Differential Distribution of β-Adrenergic Receptor Subtypes in Blood Vessels of Knockout Mice Lacking β₁- or β₂-Adrenergic Receptors

Abstract

beta-Adrenergic receptors (beta-AR) are essential regulators of cardiovascular homeostasis. In addition to their prominent function in the heart, beta-AR are located on vascular smooth muscle cells, where they mediate vasodilating effects of endogenous catecholamines. In this study, we have investigated in an isometric myograph different types of blood vessels from mice lacking beta(1)- and/or beta(2)-adrenergic receptor subtypes (beta(1)-KO, beta(2)-KO, beta(1)beta(2)-KO). In wild-type mice, isoproterenol induced relaxation of segments from thoracic aorta, carotid, femoral and pulmonary arteries, and portal vein. The relaxant effect of beta-receptor stimulation was absent in femoral and pulmonary arteries from beta(1)-KO mice. In aortic and carotid arteries and in portal veins, the vasodilating effect of isoproterenol was reduced in mice lacking beta(1)- or beta(2)-receptors. However, in these vessels the vasodilating effect was only abolished in double KO mice lacking both beta(1)- and beta(2)-receptors. Vessel relaxation induced by forskolin did not differ between wild-type and KO mice. Similar contributions of beta(1)- and beta(2)-receptors to isoproterenol-induced vasorelaxation were found when vessels from KO mice were compared with wild-type arteries in the presence of subtype-selective beta-receptor antagonists. These studies demonstrate that beta(1)-adrenergic receptors play a dominant role in the murine vascular system to mediate vasodilation. Surprisingly, beta(2)-receptors contribute to adrenergic vasodilation only in a few major blood vessels, suggesting that differential distribution of beta-adrenergic receptor subtypes may play an important role in redirection of tissue perfusion.

Regulation of the Cystic Fibrosis Transmembrane Conductance Regulator Channel by β-Adrenergic Agonists and Vasoactive Intestinal Peptide in Rat Smooth Muscle Cells and Its Role in Vasorelaxation

“…The action of ␤-adrenergic receptors involves stimulation of adenylyl cyclase via interaction of the agonist-receptor complex with G s and subsequent intracellular cAMP concentration increase (25). In addition, relaxation could be elicited by direct activation of adenylyl cyclase (22). This signal transduction pathway has also been described for CFTRdependent secretion in epithelia (14).…”

“…The cAMP pathway is an important regulator of the vascular tone. In this regard, ␤-adrenergic receptors are located on vascular smooth muscle cells and mediate vasodilating effects of endogenous catecholamines (22,25). The action of ␤-adrenergic receptors involves stimulation of adenylyl cyclase via interaction of the agonist-receptor complex with G s and subsequent intracellular cAMP concentration increase (25).…”

“…First, SMC were bathed in a classical Krebs saline (containing 4.7 mM K ϩ ) mimicking the physiological extracellular medium. Second, we used a modified Krebs solution containing 80 mM extracellular K ϩ , because it is known that high K ϩ depolarizes the cell membrane and promotes the contraction of SMC by activating voltage-gated Ca 2ϩ channels (2,22). A cAMP-promoting mixture containing 10 M forskolin, 500 M IBMX, and 500 M cpt-cAMP was used.…”

“…Among the numerous physiological regulators of SMC leading to an elevation of the cellular cAMP level, we first selected the ␤-adrenergic agonist isoproterenol (22,25). In Krebs saline, no significant stimulation was noted with 1 M isoproterenol (n ϭ 8; Fig.…”

Is overall blockade superior to selective blockade of adrenergic receptor subtypes in suppressing left ventricular remodeling in spontaneously hypertensive rats?

“…A number of studies found that both AR-b 1 and AR-b 2 were downregulated in SHR. [28][29][30][31] Chruscinski et al 32,33 reported that AR-b 1 had a dominant role in mediating vasodilation in mice. Hirota et al 34 found AR-b 2 stimulation improved inotropic and lusitropic function in the failing heart and Communal et al 35 reported that AR-b 2 inhibited cardiocyte apoptosis through a Gi-coupled pathway in rats.…”