Characterization of ␣ 2 Adrenergic Receptor Subtypes in Human Ocular Tissue Homogenates

PURPOSE. To determine the predominant ␣ 2 adrenergic receptor subtypes present in the human eye. METHODS. Saturation-and competition-receptor-binding experiments were performed with the radioligand [ 3 H]RX821002 in human ciliary body, retinal pigmented epithelium-choriocapillaris, iris, and neurosensory retina. The affinities of various adrenergic antagonists in these ocular tissues were compared with their affinities for the cloned ␣ 2A , ␣ 2B , and ␣ 2C adrenergic receptor subtypes. RESULTS. The density of ␣ 2 adrenergic receptors was highest in the iris (440 femtomoles/mg protein), lowest in the neurosensory retina (14 femtomoles/mg protein), and intermediate in the other two tissues (approximately 90 fmol/mg protein). The drug affinities in all four human ocular tissues were highly correlated (correlation coefficients between 0.94 and 0.97) with the affinities for the human ␣ 2A adrenergic receptor subtype and poorly correlated (correlation coefficients between 0.15 and 0.66) with the ␣ 2B and ␣ 2C subtypes. CONCLUSIONS. In agreement with previous studies in several animal species, the ␣ 2 adrenergic receptors in the human ciliary body, retinal pigmented epithelium-choriocapillaris, iris, and neurosensory retina are predominately of the ␣ 2A subtype. (Invest Ophthalmol Vis Sci. 1999;40: 2299 -2306 G laucoma is characterized by a progressive loss of visual sensitivity resulting from optic nerve damage. Because high intraocular pressure is the most important risk factor for glaucoma, the treatment of glaucoma has emphasized the reduction of intraocular pressure. 1 Alpha-2 adrenergic agonists such as brimonidine and apraclonidine are effective ocular hypotensive agents, 2-4 although their mechanism of action is not clear. Based on both pharmacologic and molecular evidence, there are three major types of adrenergic receptors, ␣ 1 , ␣ 2 , and ␤, each of which is further divided into three or four subtypes. 8 The evidence for ␣ 2 adrenergic receptor subtypes has come from binding and functional studies in various tissues and cell lines and more recently in cells transfected with the cDNA for the receptors. 9 On the basis of these studies, three ␣ 2 adrenergic receptor subtypes have been defined. The ␣ 2A adrenergic receptor subtype, for which prazosin has a relatively low affinity and oxymetazoline a relatively high affinity, is found in the human platelet and the HT29 cell. 11 Although this subtype also has a relatively high affinity for prazosin and a low affinity for oxymetazoline, it is pharmacologically distinct from the ␣ 2B subtype. 12 All three subtypes have been cloned from the human. In contrast to these binding data, immunofluorescence labeling of the human ciliary body indicates the presence of ␣ 2B and ␣ 2C subtypes, but not the ␣ 2A subtype

Anonymity and the Rise of Universal Occasions for Religious Ritual: An Extension of the Durkheimian Theory

An article written by Edward B. Reeves and Robert A. Bylund and published in the Journal for the Scientific Study of Religion, pages 113-130

Solubilization and Characterization of Putative Alpha -2 Adrenergic Isoceptors from the Human Platelet and the Rat Cerebral Cortex1

ABSTRACT ABBREVIATiONS: CHAPS, [3-cholamidopropyldimethyIammonloJ-1-propane sulfate; UC-14,304, 5-bromo-6-(2-imidazolrn-2-ylaminej-quinoxaline; PEG, polyethylene glycol. 60

Analysis of brain adrenergic receptors in dopamine-β-hydroxylase knockout mice

The biosynthesis of norepinephrine occurs through a multi-enzymatic pathway that includes the enzyme dopamine-β-hydroxylase (DBH). Mice with a homozygous deletion of DBH (Dbh−/−) have a selective and complete absence of norepinephrine. The purpose of this study was to assess the expression of alpha-1, alpha-2 and beta adrenergic receptors (α1-AR, α2-AR and β-AR) in the postnatal absence of norepinephrine by comparing noradrenergic receptors in Dbh−/− mice with those in Dbh heterozygotes (Dbh+/−), which have normal levels of norepinephrine throughout life. The densities of α1-AR, α2-AR and β-AR were assayed with [3H]prazosin, [3H]RX21002 and [125I]-iodo-pindolol autoradiography, respectively. The α2-AR agonist high affinity state was examined with [125I]-paraiodoclonidine autoradiography and α2-AR functionality by α2-AR agonist-stimulated [35S] GTPγS autoradiography. The density of α1-AR in Dbh−/− mice was similar to Dbh+/− mice in most brain regions, with an up-regulation in the hippocampus. Modest decreases in α2-AR were found in septum, hippocampus and amygdala, but these were not reflected in α2-AR functionality. The density of β-AR was up-regulated to varying degrees in many brain regions of Dbh−/− mice compared to the heterozygotes. These findings indicate that regulation of noradrenergic receptors by endogenous norepinephrine depends on receptor type and neuroanatomical region

Characterization of the alpha-i adrenergic receptors in the thoracic aorta of control and aldosterone hypertensive rats: Correlation of radioligand binding with potassium efflux and contraction.

ABSTRACT and 8.0±0.1)andcontrol (7.9 ± 0.2 and 8.1 ± 0.1) rats whether measured by contraction or 42K efflux. The pA2 value for the selective alpha-i antagonist prazosin (9.8 ± 0.1 to 10.7 ± 02) and the a!pha-2 antagonist yohimbine(6.6 ± 0.2 to 7.4 ± 0.2) was similar in AHR and control groups using both norepinephnne and phenylephrine as agonists. The rank order of potency was prasozin > phentolamine > yohimbine in both groups. and an increased sensitivity to NE, reflected in the lower NE ECso of 2.4 ± 0.5 nM (P < .001). These difference

Associating land cover changes with patterns of incidences of climate-sensitive infections: an example on tick-borne diseases in the Nordic area

Some of the climate-sensitive infections (CSIs) affecting humans are zoonotic vector-borne diseases, such as Lyme borreliosis (BOR) and tick-borne encephalitis (TBE), mostly linked to various species of ticks as vectors. Due to climate change, the geographical distribution of tick species, their hosts, and the prevalence of pathogens are likely to change. A recent increase in human incidences of these CSIs in the Nordic regions might indicate an expansion of the range of ticks and hosts, with vegetation changes acting as potential predictors linked to habitat suitability. In this paper, we study districts in Fennoscandia and Russia where incidences of BOR and TBE have steadily increased over the 1995–2015 period (defined as ’Well Increasing districts’). This selection is taken as a proxy for increasing the prevalence of tick-borne pathogens due to increased habitat suitability for ticks and hosts, thus simplifying the multiple factors that explain incidence variations. This approach allows vegetation types and strengths of correlation specific to the WI districts to be differentiated and compared with associations found over all districts. Land cover types and their changes found to be associated with increasing human disease incidence are described, indicating zones with potential future higher risk of these diseases. Combining vegetation cover and climate variables in regression models shows the interplay of biotic and abiotic factors linked to CSI incidences and identifies some differences between BOR and TBE. Regression model projections up until 2070 under different climate scenarios depict possible CSI progressions within the studied area and are consistent with the observed changes over the past 20 years

The Ctf18 RFC-like complex positions yeast telomeres but does not specify their replication time

Peer reviewedPreprin

Adrenoceptors in GtoPdb v.2023.1

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [64, 194]. Adrenoceptors, α1 The three α1-adrenoceptor subtypes α1A, α1B and α1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. -(-)phenylephrine, methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective for α1- relative to α2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy FLprazosin- QAPB) are used to examine cellular localisation of α1-adrenoceptors. α1-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin, with the last two compounds being α1A-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension (doxazosin, terazosin). The α1- and β2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of α1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are α1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension. Adrenoceptors, α2 The three α2-adrenoceptor subtypes α2A, α2B and α2C are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for α2- relative to α1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There are species variations in the pharmacology of the α2A-adrenoceptor. Multiple mutations of α2-adrenoceptors have been described, some associated with alterations in function. Presynaptic α2-adrenoceptors regulate many functions in the nervous system. The α2-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive (relatively little used) and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is increasingly used as a sedative and analgesic in human [33] and veterinary medicine and has sympatholytic and anxiolytic properties. The α2-adrenoceptor antagonist mirtazapine is used as an anti-depressant. The α2B subtype appears to be involved in neurotransmission in the spinal cord and α2C in regulating catecholamine release from adrenal chromaffin cells. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools. Adrenoceptors, β The three β-adrenoceptor subtypes β1, β2 and β3 are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for β-adrenoceptors relative to α1- and α2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively selective antagonists for β1- and β2- relative to β3-adrenoceptors. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for β1- relative to β2-adrenoceptors. Pharmacological differences exist between human and mouse β3-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human β3-adrenoceptor whereas CGP 12177 (low potency) and L 755507 activate human β3-adrenoceptors [88]. β3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at β3-adrenoceptors, but does not discriminate between the three β- subtypes [332] whereas L-748337 is more selective. [125I]-cyanopindolol, [125I]-hydroxy benzylpindolol and [3H]-alprenolol are high affinity radioligands that label β1- and β2- adrenoceptors and β3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol together with β1- and β2-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track β-adrenoceptors at the cellular level [8]. Somewhat selective β1-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. β1-Adrenoceptor-preferring antagonists are used to treat cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol) but also in combination with other treatments to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol) [528]. Cardiac failure is also treated with carvedilol that blocks β1- and β2-adrenoceptors, as well as α1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting β2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation β-adrenoceptor antagonists (propranolol) block both β1- and β2-adrenoceptors and there are no β2-adrenoceptor-selective antagonists used therapeutically. The β3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome. There is evidence to suggest that β-adrenoceptor antagonists can reduce metastasis in certain types of cancer [197]