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Vasodilatory Mechanisms of Beta Receptor Blockade Géraldine Rath

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Vasodilatory Mechanisms of Beta Receptor Blockade Géraldine Rath Vasodilatory Mechanisms of Beta Receptor Blockade Géraldine Rath, Jean-Luc Balligand & Dessy Chantal Current Hypertension Reports ISSN 1522-6417 Volume 14 Number 4 Curr Hypertens Rep (2012) 14:310-317 DOI 10.1007/s11906-012-0278-3 1 23 Your article is protected by copyright and all rights are held exclusively by Springer Science+Business Media, LLC. This e-offprint is for personal use only and shall not be self- archived in electronic repositories. If you wish to self-archive your work, please use the accepted author’s version for posting to your own website or your institution’s repository. You may further deposit the accepted author’s version on a funder’s repository at a funder’s request, provided it is not made publicly available until 12 months after publication. 1 23 Author's personal copy Curr Hypertens Rep (2012) 14:310–317 DOI 10.1007/s11906-012-0278-3 ANTIHYPERTENSIVE AGENTS: MECHANISMS OF DRUG ACTION (HM SIRAGY AND B WAEBER, SECTION EDITORS) Vasodilatory Mechanisms of Beta Receptor Blockade Géraldine Rath & Jean-Luc Balligand & Dessy Chantal Published online: 26 May 2012 # Springer Science+Business Media, LLC 2012 Abstract Beta-blockers are widely prescribed for the treat- Introduction ment of a variety of cardiovascular pathologies. Compared to traditional beta-adrenergic antagonists, beta-blockers of Beta-blockers are widely prescribed for the treatment of a the new generation exhibit ancillary properties such as va- variety of cardiovascular pathologies including hyperten- sodilation through different mechanisms. This translates sion, heart failure, primary treatment of myocardial infarc- into a more favorable hemodynamic profile. The relative tion, secondary prevention of ischemic cardiac events as affinities of beta-adrenoreceptor antagonists towards the three well as for other non-cardiovascular diseases. Consistent beta-adrenoreceptor isotypes matter for predicting their func- with so many different beneficial effects, a large variety of tional impact on vasomotor control. This review will focus on beta-blockers exist, which differ in their receptor selectivity, the mechanisms underlying beta-blocker-evoked vasorelaxa- their pharmacokinetic and pharmacodynamic properties. tion with a specific emphasis on agonist properties of beta3- The first generation beta-blockers with propranolol are non- adrenergic receptors. selective and block both beta1- and beta2-adrenoceptors. The second generation includes agents like metoprolol and ateno- Keywords Hypertension . Beta-blockers . Beta1-blocker . lol, which are called cardioselective and preferentially block Vasodilation . Beta3 agonism . Cardiovascular disease . beta1-adrenoreceptors. More recently, beta-blockers with ad- Arteries ditional ancillary properties have been developed, among which are Nebivolol and Carvedilol. Compared to classical beta-antagonists, they promote a vasodilation through differ- ent mechanisms, which translate into a more favorable hemo- dynamic profile compared to non-vasodilating beta-blockers. This review will focus on the mechanism(s) behind this beta- blocker-evoked vasorelaxation. G. Rath : J.-L. Balligand : D. Chantal (*) Pole de Pharmacologie et Thérapeutique (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Underlying Mechanisms of Vasodilation B01.5309, Avenue Mounier 52, 1200 Brussels, Belgium e-mail: [email protected] Endothelium-Dependent Relaxation G. Rath e-mail: [email protected] The endothelium largely contributes to vascular homeostasis through the synthesis and release of several contracting and J.-L. Balligand e-mail: [email protected] relaxing factors. Nitric oxide (NO) is the main vasodilator released from endothelial cells (ECs); the others are prostacy- J.-L. Balligand clin (PGI2) and endothelium-derived hyperpolarizing factor Cliniques Universitaires Saint-Luc, (EDHF). Université catholique de Louvain, B01.5309, Avenue Mounier 52, In the vasculature, the predominant NOS isoform is 1200 Brussels, Belgium eNOS, which is responsible for most of the NO production Author's personal copy Curr Hypertens Rep (2012) 14:310–317 311 [1]. Like other NOS isoforms, eNOS generates NO through a rat model of hypertension, carvedilol-induced decreases in the conversion of L-arginine to L-citrulline, and its activa- blood pressure are associated with increased NO plasma levels tion relies on intracellular calcium concentration as well as also suggests that Carvedilol relaxation properties partly relate on the presence of tetrahydrobiopterin (BH4) and NADPH to the NO pathway [7]. Whether this relates to an improved [2]. NO synthesis is stimulated in response to shear stress or NO production or a reduced oxidative stress-dependent NO calcium-mobilizing agonists such as acetylcholine and degradation remains to be resolved. In addition to its vaso- dilates blood vessels by inducing the formation of cGMP dilating effect, NO inhibits platelet aggregation and adhesion, from GTP in the underlying smooth muscle cells [3, 4]. In leukocyte activation and smooth muscle proliferation. Thus, the context of this review, the beta-blocker, Nebivolol, was NO is an important actor in the endogenous defense against shown to activate both NO and cGMP production in differ- vascular injury, inflammation and thrombosis [8]; these latter ent vascular beds (see Fig. 1)[5, 6]. The observation that, in properties should be taken into account when considering the Fig. 1 Schematic overview of adrenoreceptor distribution in endothelial cyclooxygenase, DAG diacylglycerol, EDH(F) endothelium-derived hy- and smooth muscle cells illustrating the potential target pathways induc- perpolarization (or hyperpolarizing factor), Gi inhibitory regulative G- ing vasomotion. Relevant interrelationships (→0activators, 0 inhib- protein, Gq heterotrimeric G protein subunit q, Gs stimulative regulative itors) between adrenoreceptors and some of the vasodilator substances G-protein, GTP guanosine triphosphate, IP3 inositol 1,4,5-triphosphate, produced by the endothelial cell (EC) and second messenger vasodilator K+ potassium from both voltage- and agonist-dependent channels, L-arg pathways in the vascular smooth muscle cell (VSMC) are represented. AA L-arginine, NADPH nicotinamide adenine dinucleotide phosphate, NO arachidonic acid, α-AR alpha-adrenoreceptors, Akt protein kinase B, ATP nitric oxide, NOS nitric oxide synthase, PGH2 prostaglandin H2, PGI2 adenosine triphosphate, β-AR beta-adrenoreceptors, Ca2+ calcium from prostacyclin, PI3K phosphoinositide-3-kinase, PIP2 phosphatidylinositol both voltage- and agonist-dependent channels, CAMKK calmodulin- bisphosphate, PKA protein kinase-A, PKG protein kinase-G, PL (C, D, dependent protein kinase kinase, cAMP adenosine 3′,5′-cyclic mono- A2) phospholipase (C, D, A2), ROS reactive oxygen species, S.R. 0 phosphate, cGMP cyclic guanosine 3′,5′-monophosphate, COX sarcoplasmic reticulum Author's personal copy 312 Curr Hypertens Rep (2012) 14:310–317 potential beneficial effects of drugs (beta-blockers in this case) KATP channel activation in beta-adrenoreceptor-mediated that promote the NO pathway. vasodilation. Indeed, using isoprenaline together with the Prostacyclin is a product of cyclooxygenase (COX) KATP channel inhibitor glibenclamide on rat mesenteric formed from arachidonic acid in ECs and causes relaxation arteries, Randall and McCulloch showed that the vasodilator via activation of an IP receptor (prostaglandin I2 receptor) potency of this beta-adrenoreceptor agonist is coupled to the [9] stimulating adenylate cyclase and increasing the intra- opening of KATP channels. They additionally demonstrated cellular cAMP level [10]. Despite the fact that its contribution that both beta1- and beta2-adrenoreceptors are implicated to endothelium-dependent relaxation is not preeminent, pros- since dobutamine and terbutaline (beta1 and beta2-agonists, tacyclin, like NO, has antiplatelet and antithrombotic activity. respectively) gave similar results [19]. Notably, the under- They act synergistically, and both effects are tightly related lying pathway was described by Wellman, Quayle and since PGI2 potentiates NO release and NO potentiates PGI2's Standen. They showed that KATP channel activation by effect on vascular smooth muscle cells (VSMCs) [11]. The beta-adrenoreceptors occurs via stimulation of PKA, result- link between beta-adrenoceptors and prostacyclin production ing from adenylyl cyclase-mediated cAMP generation [20, in the endothelium is ambiguous as beta-adrenergic stimula- 21](seeFig.1). In opposition to the endothelium- tion promotes prostacyclin synthesis, which is countered by a independent process, a very recent study demonstrated that cAMP-dependent inhibition of phospholipase D activity [12]. following focal beta-adrenoceptor stimulation, a KATP and A third pathway that is independent of the two previously endothelium-related hyperpolarization underlies the ability cited is termed “endothelium-derived hyperpolarizing fac- of vasodilatation to spread along the artery wall [22]. This tor” (EDHF). The name may be confusing since both NO latter mechanism might also be of physiological and phar- and/or PGI2 are able to hyperpolarize the underlying smooth macological relevance when considering vasorelaxing prop- muscle cells [13, 14], and the phenomenon is increasingly erties of beta-adrenoceptor modulators. Of note, it has been described as simply “endothelium-dependent hyperpolariza- shown in cat atrial myocytes that beta1-adrenoreceptor ex- tion”
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