β‐adrenergic Receptor Blocker ICI 118,551 Selectively Increases Intermediate‐Conductance Calcium‐Activated Potassium Channel (IK_Ca)‐Mediated Relaxations in Rat Main Mesenteric Artery

Abstract

Endothelial IK and/or SK channels play an important role in the control of vascular tone by participating in endothelium-dependent relaxation. Whether β-AR antagonists, mainly used in hypertension, affect endothelial K channel function is unknown. In this study, we examined the effect of the β2-AR antagonist and inverse agonist ICI 118,551 on the IK /SK channel activity by assessing functional relaxation responses to several agonists that stimulate these channels. Mesenteric arterial rings isolated from male Sprague Dawley mounted to organ baths. Acetylcholine elicited IK - and SK -mediated relaxations that were abolished by TRAM-34 and apamin, respectively. ICI 118,551, which did not dilate the arteries per se, increased the IK -mediated relaxations, whereas SK -mediated relaxations remained unaltered. Same potentiating effect was also detected on the IK -mediated relaxations to carbachol and A23187, but not to NS309. Neither acetylcholine-induced nitric oxide-mediated relaxations nor SNP relaxations changed with ICI 118,551. The PKA inhibitor KT-5720, the selective β2-AR agonist salbutamol, the selective β2-AR antagonist butoxamine, the non-selective β-AR antagonist propranolol, and the inverse agonists carvedilol or nadolol failed to affect the IK -mediated relaxations. ICI 118,551-induced increase was not reversed by salbutamol or propranolol as well. Besides, low potassium-induced relaxations in endothelium-removed arteries remained the same in the presence of ICI 118,551. These data demonstrate a previously unrecognized action of ICI 118,551, the ability to potentiate endothelial IK channel-mediated vasodilation, through a mechanism independent of β2-AR antagonistic or inverse agonistic action. Instead, the enhancement of acetylcholine relaxation seems likely to occur by a mechanism secondary to endothelial calcium increase.

A Systematic Review of Inverse Agonism at Adrenoceptor Subtypes

“…Stringent proof of IA requires that the inverse effect of one ligand is blocked by a neutral antagonist; however, most studies in the field have assumed that a given compound shown once or more often to reduce the basal receptor output agonist consistently acts via IA, but this is not necessarily the case. For instance, ICI 118,551 has repeatedly been shown to be an inverse agonist at β 2 -AR (see below); however, its inhibitory effect in the rat endothelium was neither mimicked by other known inverse agonists (e.g., carvedilol or nadolol) nor blocked or reversed by antagonists (e.g., propranolol) or agonists (e.g., salbutamol) [ 60 ], indicating that it may have acted by β-AR-independent mechanisms in this model. While this may be the exception, IA as an explanation of an observed effect should not be assumed too easily.…”

The β2-adrenergic receptor antagonist ICI-118,551 blocks the constitutively activated HIF signalling in hemangioblastomas from von Hippel-Lindau disease

“…Based on the clinical trials and in vivo assays done, systemic doses have been used without toxicity in humans (up to 20 mg/kg), rodents (0.5 or 1 mg/kg) or rhesus monkeys (0.1 μg/kg). ICI, nowadays, is mainly used as control of β-blockers's specificity in physiological processes such us control of heart and vascular tone and SNC and muscular signaling [37][38][39][40] . Finally, ICI has been also used in cancer research showing a role in cell proliferation and signalling regulation 41,42 .…”

Effect of β1/β2‐adrenoceptor blockade on β3‐adrenoceptor activity in the rat cremaster muscle artery

“…Asterisk (*) indicates a significantly inhibition of responses by L-NAME/ODQ. Δ indicates significant further inhibitions of responses by TRAM-34 (P < .05, two-way ANOVA with Sidak's post hoc comparison) (Ozkan & Uma, 2017). These effects were mediated through interaction with K Ca 3.1, which contributed to β 3 -adrenoceptor-mediated vasorelaxation in the present study.…”

“…The effects of PKI further suggest that β 1/2 ‐adrenoceptors inhibit β 3 ‐adrenoceptors through a PKA‐mediated mechanism. β 1 ‐adrenoceptors were shown to inhibit ACh‐induced, endothelium‐dependent relaxation of the rat mesenteric artery through cAMP/PKA (Yarova et al, 2013), while ICI 118,551 enhanced aspects of endothelium‐dependent vasodilation in the same vessel type (Ozkan & Uma, 2017). These effects were mediated through interaction with K Ca 3.1, which contributed to β 3 ‐adrenoceptor‐mediated vasorelaxation in the present study.…”