Clonidine has proved to be a clinically useful adjunct in clinical anaesthetic practice as well as in chronic pain therapy because it has both anaesthetic and analgesic-sparing activity. The more selective alpha-2 adrenoceptor agonists, dexmedetomidine and mivazerol, may also have a role in providing haemodynamic stability in patients who are at risk of peri-operative ischaemia. The side-effects of hypotension and bradycardia have limited the routine use of alpha-2 adrenoceptor agonists. Investigations into the molecular pharmacology of alpha-2 adrenoceptors have elucidated their role in the control of wakefulness, blood pressure and antinociception. We discuss the pharmacology of alpha-2 adrenoceptors and their therapeutic role in this review. The alpha-2 adrenoceptor agonists are agonists at imidazoline receptors which are involved in central blood pressure control. Selective imidazoline agonists are now available for clinical use as antihypertensive agents and their pharmacology is discussed.

alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role.

Arginine has multiple metabolic fates and thus is one of the most versatile amino acids. Not only is it metabolically interconvertible with the amino acids proline and glutamate, but it also serves as a precursor for synthesis of protein, nitric oxide, creatine, polyamines, agmatine, and urea. These processes do not all occur within each cell but are differentially expressed according to cell type, age and developmental stage, diet, and state of health or disease. Arginine metabolism also is modulated by activities of various transporters that move arginine and its metabolites across the plasma and mitochondrial membranes. Moreover, several key enzymes in arginine metabolism are expressed as multiple isozymes whose expression can change rapidly and dramatically in response to a variety of different stimuli in health and disease. As illustrated by the questions raised in this article, we currently have an imperfect and incomplete picture of arginine metabolism for any mammalian species. It has become clear that a more complete understanding of arginine metabolism will require integration of information obtained from multiple approaches, including genomics, proteomics, and metabolomics.

Arginine Metabolism: Boundaries of Our Knowledge

α 2 -Adrenergic receptors (α 2 ARs) present in the brainstem decrease blood pressure and are targets for clinically effective antihypertensive drugs. The existence of three α 2 AR subtypes, the lack of subtype-specific ligands, and the cross-reactivity of α 2 AR agonists with imidazoline receptors has precluded an understanding of the role of individual α 2 AR subtypes in the hypotensive response. Gene targeting was used to introduce a point mutation into the α 2a AR subtype in the mouse genome. The hypotensive response to α 2 AR agonists was lost in the mutant mice, demonstrating that the α 2a AR subtype plays a principal role in this response.

Central hypotensive effects of the alpha2a-adrenergic receptor subtype.

A review is presented of the recent developments in the metabolism andfunction of polyamines in plants. Polyamines appear to be involved in a widerange of plant processes so their exact role is not completely understood. Inthis review, the metabolic pathways involved in polyamine biosynthesis anddegradation are explained, along with the transport and conjugation of thesecompounds. The methodologies involved in the analysis of polyamine functionusing metabolic inhibitors and genetic and molecular approaches are described.The occurrence and distribution of polyamine-derived alkaloids are also dealtwith. The direction of future research in the study of plant polyamines isindicated.

Metabolism and function of polyamines in plants: recent development (new approaches)

The serotonergic and noradrenergic systems of the hippocampus: their interactions and the effects of antidepressant treatments

Clonidine, an antihypertensive drug, binds to alpha 2-adrenergic and imidazoline receptors The endogenous ligand for imidazoline receptors may be a clonidine-displacing substance, a small molecule isolated from bovine brain This clonidine-displacing substance was purified and determined by mass spectroscopy to be agmatine (decarboxylated arginine), heretofore not detected in brain Agmatine binds to alpha 2-adrenergic and imidazoline receptors and stimulates release of catecholamines from adrenal chromaffin cells Its biosynthetic enzyme, arginine decarboxylase, is present in brain Agmatine, locally synthesized, is an endogenous agonist at imidazoline receptors, a noncatecholamine ligand at alpha 2-adrenergic receptors and may act as a neurotransmitter

https://science.sciencemag.org/content/sci/263/5149/966.full.pdf

Agmatine: an endogenous clonidine-displacing substance in the brain

Agmatine, the bacterial amine, is widely distributed in mammalian tissues

Agmatine Is Synthesized by a Mitochondrial Arginine Decarboxylase in Rat Brain

We recently discovered' that agmatine, a primary amine generated by decarboxylation of arginine by the enzyme arginine decarboxylase (ADC),2*3 is stored in bovine brain. As such it is the first clonidine-displacing substance (CDS) isolated whose structure has been determined. (See Reis et al., this volume: for a review.) Like clonidine, agmatine binds to imidazoline (I-) receptors of both 11 and Iz subclass and to a2adrenergic receptors.' While prevalent in bacteria, plants, and invertebrates, neither agmatine nor ADC has been considered present in mammalian tissues?v3 Our observation' that brain also expresses ADC indicates that the amine is locally synthesized and is not a product of diet or enteric bacteria. To determine if agmatine is present in rat brain and other organs, we developed a method to allow separation of agmatine from other amines in tissue extracts, permitting its measurement by reversed-phase high pressure liquid chromatography (RP-HPLC). We demonstrate that agmatine is present in this species and widely and unequally distributed throughout the body.

Agmatine Is Widely and Unequally Distributed in Rat Organs

1. There are several endogenous ligands that bind to I-receptors of both the I1 and I2 subclass. These include: (a) classic CDS, a partially purified entity isolated by the criteria that it displaces binding ligands to alpha 2- and I-receptors; (b) immunoreactive (ir)-CDS, a moiety that binds to antibodies raised against clonidine, para-amino-clonidine, or idazoxan; and (c) agmatine. 2. Classic-CDS, not yet defined structurally, binds to I1, I2, and alpha 2-adrenergic receptors, is neither a peptide nor a catecholamine, and has purportedly a molecular weight of 588 Da. By ligand binding assays, it was found in brain, serum, CSF, and placenta and in a neural-glial cell line. Partially purified classic CDS is bioactive. Like clonidine, it contracts aorta and vas deferens and inhibits platelet aggregation, effects largely attributable to agonism at alpha 2-adrenergic receptors. Unlike clonidine, it contracts rat gastric fundus and releases catecholamines from chromaffin cells, effects attributable to actions at I-receptors. Injected into the RVL, classic CDS alters arterial pressure, but the direction of change of pressure has differed between groups of investigators. However, in the absence of structure, it is possible that ligand binding and bioactivity may be attributable to different molecules. 3. Ir-CDS, also of unknown structure, is a material(s) that binds to antibodies raised against clonidine, PAC, or idazoxan. Ir-CDS, measured by radioimmunoassay, is unevenly distributed in brain with highest concentrations in the hypothalamus, midbrain, and dorsal medulla. It is contained in the gastric fundus, adrenal gland, heart, kidney, and serum in amounts substantially higher than found in brain. Ir-CDS may be elevated in the serum of some patients with hypertension and in the CSF of patients with structural brain disease. The concentration of ir-CDS and bioactivity on gastric fundus directly correlates, suggesting that it may share similarities with classic-CDS. However, until the structure of classic and ir-CDS is determined, the possibility that ligand binding and antibody recognition are properties of different molecules must be considered. 4. Agmatine (decarboxylated arginine) is the only endogenous molecule that, like CDS, binds to alpha 2- and I-receptors of both classes. It and its biosynthetic enzyme arginine decarboxylase are present in brain, and agmatine is widely distributed throughout the body. However, the distribution of agmatine and ir-CDS differs, whereas the biological actions of agmatine do not mimic those of classic CDS. Its presence raises the possibility of an alternative pathway for polyamine biosynthesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Gen Li

Papers

Agmatine: an endogenous clonidine-displacing substance in the brain

Agmatine, the bacterial amine, is widely distributed in mammalian tissues

Agmatine Is Synthesized by a Mitochondrial Arginine Decarboxylase in Rat Brain

Agmatine Is Widely and Unequally Distributed in Rat Organs

Endogenous Ligands of Imidazoline Receptors: Classic and Immunoreactive Clonidine‐Displacing Substance and Agmatine