Affinity Of Alpha 2-receptors Research Articles

Commentary: Role of alpha-2 agonists in regional ophthalmic anaesthesia.

Regional anaesthesia is the most common mode of anaesthesia used in ophthalmic surgical procedures. Among regional blocks, peribulbar anaesthesia is the safest and most commonly employed. However, in procedures with prolonged operating time, such as vitreoretinal surgeries, repeated need for block supplementation and patient anxiety, are a challenge. Adjuvants to peribulbar anaesthetics, namely, hyaluronidase and adrenaline along with preoperative anxiolytics/sedatives have been tried to overcome these challenges.[1] Alpha-2 agonists are drugs which bind selectively to alpha-2 adrenergic receptors in the central, peripheral and autonomic nervous system as well as in vital organs and blood vessels. They produce dose-dependent analgesia, anxiolysis and sedation without causing respiratory depression by acting on the G protein-coupled alpha-2 receptors.[2] Two main alpha-2 agonists that are commercially available include clonidine and dexmedetomidine. Although neither of them is completely selective for alpha-2 receptors, dexmedetomidine is 8-10 times more selective towards these receptors compared to clonidine. Dexmedetomidine has a higher avidity and affinity for alpha-2 receptors, shorter elimination half-life and higher clinical efficacy with a lesser side-effect profile compared to clonidine.[3] The study by Gujral et al. adds credence to the anxiolytic effect of dexmedetomidine which is coupled with hemodynamic safety in patients receiving peribulbar block for vitreoretinal surgery.[4] Clonidine was the first alpha-2 agonist to be used as an adjuvant by Mjahed et al. who found that its addition to peribulbar block decreased intraocular pressure, enhanced anaesthesia, akinesia and intraoperative sedation.[5] However, use of clonidine was associated with hemodynamic side-effects such as bradycardia, arterial and orthostatic hypotension, rebound hypertension and syncope. The long half-life of clonidine meant that the hemodynamic instability was not only seen intra-operatively but also for up to 8 hours in the post-operative period.[6] Dexmedetomidine, a newer alpha-2 agonist, has shown potential with a better safety profile due to its higher selectivity and shorter half-life. Two recent studies have evaluated its efficacy and side-effect profile when used as an adjunct to peribulbar block during vitreoretinal surgery.[78] Ahmed et al.[7] used 20 μg of dexmedetomidine along with lidocaine, bupivacaine and hyaluronidase. They found faster onset of anaesthesia, akinesia, increased duration of anaesthesia and increased patient sedation in comparison to a control group using normal saline. EL-Shmaa et al.[8] compared two doses of dexmedetomidine, 15 and 30 μg, as adjuvants to routine peribulbar anaesthetic agents. They also found similar results in terms of onset and duration of anaesthesia in the dexmedetomidine groups compared with the control group. The two doses did not differ significantly in terms of their efficacy or side-effect profile. The current study in contrast did not find any difference in the time of onset of anaesthesia between the study and the control groups; however, the patient and surgeon comfort were significantly better with dexmedetomidine. This study is also unique in keeping the systemic stability as its primary outcome measure.[4] No significant systemic side-effects have been reported with either of the studies while using this drug in vitreoretinal surgeries. There is increasing evidence that supports the use of dexmedetomidine as an adjunct to regional blocks for ophthalmic anaesthesia. This drug seems to be especially useful in cases with prolonged operating times such as complex vitreoretinal surgeries and for apprehensive patients. However, use of dexmedetomidine in patients with heart block, heart failure, renal/hepatic insufficiency, uncontrolled diabetes, obesity and/or chronic obstructive pulmonary disease is contraindicated. Meticulous pre-operative evaluation by the anaesthesia team is thus essential before subjecting a patient to peribulbar block with dexmedetimidine as an additive. Establishment of standard pre-anaesthetic evaluation and intra-operative monitoring protocols are needed before this drug gains popularity as an adjunct for regional anaesthesia in ophthalmic surgery. Hence, further studies on the requirement of systemic monitoring during surgery and long-term safety profile of these agents are warranted.

Comparison of effects of intravenous clonidine and dexmedetomidine for blunting pressor response during laryngoscopy and tracheal intubation: A randomized control study.

Context:Laryngoscopy and endotracheal intubation activates the sympathetic nervous system, causing tachycardia and hypertension. Dexmedetomidine has an affinity for alpha2 receptors 8 times greater than that of clonidine. It diminishes norepinephrine release and inhibits sympathetic activity leading to decreased heart rate (HR) and blood pressure.Aims:The aim was to compare the effect of intravenous (IV) infusion of dexmedetomidine and clonidine on the pressor response among patients undergoing tracheal intubation in elective surgeries under general anesthesia.Settings and Design:A prospective, randomized control study.Subjects and Methods:Seventy-five adult patients of age 18-55 years in American Society of Anesthesiologists physical status I and II were included in this study. Patients were allocated randomly into Group P, Group D and Group C of 25 patients each. In the operation theatre, clonidine (3 μg/kg) or dexmedetomidine (0.5 μg/kg) or placebo (0.9% normal saline) diluted in 100 ml NaCl 0.9% were infused over a period of 10 min.Statistical Analysis Used:Statistical analysis was done using Statistical Package for Social Sciences version 15.0. Chi-square test, ANOVA, Student's t-test, and Paired t-test were used.Results:As compared to Group P, the mean systolic blood pressure in Group D and Group C were significantly lower (<0.01) after intubation and all the subsequent intervals. After infusion and after the induction interval, the maximum value was observed in Group D while minimum mean value was observed in Group C. As compared to Group P, the mean arterial pressure in Group D was significantly higher at after infusion and after induction intervals but significantly lower after intubation and subsequent intervals. However, in Group C, the mean value was significantly lower as compared to Group P at all-time intervals except after infusion and after induction intervals. As compared to Group P, the mean HR in Group D was significantly higher at after infusion and after induction intervals. However at all the subsequent intervals, Group D was significantly lower as compared to Group P.Conclusion:It was found that attenuating response to hemodynamic changes were observed with dexmedetomidine and clonidine IV infusion. The early onset of dexmedetomidine makes it a promising choice. Hence premedication with IV infusion of dexmedetomidine can safely be recommended for attenuation of hemodynamic response to endotracheal intubation.

Action of alpha 2A-adrenergic receptors in circular smooth muscle of canine proximal colon.

Addition of the alpha 2-adrenergic receptor agonist clonidine (1 microM) to tetrodotoxin-treated strips of canine colonic circular smooth muscle resulted in a significant increase in contractile force that was blocked by addition of the alpha 2-antagonist yohimbine (0.1 microM). The alpha 2-receptor antagonist radioligand [3H]rauwolsine bound rapidly and reversibly to a single class of saturable sites (Bmax, 38.4 +/- 6.2 fmol/mg protein) in colonic circular smooth muscle membranes with an affinity (KD = 5.1 +/- 0.9 nM) characteristic of alpha 2-adrenergic receptors in smooth muscle. Studies in cells freshly isolated from circular muscle of canine proximal colon verified the smooth muscle origin of these receptors. Rank order of potency of alpha 2-adrenergic receptor antagonists in competition for [3H]rauwolsine binding was yohimbine greater than oxymetazoline much greater than prazosin. Affinity of alpha 2-receptors for yohimbine was indistinguishable from that of its optical isomer, rauwolsine, in both competition studies (KI = 3.4 nM) and in saturation-binding experiments employing [3H]yohimbine directly (KD = 4.2 nM). The alpha-receptor agonist epinephrine, in competition studies employing [3H]rauwolsine, revealed high-affinity binding sites that were converted to low-affinity binding sites for agonist by addition of 100 microM GTP gamma S. Addition of the alpha 2 more-selective agonist clonidine (100 microM) resulted in inhibition of adenylate cyclase activity that was abolished by pretreatment of tissue strips with pertussis toxin suggesting coupling of the alpha 2-receptor in colon to adenylate cyclase via the GTP-binding protein Gi. Our data demonstrate a physiological role for adenylate cyclase-coupled receptors of the alpha 2A-subtype in canine colon circular smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Noradrenergic receptor binding during sleep-waking states in the rat.

It was recently shown that the number of muscarinic receptors in the rat pons undergoes short-term changes which are related to sleep-waking states and may thus play a role in determining their time course. In this study we investigated whether also noradrenergic receptors change in relation to polygraphically documented wakefulness (W), synchronized (S) and desynchronized sleep (D). Brain noradrenergic systems are deeply involved in the control of vigilance states, and a new hypothesis about the function of D has suggested that adrenoceptors would be desensitized or downregulated during W and upregulated during D. We examined the number of alpha 1-, alpha 2- and beta-adrenergic receptors in the forebrain and the cerebellum, and the number and affinity of alpha 2-receptors in a brainstem region including the locus coeruleus. The results indicate that the number of alpha 1-, alpha 2- and beta-adrenergic receptors does not change in relation to sleep-waking states either in the forebrain or in the cerebellum, and that the number and the affinity of alpha 2-adrenergic receptors in the brainstem are stable as well.

Alterations in platelet alpha 2-adrenoceptors by aspirin.

Epinephrine-induced platelet aggregation (mediated through interaction with alpha 2-adrenoceptors) is inhibited by aspirin. To determine if aspirin modulates alpha 2-adrenoceptors, we quantitated dissociation constant (KD) and maximum number of binding sites (Bmax) on isolated platelet membranes using alpha 2-antagonist 3H-yohimbine in normal subjects given 650 mg of aspirin orally. Alpha 2-receptor KD increased from 3.20 +/- 1.80 to 7.32 +/- 3.32 nM (p less than 0.02) and Bmax from 115 +/- 77 to 190 +/- 140 fmol/mg protein. To determine if these alterations in alpha 2-receptors by aspirin were mediated through circulatory or intracellular effects, intact platelets or isolated platelet membranes were incubated with aspirin for 30 minutes in vitro. In these in vitro experiments, alpha 2-receptor KD increased from 2.92 +/- 1.76 to 9.83 +/- 8.55 nM and Bmax from 140 +/- 81 to 191 +/- 129 fmol/mg protein (p less than 0.05). Oral ingestion of aspirin or incubation of aspirin with intact platelets or lysates increased (3 to 10 fold) the concentration of 1-epinephrine required for inhibition of 3H-yohimbine binding by 50% (p less than 0.05). Basal platelet cyclic AMP as well as its elevation with PGE1 or PGI2 and decrease with catecholamines were not influenced by aspirin treatment of platelets. These data indicate that aspirin decreases platelet alpha 2-receptor affinity for agonist as well as antagonist. These effects of aspirin are independent of circulatory or dynamic intraplatelet changes.

5'-p-Fluorosulfonylbenzoyl guanosine as a probe for the GTP-binding protein in alpha 2-adrenergic receptor-adenylate cyclase systems.

An analog of GTP, 5'-p-fluorosulfonylbenzoyl guanosine (5'-p-FSO2BzGuo), appears to interact irreversibly with guanine nucleotide-binding sites on human platelet membranes. This conclusion is based on the observation that incubation of human platelet membranes with 1.4 mM 5'-p-FSO2BzGuo followed by extensive membrane washing results in a reduction in the density of binding sites for [3H]guanylylimidodiphosphate (Gpp(NH)p), a hydrolysis-resistant analog of GTP. The alpha 2-adrenergic receptor of human platelets is felt to interact with a GTP-binding protein that modulates alpha 2-receptor-agonist interactions and mediates inhibition of adenylate cyclase. The present data suggest that 5'-p-FSO2BzGuo attains saturating, or near saturating, occupancy of this alpha 2-receptor-associated GTP-binding protein, since incubation of human platelet membranes with 5'-p-FSO2BzGuo mimics the effects of optimal concentrations of Gpp(NH)p (0.1 mM) in reducing alpha 2-receptor affinity for agonist agents: 5'-p-FSO2BzGuo increases the EC50 for epinephrine competition for [3H]yohimbine antagonist binding to alpha 2-receptors from 0.15 to 1.5 microM and promotes a time- and concentration-dependent decrease in high affinity [3H]epinephrine agonist binding. The persistent effects of 5'-p-FSO2BzGuo on alpha 2-receptor-agonist interactions following extensive washing of the platelet membranes suggest that 5'-p-FSO2BzGuo modification of the alpha 2-receptor-associated GTP-binding protein is irreversible. Taken together, the above findings suggest that 5'-p-FSO2BzGuo may be the appropriate reagent to prepare in a radiolabeled form to affinity label the GTP-binding proteins in human platelet membranes and compare the properties of alpha 2-adrenergic receptor-associated GTP-binding protein(s) with those of the presumably distinct GTP-binding protein that mediates stimulation of adenylate cyclase.

Regulation of norepinephrine release by peripheral alpha 2-receptor stimulation.

Although extensive evidence obtained in animals and in vitro supports the existence of an alpha-receptor-mediated inhibitory regulation of norepinephrine release, the importance of such a system in man is not established. Norepinephrine release was physiologically stimulated by change of posture and dynamic exercise in subjects while they were infused with phenylephrine, a predominant alpha 1-receptor agonist, alpha-methylnorepinephrine, a predominant alpha 2-agonist, and saline. Agonist infusions were administered both at rates that induced a slight elevation in supine systolic pressure and at nonpressor rates. Agonist concentrations that induced much the same pressor responses (alpha 1) were assumed on the basis of in vitro experiments to differ substantially in their affinity for alpha 2-receptors. The hemodynamic response and the increase of plasma norepinephrine induced by changes in posture and exercise were of the same order during infusions of alpha-methylnorepinephrine, phenylephrine, and saline. Similar results from the "nonpressor" as from "pressor" agonist infusions suggested that baroreflex-induced reduction in sympathetic neuronal activity had not confounded the results. Correction of plasma concentrations for individual values of norepinephrine clearance provided an index of norepinephrine release into the circulation that was not changed by phenylephrine or alpha-methylnorepinephrine. These results raise the question of the importance of peripheral alpha 2-receptors in the regulation of norepinephrine release in man.