min) in humans. Infusion at these low doses is frequently referred to as “renal dopamine” because the primary effect is enhanced renal blood flow with diuresis. As the infusion rate is increased (approximately 2 to 4 pg/kg/min) and the circulating concentration of dopamine increases, fi-adrenoceptors are activated. This leads to increased heart rate and cardiac contractility with enhanced cardiac output. This dose range is most appropriate for the treatment of congestive heart failure because it combines improvement in cardiac output with enhanced renal blood flow and diuresis. As the infusion rate of dopamine is increased further, a-adrenoceptor stimulation occurs, leading to arterial vasoconstriction with increased peripheral resistance. This infusion rate is most appropriate for the treatment of circulatory shock. However, it should be noted that although vasoconstriction is noted at infusion rates as low as 5 pg/kg/min in normal volunteers, doses exceeding 20 pglkglmin may be required to achieve this effect in patients with shock.
RECEPTORS ACTED ON BY DOPAMINE
The introduction of dopamine by Goldberg and his colleagues for the treatment of heart fail-
Dopamine is an agonist at several different receptors6 among which two are unique, DAi and DA*. DA1 receptors are located on vascular smooth muscle cells, are linked to adenylate cyclase, and mediate smooth muscle relaxation. They are found in the skeletal, coronary, cerebral, and cutaneous arteries, but are most numerous in the renal and mesenteric vasculature. DA, rehma/
ofCardiorhomcic Anesthesia, Vol4,
No 4,
Suppl 1
MODERN USE OF DOPAMINE IN CRITICAL CARE MEDICINE
From the Committee on Clinical Pharmacology, University of Chicago, Chicago, IL. Address reprint requests to Michael B. Murphy, MD, Committee on Clinical Pharmacology, University of Chicago, 947 E 58th St, Abbott Hall 504, Chicago, IL 60637. 0 1990 by W.B. Saunders Company. 0888-6296/90/0404-1004$03.00/O
(August), 1990: pp 23-26
23
MICHAEL B. MURPHY
24
ure and circulatory shock was a milestone in the treatment of these conditions. The mosaic of pharmacological effects of the drug was perfectly matched to the hemodynamic abnormalities. For example, in the treatment of shock, dopamine exhibits complementary effects in increasing cardiac output by &receptor stimulation to increase systemic blood pressure; simultaneously through DA,-receptor stimulation, it protects perfusion of vital organs such as the brain, heart, and kidney by selectively enhancing flow to these areas. On the other hand, the wide interindividual variability in the dose or concentration-effect relationships has led to a reevaluation of its role in modem practice. Accordingly, dopamine may be used as an adjunct to other therapy, combining its renal effects at low dose with the hemodynamic effects of a second drug chosen to specifically counteract the hemodynamic abnormality. In the treatment of heart failure, dopamine is now frequently combined with the /3-adrenergic agonist dobutamine. For example, El Allaf et al’ have investigated the effects of low-dose dopamine (2.5 pg/kg/min) or dobutamine (approximately 7 pg/kg/min) alone and in combination. In 12 patients experiencing heart failure following acute myocardial infarction, combining dopamine with dobutamine led to a doubling of urine flow rate without altering the hemodynamic benefits of dobutamine. The combination increased cardiac output, but the addition of dopamine enhanced renal function to an extent not achievable with dobutamine alone. Comparable results have been achieved when low-dose dopamine has been added to nitroglycerin8 A similar approach has also been applied in the treatment of shock where enhanced cardiac output, vasoconstriction of some vascular beds, and concomitant preservation of flow to vital organs are simultaneous objectives. In this case, inotropy and vasoconstriction can be achieved by incremental norepinephrine infusions, whereas renal function can be preserved by combining it with a low-dose dopamine infusion.9 DOPAMINE PRO-DRUGS
The clinical use of dopamine has been limited by two factors: the complicated nature of its pharmacology resulting from stimulation of several different receptors, and its poor oral bioavailability resulting from oxidation and conju-
gation in the gut and liver. Attempts to circumvent limited oral bioavailability have largely focused on the development of pro-drugs that reach the systemic circulation following oral administration, with subsequent biotransformation to dopamine or other entities active at dopamine receptors. Levodopa, which is converted to dopamine by the enzyme dopadecarboxylase, has been the most widely studied pro-drug. Used for many decades in the treatment of Parkinson’s disease, where it is coadministered with the peripheral decarboxylase inhibitor carbidopa, it permits the achievement of therapeutic concentrations of dopamine within the central nervous system. On the other hand, administration of levodopa alone leads to the generation of significant amounts of dopamine in the circulation with predictable hemodynamic effects. In recent years, Rajfer et al”,” have demonstrated the beneficial hemodynamic effects of oral levodopa in patients with congestive heart failure. Although its use may be limited by nausea, dysrhythmias, or orthostatic hypotension, it has proved highly efficacious. Further evaluation of its effects on exercise tolerance, sense of well-being, and long-term prognosis remains to be completed. Ibopamine, the diisobuteric ester of nmethyl dopamine (epinine), is already marketed in several countries for the long-term oral treatment of heart failure. Following oral absorption, it is deesterified releasing epinine, an agonist at DA1 , a-, and P-adrenoceptors. Although there is controversy about the long-term efficacy of ibopamine, several short-term studies have confirmed its inotropic effects.‘2,‘3 SELECTIVE DOPAMINE-RECEPTOR AGONISTS
A major goal of research in dopamine pharmacology during the past three decades has been the development of drugs that might act specifically at dopamine receptors. Recently a novel compound, a benzazepine derivative, fenoldopam, has been investigated.‘4s’5 Although subject to extensive presystemic metabolism and requiring parenteral administration, it is devoid of activity at DA2, fi- and a-adrenoceptors at therapeutic concentrations. Its plasma half-life is approximately 9 minutes. l 5 Several studies in patients with hypertension have demonstrated the hypotensive efficacy
CARDIOVASCULAR
DOPAMINE
RESPONSES
25
of fenoldopam. i6,” It lowers blood pressure in mild hypertensives in a dose-dependent fashion and the blood pressure reduction is accompanied by slight tachycardia. Like low-dose dopamine, fenoldopam increases renal blood flow and sodium and water excretion.” In a recent study comparing fenoldopam with nitroprusside in the treatment of severe hypertension, both drugs were equally effective in lowering pressure, but fenoldopam increased creatinine clearance and sodium excretion, whereas nitroprusside either had no effect or reduced these indices. l9 Accordingly, it seems that fenoldopam might be a particularly useful drug in the treatment of patients with severe hypertension and renal impairment with the potential of avoiding the need for the short-term dialysis sometimes required following acute blood pressure reduction in these patients. Studies in anesthetized dogs have also suggested that fenoldopam may offer an advantage over nitroprusside in the achievement of controlled intraoperative hypotension. 2o Whereas nitroprusside reduced renal blood flow as systemic blood pressure was reduced, fenoldopam increased flow in the face of similar blood pressure reduction. However, this application has not yet been studied in humans. SELECTIVE DA,-RECEPTOR AGONISTS
The DA2-receptor agonist bromocriptine has been used for many years in the treatment of Parkinson’s disease and in suppressing prolac-
tin secretion from pituitary tumors. By activating peripheral DA2 receptors, bromocriptine has also been shown to lower blood pressure. Administration of bromocriptine, 5 to 15 mg twice daily, lowered blood pressure by about 20 mm Hg in patients with mild to moderate essential hypertension. These data were confirmed in several studies of both normotensive and hypertensive patients. 2’322However, DA2-receptor agonism has the distinct disadvantage of inducing nausea and vomiting, and this adverse reaction, coupled with the expense of bromocriptine, has prevented its widespread use in the treatment of hypertension. Hydergine, a mixture of several ergot alkaloids that are selective for DA2 receptors, has also been examined in clinical studies in hypertension.23 They confirm its ability to lower blood pressure, but the side-effect profile was similar to that of bromocriptine. SUMMARY
The introduction of dopamine heralded a new era in cardiovascular pharmacology and critical care. With the advent of new selective adrenergic-receptor agonists, its role has been modified to that of adjunctive therapy, although it is still widely used as primary therapy. Efforts continue to circumvent its poor bioavailability by the use of pro-drugs or the development of orally bioavailable selective agonists. The recent development of fenoldopam is a significant advance in the role of the dopaminergic system in the treatment of cardiovascular disease.
REFERENCES I. Goldberg Ll: Cardiovascular and renal actions of dopamine: Potential clinical applications. Pharmacol Rev 24: l-29, 1972 2. Holtz P, Credner K: Die enzymatische Entstehung von Oxytyramin im Organismus und die physiologische Bedeutung der dopadecarboxylase. Arch Pharmacol Exp Path01 200~356-388, 1942 3. Goldberg LI, Sjoerdsma A: Effects of several monoamine oxidase inhibitors on the cardiovascular actions of naturally occurring amines in the dog. J Pharmacol Exp Ther 127:212-218, 1959 4. Goldberg LI: The pharmacological basis of the clinical use of dopamine. Proc R Sot Med 70:7-15, 1977 5. McDonald RH, Goldberg LI: Analysis of the cardiovascular effects of dopamine in the dog. J Pharmacol Exp Ther 140:60-66, I963 6. Lokhandwala MF, Barrett RJ: Cardiovascular dopamine receptors: Physiological, pharmacological and therapeutic implications. J Autonom Pharmacol3: 189-2 15, 1982 7. El Allaf D, Cremers S, D’Orio V, et al: Combined
hemodynamic effects of low doses of dopamine and dobutamine in patients with acute infarction and cardiac failure. Arch Int Physiol Biochim 92:S49-S55, 1986 (suppl) 8. Loeb HS, Ostrenga JP, Gaul W, et al: Beneficial effects of dopamine combined with intravenous nitroglycerin on hemodynamics in patients with severe left ventricular failure. Circulation 68:s 13-820, 1982 9. Schaer GL, Fink MP, Parrillo JE: Norepinephrine alone versus norepinephrine plus low-dose dopamine: Enhanced renal blood flow with combination pressor therapy. Crit Care Med 13:492-496, 1985 10. Rajfer Sl, Anton AH, Rossen JD, et al: Beneficial hemodynamic effects of oral levodopa in heart failure: Relation to the generation of dopamine. N Engl J Med 3 10: 1357- 1362, 1984 11. Rajfer SI, Rossen JD, Nemanich JW, et al: Sustained hemodynamic improvement during long-term therapy with levodopa in heart failure: Role of plasma catecholamines. J Am Coll Cardiol l&1286-1293, 1987 12. Itoh H, Kohli JD, Rajfer SI, et al: Comparison of
26 the cardiovascular actions of dopamine and epinine in the dog. J Pharmacol Exp Ther 23387-93, 1985 13. Dei Cass L, Bolognesi R, Cucchini F, et al: Hemodynamic effects of ibopamine in patients with idiopathic congestive cardiomyopathy. J Cardiovasc Pharmacol 5:249253, 1983 14. Hahn RA, Wardell JR Jr, Sarau HM, et al: Characterization of the peripheral and central effects of SK&F 82526, a novel dopamine receptor agonist. J Pharmacol Exp Ther 223:305-311, 1982 15. Weber RR, McCoy CE, Ziemniak JA, et al: Pharmacokinetic and pharmacodynamic properties of intravenous fenoldopam, a dopamine,-receptor agonist, in hypertensive patients. Br J Clin Pharmacol 25: 17-2 1, 1988 16. White WB, Radford MJ, Gonzalez FM, et al: Selective dopamine, agonist therapy in severe hypertension: Effects of intravenous fenoldopam. J Am Co11Cardiol 11: 11181123, 1988 17. Carey RM, Stote RM, Dubb JW, et al: Selective peripheral dopaminei-receptor stimulation with fenoldopam in human essential hypertension. J Clin Invest 74:2 198-2207, 1984 18. Murphy MB, McCoy CE, Weber RR, et al: Augmentation of renal blood flow and sodium excretion in hy-
MICHAEL B. MURPHY
pertensive patients during blood pressure reduction by intravenous administration of the dopamine, agonist fenoldopam. Circulation 76:1312-1318, 1987 19. Elliott WJ, Weber RR, Nelson KS, et al: Renal and cardiovascular effects of intravenous fenoldopam or nitroprusside in severe hypertension. Circulation 8 1:970-977, 1990 20. Aronson S, Roth S, Glock D, et al: Preservation of renal blood flow during controlled hypotension with fenoldopam. Clin Res 35:88 1A, 1987 2 1. Mercuro G, Rossetti ZL, Tocco L, et al: Bromocriptine reduces plasma noradrenaline and 3,4-dihydroxyphenylacetic acid in normal and hypertensive subjects. Eur J Pharmacol 27:671-675, 1985 22. Whitworth JA, MacDonald I, Kincaid-Smith P: Bromocriptine in mild-to-moderate hypertension. Aust N Z J Med 17:457-458, 1987 23. Mercuro G, Rivano AC, Ruscazio M, et al: Effects of long-term treatment with dihydroergotoxine (hydergine) on blood pressure and plasma norepinephrine in essential hypertensive patients, in Biggie A (ed): Modulation of Central and Peripheral Transmitter Function, Fidia Research Series, Symposia in Neuroscience III. Padua, Italy, Liviana, 1986, pp 189-193