Trends in Pharmacological Sciences
Reviewβ3-Adrenoceptors in the cardiovascular system
Section snippets
Expression of β3-adrenoceptors
The gene encoding the human β3-adrenoceptor contains introns, unlike the genes encoding β1- and β2-adrenoceptors (Fig. 1). The first exon encodes most of the peptide chain with the addition of 12 and 6 amino acids from 3′ exons 7. To date, only the 408-amino-acid isoform (isoform ‘c’ in Fig. 1) has been detected in human tissues. In rodents, 12 amino acids are encoded by a 3′ exon. The existence of several exons raises the possibility, through alternative splicing, of different receptor
Human ventricle
Classically, the activation of β-adrenoceptors has exclusively been associated with a stimulation of cardiac contraction. The atypical effect of isoprenaline on human ventricular endomyocardial biopsies in the presence of nadolol, a β1- and β2-adrenoceptor antagonist, modified this paradigm. Indeed, in such conditions, isoprenaline decreased cardiac contractility 13. A similar cardiodepression was also observed with the endogenous catecholamine noradrenaline in the presence of α1-, β1- and β2
Effects of β3-adrenoceptor stimulation in vessels
Stimulation of β1- and β2-adrenoceptors in several vascular beds produces vasorelaxation. Recently, the use of dual β1–β2-adrenoceptor antagonists and β3-adrenoceptor agonists in several studies in vivo and in vitro provided evidence for the functional expression of β3-adrenoceptors in some vascular tissues in addition to β1- and β2-adrenoceptor subtypes. Similar to its effects in adipose and cardiac tissues, β3-adrenoceptor agonists elicit effects in vessels that vary across species.
Cardiac tissue
The intracellular signaling pathways relaying catecholamine stimulation of β3-adrenoceptors are summarized in Fig. 3. Although most of the available data have been generated in studies of adipocytes or recombinant cell lines, the pathways that were shown to be operative in cardiac tissues will be discussed.
The effect of BRL37344 on human ventricular tissue was shown to be sensitive to pertussis toxin, thereby implicating Gi/oα subunits as coupling proteins. Interestingly, the downstream
Concluding remarks
The coexpression of three subtypes of β-adrenoceptors coupled to inverse cardiac inotropic effects somewhat recapitulates, in the myocardium, a well-known vascular paradigm. In vessels, catecholamines activate both contracting (α-adrenoceptor-mediated) and relaxing (β-adrenoceptor-mediated) effects. Aside from the differential expression and sensitivity of each receptor subtype to catecholamines, the local vascular tone is controlled by endothelium-derived relaxing factors, including NO, that
Potential pathophysiological role of β3-adrenoceptors in cardiovascular tissues
Several studies have indeed demonstrated the deleterious effect of long-term, unregulated sympathetic stimulation of the heart 53., 54.. These include transgenic mouse studies with low-level overexpression of Gsa or β1-adrenoceptors that progressively developed left ventricular dilatation and cardiac insufficiency 53., 55., accompanied by enhanced myocyte apoptosis 53. The implication of β2-adrenoceptors in the chronic toxicity of catecholamines on the heart crucially varies according to the
Potential therapeutic developments
The discovery of functional β3-adrenoceptors in the human heart is likely to shed new light on the understanding of the protective effect of therapeutic β-adrenoceptor blockade in heart failure 66. According to the hypothesis outlined above, one would expect qualitatively different actions of β-blockers depending on their specificity for each of the three β-adrenoceptor subtypes. β-blockers specifically targeting β1- and β2-adrenoceptors might be more appropriate to preserve the countervailing β
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