Review articleThe paradox of α-adrenergic coronary vasoconstriction revisited
Research highlights
► The coronary circulation has α1– and α2-adrenoceptors. ► α-Adrenergic coronary vasoconstriction competes with metabolic and endothelium-dependent vasodilation. ► α-Adrenoceptor blockade improves blood flow to all transmural layers. ► The dog coronary circulation is a good model for the human coronary circulation. ► Adrenoceptor blockade improves blood coronary blood flow and attenuates ischemia in patients.
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], [5], [6]. The activation of coronary vascular α-adrenoceptors by neuronal and humoral catecholamines induces vasoconstriction [7], [8], [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 [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?
Section snippets
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-dose β-adrenoceptor blockade. β-Adrenoceptor blockade serves two purposes: a)
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
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 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 –
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], [56], [57], [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
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
Perspective
In conclusion, the idea of a beneficial effect of α-adrenergic coronary vasoconstriction on myocardial blood flow and function or 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
References (75)
- et al.
Alpha1-adrenergic receptor regulation: basic science and clinical implications
Pharmacol Ther
(2000) - et al.
Cardiac sympathetic nerve activity and progressive vasoconstriction distal to coronary stenoses: feed-back aggravation of myocardial ischemia
J Auton Nerv Syst
(1985) - et al.
Variation in the alpha2B-adrenoceptor gene as a risk factor for prehospital fatal myocardial infarction and sudden cardiac death
J Am Coll Cardiol
(2003) Emerging importance of alpha-adrenergic coronary vasoconstriction in acute coronary syndromes and its genetic background
J Am Coll Cardiol
(2003)- et al.
α-Adrenoceptor blockade prevents exercise-induced vasoconstriction of stenotic coronary arteries
J Am Coll Cardiol
(1999) - et al.
Role of alpha- adrenergic coronary tone in exercise-induced angina pectoris
Am J Cardiol
(1986) - et al.
Postischemic left ventricular dysfunction is abolished by alpha-adrenergic blocking agents
J Am Coll Cardiol
(1998) - et al.
Poststenotic ischemic myocardial dysfunction induced by peripheral nociceptive stimulation
Eur Heart J
(1989) - et al.
Alpha-receptor constriction induced by atrial fibrillation during maximal coronary dilatation
Basic Res Cardiol
(1986) - et al.
The effects of atrial fibrillation on coronary blood flow and performance of ischaemic myocardium in dogs with coronary artery stenosis
Clin Sci
(1987)
Coronary physiology
Physiol Rev
Endothelial and neuro-humoral control of coronary blood flow in health and disease
Rev Physiol Biochem Pharmacol
Matching coronary blood flow to myocardial oxygen consumption
J Appl Physiol
Sympathetic control of coronary circulation
Circ Res
The paradox of adrenergic coronary vasoconstriction
Circulation
α-Adrenergic mechanisms in myocardial ischemia
Circulation
Control of myocardial oxygen tension by sympathetic coronary vasoconstriction in the dog
Circ Res
Competition between sympathetic vasoconstriction and metabolic vasodilation in the canine coronary circulation
Circ Res
Differences in direct effects of adrenergic stimuli on coronary, cutaneous and muscular vessels
J Clin Invest
Analysis of coronary vascular beta receptors in situ
Am J Physiol
Feedforward control of coronary blood flow via coronary β-receptor stimulation
Circ Res
Role of prejunctional alpha 2-adrenergic receptors in the regulation of myocardial performance during exercise in conscious dogs
Circ Res
Myocardial effects of selective alpha-adrenoceptor blockade during exercise in dogs
Circ Res
Extrasynaptic location of alpha-2 and noninnervated beta-2 adrenoceptors in the vascular system of the pithed normotensive rat
J Pharmacol Exp Ther
α1- and α2-Adrenoceptor-mediated vasoconstriction of large and small canine coronary arteries in vivo
J Cardiovasc Pharmacol
Postsynaptic α1- and α2-adrenergic mechanisms in coronary vasoconstriction
J Cardiovasc Pharmacol
Functional distribution of α1- and α2-adrenergic receptors in the coronary microcirculation
Circulation
Endothelium-dependent relaxation competes with α1- and α2-adrenergic constriction in the canine epicardial coronary microcirculation
Circulation
Heterogeneous microvascular coronary α1- and α2-adrenergic vasoconstriction
Circ Res
Endogenous adenosine modulates α2- but not α1-adrenergic constriction of coronary arterioles
Am J Physiol
α-Adrenergic coronary vasoconstriction and myocardial ischemia in humans
Circulation
Augmented α-adrenergic constriction of atherosclerotic human coronary arteries
Circulation
Effects of selective α1- and α2-adrenergic blockade on coronary flow reserve after coronary stenting
Circulation
Minimal α1- and α2-adrenoceptor-mediated coronary vasoconstriction in the anaesthetized swine
Naunyn Schmiedebergs Arch Pharmacol
The α1A/C- and α1B-adrenergic receptors are required for physiological cardiac hypertrophy in the double-knockout mouse
J Clin Invest
Alpha 1-adrenoceptor activity regulates release of adenosine from the ischemic myocardium in dogs
Circ Res
α1-Adrenoceptor activation increases ecto-5′-nucleotidase activity and adenosine release in rat cardiomyocytes by activating protein kinase C
Circulation
Cited by (43)
Microvascular dysfunction, vasospastic angina, and silent ischaemia
2021, Medicine (Spain)The Role of the Autonomic Nervous System in Cardiovascular Toxicity
2018, Comprehensive Toxicology: Third EditionOnset of a hypotensive effect following ingestion of flavan 3-ols involved in the activation of adrenergic receptors
2016, Free Radical Biology and MedicineCitation Excerpt :In clinical studies, several α2AR agonists have been used to control hypertension, because the vasodilatation induced by the sympathomimetic action of α2AR agonists is greater than peripheral vasoconstriction [41]. Accordingly, we investigated whether α2AR had an antagonistic action against α1AR after ingestion of 100 mg/kg FL using yohimbine that inhibits α2AR in pre-synapses and the vasomotor center to a greater extent than peripheral α2AR [43]. MBP increased to a greater degree after ingestion of a combination of an α2AR blocker and 100 mg/kg FL.
Age-related effects of dexmedetomidine on myocardial contraction and coronary circulation in isolated guinea pig hearts
2016, Journal of Pharmacological SciencesCitation Excerpt :In the coronary circulation, α1 and α2 adrenoceptors contribute to coronary vasoconstriction. While α1 receptors induce vasoconstriction of epicardial conduit vessels and participate in microvascular vasoconstriction of resistive vessels, α2 receptors predominantly mediate microvascular resistive vessel constriction (33), although the specific receptor subtypes mediating this constriction have not been defined. It has been reported that intracoronary infusion of the selective α2 agonist xylometazoline increased coronary resistance by a maximum of 60% (33).
Differences in vasomotor function of mesenteric arteries between Ossabaw minipigs with predisposition to metabolic syndrome and Gottingen minipigs
2024, American Journal of Physiology - Heart and Circulatory PhysiologyGlial cell activity in cardiovascular diseases and risk of acute myocardial infarction
2023, American Journal of Physiology - Endocrinology and Metabolism