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The paradox of α-adrenergic coronary vasoconstriction revisited
Journal of Molecular and Cellular Cardiology 51 (2011) 16–23
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Journal of Molecular and Cellular Cardiology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y j m c c
Review article
The paradox of α-adrenergic coronary vasoconstriction revisited Gerd Heusch ⁎ Institut für Pathophysiologie, Universitätsklinikum Essen, Hufelandstr. 55, 45122 Essen, Germany
a r t i c l e
i n f o
Article history: Received 16 February 2011 Received in revised form 10 March 2011 Accepted 13 March 2011 Available online 30 March 2011 Keywords: α-Adrenoceptor Coronary blood flow Coronary microcirculation Coronary vasomotion Myocardial ischemia
a b s t r a c t Activation of coronary vascular α-adrenoceptors results in vasoconstriction which competes with metabolic vasodilation during sympathetic activation. Epicardial conduit vessel constriction is largely mediated by α1adrenoceptors; the constriction of the resistive microcirculation largely by α2-adrenoceptors, but also by α1adrenoceptors. There is no firm evidence that α-adrenergic coronary vasoconstriction exerts a beneficial effect on transmural blood flow distribution. In fact, α-blockade in anesthetized and conscious dogs improves blood flow to all transmural layers, during normoperfusion and hypoperfusion. Also, in patients with coronary artery disease, blockade of α1- and α2-adrenoceptors improves coronary blood flow, myocardial function and metabolism. © 2011 Elsevier Ltd. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Vascular α-adrenoceptor subtypes and pharmacological tool drugs . . . . . . . . . 3. Magnitude of α-adrenergic coronary vasoconstriction and interaction with myocardial 4. α-Adrenergic vasoconstrictor impact on the transmural blood flow distribution . . . 5. α-Adrenergic coronary vasoconstriction during myocardial ischemia — experimental . 6. α-Adrenergic coronary vasoconstriction during myocardial ischemia — clinical . . . . 7. Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Sympathetic activation during excitement, exercise and other situations of stress (e.g. pain [1] or atrial fibrillation [2,3]) results in β-adrenoceptor mediated increases in heart rate and ventricular function. The resulting increase in myocardial oxygen consumption is matched by an increased coronary blood flow through metabolic coronary vasodilation [4–6]. The activation of coronary vascular α-adrenoceptors by neuronal and humoral catecholamines induces vasoconstriction [7–9]. Such α-adrenergic coronary vasoconstriction in a situation of increased myocardial oxygen requirements appears paradox [8]. Indeed, in a normal coronary circulation, metabolic vasodilation prevails, but α-adrenergic vasoconstriction nevertheless competes and limits the increase in coronary blood flow [10,11] such that myocardial oxygen extraction must also increase to match the increased myocardial oxygen requirements ⁎ Tel.: + 49 201 723 4480; fax: + 49 201 723 4481. E-mail address: [email protected]. 0022-2828/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.yjmcc.2011.03.007
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[6]. However, as compared to the cutaneous or skeletal muscle circulation, α-adrenergic vasoconstriction in the coronary circulation is only modest [12]. The apparent paradox of α-adrenergic coronary vasoconstriction has raised two fundamental questions: 1) Is there a physiological function for such α-adrenergic coronary vasoconstriction?, and 2) Does α-adrenergic coronary vasoconstriction contribute to the precipitation of ischemia in the presence of coronary stenoses and a limited coronary reserve? 2. Vascular α-adrenoceptor subtypes and pharmacological tool drugs α-Adrenoceptors can be identified and classified on the basis of their binding characteristics and their molecular properties. However, the participation of α-adrenoceptors in the regulation of coronary vasomotor tone is largely determined from their activation by selective agonists and their inhibition by selective antagonists (Table 1) [9]. Usually, α-adrenoceptor agonists and antagonists are given after high-
G. Heusch / Journal of Molecular and Cellular Cardiology 51 (2011) 16–23 Table 1 α-Adrenoceptor subtypes, their cardiac actions, and tool drugs. Site α1 Presynaptic
α2
Effects of activation
Feedback inhibition of norepinephrine release Postsynaptic Coronary vasoconstriction, release of adenosine and endothelin, increased inotropism, arrhythmias Presynaptic Feedback inhibition of norepinephrine release Postsynaptic Coronary vasoconstriction
Selective agonists
Selective antagonists
Phenylephrine, methoxamine
Prazosin and derivatives, urapidil
Yohimbine, (clonidine), BHT 920, BHT 933, rauwolscine, idazoxan UK 14.304, xylometazoline
Norepinephrine is a non-selective α-adrenoceptor agonist and phentolamine a nonselective α-adrenoceptor antagonist. Phenoxybenzamine is an irreversible, noncompetitive α-adrenoceptor antagonist with preference for α1- over α2-adrenoceptors.
dose β-adrenoceptor blockade. β-Adrenoceptor blockade serves two purposes: a) elimination of direct, β-adrenoceptor mediated dilation [13,14], and b) elimination of enhanced myocardial β-adrenoceptor activation secondary to blockade of presynaptic α-adrenoceptors with subsequently enhanced neuronal norepinephrine release, increased heart rate and ventricular function and ultimately metabolic coronary vasodilation [15,16]. Unfortunately, β-adrenoceptor blockade comes at the price of largely limiting the potential for increments in myocardial function, such that the interaction of α-adrenergic coronary vasoconstriction with metabolic vasodilation can only be studied in a limited range. In the presence of β-adrenoceptor blockade, norepinephrine activates vascular α-adrenoceptors and phentolamine antagonizes them competitively. Phenoxybenzamine is a non-competitive, irreversible α-adrenoceptor antagonist which induces only incomplete α2-adrenoceptor blockade [9]. Coronary vascular adrenoceptors of the α1-subtype are activated by phenylephrine or methoxamine and antagonized by prazosin or its derivatives. Coronary vascular adrenoceptors of the α2-subtype are activated by BHT 920 or BHT 933 or UK 14.304 and are antagonized by idazoxan, rauwolscine or yohimbine [9]. An extrajunctional localization of vascular α2-adrenoceptors with preferential activation by circulating rather than neuronally released norepinephrine has been proposed [17], but this idea was never tested in the coronary circulation. Both, α1- and α2-adrenoceptors contribute to coronary vasoconstriction. α1-Adrenoceptors induce vasoconstriction of epicardial conduit vessels [18–21] and participate in the microvascular vasoconstriction of resistive vessels. α2-Adrenoceptors are predominant in mediating microvascular resistive vessel constriction [18–21]. Microvascular α-adrenergic coronary constriction predominates in vessels larger than 100 μm in diameter [22]. Endotheliumdependent, NO-mediated vasodilation in the coronary microcirculation attenuates both α1- and α2-adrenergic vasoconstriction [21]. Endogenous adenosine attenuates α2-, but not α1-adrenergic coronary vasoconstriction [23]. Responses to α1- and α2-adrenergic adrenoceptor activation are enhanced when autoregulatory mechanisms are blunted during coronary hypoperfusion [20]. Most data on coronary vascular α-adrenoceptor subtypes are derived from studies in dogs; fortunately, the available data from humans confirm that the dog is indeed a good model for α-adrenergic coronary vasoconstriction [9,24]. Epicardial α1-adrenenergic vasoconstriction and mostly α2-adrenergic vasoconstriction in resistance vessels have in fact been documented in humans [25,26]. Coronary vascular α-adrenoceptor subtypes have also been identified in other species [9], but no data are available for their potential effect on transmural blood flow distribution. In contrast to dogs, pigs have little coronary vasoconstrictor responses to α1- and α2-adrenoceptor activation [27]. Apart from mediating coronary vasoconstriction, activation of α1-adrenoceptors on cardiomyocytes in rodent hearts increases contractile function and metabolism acutely [28] and growth
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chronically [29]. Activation of cardiomyocyte α1-adrenoceptors contributes to the release of adenosine [30,31] and endothelin [32,33] with respective vasomotor consequences in dogs; therefore, conclusions from data with selective α1-adrenoceptor blockade must consider for such effects.
3. Magnitude of α-adrenergic coronary vasoconstriction and interaction with myocardial function and metabolism Due to the competition with metabolic vasodilation, the extent of α-adrenergic coronary vasoconstriction is somewhat difficult to quantify. In the presence of β-blockade and at a coronary perfusion pressure well above the autoregulatory range, the intracoronary infusion of the selective α2-agonist xylometazoline increased coronary resistance by a maximum of 60% and the intracoronary infusion of the non-selective α-antagonist phentolamine decreased coronary resistance by a maximum of 60% in anesthetized dogs [34]. Cardiac sympathetic nerve stimulation in the presence of β-blockade increased coronary resistance by 23% [35] to 30% [18] in anesthetized dogs. In exercising dogs with β-blockade, phentolamine decreased coronary vascular resistance by 35% [36]. Different attempts have been made to eliminate regulatory mechanisms which compete with α-adrenergic coronary vasoconstriction: perfusion pressure has been raised above the autoregulatory range to provide a luxury perfusion [34], perfusion pressure has also been lowered below the autoregulatory range [20]. Maximum vasodilation with adenosine has also been used to eliminate regulatory mechanisms [37,38]. Also, various attempts have been made to consider for changes in myocardial metabolism during neuronal or humoral adrenergic activation: Mohrman and Feigl plotted oxygen delivery (flow × arterial oxygen content) vs. myocardial oxygen consumption [11] and Heyndrickx et al. first proposed plots of coronary blood flow vs. myocardial oxygen consumption and of coronary sinus pO2 vs. myocardial oxygen consumption [39]. Coronary sinus pO2 is used as a surrogate for myocardial pO2, and therefore any decrease in coronary sinus pO2 is taken to reflect “relative” myocardial tissue hypoxia. Particularly, a decrease in coronary sinus pO2 at increased myocardial oxygen consumption was taken to reflect inadequate matching of coronary oxygen delivery to myocardial oxygen consumption/demand during exercise in dogs, and consequently an attenuated decrease in coronary sinus pO2 at a given myocardial oxygen consumption after α-blockade with phentolamine was taken to reflect the α-adrenergic coronary vasoconstrictor component of the sympathetic activation by exercise [39]. Subsequently, such plot of coronary sinus pO2 vs. myocardial oxygen consumption has been used by many investigators to quantify and interpret coronary vascular responses to a whole variety of interventions [6], including α-adrenergic coronary vasoconstriction [40–43]. While the plot of coronary sinus pO2 vs. myocardial oxygen consumption clearly has the merit to consider for metabolic regulation of coronary blood flow, it has subsequently been largely overinterpreted, such that differences in slope and/or intercept between two regression lines of coronary sinus pO2 vs. myocardial oxygen consumption were taken to reflect mechanisms and adequacy of coronary vasomotion [6]. When considering α-adrenergic coronary vasoconstriction, the linear regression lines were often determined from a limited range of myocardial oxygen consumption (as a consequence of concomitant β-blockade). Unfortunately, the biological relation between coronary venous pO2 and myocardial oxygen consumption is nonlinear [6]. Apart from these statistical concerns, including interpolation of data in some studies [44], the plot of coronary sinus pO2 vs. myocardial oxygen consumption entails a certain amount of tautology, since myocardial oxygen consumption is practically not measured but calculated from coronary blood flow, hemoglobin,
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G. Heusch / Journal of Molecular and Cellular Cardiology 51 (2011) 16–23
A 4.0
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Fig. 1. Effects of intracoronary phentolamine (non-selective α-adrenoceptor antagonist, P) on transmural blood flow and its distribution into subendocardial, midmyocardial and subepicardial layers. Top (A): After measurement at rest (R), atropine (A) was given intravenously and heart rate increased by atrial pacing (AP). Humoral adrenergic activation (HAA) was achieved with intravenous norepinephrine. Bottom (B): Neuronal adrenergic activation (NAA) was achieved with cardiac sympathetic nerve stimulation after β-blockade with propranolol (PR) and after atropine (A). Phentolamine increases blood flow to all layers, with humoral and neuronal adrenergic activation. Shadowed inserts give endo/epi blood flow ratios.
G. Heusch / Journal of Molecular and Cellular Cardiology 51 (2011) 16–23
B without stenosis moderate stenosis severe stenosis
2.0
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Severe stenosis+ Rauwolscine Prazosin
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58.63 Y = -0.487 + 40.76 + X R = 0.81
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N = 122 X(Y=0) = 79%
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Reactive hyperemia [%] Fig. 2. Left (A): Changes in end-diastolic coronary resistance during cardiac sympathetic nerve stimulation vs. coronary reserve. Electrical cardiac sympathetic nerve stimulation decreases coronary resistance at higher coronary reserve (reactive hyperemia %); with decreasing coronary reserve distal to progressively more severe stenoses, the resistance response to cardiac sympathetic nerve stimulation is reversed to a substantial increase. Right (B): Absolute end-diastolic coronary resistance at baseline (black) and during cardiac sympathetic nerve stimulation (gray). Phentolamine (non-selective α-adrenoceptor antagonist) and rauwolsine (selective α2-adrenoceptor antagonist), but not prazosin (selective α1-adrenoceptor antagonist) prevent an increase in poststenotic coronary resistance during cardiac sympathetic nerve stimulation. From [60].
Hüfner's number and arterio-coronary venous pO2 difference. Finally, even if one accepted such plot as valid, it is unclear how the magnitude of α-adrenergic vasoconstriction is then quantified (e.g. the angle between regression lines without and with α-blockade? differences in slope or in intercept or in both?). The interpretation of these plots is still largely elusive.
4. α-Adrenergic vasoconstrictor impact on the transmural blood flow distribution The proponents for a physiological function of α-adrenergic coronary vasoconstriction argue that in situations of sympathetic activation, such as exercise, excitement, pain etc., the increased heart
Fig. 3. Top: Original recordings of hemodynamics and regional contractile function in a conscious dog under β-blockade. During exercise, a stenosis is created on the left circumflex coronary artery which decreases regional contractile function. Selective intracoronary α2-adrenoceptor-blockade with idazoxan during continued exercise improves regional contractile function ED: end-diastole;ES: end-systole. Bottom: Idazoxan improves regional myocardial blood flow, particularly into the most ischemic inner myocardium. Shadowed insert gives endo/epi blood flow ratio. From [63].
G. Heusch / Journal of Molecular and Cellular Cardiology 51 (2011) 16–23
A
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rate (and reduced diastolic duration) as well as the increased left ventricular pressure tend to limit increases in blood flow to the inner myocardial layers, and that α-adrenergic coronary vasoconstriction tends to counteract the enhanced extravascular compression, thus – in a teleological sense – preserving homogeneous transmural blood flow distribution [8]. Giudicelli et al. first observed in anesthetized dogs during left stellate ganglion stimulation in the presence of β-blockade more pronounced decreases in subepicardial than in subendocardial blood flow and thus a better calculated endo/epi flow ratio, and this effect was abolished by α-blockade [45]. Such beneficial flow distribution was more pronounced in ischemic myocardium such that ischemic subendocardial blood flow was even increased during sympathetic stimulation [45]. The authors interpreted these data as evidence for a “reverse coronary steal-phenomenon”, which was previously reported by Chiariello et al. [46] in response to intravenous infusion of the α1-antagonist methoxamine in anesthetized dogs with coronary occlusion. Johannsen et al. eliminated active regulatory mechanisms by adenosine and, again in anesthetized dogs with cardiac sympathetic nerve stimulation in the presence of β-blockade, reported decreased subepicardial with unchanged subendocardial blood flow and thus again an improved endo/epi flow ratio [37]. Interestingly, such improved flow distribution was only seen with neuronal, but not with humoral norepinephrine. Using surgical and chemical local denervation in conscious dogs, Holtz et al. [47] reported increased coronary blood flow with denervation, Chilian et al. [48] in contrast did not. Their different data were most likely explained by the difference in resting conditions, as reflected by heart rate which was higher in the Holtz et al. study. Importantly, both studies agree that there is no preferential effect of α-adrenergic coronary vasoconstriction to affect blood flow distribution. Feigl and collaborators subsequently extended and modified the hypothesis of a beneficial effect of α-adrenergic coronary vasoconstriction on transmural myocardial blood flow distribution [8,49]. Whereas Giudicelli et al. [45] and Johannsen et al. [37] had focussed on neuronal norepinephrine release during sympathetic nerve stimulation, Feigl et al. extended the potential beneficial role of α-adrenergic coronary vasoconstriction to intracoronary norepinephrine [50] and to exercise, where adrenergic vasoconstriction is largely produced by circulating catecholamines in dogs [51]. During intracoronary norepinephrine infusion in anesthetized dogs, α-adrenergic constriction was transmurally homogenous in normoperfused myocardium; with reduction in perfusion pressure, α-adrenergic vasoconstriction was reduced, and there was no evidence for a more favorable blood flow distribution in α-adrenoceptor intact vs. α-adrenoceptor-blocked myocardium [50]. In contrast, during dynamic exercise in dogs, the ratio of subendocardial to subepicardial blood flow in an α-adrenoceptor intact myocardial region was better than in an α-adrenoceptor-blocked (phenoxybenzamine) region [49]. However, when taking a closer look at these data, a number of questions and problems arise: a) the comparison of α-intact vs. αblocked regions was confounded by regional differences between LAD and CX blood flow even with vehicle; b) no absolute subendocardial and subepicardial blood flow data are reported; c) statistical significances are derived from comparisons of linear regression analyses between endo/epi blood flow ratios vs. myocardial oxygen consumption (see above discussion); d) in the presence β-blockade, such comparison became only significant beyond myocardial oxygen consumption of 400 μl/min∙g by extrapolation to a range where no data exist. With these caveats in mind, Baumgart et al. [38] designed experiments together with Feigl to re-examine the idea of a favorable effect of α-adrenergic coronary vasoconstriction on transmural blood flow distribution. In anesthetized dogs with β-blockade, neither neuronal (cardiac sympathetic nerve stimulation) nor humoral (intravenous) norepinephrine exerted a beneficial effect on absolute subendocardial blood flow; in fact, α-blockade with phentolamine
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Fig. 4. Coronary blood flow (CBF) responses in patients with single coronary stenosis to increasing doses of the selective α1-adrenoceptor agonist methoxamine (A) and the selective α2-adrenoceptor agonist BHT 933 (B). Data at baseline, then with 5 mg and 10 mg of each agonist, finally in the time course of 3 min after the 10 mg dose. Both, with methoxamine and BHT 933, net lactate uptake is reversed to net lactate release. The more pronounced coronary vasoconstrictor response to BHT 933 is associated with greater net lactate release (C). From [25].
improved blood flow to subendocardial blood flow at baseline vasomotor tone (Fig. 1). After elimination of baseline vasomotor tone by dipyridamole, phentolamine still improved absolute subendocardial blood flow during humoral norepinephrine administration. However, with dipyridamole and during cardiac sympathetic nerve stimulation, phentolamine increased absolute subepicardial blood flow at the expense of subendocardial blood flow, thus confirming the original Johannsen et al. data [37]. The observed changes in blood flow in response to phentolamine had no effect on regional contractile function or myocardial oxygen consumption [38], consistent with lack of a Gregg or gardenhose phenomenon in an insitu heart preparation [52]. Gwirtz et al. found improvement of both subendocardial and subepicardial blood flow with prazosin during
G. Heusch / Journal of Molecular and Cellular Cardiology 51 (2011) 16–23
cardiac sympathetic nerve stimulation in dogs, supporting the notion of transmurally uniform α1-adrenergic coronary vasoconstriction; yet, in their study, subendocardial contractile function was also improved with prazosin [53], possibly through a presynaptic effect in the absence of ß-blockade [16]. Feigl further modified the original Giudicelli et al. and Johannsen et al. [37] idea of greater α-adrenergic coronary vasoconstriction in subepicardial myocardium in that stiffening of transmurally penetrating vessels by vasoconstriction would reduce a capacitance effect and help resist their compressive narrowing during systole and facilitate their re-expansion during diastole, i.e. thus lessen to- and from-oscillation of blood flow [8]. In support of this idea, α-blockade with phenoxybenzamine during intravenous norepinephrine infusion and right ventricular pacing in anesthetized dogs increased systolic retrograde blood flow in the septal artery [54]. Also, at a pacing rate of 250/min, blood flow to all layers was decreased with α-blockade; however, this occurred in the absence of β-blockade, at decreased blood pressure and not preferentially in any particular myocardial layer, and it did therefore not support the idea of a better transmural distribution of blood flow by α-adrenergic coronary vasoconstriction. In conclusion, evidence for a favorable effect of α-adrenergic coronary vasoconstriction on the transmural blood flow distribution under physiological conditions is sparse. Sophisticated analyses are required to demonstrate any effect, which is then modest at best and only seen with sympathetic nerve activation. Although several studies demonstrated an improved endo/epi blood flow ratio during cardiac sympathetic nerve stimulation, the effect was small, particular to the specific experimental conditions and easily overridden in many circumstances. 5. α-Adrenergic coronary vasoconstriction during myocardial ischemia — experimental The traditional view that myocardial ischemia is such a powerful stimulus for coronary vasodilation that vasoconstrictor mechanisms are no longer operative is certainly not correct. In fact, a number of studies have clearly demonstrated persistent vasoconstrictor tone in ischemic myocardium [55–58]. Also, α-adrenergic coronary vasoconstriction is still operative in ischemic myocardium. In fact, when perfusion pressure was lowered below the autoregulatory range, α-adrenergic coronary vasoconstriction was attenuated but persistent [44,50,59] or even exaggerated [20,60]. Heusch and Deussen first reported a reversal from coronary vasodilation in the intact coronary circulation of anesthetized dogs during cardiac sympathetic nerve stimulation to coronary vasoconstriction distal to severe coronary stenoses, which resulted in net lactate production and regional contractile dysfunction and was abolished by non-selective α-blockade with phentolamine and selective α2-blockade with rauwolscine (with and without β-blockade) (Fig. 2) [60]. The resulting myocardial ischemia initiates a cardio-cardiac sympathoexcitatory reflex which further aggravates α-adrenergic coronary vasoconstriction and the resulting ischemia and is again eliminated by α-blockade, but also by epidural anesthesia of the cardiac sympathetic innervation [61]. Subsequent studies have addressed the responses of transmural blood flow distribution to α-adrenergic vasoconstriction during coronary hypoperfusion. During constant pressure hypoperfusion, αadrenergic coronary vasoconstriction had no impact on transmural blood flow distribution [50], whereas during constant flow hypoperfusion there was a better endo/epi flow ratio without α-blockade [59]. However, again phenoxybenzamine was used which does not adequately block α2-adrenoceptors, i.e. the more important α-adrenoceptor subtype during coronary hypoperfusion. A better transmural blood flow distribution was also suggested from studies in exercising dogs with coronary stenosis, where subendocardial blood flow in sympathectomized myocardium was lower than in innervated myocardium [62]; however, during exercise coronary vasomotor tone is largely
21
determined by humoral cathecholamines [51], and accordingly αblockade with phentolamine improved subendocardial blood flow in both, sympathectomized and innervated myocardium [62]. A predominant role for α2-adrenergic coronary vasoconstriction during coronary hypoperfusion, as observed by Heusch and Deussen [60] and Chilian [20] in anesthetized dogs, was confirmed in exercising dogs with coronary stenosis [63]. Selective intracoronary α2-blockade with idazoxan improved subendocardial blood flow and regional contractile function (Fig. 3) [63]. Laxson et al. confirmed αadrenergic coronary vasoconstriction in exercising dogs with coronary stenosis; in their study, selective α1-blockade with prazosin improved subendocardial blood flow even more than selective α2blockade with idazoxan [64]. Collectively, these data demonstrate that α-adrenergic coronary vasoconstriction is still operative in ischemic myocardium. While there is no single study which provides evidence for improved inner layer blood flow with α-adrenergic coronary vasoconstriction, most studies consistently demonstrate improved subendocardial blood flow, contractile function and lactate metabolism with α-blockade. 6. α-Adrenergic coronary vasoconstriction during myocardial ischemia — clinical The available small-scale, proof-of-concept studies provide reasonable evidence for a favorable effect of α-blockade in patients with coronary artery disease [24]. As in dogs, the human coronary circulation processes α1-adrenoceptors, predominantly in epicardial conduit vessels [25,65,66], and α2-adrenoceptors, predominantly in the resistive microcirculation [25]. Endothelial dysfunction predisposes to enhanced sympathetic vasoconstriction during the cold pressor test [67], and atherosclerosis augments the vasoconstrictor responses to both, selective α1- and α2-adrenoceptor activation [25]. Of note, α2-adrenoceptor activation even induces net lactate production, ST-segment depression and angina in patients with coronary stenosis (Fig. 4) [25]. Apart from a predisposition by atherosclerosis, there is also a genetic predisposition, in that patients with the 825T allele of the G protein β3 subunit [68] and patients with the deletion polymorphism in the α2B-adrenoceptor [69] have increased coronary vasoconstriction and a greater risk for myocardial infarction and sudden cardiac death [70]. α-Adrenergic coronary vasoconstriction of epicardial segments is also seen during exercise and again abolished by α-blockade with intracoronary phentolamine [71], and intracoronary phentolamine also attenuates ST segment depression during exercise [72]. A number of more recent studies identified α-adrenergic coronary vasoconstriction as a significant pathomechanism during and immediately following a percutaneous coronary intervention (PCI), reminiscent of the experimental studies with a positive feed-back aggravation of vasoconstriction and ischemia through a cardio-cardiac sympathoexcitatory reflex [61]. Accordingly, intracoronary α-blockade improved myocardial perfusion and function in patients undergoing elective PCI [26,73] or PCI after acute myocardial infarction [74]; again, both selective α1- and α2-blockade improved coronary blood flow [26]. The importance of the sympathoexcitatory reflex was confirmed also in patients with coronary artery disease by the improvement of coronary blood flow with epidural anesthesia [75]. Unfortunately, there are no systematic, large-scale clinical trials on the effects of α-blockade in patients with coronary artery disease. Clearly, there is not a single study reporting a beneficial effect of αadrenergic activation or, conversely, a detrimental effect of αblockade on the coronary circulation in patients. 7. Perspective In conclusion, the idea of a beneficial effect of α-adrenergic coronary vasoconstriction on myocardial blood flow and function or
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metabolism is not thoroughly supported by the available data; there is no firm evidence to support better blood flow to the inner myocardial layers or better function/metabolism with α-adrenergic coronary vasoconstriction. Although under some specific experimental circumstances (such as maximal vasodilation and electrical cardiac sympathetic nerve stimulation) an improved endo/epi flow ratio is seen in some studies, this phenomenon is not as robust as many other mechanisms in the regulation of coronary blood flow and easily overridden. In this respect, it is – in a teleological sense – rather fortunate that the α-adrenergic vasoconstriction in the coronary circulation is much less pronounced than in the skin or in skeletal muscle [12] and that it is physiologically overcome by metabolic and endothelium-dependent vasodilation. The available experimental studies, mostly in dogs, and proof-of-concept clinical studies consistently show that α-adrenergic coronary vasoconstriction persists and contributes to myocardial ischemia. Epicardial vasoconstriction is mostly mediated by α1-adrenoceptors, that of the resistive microcirculation largely by α2-adrenoceptors but also by α1-adrenoceptors, both in dogs and in humans. Rather than continuing the discussion on a potential favorable action of α-adrenergic coronary vasoconstriction, we must move on to even better define the predisposition for enhanced αadrenergic coronary vasoconstriction, develop more potent and specific α-blockade and conduct large-scale prospective clinical trial to explore the full potential for treatment with specific α-blockade in coronary artery disease. It may be difficult, close to impossible, to develop an αantagonistic drug with selectivity for the coronary circulation which avoids side effects in other vascular beds with more potent α-adrenergic vasoconstriction. A potential way to circumvent this problem could be to target a signaling step distal to coronary vascular α-adrenoceptors, but again such drug development remains a challenge.
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Contents lists available at ScienceDirect
Journal of Molecular and Cellular Cardiology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y j m c c
Review article
The paradox of α-adrenergic coronary vasoconstriction revisited Gerd Heusch ⁎ Institut für Pathophysiologie, Universitätsklinikum Essen, Hufelandstr. 55, 45122 Essen, Germany
a r t i c l e
i n f o
Article history: Received 16 February 2011 Received in revised form 10 March 2011 Accepted 13 March 2011 Available online 30 March 2011 Keywords: α-Adrenoceptor Coronary blood flow Coronary microcirculation Coronary vasomotion Myocardial ischemia
a b s t r a c t Activation of coronary vascular α-adrenoceptors results in vasoconstriction which competes with metabolic vasodilation during sympathetic activation. Epicardial conduit vessel constriction is largely mediated by α1adrenoceptors; the constriction of the resistive microcirculation largely by α2-adrenoceptors, but also by α1adrenoceptors. There is no firm evidence that α-adrenergic coronary vasoconstriction exerts a beneficial effect on transmural blood flow distribution. In fact, α-blockade in anesthetized and conscious dogs improves blood flow to all transmural layers, during normoperfusion and hypoperfusion. Also, in patients with coronary artery disease, blockade of α1- and α2-adrenoceptors improves coronary blood flow, myocardial function and metabolism. © 2011 Elsevier Ltd. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Vascular α-adrenoceptor subtypes and pharmacological tool drugs . . . . . . . . . 3. Magnitude of α-adrenergic coronary vasoconstriction and interaction with myocardial 4. α-Adrenergic vasoconstrictor impact on the transmural blood flow distribution . . . 5. α-Adrenergic coronary vasoconstriction during myocardial ischemia — experimental . 6. α-Adrenergic coronary vasoconstriction during myocardial ischemia — clinical . . . . 7. Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Sympathetic activation during excitement, exercise and other situations of stress (e.g. pain [1] or atrial fibrillation [2,3]) results in β-adrenoceptor mediated increases in heart rate and ventricular function. The resulting increase in myocardial oxygen consumption is matched by an increased coronary blood flow through metabolic coronary vasodilation [4–6]. The activation of coronary vascular α-adrenoceptors by neuronal and humoral catecholamines induces vasoconstriction [7–9]. Such α-adrenergic coronary vasoconstriction in a situation of increased myocardial oxygen requirements appears paradox [8]. Indeed, in a normal coronary circulation, metabolic vasodilation prevails, but α-adrenergic vasoconstriction nevertheless competes and limits the increase in coronary blood flow [10,11] such that myocardial oxygen extraction must also increase to match the increased myocardial oxygen requirements ⁎ Tel.: + 49 201 723 4480; fax: + 49 201 723 4481. E-mail address: [email protected]. 0022-2828/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.yjmcc.2011.03.007
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[6]. However, as compared to the cutaneous or skeletal muscle circulation, α-adrenergic vasoconstriction in the coronary circulation is only modest [12]. The apparent paradox of α-adrenergic coronary vasoconstriction has raised two fundamental questions: 1) Is there a physiological function for such α-adrenergic coronary vasoconstriction?, and 2) Does α-adrenergic coronary vasoconstriction contribute to the precipitation of ischemia in the presence of coronary stenoses and a limited coronary reserve? 2. Vascular α-adrenoceptor subtypes and pharmacological tool drugs α-Adrenoceptors can be identified and classified on the basis of their binding characteristics and their molecular properties. However, the participation of α-adrenoceptors in the regulation of coronary vasomotor tone is largely determined from their activation by selective agonists and their inhibition by selective antagonists (Table 1) [9]. Usually, α-adrenoceptor agonists and antagonists are given after high-
G. Heusch / Journal of Molecular and Cellular Cardiology 51 (2011) 16–23 Table 1 α-Adrenoceptor subtypes, their cardiac actions, and tool drugs. Site α1 Presynaptic
α2
Effects of activation
Feedback inhibition of norepinephrine release Postsynaptic Coronary vasoconstriction, release of adenosine and endothelin, increased inotropism, arrhythmias Presynaptic Feedback inhibition of norepinephrine release Postsynaptic Coronary vasoconstriction
Selective agonists
Selective antagonists
Phenylephrine, methoxamine
Prazosin and derivatives, urapidil
Yohimbine, (clonidine), BHT 920, BHT 933, rauwolscine, idazoxan UK 14.304, xylometazoline
Norepinephrine is a non-selective α-adrenoceptor agonist and phentolamine a nonselective α-adrenoceptor antagonist. Phenoxybenzamine is an irreversible, noncompetitive α-adrenoceptor antagonist with preference for α1- over α2-adrenoceptors.
dose β-adrenoceptor blockade. β-Adrenoceptor blockade serves two purposes: a) elimination of direct, β-adrenoceptor mediated dilation [13,14], and b) elimination of enhanced myocardial β-adrenoceptor activation secondary to blockade of presynaptic α-adrenoceptors with subsequently enhanced neuronal norepinephrine release, increased heart rate and ventricular function and ultimately metabolic coronary vasodilation [15,16]. Unfortunately, β-adrenoceptor blockade comes at the price of largely limiting the potential for increments in myocardial function, such that the interaction of α-adrenergic coronary vasoconstriction with metabolic vasodilation can only be studied in a limited range. In the presence of β-adrenoceptor blockade, norepinephrine activates vascular α-adrenoceptors and phentolamine antagonizes them competitively. Phenoxybenzamine is a non-competitive, irreversible α-adrenoceptor antagonist which induces only incomplete α2-adrenoceptor blockade [9]. Coronary vascular adrenoceptors of the α1-subtype are activated by phenylephrine or methoxamine and antagonized by prazosin or its derivatives. Coronary vascular adrenoceptors of the α2-subtype are activated by BHT 920 or BHT 933 or UK 14.304 and are antagonized by idazoxan, rauwolscine or yohimbine [9]. An extrajunctional localization of vascular α2-adrenoceptors with preferential activation by circulating rather than neuronally released norepinephrine has been proposed [17], but this idea was never tested in the coronary circulation. Both, α1- and α2-adrenoceptors contribute to coronary vasoconstriction. α1-Adrenoceptors induce vasoconstriction of epicardial conduit vessels [18–21] and participate in the microvascular vasoconstriction of resistive vessels. α2-Adrenoceptors are predominant in mediating microvascular resistive vessel constriction [18–21]. Microvascular α-adrenergic coronary constriction predominates in vessels larger than 100 μm in diameter [22]. Endotheliumdependent, NO-mediated vasodilation in the coronary microcirculation attenuates both α1- and α2-adrenergic vasoconstriction [21]. Endogenous adenosine attenuates α2-, but not α1-adrenergic coronary vasoconstriction [23]. Responses to α1- and α2-adrenergic adrenoceptor activation are enhanced when autoregulatory mechanisms are blunted during coronary hypoperfusion [20]. Most data on coronary vascular α-adrenoceptor subtypes are derived from studies in dogs; fortunately, the available data from humans confirm that the dog is indeed a good model for α-adrenergic coronary vasoconstriction [9,24]. Epicardial α1-adrenenergic vasoconstriction and mostly α2-adrenergic vasoconstriction in resistance vessels have in fact been documented in humans [25,26]. Coronary vascular α-adrenoceptor subtypes have also been identified in other species [9], but no data are available for their potential effect on transmural blood flow distribution. In contrast to dogs, pigs have little coronary vasoconstrictor responses to α1- and α2-adrenoceptor activation [27]. Apart from mediating coronary vasoconstriction, activation of α1-adrenoceptors on cardiomyocytes in rodent hearts increases contractile function and metabolism acutely [28] and growth
17
chronically [29]. Activation of cardiomyocyte α1-adrenoceptors contributes to the release of adenosine [30,31] and endothelin [32,33] with respective vasomotor consequences in dogs; therefore, conclusions from data with selective α1-adrenoceptor blockade must consider for such effects.
3. Magnitude of α-adrenergic coronary vasoconstriction and interaction with myocardial function and metabolism Due to the competition with metabolic vasodilation, the extent of α-adrenergic coronary vasoconstriction is somewhat difficult to quantify. In the presence of β-blockade and at a coronary perfusion pressure well above the autoregulatory range, the intracoronary infusion of the selective α2-agonist xylometazoline increased coronary resistance by a maximum of 60% and the intracoronary infusion of the non-selective α-antagonist phentolamine decreased coronary resistance by a maximum of 60% in anesthetized dogs [34]. Cardiac sympathetic nerve stimulation in the presence of β-blockade increased coronary resistance by 23% [35] to 30% [18] in anesthetized dogs. In exercising dogs with β-blockade, phentolamine decreased coronary vascular resistance by 35% [36]. Different attempts have been made to eliminate regulatory mechanisms which compete with α-adrenergic coronary vasoconstriction: perfusion pressure has been raised above the autoregulatory range to provide a luxury perfusion [34], perfusion pressure has also been lowered below the autoregulatory range [20]. Maximum vasodilation with adenosine has also been used to eliminate regulatory mechanisms [37,38]. Also, various attempts have been made to consider for changes in myocardial metabolism during neuronal or humoral adrenergic activation: Mohrman and Feigl plotted oxygen delivery (flow × arterial oxygen content) vs. myocardial oxygen consumption [11] and Heyndrickx et al. first proposed plots of coronary blood flow vs. myocardial oxygen consumption and of coronary sinus pO2 vs. myocardial oxygen consumption [39]. Coronary sinus pO2 is used as a surrogate for myocardial pO2, and therefore any decrease in coronary sinus pO2 is taken to reflect “relative” myocardial tissue hypoxia. Particularly, a decrease in coronary sinus pO2 at increased myocardial oxygen consumption was taken to reflect inadequate matching of coronary oxygen delivery to myocardial oxygen consumption/demand during exercise in dogs, and consequently an attenuated decrease in coronary sinus pO2 at a given myocardial oxygen consumption after α-blockade with phentolamine was taken to reflect the α-adrenergic coronary vasoconstrictor component of the sympathetic activation by exercise [39]. Subsequently, such plot of coronary sinus pO2 vs. myocardial oxygen consumption has been used by many investigators to quantify and interpret coronary vascular responses to a whole variety of interventions [6], including α-adrenergic coronary vasoconstriction [40–43]. While the plot of coronary sinus pO2 vs. myocardial oxygen consumption clearly has the merit to consider for metabolic regulation of coronary blood flow, it has subsequently been largely overinterpreted, such that differences in slope and/or intercept between two regression lines of coronary sinus pO2 vs. myocardial oxygen consumption were taken to reflect mechanisms and adequacy of coronary vasomotion [6]. When considering α-adrenergic coronary vasoconstriction, the linear regression lines were often determined from a limited range of myocardial oxygen consumption (as a consequence of concomitant β-blockade). Unfortunately, the biological relation between coronary venous pO2 and myocardial oxygen consumption is nonlinear [6]. Apart from these statistical concerns, including interpolation of data in some studies [44], the plot of coronary sinus pO2 vs. myocardial oxygen consumption entails a certain amount of tautology, since myocardial oxygen consumption is practically not measured but calculated from coronary blood flow, hemoglobin,
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G. Heusch / Journal of Molecular and Cellular Cardiology 51 (2011) 16–23
A 4.0
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endo/epi 1.06 0.15
endo/epi 1.11 0.20
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Fig. 1. Effects of intracoronary phentolamine (non-selective α-adrenoceptor antagonist, P) on transmural blood flow and its distribution into subendocardial, midmyocardial and subepicardial layers. Top (A): After measurement at rest (R), atropine (A) was given intravenously and heart rate increased by atrial pacing (AP). Humoral adrenergic activation (HAA) was achieved with intravenous norepinephrine. Bottom (B): Neuronal adrenergic activation (NAA) was achieved with cardiac sympathetic nerve stimulation after β-blockade with propranolol (PR) and after atropine (A). Phentolamine increases blood flow to all layers, with humoral and neuronal adrenergic activation. Shadowed inserts give endo/epi blood flow ratios.
G. Heusch / Journal of Molecular and Cellular Cardiology 51 (2011) 16–23
B without stenosis moderate stenosis severe stenosis
2.0
Enddiastolic coronary resistance
1.5
Phentolamine
Severe stenosis+ Rauwolscine Prazosin
1.0 1.0
58.63 Y = -0.487 + 40.76 + X R = 0.81
0.5
N = 122 X(Y=0) = 79%
0 0.5 1.0
mmHg·min·100g ml
Enddiastolic coronary resistance [mmHg·min·100g/ml]
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Reactive hyperemia [%] Fig. 2. Left (A): Changes in end-diastolic coronary resistance during cardiac sympathetic nerve stimulation vs. coronary reserve. Electrical cardiac sympathetic nerve stimulation decreases coronary resistance at higher coronary reserve (reactive hyperemia %); with decreasing coronary reserve distal to progressively more severe stenoses, the resistance response to cardiac sympathetic nerve stimulation is reversed to a substantial increase. Right (B): Absolute end-diastolic coronary resistance at baseline (black) and during cardiac sympathetic nerve stimulation (gray). Phentolamine (non-selective α-adrenoceptor antagonist) and rauwolsine (selective α2-adrenoceptor antagonist), but not prazosin (selective α1-adrenoceptor antagonist) prevent an increase in poststenotic coronary resistance during cardiac sympathetic nerve stimulation. From [60].
Hüfner's number and arterio-coronary venous pO2 difference. Finally, even if one accepted such plot as valid, it is unclear how the magnitude of α-adrenergic vasoconstriction is then quantified (e.g. the angle between regression lines without and with α-blockade? differences in slope or in intercept or in both?). The interpretation of these plots is still largely elusive.
4. α-Adrenergic vasoconstrictor impact on the transmural blood flow distribution The proponents for a physiological function of α-adrenergic coronary vasoconstriction argue that in situations of sympathetic activation, such as exercise, excitement, pain etc., the increased heart
Fig. 3. Top: Original recordings of hemodynamics and regional contractile function in a conscious dog under β-blockade. During exercise, a stenosis is created on the left circumflex coronary artery which decreases regional contractile function. Selective intracoronary α2-adrenoceptor-blockade with idazoxan during continued exercise improves regional contractile function ED: end-diastole;ES: end-systole. Bottom: Idazoxan improves regional myocardial blood flow, particularly into the most ischemic inner myocardium. Shadowed insert gives endo/epi blood flow ratio. From [63].
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rate (and reduced diastolic duration) as well as the increased left ventricular pressure tend to limit increases in blood flow to the inner myocardial layers, and that α-adrenergic coronary vasoconstriction tends to counteract the enhanced extravascular compression, thus – in a teleological sense – preserving homogeneous transmural blood flow distribution [8]. Giudicelli et al. first observed in anesthetized dogs during left stellate ganglion stimulation in the presence of β-blockade more pronounced decreases in subepicardial than in subendocardial blood flow and thus a better calculated endo/epi flow ratio, and this effect was abolished by α-blockade [45]. Such beneficial flow distribution was more pronounced in ischemic myocardium such that ischemic subendocardial blood flow was even increased during sympathetic stimulation [45]. The authors interpreted these data as evidence for a “reverse coronary steal-phenomenon”, which was previously reported by Chiariello et al. [46] in response to intravenous infusion of the α1-antagonist methoxamine in anesthetized dogs with coronary occlusion. Johannsen et al. eliminated active regulatory mechanisms by adenosine and, again in anesthetized dogs with cardiac sympathetic nerve stimulation in the presence of β-blockade, reported decreased subepicardial with unchanged subendocardial blood flow and thus again an improved endo/epi flow ratio [37]. Interestingly, such improved flow distribution was only seen with neuronal, but not with humoral norepinephrine. Using surgical and chemical local denervation in conscious dogs, Holtz et al. [47] reported increased coronary blood flow with denervation, Chilian et al. [48] in contrast did not. Their different data were most likely explained by the difference in resting conditions, as reflected by heart rate which was higher in the Holtz et al. study. Importantly, both studies agree that there is no preferential effect of α-adrenergic coronary vasoconstriction to affect blood flow distribution. Feigl and collaborators subsequently extended and modified the hypothesis of a beneficial effect of α-adrenergic coronary vasoconstriction on transmural myocardial blood flow distribution [8,49]. Whereas Giudicelli et al. [45] and Johannsen et al. [37] had focussed on neuronal norepinephrine release during sympathetic nerve stimulation, Feigl et al. extended the potential beneficial role of α-adrenergic coronary vasoconstriction to intracoronary norepinephrine [50] and to exercise, where adrenergic vasoconstriction is largely produced by circulating catecholamines in dogs [51]. During intracoronary norepinephrine infusion in anesthetized dogs, α-adrenergic constriction was transmurally homogenous in normoperfused myocardium; with reduction in perfusion pressure, α-adrenergic vasoconstriction was reduced, and there was no evidence for a more favorable blood flow distribution in α-adrenoceptor intact vs. α-adrenoceptor-blocked myocardium [50]. In contrast, during dynamic exercise in dogs, the ratio of subendocardial to subepicardial blood flow in an α-adrenoceptor intact myocardial region was better than in an α-adrenoceptor-blocked (phenoxybenzamine) region [49]. However, when taking a closer look at these data, a number of questions and problems arise: a) the comparison of α-intact vs. αblocked regions was confounded by regional differences between LAD and CX blood flow even with vehicle; b) no absolute subendocardial and subepicardial blood flow data are reported; c) statistical significances are derived from comparisons of linear regression analyses between endo/epi blood flow ratios vs. myocardial oxygen consumption (see above discussion); d) in the presence β-blockade, such comparison became only significant beyond myocardial oxygen consumption of 400 μl/min∙g by extrapolation to a range where no data exist. With these caveats in mind, Baumgart et al. [38] designed experiments together with Feigl to re-examine the idea of a favorable effect of α-adrenergic coronary vasoconstriction on transmural blood flow distribution. In anesthetized dogs with β-blockade, neither neuronal (cardiac sympathetic nerve stimulation) nor humoral (intravenous) norepinephrine exerted a beneficial effect on absolute subendocardial blood flow; in fact, α-blockade with phentolamine
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Fig. 4. Coronary blood flow (CBF) responses in patients with single coronary stenosis to increasing doses of the selective α1-adrenoceptor agonist methoxamine (A) and the selective α2-adrenoceptor agonist BHT 933 (B). Data at baseline, then with 5 mg and 10 mg of each agonist, finally in the time course of 3 min after the 10 mg dose. Both, with methoxamine and BHT 933, net lactate uptake is reversed to net lactate release. The more pronounced coronary vasoconstrictor response to BHT 933 is associated with greater net lactate release (C). From [25].
improved blood flow to subendocardial blood flow at baseline vasomotor tone (Fig. 1). After elimination of baseline vasomotor tone by dipyridamole, phentolamine still improved absolute subendocardial blood flow during humoral norepinephrine administration. However, with dipyridamole and during cardiac sympathetic nerve stimulation, phentolamine increased absolute subepicardial blood flow at the expense of subendocardial blood flow, thus confirming the original Johannsen et al. data [37]. The observed changes in blood flow in response to phentolamine had no effect on regional contractile function or myocardial oxygen consumption [38], consistent with lack of a Gregg or gardenhose phenomenon in an insitu heart preparation [52]. Gwirtz et al. found improvement of both subendocardial and subepicardial blood flow with prazosin during
G. Heusch / Journal of Molecular and Cellular Cardiology 51 (2011) 16–23
cardiac sympathetic nerve stimulation in dogs, supporting the notion of transmurally uniform α1-adrenergic coronary vasoconstriction; yet, in their study, subendocardial contractile function was also improved with prazosin [53], possibly through a presynaptic effect in the absence of ß-blockade [16]. Feigl further modified the original Giudicelli et al. and Johannsen et al. [37] idea of greater α-adrenergic coronary vasoconstriction in subepicardial myocardium in that stiffening of transmurally penetrating vessels by vasoconstriction would reduce a capacitance effect and help resist their compressive narrowing during systole and facilitate their re-expansion during diastole, i.e. thus lessen to- and from-oscillation of blood flow [8]. In support of this idea, α-blockade with phenoxybenzamine during intravenous norepinephrine infusion and right ventricular pacing in anesthetized dogs increased systolic retrograde blood flow in the septal artery [54]. Also, at a pacing rate of 250/min, blood flow to all layers was decreased with α-blockade; however, this occurred in the absence of β-blockade, at decreased blood pressure and not preferentially in any particular myocardial layer, and it did therefore not support the idea of a better transmural distribution of blood flow by α-adrenergic coronary vasoconstriction. In conclusion, evidence for a favorable effect of α-adrenergic coronary vasoconstriction on the transmural blood flow distribution under physiological conditions is sparse. Sophisticated analyses are required to demonstrate any effect, which is then modest at best and only seen with sympathetic nerve activation. Although several studies demonstrated an improved endo/epi blood flow ratio during cardiac sympathetic nerve stimulation, the effect was small, particular to the specific experimental conditions and easily overridden in many circumstances. 5. α-Adrenergic coronary vasoconstriction during myocardial ischemia — experimental The traditional view that myocardial ischemia is such a powerful stimulus for coronary vasodilation that vasoconstrictor mechanisms are no longer operative is certainly not correct. In fact, a number of studies have clearly demonstrated persistent vasoconstrictor tone in ischemic myocardium [55–58]. Also, α-adrenergic coronary vasoconstriction is still operative in ischemic myocardium. In fact, when perfusion pressure was lowered below the autoregulatory range, α-adrenergic coronary vasoconstriction was attenuated but persistent [44,50,59] or even exaggerated [20,60]. Heusch and Deussen first reported a reversal from coronary vasodilation in the intact coronary circulation of anesthetized dogs during cardiac sympathetic nerve stimulation to coronary vasoconstriction distal to severe coronary stenoses, which resulted in net lactate production and regional contractile dysfunction and was abolished by non-selective α-blockade with phentolamine and selective α2-blockade with rauwolscine (with and without β-blockade) (Fig. 2) [60]. The resulting myocardial ischemia initiates a cardio-cardiac sympathoexcitatory reflex which further aggravates α-adrenergic coronary vasoconstriction and the resulting ischemia and is again eliminated by α-blockade, but also by epidural anesthesia of the cardiac sympathetic innervation [61]. Subsequent studies have addressed the responses of transmural blood flow distribution to α-adrenergic vasoconstriction during coronary hypoperfusion. During constant pressure hypoperfusion, αadrenergic coronary vasoconstriction had no impact on transmural blood flow distribution [50], whereas during constant flow hypoperfusion there was a better endo/epi flow ratio without α-blockade [59]. However, again phenoxybenzamine was used which does not adequately block α2-adrenoceptors, i.e. the more important α-adrenoceptor subtype during coronary hypoperfusion. A better transmural blood flow distribution was also suggested from studies in exercising dogs with coronary stenosis, where subendocardial blood flow in sympathectomized myocardium was lower than in innervated myocardium [62]; however, during exercise coronary vasomotor tone is largely
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determined by humoral cathecholamines [51], and accordingly αblockade with phentolamine improved subendocardial blood flow in both, sympathectomized and innervated myocardium [62]. A predominant role for α2-adrenergic coronary vasoconstriction during coronary hypoperfusion, as observed by Heusch and Deussen [60] and Chilian [20] in anesthetized dogs, was confirmed in exercising dogs with coronary stenosis [63]. Selective intracoronary α2-blockade with idazoxan improved subendocardial blood flow and regional contractile function (Fig. 3) [63]. Laxson et al. confirmed αadrenergic coronary vasoconstriction in exercising dogs with coronary stenosis; in their study, selective α1-blockade with prazosin improved subendocardial blood flow even more than selective α2blockade with idazoxan [64]. Collectively, these data demonstrate that α-adrenergic coronary vasoconstriction is still operative in ischemic myocardium. While there is no single study which provides evidence for improved inner layer blood flow with α-adrenergic coronary vasoconstriction, most studies consistently demonstrate improved subendocardial blood flow, contractile function and lactate metabolism with α-blockade. 6. α-Adrenergic coronary vasoconstriction during myocardial ischemia — clinical The available small-scale, proof-of-concept studies provide reasonable evidence for a favorable effect of α-blockade in patients with coronary artery disease [24]. As in dogs, the human coronary circulation processes α1-adrenoceptors, predominantly in epicardial conduit vessels [25,65,66], and α2-adrenoceptors, predominantly in the resistive microcirculation [25]. Endothelial dysfunction predisposes to enhanced sympathetic vasoconstriction during the cold pressor test [67], and atherosclerosis augments the vasoconstrictor responses to both, selective α1- and α2-adrenoceptor activation [25]. Of note, α2-adrenoceptor activation even induces net lactate production, ST-segment depression and angina in patients with coronary stenosis (Fig. 4) [25]. Apart from a predisposition by atherosclerosis, there is also a genetic predisposition, in that patients with the 825T allele of the G protein β3 subunit [68] and patients with the deletion polymorphism in the α2B-adrenoceptor [69] have increased coronary vasoconstriction and a greater risk for myocardial infarction and sudden cardiac death [70]. α-Adrenergic coronary vasoconstriction of epicardial segments is also seen during exercise and again abolished by α-blockade with intracoronary phentolamine [71], and intracoronary phentolamine also attenuates ST segment depression during exercise [72]. A number of more recent studies identified α-adrenergic coronary vasoconstriction as a significant pathomechanism during and immediately following a percutaneous coronary intervention (PCI), reminiscent of the experimental studies with a positive feed-back aggravation of vasoconstriction and ischemia through a cardio-cardiac sympathoexcitatory reflex [61]. Accordingly, intracoronary α-blockade improved myocardial perfusion and function in patients undergoing elective PCI [26,73] or PCI after acute myocardial infarction [74]; again, both selective α1- and α2-blockade improved coronary blood flow [26]. The importance of the sympathoexcitatory reflex was confirmed also in patients with coronary artery disease by the improvement of coronary blood flow with epidural anesthesia [75]. Unfortunately, there are no systematic, large-scale clinical trials on the effects of α-blockade in patients with coronary artery disease. Clearly, there is not a single study reporting a beneficial effect of αadrenergic activation or, conversely, a detrimental effect of αblockade on the coronary circulation in patients. 7. Perspective In conclusion, the idea of a beneficial effect of α-adrenergic coronary vasoconstriction on myocardial blood flow and function or
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metabolism is not thoroughly supported by the available data; there is no firm evidence to support better blood flow to the inner myocardial layers or better function/metabolism with α-adrenergic coronary vasoconstriction. Although under some specific experimental circumstances (such as maximal vasodilation and electrical cardiac sympathetic nerve stimulation) an improved endo/epi flow ratio is seen in some studies, this phenomenon is not as robust as many other mechanisms in the regulation of coronary blood flow and easily overridden. In this respect, it is – in a teleological sense – rather fortunate that the α-adrenergic vasoconstriction in the coronary circulation is much less pronounced than in the skin or in skeletal muscle [12] and that it is physiologically overcome by metabolic and endothelium-dependent vasodilation. The available experimental studies, mostly in dogs, and proof-of-concept clinical studies consistently show that α-adrenergic coronary vasoconstriction persists and contributes to myocardial ischemia. Epicardial vasoconstriction is mostly mediated by α1-adrenoceptors, that of the resistive microcirculation largely by α2-adrenoceptors but also by α1-adrenoceptors, both in dogs and in humans. Rather than continuing the discussion on a potential favorable action of α-adrenergic coronary vasoconstriction, we must move on to even better define the predisposition for enhanced αadrenergic coronary vasoconstriction, develop more potent and specific α-blockade and conduct large-scale prospective clinical trial to explore the full potential for treatment with specific α-blockade in coronary artery disease. It may be difficult, close to impossible, to develop an αantagonistic drug with selectivity for the coronary circulation which avoids side effects in other vascular beds with more potent α-adrenergic vasoconstriction. A potential way to circumvent this problem could be to target a signaling step distal to coronary vascular α-adrenoceptors, but again such drug development remains a challenge.
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