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Protecting the Myocardium From Ischemic Injury^*

A Critical Role for ₁-Adrenoreceptors?

^* From the Department of Medicine, Southampton General Hospital, Southampton, UK.

Correspondence to: Sundeep Salvi, MD, DNB, PhD, University Medicine, Level D Centre Block, Southampton General Hospital, Southampton SO16 6YD, UK; e-mail: sundeepsalvi{at}hotmail.com

	Abstract

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Ischemic preconditioning (IPC) refers to the ability of short periods of ischemia to make the myocardium more resistant to a subsequent ischemic insult. It is the most powerful form of endogenous protection against myocardial infarction and has been demonstrated in all species evaluated to date. However, the cellular mechanisms that drive IPC remain poorly understood. This hypothesis describes an important role for ₁-adrenoreceptors in mediating IPC and discusses the underlying mechanisms by which this is likely achieved. ₁-Adrenoreceptors are present in the myocardium of all mammalian species, and several lines of evidence suggest that they play an important role in mediating IPC. During periods of myocardial hypoxia/ischemia, cardiomyocytes have to rely solely on anaerobic glycolysis for energy production; for this, the cells have to depend on increased glucose entry inside the cell as well as increased glycolysis. Stimulation of ₁-adrenoreceptors increases glucose transport inside the cardiomyocytes by translocating glucose transporter (GLUT)-1 and GLUT-4 from the cytoplasm to the plasma membrane, enhances glycogenolysis by activating phosphorylase kinase, increases the rate of glycolysis by activating the enzyme phosphofructokinase, reduces intracellular acidity produced during excessive glycolysis by activating the Na⁺/H⁺ exchanger, and inhibits apoptosis by increasing the levels of the antiapoptotic protein Bcl-2. Myocardial ischemia produces an increase in the expression of ₁-adrenoreceptors in cardiomyocytes, as well as increases the levels of its agonist norepinephrine by several fold. During ischemic states, upregulation of ₁-adrenoreceptors and increase in norepinephrine release could be a powerful adaptive mechanism that drives IPC. An understanding into the role of ₁-adrenoreceptors in mediating IPC could not only point to newer treatments for limiting myocardial damage during myocardial infarction or heart surgery, but could also help in avoiding the use of ₁-antagonists in patients with ischemic heart disease.

Key Words: ₁-adrenoreceptor • apoptosis • glucose • glucose transporter • ischemic preconditioning • Na⁺/H⁺ exchange • phosphofructokinase • protein kinase C

	Introduction

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Ischemic preconditioning (IPC) of the myocardium, a phenomenon first described by Murry et al¹ in 1986, refers to the ability of the heart to protect itself against the detrimental effects of an extended period of ischemia by prior exposure to one or more brief periods of ischemia.² It is a powerful form of endogenous protection and has been demonstrated in all species and experimental models evaluated to date, including humans.² This protection may be manifest as a reduction of infarct size and arrhythmias or an improvement in postischemic function. Patients with acute myocardial infarction preceded by unstable angina show smaller infarct sizes and a beneficial effect on in-hospital outcome when compared to those without preinfarct ischemia.³ IPC also occurs in a variety of other clinical settings, such as aortic cross-clamping before the establishment of extracorporeal circulation and repeated balloon inflation during angioplasty of a coronary artery lesion.²

The possibility that such adaptive mechanisms might be inducible in the human heart has generated considerable excitement. However, despite more than a decade of intensive investigation, the cellular mechanisms that drive this powerful adaptive response remain poorly understood. Several hypotheses have been put forward that suggest a role for adenosine, bradykinin, potassium-adenosine triphosphate (K-ATP) channels, and ₁-adrenoreceptors in mediating IPC.² Among these, ₁-adrenoreceptor-mediated preconditioning has been demonstrated to be more uniform and reported in all animal species studied to date.^{2 4} A substantial body of evidence exists to support the view that ₁-adrenergic stimulation is an important component mechanism in the protection afforded by preconditioning. However, the underlying mechanisms by which this is achieved is not known. Based on the physiologic role of ₁-adrenoreceptors in regulating various cellular functions, this hypothesis ascribes a central role to ₁-adrenoreceptors in mediating IPC and discusses the underlying mechanisms by which this is achieved.

	1-Adrenoreceptors in the Normal Myocardium

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Cardiomyocytes of all mammalian species express _1A-, _1B-, and _1D-adrenoreceptor subtypes, although their numbers represent only 25% to those of ß-adrenoreceptors.⁵ In contrast to ß-adrenoreceptors, ₁-adrenoreceptors are believed to play only a modest role in myocardial contractile function. However, they play an important role in cardiac growth during early development by inducing cardiomyocyte proliferation, while in the adult heart they have been shown to inhibit the generation of atrial and ventricular arrhythmias by decreasing the conduction rate and automaticity of Purkinje fibers.^{4 6}

	1-Adrenoreceptors Play a Role in Mediating IPC

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Several lines of evidence suggest that ₁-adrenoreceptors play an important role in mediating ischemic preconditioning. Pretreatment of rabbit and rat hearts with phenylephrine (a specific ₁-agonist) have demonstrated a significant decrease in infarct size following global ischemia both in vivo and ex vivo.^{7 8} Similarly, IPC-mediated reduction of myocardial infarct size, reduction of ST-segment elevation, and prevention of loss of R wave on ECG monitoring has been shown to be inhibited by prazosin, a specific ₁-antagonist in different animal species.^{9 10 11} Reduction in ST-segment changes and cardiac pain severity during ischemia observed in humans after two sequential coronary balloon inflations have been shown to be abolished by pretreatment with phentolamine, an -antagonist, suggesting that IPC is mediated by -adrenoreceptors in human cardiomyocytes.¹² Moreover, human atrial trabeculae obtained during coronary bypass surgery and subjected to ischemia in vitro demonstrate the development of IPC, which is specifically mediated by ₁-adrenergic receptors.¹³

The underlying mechanism(s) by which ₁-adrenoreceptors mediate IPC remain unknown. To understand this, it is important to know the mechanisms of energy production by cardiomyocytes during normoxic states, and the adaptive response it develops during hypoxic states.

	Energy Production by Cardiomyocytes During Normoxia and During Ischemic/Hypoxic States

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Oxygen, the final acceptor of electrons in the respiratory chain, has become an evolutionary advantage by allowing a complete utilization of energy sources . Under normoxic conditions, cardiac myocytes produce most of their K-ATP by oxidative phosphorylation. It is estimated that 60 to 70% of myocardial energy is obtained from the oxidative metabolism of fatty acids, while the remainder is derived from carbohydrates, ketone bodies, and amino acids.¹⁴ Glucose is generally not a preferred substrate by the cardiomyocytes during normoxic states because its metabolism is inhibited by fatty acids and ketone bodies.¹⁵ However, during myocardial ischemia, which arises as a result of disproportion between the amount of oxygen supplied to the cardiac cell and the amount actually required, cardiac myocytes have to rely solely on anaerobic glycolysis as a source of available energy (Fig 1) . This fact is evident from the observation that cardiac myocytes cultured under glucose-free normoxic conditions remain viable and beat synchronously for several days, but during ischemia, glucose uptake and glycolysis become critical for the maintenance of myocardial viability and function.^{16 17}

View larger version (70K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Energy production in (top, A) normal myocardial cell and (bottom, B) ischemic cell. ATP = adenosine triphosphate.

Glucose, being hydrophilic, cannot diffuse across the plasma membrane unaided and instead must be carried into the cell interior by specialized transport proteins, called glucose transporters (GLUTs). Among the several GLUT isoforms discovered, human cardiomyocytes mainly contain the isoforms GLUT-1 and GLUT-4. These molecules are normally situated in the cell cytoplasm in the form of intramembrane vesicles and need to be activated in order to be translocated to the cell membrane, where they allow rapid passage of glucose inside the cell. A number of observations indicate that myocardial glucose utilization is greatly increased postischemia and is mediated by increased translocation of GLUTs to the cell surface.²¹ Myocardial cells expressing low levels of GLUTs have been shown to be significantly less tolerant to ischemia than age-matched controls.²²

Along with a rapid increase in intracellular glucose levels, ischemic cardiomyocytes also have to show increased activity of the enzymes involved in glycolysis in order to generate K-ATP rapidly.

	How Do 1-Adrenoreceptors Mediate IPC?

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1. ₁-Adrenoreceptor Stimulation Enhances Glucose Entry Into Cardiomyocytes by Activating GLUT-1 and GLUT-4
The transport of glucose across the cell membrane is the rate-limiting step of glucose utilization in mammals . The numbers of GLUTs expressed on the plasma membrane determines the amount of glucose entering inside the cell. Phosphorylation of tyrosine kinase and generation of intracellular phosphatidyl-inositol 3-kinase or activation of intracellular protein kinase C (PKC) by various extracellular signaling mechanisms translocates GLUTs from the cytoplasm to the plasma membrane.²³ In addition to insulin, catecholamines have long been known to independently stimulate glucose transport inside cells; however, their underlying mechanisms have become clear only very recently. Several studies have demonstrated that stimulation of ₁-adrenergic receptors increases glucose entry into cardiomyocytes by up to 3.4-fold by translocating the GLUT molecules GLUT-1 and GLUT-4 from the intramembrane vesicles to the plasma membrane.^{24 25 26} This effect is independent of insulin and the contractile state of the myocardium and is thought to be mediated by activation of PKC and/or phosphatidyl-inositol 3-kinase, although the isoforms involved are not known.^{25 26}

2. ₁-Adrenoreceptor Stimulation Induces Glycogenolysis
Cardiomyocytes have large intracellular stores of glycogen, which can be rapidly broken down to glucose during periods of increased need. Stimulation of ₁-adrenoreceptors has been shown to induce glycogenolysis in several tissues, which is mediated by an increase in cytosolic Ca⁺⁺ concentration, leading to increased activity of phosphorylase kinase, the rate-limiting enzyme in glycogenolysis.²⁷

₁-Adrenoreceptors therefore not only stimulate glucose entry inside the cell, but also enhance glycogenolysis to increase intracellular glucose levels, the major substrate for energy production during ischemic states.

3. ₁-Adrenergic Stimulation Increases the Rate of Glycolysis by Activating Myocardial Phosphofructokinase Activity
Phosphofructokinase, the principal rate-limiting enzyme in the glycolytic pathway, catalyzes the conversion of a nucleotide triphosphate and a sugar phosphate to a nucleotide diphosphate and a sugar diphosphate (glucose-6-phosphate to fructose-1–6-biphosphate) and drives the glycolytic pathway to generate K-ATP. Stimulation of ₁-adrenergic receptors has been shown to enhance the activity of phosphofructokinase in cardiomyocytes and thereby greatly increase the rate of glycolysis.²⁸

4. ₁-Adrenergic Stimulation Activates the Na⁺/H⁺ Exchanger and Maintains Intracellular pH
During periods of ischemia when anaerobic glycolysis provides all the necessary fuel for generating K-ATP, there is excess accumulation of pyruvate and hydrogen (protons) within the cell. This increase in intracellular acidity can greatly hamper cardiomyocyte function and viability. Human cardiomyocytes express the Na⁺/H⁺ exchanger (NHE) isoform-1 on the plasma membrane, activation of which drives intracellular H⁺ outside the cell in place of Na⁺ entry. During IPC, cardiomyocytes have been shown to maintain their pH and reduce intracellular acidity produced by anaerobic glycolysis by the activation of NHE.²⁹

Stimulation of ₁-adrenergic receptors has been shown to activate the NHE in several tissues, including the renal proximal tubules, where it accounts for the bulk of Na⁺ reabsorption.³⁰ Previous studies^{31 32 33} have shown that during periods of ischemia, stimulation of ₁-adrenergic receptors in isolated hearts and cardiomyocytes activates the NHE and attenuates ischemia-induced acidosis, an effect that is mediated by activating intracellular PKC.³⁴

5. ₁-Adrenergic Stimulation Inhibits Apoptosis of Cardiomyocytes
Apoptosis is one of the major mechanisms of cell death and loss of viable tissue due to myocardial ischemia and infarction.³⁵ It has been recently demonstrated³⁶ that cultured neonatal rat cardiac myocytes stimulated with phenylephrine (₁-agonist) showed significantly reduced myocardial apoptosis, an effect which can be completely blocked by prazosin. Similarly, pretreatment of rabbits with phenylephrine has shown a significant reduction in infarct size by up to 35%, which was associated with reduced numbers of apoptotic nuclei by 50% and increased levels of the antiapoptotic protein Bcl-2 by up to 2.65-fold.⁷ ₁-Adrenergic stimulation has also been shown to inhibit apoptosis of vascular smooth muscle cells by activating PKC and increasing the levels of Bcl-2.³⁷ These studies therefore suggest that stimulation of ₁-adrenergic receptors in cardiomyocytes inhibits apoptosis and enhances myocardial viability by increasing the levels of the antiapoptotic protein Bcl-2. Enhanced glycolysis and thereby increased energy production by ₁-adrenergic stimulation during ischemic states could also be an additional underlying mechanism for improving cardiomyocyte survival.

	Myocardial Ischemia Induces an Increase in 1-Adrenergic Receptors and Norepinephrine Levels

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Ischemia/hypoxia has been shown to increase the numbers of ₁-adrenoreceptors in several tissues studied, including cardiac myocytes,^{38 39} gut, spleen, liver, and lung.⁴⁰ Cardiomyocytes exposed to acute ischemia for as short as 10 min have been shown to exhibit a two- to threefold increase in the numbers of ₁-adrenoreceptors.^{38 39} This is mediated by hypoxia-induced inhibition of ß-oxidation fatty acids, which leads to accumulation of long-chain acylcarnitines, thereby altering membrane fluidity and increasing the expression of ₁-adrenoreceptors.³⁸ Long-term exposure to hypoxia has been shown to increase the gene transcription and protein synthesis of ₁-adrenoreceptors in vascular smooth muscle cells by activating several hypoxia-sensitive cis-acting elements (such as hypoxia-inducible factor-1) situated in the promoter region of the gene.⁴¹ Acute as well as chronic hypoxia/ischemia therefore increase the expression of ₁-adrenoreceptors.

Myocardial ischemia or other hypoxic states produce an increase in the endogenous levels of its agonist, norepinephrine, by up to 1,000-fold,^{40 42} thereby greatly enhancing ₁-adrenergic activity.

During periods of myocardial ischemia, upregulation of ₁-adrenoreceptors and increased levels of endogenous norepinephrine could therefore be a powerful adaptive mechanism utilized by cardiomyocytes that drive IPC. Stimulation of ₁-adrenoreceptors increases glucose transport inside cells by translocating the GLUTs from the cytoplasm to the plasma membrane, enhances glycogenolysis thereby increasing the levels of available glucose, enhances the rate of glycolysis by increasing the activity of phosphofructokinase, reduces intracellular acidity produced by excessive glycolysis by activating the NHE, and inhibits apoptosis by increasing the levels of Bcl-2 (Fig 2) . These mechanisms appear to be mediated by increasing cytosolic Ca⁺⁺ levels and activation of PKC, which phosphorylates several membrane-bound intracellular enzymes to produce these adaptive responses.

View larger version (43K): [in this window] [in a new window] [Download PPT slide]   Figure 2.. Mechanism of 1-adrenoreceptor-mediated IPC. PLC = phospholipase C; DAG = diacylglycerol; IP3 = inositol triphosphate; G = G protein; PIP2 = phosphatidylinositol diphosphate; see Figure 1 for other abbreviation.

	Clinical Implications

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Norepinephrine activates both -adrenergic and ß-adrenergic receptors in cardiomyocytes, the stimulation of which largely produces opposite physiologic responses. If norepinephrine-induced IPC is mediated primarily by activation of ₁-adrenoreceptors, then blockade of ß-adrenoreceptors would further increase activation of ₁-adrenoreceptors, and thereby enhance the development of IPC. Considerable evidence supports the routine long-term use of ß-blockers in patients who have had myocardial infarction, with substantial benefits in terms of reduced morbidity and mortality by as much as 40%.^{43 44} In addition to its known effects on reducing myocardial oxygen need, it is possible that ß-blocker-induced reduction in mortality and morbidity in patients with myocardial infarction may also be mediated by induction of IPC by allowing norepinephrine to activate ₁-adrenoreceptors.

However, ₁-antagonists that are currently recommended as one of the first-line drugs in the management of hypertension⁴⁵ could be potentially deleterious agents that may either abolish or prevent the development of IPC. A previous study in a small number of patients with unstable angina has demonstrated that use of prazosin (selective ₁-antagonist), although inducing a significant reduction in systemic arterial pressure, produced a trend toward an increase in the number of chest pain episodes, use of nitroglycerin tablets, and ST-segment deviations on ECG from the baseline.⁴⁶ Moreover, very recently the Data Safety Monitoring Board for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial⁴⁷ decided to discontinue the doxazosin-treatment arm of the study. The premature stoppage of the doxazosin-treatment group in one of the largest trials in hypertension, involving 42,448 patients (due to complete in the year 2002), was based on a significantly higher percentage of patients in the doxazosin group developing congestive cardiac failure and increased cardiac morbidity. Compared to chlorthalidone, patients receiving doxazosin had a 16% increased relative risk of angina, 25% increased relative risk of combined cardiovascular disease, and a twofold increased risk of congestive heart failure.⁴⁸ Messerli⁴⁷ has suggested that a yet unknown powerful risk factor associated with doxazosin counteracts its beneficial effects on lowering BP and recommends that the whole class of -blockers should no longer be considered as first-line antihypertensive therapy in view of these results. These observations likely support the view that ₁-adrenoreceptors could be playing an important role in mediating IPC. Avoidance of ₁-blockers in patients with hypertension and associated ischemic heart disease could therefore be important in allowing the development of IPC.

	Footnotes

 
Abbreviations: GLUT = glucose transporter; IPC = ischemic preconditioning; K-ATP = potassium-adenosine triphosphate; NHE = Na⁺/H⁺ exchanger; PKC = protein kinase C

Received for publication April 3, 2000. Accepted for publication August 1, 2000.

	References

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1. Murry, CE, Jennings, RB, Reimer, KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74,1124-1136[Abstract/Free Full Text]
2. Tomai, F, Crea, F, Chiariello, L, et al (1999) Ischemic preconditioning in humans: models, mediators, and clinical relevance. Circulation 100,559-563[Abstract/Free Full Text]
3. Andreotti, F, Pasceri, V, Hackett, DR, et al (1996) Preinfarction angina as a predictor of more rapid coronary thrombolysis in patients with acute myocardial infarction. N Engl J Med 334,7-12[Abstract/Free Full Text]
4. Li, K, He, H, Li, C, et al (1997) Myocardial ₁-adrenoreceptor: ionotropic effect and physiologic implications. Life Sci 60,1305-1318[CrossRef][ISI][Medline]
5. Bohm, M, Diet, F, Feiler, G, et al (1988) -Adrenoceptors and -adrenoceptor-mediated positive inotropic effects in failing human myocardium. J Cardiovasc Pharmacol 12,357-364[ISI][Medline]
6. Kurz, T, Yamada, KA, DaTorre, SD, et al (1991) ₁-Adrenergic system and arrhythmias in ischemic heart disease. Eur Heart J 12(suppl F),88-98[Abstract/Free Full Text]
7. Baghelai, K, Graham, LJ, Wechsler, AS, et al (1999) Delayed myocardial preconditioning by ₁-adrenoceptors involves inhibition of apoptosis. J Thorac Cardiovasc Surg 117,980-986[Abstract/Free Full Text]
8. Hale, SL, Kloner, RA (1994) Protection of myocardium by transient, preischemic administration of phenylephrine in the rabbit. Coron Artery Dis 5,605-610[ISI][Medline]
9. Node, K, Kitakaze, M, Sato, H, et al (1997) Role of intracellular Ca2+ in activation of protein kinase C during ischemic preconditioning. Circulation 96,1257-1265[Abstract/Free Full Text]
10. Kitakaze, M, Hori, M, Morioka, T, et al (1994) ₁-Adrenoceptor activation mediates the infarct size-limiting effect of ischemic preconditioning through augmentation of 5'- nucleotidase activity. J Clin Invest 93,2197-2205
11. Banerjee, A, Locke-Winter, C, Rogers, KB, et al (1993) Preconditioning against myocardial dysfunction after ischemia and reperfusion by an ₁-adrenergic mechanism. Circ Res 73,656-670[Abstract/Free Full Text]
12. Tomai, F, Crea, F, Gaspardone, A, et al (1997) Phentolamine prevents adaptation to ischemia during coronary angioplasty: role of -adrenergic receptors in ischemic preconditioning. Circulation 96,2171-2177[Abstract/Free Full Text]
13. Cleveland, JC, Jr, Meldrum, DR, Rowland, RT, et al (1997) Ischemic preconditioning of human myocardium: protein kinase C mediates a permissive role for ₁-adrenoceptors. Am J Physiol 273(2 pt 2),H902-H908[Abstract/Free Full Text]
14. Tahiliani, AG (1992) The heart and cardiovascular system: scientific foundations 2nd ed. ,28-41 Raven Press New York, NY.
15. Crass, MF, III, McCaskill, ES, Shipp, JC (1970) Glucose-free fatty acid interactions in the working heart. J Appl Physiol 29,87-91[Free Full Text]
16. Eberli, FR, Weinberg, EO, Grice, WN, et al (1991) Protective effect of increased glycolytic substrate against systolic and diastolic dysfunction and increased coronary resistance from prolonged global under-perfusion and reperfusion in isolated rabbit hearts perfused with erythrocyte suspensions. Circ Res 68,466-481[Abstract/Free Full Text]
17. Malhotra, R, Brosius, FC, III (1999) Glucose uptake and glycolysis reduce hypoxia-induced apoptosis in cultured neonatal rat cardiac myocytes. J Biol Chem 274,12567-12575[Abstract/Free Full Text]
18. Opie, LH (1988) Hypothesis: glycolytic rates control cell viability in ischemia. J Appl Cardiol 3,407-414[ISI]
19. Fath-Ordoubadi, F, Beatt, KJ (1997) Glucose-insulin-potassium therapy for treatment of acute myocardial infarction: an overview of randomized placebo-controlled trials. Circulation 96,1152-1156[Abstract/Free Full Text]
20. Opie, LH (1999) Proof that glucose-insulin-potassium provides metabolic protection of ischemic myocardium? Lancet 353,768-769[CrossRef][ISI][Medline]
21. Tardy-Cantalupi, I, Montessuit, C, Papageorgiou, I, et al (1999) Effect of transient ischemia on the expression of glucose transporters GLUT-1 and GLUT-4 in rat myocardium. J Mol Cell Cardiol 31,1143-1155[CrossRef][ISI][Medline]
22. Takeuchi, K, McGowan, FX, Jr, Glynn, P, et al (1998) Glucose transporter upregulation improves ischemic tolerance in hypertrophied failing heart. Circulation 98(19 suppl),II234-II239
23. Czech, MP, Corvera, S (1999) Signaling mechanisms that regulate glucose transport. J Biol Chem 274,1865-1868[Free Full Text]
24. Rattigan, S, Appleby, GJ, Clark, MG (1991) Insulin-like action of catecholamines and Ca2+ to stimulate glucose transport and GLUT4 translocation in perfused rat heart. Biochim Biophys Acta 1094,217-223[Medline]
25. Doenst, T, Taegtmeyer, H (1999) -Adrenergic stimulation mediates glucose uptake through phosphatidylinositol 3-kinase in rat heart. Circ Res 84,467-474[Abstract/Free Full Text]
26. Fischer, Y, Kamp, J, Thomas, J, et al (1996) Signals mediating stimulation of cardiomyocyte glucose transport by the -adrenergic agonist phenylephrine. Am J Physiol 270(4 pt 1),C1211-C1220[Abstract/Free Full Text]
27. Price, DT, Lefkowitz, RJ, Caron, MG, et al (1994) Localization of mRNA for three distinct ₁-adrenergic receptor subtypes in human tissues: implications for human alpha-adrenergic physiology. Mol Pharmacol 45,171-175[Abstract]
28. Patten, GS, Filsell, OH, Clark, MG (1982) Epinephrine regulation of phosphofructokinase in perfused rat heart: a calcium ion-dependent mechanism mediated via -receptors. J Biol Chem 257,9480-9486[Free Full Text]
29. Ramasamy, R, Liu, H, Anderson, S, et al (1995) Ischemic preconditioning stimulates sodium and proton transport in isolated rat hearts. J Clin Invest 96,1464-1472
30. Liu, F, Nesbitt, T, Drezner, MK, et al (1997) Proximal nephron Na+/H+ exchange is regulated by ₁A- and ₁B-adrenergic receptor subtypes. Mol Pharmacol 52,1010-1018[Abstract/Free Full Text]
31. Yokoyama, H, Yasutake, M, Avkiran, M (1998) ₁-Adrenergic stimulation of sarcolemmal Na+-H+ exchanger activity in rat ventricular myocytes: evidence for selective mediation by the ₁A-adrenoceptor subtype. Circ Res 82,1078-1085[Abstract/Free Full Text]
32. Iwakura, K, Hori, M, Watanabe, Y, et al (1990) ₁-Adrenoceptor stimulation increases intracellular pH and Ca2+ in cardiomyocytes through Na+/H+ and Na+/Ca2+ exchange. Eur J Pharmacol 186,29-40[CrossRef][ISI][Medline]
33. Wallert, MA, Frohlich, O (1992) ₁-Adrenergic stimulation of Na-H exchange in cardiac myocytes. Am J Physiol 263(5 pt 1),C1096-C1102[Abstract/Free Full Text]
34. Rehring, TF, Shapiro, JI, Cain, BS, et al (1998) Mechanisms of pH preservation during global ischemia in preconditioned rat heart: roles for PKC and NHE. Am J Physiol 275(3 pt 2),H805-H813
35. Anversa, P, Cheng, W, Liu, Y, et al (1998) Apoptosis and myocardial infarction. Basic Res Cardiol 93(suppl 3),8-12
36. Iwai-Kanai, E, Hasegawa, K, Araki, M, et al (1999) - and ß-Adrenergic pathways differentially regulate cell type-specific apoptosis in rat cardiac myocytes. Circulation 100,305-311[Abstract/Free Full Text]
37. Leszczynski, D, Zhao, Y, Luokkamaki, M, et al (1994) Apoptosis of vascular smooth muscle cells: protein kinase C and oncoprotein Bcl-2 are involved in regulation of apoptosis in non-transformed rat vascular smooth muscle cells. Am J Pathol 145,1265-1270[Abstract]
38. Allely, MC, Brown, CM, Kenny, BA, et al (1993) Modulation of ₁-adrenoceptors in rat left ventricle by ischemia and acylcarnitines: protection by ranolazine. J Cardiovasc Pharmacol 21,869-873[ISI][Medline]
39. Heathers, GP, Evers, AS, Corr, PB (1989) Enhanced inositol trisphosphate response to ₁-adrenergic stimulation in cardiac myocytes exposed to hypoxia. J Clin Invest 83,1409-1413
40. Salvi, SS (1999) ₁-Adrenergic hypothesis for pulmonary hypertension. Chest 115,1708-1719[Abstract/Free Full Text]
41. Eckhart, AD, Zhu, Z, Arendshorst, WJ, et al (1996) Oxygen modulates ₁B-adrenergic receptor gene expression by arterial but not venous vascular smooth muscle. Am J Physiol 271(4 pt 2),H1599-H1608[Abstract/Free Full Text]
42. Schomig, A, Richardt, G, Kurz, T (1995) Sympatho-adrenergic activation of the ischemic myocardium and its arrhythmogenic impact. Herz 20,169-186[ISI][Medline]
43. Freemantle, N, Cleland, J, Young, P, et al (1999) ß-Blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 318,1730-1737[Abstract/Free Full Text]
44. Gottlieb, SS, McCarter, RJ, Vogel, RA (1998) Effect of ß-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med 339,489-497[Abstract/Free Full Text]
45. Lund-Johansen, P, Hjermann, I, Iversen, BM, et al (1993) Selective ₁-inhibitors: first- or second-line antihypertensive agents? Cardiology 83,150-159[ISI][Medline]
46. Winniford, MD, Filipchuk, N, Hillis, LD (1983) -Adrenergic blockade for variant angina: a long-term, double-blind, randomized trial. Circulation 67,1185-1188[Abstract/Free Full Text]
47. Messerli, FH (2000) Implications of discontinuation of doxazosin arm of ALLHAT: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Lancet 355,863-864[CrossRef][ISI][Medline]
48. . ALLHAT Collaborative Research Group. (2000) Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 283,1967-1975[Abstract/Free Full Text]

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