https://pharmrev.aspetjournals.org/content/pharmrev/46/2/121.full.pdf

International Union of Pharmacology nomenclature of adrenoceptors.

Since the classification of beta-adrenergic receptors (beta-ARs) into beta 1 and beta 2 subtypes, additional beta-ARs have been implicated in the control of various metabolic processes by catecholamines. A human gene has been isolated that encodes a third beta-AR, here referred to as the "beta 3-adrenergic receptor." Exposure of eukaryotic cells transfected with this gene to adrenaline or noradrenaline promotes the accumulation of adenosine 3',5'-monophosphate; only 2 of 11 classical beta-AR blockers efficiently inhibited this effect, whereas two others behaved as beta 3-AR agonists. The potency order of beta-AR agonists for the beta 3-AR correlates with their rank order for stimulating various metabolic processes in tissues where atypical adrenergic sites are thought to exist. In particular, novel beta-AR agonists having high thermogenic, antiobesity, and antidiabetic activities in animal models are among the most potent stimulators of the beta 3-AR.

https://science.sciencemag.org/content/sci/245/4922/1118.full.pdf

Molecular characterization of the human beta 3-adrenergic receptor

The total and regional peripheral resistance and capacitance of the vascular system is regulated by the sympathetic nervous system, which influences the vasculature mainly through changes in the release of catecholamines from both the sympathetic nerve terminals and the adrenal medulla. The knowledge of the targets for noradrenaline and adrenaline, the main endogenous catecholamines mediating that influence, has recently been greatly expanded. From two types of adrenoceptors (α and β), we have now nine subtypes (α 1A , α 1B , α 1D , α 2A/D , α 2B , α 2A/D , β 1 , β 2 , and β 3 ) and two other candidates (α 1L and β 4 ), which may be conformational states of α 1A and β 1 -adrenoceptors, respectively. The vascular endothelium is now known to be more than a pure anatomical entity, which smoothly contacts the blood and forms a passive barrier against plasma lipids. Instead, the endothelium is an important organ possessing at least five different adrenoceptor subtypes (α 2A/D , α 2C , β 1 , β 2 , and β 3 ), which either directly or through the release of nitric oxide actively participate in the regulation of the vascular tone. The availability of transgenic models has resulted in a stepwise progression toward the identification of the role of each adrenoceptor subtype in the regulation of blood pressure and fine-tuning of blood supply to the different organs: α 2A/D -adrenoceptors are involved in the central control of blood pressure; α 1 -(primarily) and α 2B -adrenoceptors (secondarily) contribute to the peripheral regulation of vascular tone; and α 2A/D - and α 2C -adrenoceptors modulate transmitter release. The increased knowledge on the involvement of vascular adrenoceptors in many diseases like Raynaud9s, scleroderma, several neurological degenerative diseases (familial amyloidotic polyneuropathy, Parkinson disease, multiple-system atrophy), some kinds of hypertension, etc., will contribute to new and better therapeutic approaches.

Vascular Adrenoceptors: An Update

Fat cell adrenergic receptors and the control of white and brown fat cell function.

A potassium (K) channel that was inhibited by physiological (f1M) concen­ trations of intracellular ATP ([ATP]i) and that opened as [ATP]i decreased was first described in the heart ( l). Subsequently, similar K -channels all with unitary conductances in the range of 40-80 pS (measured under symmetrical high K+ conditions) were also found to exist in insulin-secreting cells and in skeletal muscle (2_5).1 Such channels constitute what are classically described as ATP-sensitive K-channels and were termed Type 1 by Ashcroft & Ashcroft (6). In this review they are designated KATP and the current flowing through them is defined as IK(ATP) . Type 1 KATP channels are essentially calciumand voltage-independent, K+ -selective, and are half-maximally inhibited by [ATP]i in the range 10-100 fJ.M. They exhibit inward rectification and a key pharmacological feature is their inhibition by agents like tolbutamide and glyburide . Other ATP-sensitive K-channels exist and these were designated Types 2, 3, 4, and 5 (6). Such channels vary not only in their sensitivity to calcium and to the inhibitory effects of [ATP]i, but also in their selectivity for potassium and their susceptibility to pharmacological modulation.

The Pharmacology of ATP-Sensitive Potassium Channels

The rat lipolytic β-adrenoceptor: Studies using novel β-adrenoceptor agonists

1. In rat isolated thoracic aortic rings pre-contracted with noradrenaline (10(-6) M), cromakalim (3 x 10(-7)-3 x 10(-5) M) produced concentration-related relaxation. This effect was progressively inhibited by increasing concentrations of the anti-diabetic sulphonylurea drug, glibenclamide (10(-6)-10(-5) M). 2. In rat isolated portal veins, cromakalim (3 x 10(-8)-10(-6) M) produced concentration-related inhibition of the spontaneous contractive activity and glibenclamide (3 x 10(-7)-3 x 10(-6) M) prevented this inhibitory action in a concentration-dependent manner. 3. In both rat aortic rings and portal veins, cromakalim (10(-5) M) stimulated 86Rb efflux. Prior exposure to glibenclamide (10(-7)-10(-6) M) produced a concentration-related inhibition of this response. 4. In conscious rats, cromakalim, 0.075 mg kg-1 i.v., produced a rapid and sustained fall in arterial blood pressure which was not influenced by pretreatment (2 h) with a large oral dose of glibenclamide (100 mg kg-1). 5. In conscious rats, the hypotensive action of cromakalim, 0.075 mg kg-1 i.v., was abolished by pretreatment (30 min) with glibenclamide, 20 mg kg-1, given by the intravenous route. 6. The results suggest that the vasorelaxant and hypotensive actions of cromakalim involve a K+ channel which can be inhibited by glibenclamide, but which may be distinct from the ATP-sensitive K+ channel of the pancreatic beta-cell.

/pdf/inhibition-by-glibenclamide-of-the-vasorelaxant-action-of-475ojcpjfw.pdf

Inhibition by glibenclamide of the vasorelaxant action of cromakalim in the rat.

Comparative effects of K+ channel blockade on the vasorelaxant activity of cromakalim, pinacidil and nicorandil

1. The relaxant effects of Zeneca ZD7114, BRL37344 (putative beta 3-adrenoceptor agonists) and various phenylethylamine-based agonists were studied in isolated ileum of the rat where tone was increased with carbachol (0.5 microM). Agonist-induced relaxation.was measured under equilibrium conditions with alpha-, beta 1- and beta 2-adrenoceptors inhibited. 2. Relaxant responses were obtained to isoprenaline, noradrenaline, and BRL37344, although, the efficacy of this latter agent was significantly.lower than that of isoprenaline. Salbutamol caused weak relaxation (< 20%) at high concentrations (10 microM) and ZD7114 was without significant relaxant effect even at high concentrations (10 microM). 3. Relaxant responses to isoprenaline and BRL37344 were weakly antagonized by high concentrations of (+/-)-propranolol (10 and 100 microM) yielding pKB values of 5.7 with isoprenaline as the agonist and 5.5 with BRL37344 as the agonist. 4. The non-selective beta-adrenoceptor antagonist, (+/-)-alprenolol (1-100 microM) caused competitive antagonism of the relaxant responses to isoprenaline (pA2 value = 6.5). A similar pKB value was obtained when BRL37344 was used as the agonist (6.4). 5. Relaxant effects of isoprenaline and BRL37344 were also antagonized by ZD7114 (1-100 microM) yielding pA2 and pKB values of 6.3 and 6.7 respectively. 6. The low potencies of (+/-)-propranolol and (+/-)-alprenolol as antagonists of the relaxant responses to isoprenaline and BRL37344 indicate that both the agonists and antagonists employed in the current study may interact with beta 3-adrenoceptors in the rat isolated ileum. Contrary to the previous findings in guinea-pig ileum, where BRL37344 and ZD7114 were full agonists, in the current study, BRL37344 was a partial agonist and ZD7114 an antagonist at the beta 3-adrenoceptor in rat ileum.

Zeneca ZD7114 acts as an antagonist at β3‐adrenoceptors in rat isolated ileum

1. Experiments were performed to characterize the effects of the novel brown adipocyte stimulant, ICI D7114, in the guinea-pig isolated ileum, right atrium and tracheal chain. In the ileum, agonist-induced inhibition of the contractile response to either histamine or prostaglandin E2 (PGE2) was assessed, along with effects on resting rate in the atrium and resting tone in the tracheal chain. In the latter two preparations, antagonism of isoprenaline-induced responses by ICI D7114 was also assessed. 2. Inhibitory responses were obtained in the ileum to ICI D7114, isoprenaline, BRL37344, and noradrenaline. The responses to ICI D7114, isoprenaline and BRL37344 were resistant to blockade with propranolol (5 microM), naloxone (1 microM), methysergide (0.1 microM), cimetidine, indomethacin and 8-phenyltheophylline (all 10 microM). These responses to isoprenaline, in the presence of propranolol (5 microM), were competitively antagonized by alprenolol (1-100 microM) with a pA2 value of 6.44. The responses to ICI D7114 and BRL37344 were antagonized by single concentrations of alprenolol (1 microM) with apparent pKB values of 6.53 and 6.57 respectively. These data indicate an effect of ICI D7114 at the atypical beta-adrenoceptor in the guinea-pig ileum. 3. The order and relative potency of agonists at the atypical beta-adrenoceptor was BRL37344 (4) noradrenaline (0.5). 4. ICI D7114 (1 nM - 10 microM) caused no significant change in the rate of beating or the resting tone of the guinea-pig right atrium or tracheal chain respectively. It did, however, cause selective blockade of the responses to isoprenaline in these tissues (apparent pKB values 7.63 and 5.85 in atrium and tracheal chain respectively). Responses to histamine (atrium) and aminophylline (tracheal chain) were not significantly affected by 10 microM ICI D7114.5. These results demonstrate that ICI D7114 possesses selective agonist activity at atypical beta-adrenoceptors in the guinea-pig ileum and its use as a tool may help to establish a role for the atypical beta-adrenoceptor in the control of gastrointestinal motility.

Campbell Wilson

Papers

The rat lipolytic β-adrenoceptor: Studies using novel β-adrenoceptor agonists

Inhibition by glibenclamide of the vasorelaxant action of cromakalim in the rat.

Comparative effects of K+ channel blockade on the vasorelaxant activity of cromakalim, pinacidil and nicorandil

Zeneca ZD7114 acts as an antagonist at β3‐adrenoceptors in rat isolated ileum

Evaluation of ICI D7114, a putative stimulant of brown adipocytes, on histamine-contracted guinea-pig ileum.