Postsynaptic Alpha-adrenoceptors Research Articles

Cooling-evoked hemodynamic perturbations facilitate sympathetic activity with subsequent myogenic vascular oscillations via alpha2-adrenergic receptors.

This study extends our previous work by examining the effects of alpha2-adrenoceptors under cold stimulation involving the increase of myogenic vascular oscillations as increases of very-low-frequency and low-frequency of the blood pressure variability. Forty-eight adult male Sprague-Dawley rats were randomly divided into four groups: vehicle; yohimbine; hexamethonium+yohimbine; guanethidine+yohimbine. Systolic blood pressure, heart rate, power spectral analysis of spontaneous blood pressure and heart rate variability and spectral coherence at very-low-frequency (0.02 to 0.2 Hz), low-frequency (0.2 to 0.6 Hz), and high-frequency (0.6 to 3.0 Hz) regions were monitored using telemetry. Key findings are as follows: 1) Cooling-induced pressor response was attenuated by yohimbine and further attenuated by hexamethonium+yohimbine and guanethidine+yohimbine, 2) Cooling-induced tachycardia response of yohimbine was attenuated by hexamethonium+yohimbine and guanethidine+yohimbine, 3) Different patterns of power spectrum reaction and coherence value compared hexamethonium+yohimbine and guanethidine+yohimbine to yohimbine alone under cold stimulation. The results suggest that sympathetic activation of the postsynaptic alpha2-adrenoceptors causes vasoconstriction and heightening myogenic vascular oscillations, in turn, may increase blood flow to prevent tissue damage under stressful cooling challenge.

Comparative pharmacodynamic analysis of imidazoline compounds using rat model of ocular mydriasis with a test of quantitative structure–activity relationships

Imidazol(in)e derivatives, having the chemical structure similar to clonidine, exert diverse pharmacological activities connected with their interactions with alpha2-adrenergic receptors, e.g. hypotension, bradycardia, sedation as well as antinociceptive, anxiolytic, antiarrhythmic, muscle relaxant and mydriatic effects. The mechanism of pupillary dilation observed after systemic administration of imidazol(in)es to rats, mice and cats depends on the stimulation of postsynaptic alpha2-adrenoceptors within the brain. It was proved that the central nervous system (CNS)-localized I1-imidazoline receptors are not engaged in those effects. It appeared interesting to analyze the CNS-mediated pharmacodynamics of imidazole(in)e agents in terms of their chromatographic and calculation chemistry-derived parameters.In the present study a systematic determination and comparative pharmacometric analysis of mydriatic effects in rats were performed on a series of 20 imidazol(in)e agents, composed of the well-known drugs and of the substances used in experimental pharmacology. The eye pupil dilatory activities of the compounds were assessed in anesthetized Wistar rats according to the established Koss method. Among twenty imidazol(in)e derivatives studied, 18 produced diverse dose-dependent mydriatic effects. In the quantitative structure–activity relationships (QSAR) analysis, the pharmacological data (half maximum mydriatic effect – ED50 in μmol/kg) were considered along with the structural parameters of the agents from molecular modeling. The theoretically calculated lipophilicity parameters, CLOGP, of imidazol(in)es, as well as their lipophilicity parameters from HPLC, logkw, were also considered. The attempts to derive statistically significant QSAR equations for a full series of the agents under study were unsuccessful. However, for a subgroup of eight apparently structurally related imidazol(in)es a significant relationship between log(1/ED50) and logkw values was obtained. The lack of “predictive” QSAR for the whole series of the structurally diverse agents is probably due to a complex mechanism of the ligand–alpha2-adrenergic receptor interactions, which are predominantly of a highly structurally specific polar nature. Such interactions are difficult to quantify with the established chemical structural descriptors, contrary to the less specific, molecular bulkiness-related interactions.

Effects of St−587 on the α-adrenoceptors in the Bisected Rat Vas Deferens

The effects of the alpha-adrenoceptor agonist St-587 have been studied on the twitch responses induced by field stimulation in the prostatic portion of rat vas deferens. Moreover the drug's influence on the unstimulated prostatic and epididymal halves of rat vas deferens has also been determined. Alone and after addition of yohimbine (0.3 microM) it enhanced in a concentration-dependent manner the twitch responses in the prostatic half. Prazosin competitively antagonized (pA2 = 8.41 +/- 0.03) this effect. The enhancing effect of St-587 was not reduced in reserpinized animals. These results suggest that post-synaptic alpha 1-adrenoceptors are involved in the potentiation of twitch responses induced by St-587. When alpha 1-adrenoceptors were blocked by prazosin (0.1 microM), St-587 partially inhibited the twitch responses of the prostatic portion of rat vas deferens (Emax = 49.5 +/- 3.5%). Yohimbine completely reversed the inhibitory effects of both St-587 and clonidine. Furthermore St-587 antagonized the inhibitory effects of clonidine on twitch responses. Thus it appears that St-587 also behaves as a partial agonist of presynaptic alpha 2-adrenoceptors in this portion of rat vas deferens, but it did not induce contractions in the unstimulated prostatic half of the vas deferens. However, it competitively antagonized the alpha 1-adrenoceptor agonist phenylephrine by acting as an antagonist of prostatic postsynaptic alpha 1 adrenoceptors. These alpha 1-adrenoceptors are probably different from those that mediate the twitch enhancing response to St-587 in that portion. On the other hand, St-587 was a partial agonist of alpha 1-adrenoceptors in the epididymal half.(ABSTRACT TRUNCATED AT 250 WORDS)

Postsynaptic alpha 1-adrenoceptor mechanisms in rat vas deferens and ageing.

Postsynaptic alpha 1-adrenoceptor mechanisms in vasa deferentia isolated from 3, 6, 18 and 40 week-old rats were studied by analysis of the concentration-response curve of noradrenaline and the Scatchard plot of specific binding of [3H]prazosin to microsomal fractions. The maximum tension developed by noradrenaline also increased with age from 3 to 18 weeks. The efficacy of noradrenaline and capacity of the maximum binding sites of [3H]prazosin increased with increasing age, while the dissociation constants of noradrenaline (KA) and prazosin (Kd) were not changed with age. The increase of the maximum tension was proportional to the increase in efficacy. The increase of efficacy for noradrenaline in the vasa deferentia from rats of different ages is due to the increase in the total concentration of postsynaptic alpha 1-adrenoceptors.

The effects of bromocriptine on pre-synaptic and post-synaptic alpha-adrenoceptors in the mouse vas deferens.

Noradrenaline (NA) and dopamine (DA) contracted the mouse vas deferens and reduced the responses to low frequency nerve stimulation (0.1 Hz). The relative potencies of antagonists suggested that these effects were due to stimulation of post-synaptic and pre-synaptic alpha-adrenoceptors respectively. Bromocriptine produced a non-competitive antagonism of contractile responses to NA (pD2' = 7.6) and DA (pD2' = 8.0) but had no effect on responses to carbachol. Bromocriptine also reduced single twitch responses of the vas to low frequency field stimulation (0.1 Hz), but did not affect stimulation at higher frequencies (1--20 Hz). Yohimbine selectively and rapidly reversed the inhibiting effects of bromocriptine on single twitches, although they could not easily be reversed by washing. Bromocriptine produced a yohimbine-reversible reduction in the stimulated overflow of tritium from vasa previously loaded with 3H--NA. Thus the mouse vas deferens does not appear to contain specific DA receptors and the results suggest that bromocriptine acts as a pre-synaptic alpha-adrenoceptor agonist and post-synaptic alpha-adrenoceptor antagonist in this tissue.

Differential blockade of pre- and postsynaptic alpha-adrenoceptors by the 2-R and 2-S enantiomers of WB4101.

Agonists and antagonists of the alpha-adrenoceptor have been shown to possess different degrees of potency at the pre- and postsynaptic levels. The present investigation was undertaken to see whether the two optical isomers of WB4101 likewise exhibit differential blockade at the two receptor sites. This was achieved by measuring the potencies of 2-R and 2-S WB4101 against noradrenaline-induced contractions of the rat isolated vas deferens and against clonidine-induced inhibition of the twitch response in field stimulated rat vas deferens. Results showed that though the enantiomers exhibited widely differing potency, as indicated by calculations of pA2 values, at the postsynaptic level, they possessed almost identical potency presynaptically. In addition, 2-aminomethyl-1,4-benzodioxan itself both exhibited reasonable presynaptic alpha-adrenoceptor blocking activity, whilst being devoid of activity postsynaptically. The values for slope on the Schild plots for 2-R and 2-S WB4101 indicated that they produced classical competitive antagonism at the postsynaptic receptor but at the presynaptic level the values for slope were indicative of a non-competitive type of blockade. Results are discussed in terms of recent suggestions of that agonists and antagonists of the alpha-adrenoceptor may not share a common mechanism or site of action at the presynaptic level.

The postsynaptic effects of antidepressant drugs in the rat anococcygeus muscle.

The effects of antidepressants of tricyclic (amitriptyline, nortriptyline, protriptyline, doxepin, imipramine, and desipramine) and atypical (maprotiline, nomifensine, tandamine, viloxazine, CGP 6085A, and YM-08054-1) structures on contractile responses to exogenously applied acetylcholine and (-) noradrenaline were studied in rat isolated anococcygeus muscle previously incubated with 6-hydroxydopamine. Atropine, amitriptyline, protriptyline, doxepin, imipramine, maprotiline and nortriptyline inhibited contractile responses to acetylcholine whereas desipramine, nomifensine, tandamine, viloxazine, CGP 6085A and YM 08054-1 did not. The contractile responses to (-)-noradrenaline were inhibited by low concentrations of tricyclic antidepressants and by higher concentrations of the atypical agents. These results illustrate that, in the preparation, the order of potency of antidepressants as muscarinic and as postsynaptic alpha-adrenoceptor antagonists is similar. The ability of tricyclic, but not atypical agents, to increase the concentration of noradrenaline bound to postsynaptic alpha-adrenoceptors may be severely limited by the antagonistic effect these agents have at this receptor.

Stimulation of postsynaptic D2− dopamine receptors by B-HT 958 is revealed by co-treatment with the D1− receptor agonist SKF 38393

The motor activity of reserpine-treated mice was used to study effects of B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo-[5,4-d]- azepine) on postsynaptic dopamine and noradrenaline receptors. The motor activity was only slightly stimulated by B-HT 958 or by the D1- receptor agonist SKF 38393 but it was markedly increased by the two drugs given in combination. The effect of B-HT 958 peaked earlier following low rather than high doses. The enhanced motor activity was inhibited by the D2- receptor antagonist sulpiride or the D1- receptor antagonist SCH 23390, indicating that it was caused by stimulation of both receptor types. The results suggest that B-HT 958 stimulates postsynaptic D2- receptors in addition to D2- autoreceptors and that its blockade of postsynaptic alpha 2-adrenoceptors is of no importance for the motor activity.

Pretreatment with aspirin does not influence the pressor response to alpha 2-adrenoceptor agonists in conscious rabbits.

It has proved relatively easy to demonstrate pressor responses mediated via alpha 2-adrenoceptors in-vivo and in whole blood perfused vascular beds, but not in in-vitro work. The possibility that platelet alpha 2-adrenoceptor activation, with subsequent release of vasoactive prostanoids, contributes to the pressor response to alpha 2-adrenoceptor agonists was investigated. The pressor response to the alpha 2-adrenoceptor agonist BHT 920 (Alefexole) was compared in rabbits pretreated with distilled water or aspirin (3 X 200 mg kg-1 by gavage). Aspirin pretreatment had no significant effect on responses to BHT 920; thus, prostanoid formation does not appear to be an important mechanism contributing to postsynaptic alpha 2-adrenoceptor activation.

Agonist profile of ergometrine (ergonovine) on a population of postsynaptic alpha-adrenoceptors.

Ergometrine (0.02-5 microM) produced concentration-related contractions of the mouse anococcygeus muscle, which were unaffected by cocaine (2 microM) or by pretreatment of mice with 6-hydroxydopamine. Contractions were reduced by alpha-adrenoceptor antagonists; the rank order of potency was prazosin greater than phentolamine greater than yohimbine. With phenoxybenzamine as antagonist, the estimated dissociation constant (KD) for ergometrine was 0.41 microM. It is concluded that ergometrine causes direct activation of postsynaptic alpha 1-adrenoceptors, and it is suggested that it acts on the same subtype of the receptor as imidazoline agonists.

Pharmacological characterization of the postsynaptic alpha-adrenoceptors in human uterine artery.

Prazosin and yohimbine were used to differentiate postjunctional alpha-adrenoceptors in the human uterine artery in-vitro. Two postjunctional alpha-adrenoceptor subtypes were distinguished by the affinities of the receptor for yohimbine and prazosin. The pA2 for prazosin was 8.91 against phenylephrine with a slope not significantly different from unity (0.91), and the pA2 for yohimbine was 7.25 against naphazoline and 8.70 against clonidine, with slopes not significantly different from unity (1.11 and 1.18, respectively). Yohimbine was not very active against phenylephrine, while prazosin was very active against the mixed and selective alpha 2-adrenoceptor agonist noradrenaline and clonidine; the intercepts of the Schild plot were 8.80 and 8.82 but with slopes significantly less than unity (0.77 and 0.67, respectively). Prazosin competitively antagonized phenylephrine at the alpha 1-adrenoceptor, whereas yohimbine competitively antagonized naphazoline and clonidine at the alpha 2-adrenoceptor. It is concluded that both alpha 1- and alpha 2-adrenoceptors are present in the human uterine artery.

Pre- and postsynaptic alpha-adrenoceptor antagonism by indoramin in isolated tissues of the rat.

Journal Article Pre- and postsynaptic α-adrenoceptor antagonism by indoramin in isolated tissues of the rat Get access K F Rhodes, K F Rhodes Wyeth Laboratories, Huntercombe Lane South, Taplow, Maidenhead, Berks, UK Correspondence: Wyeth Laboratories, Huntercombe Lane South, Taplow, Maidenhead, Berks, U.K. Search for other works by this author on: Oxford Academic Google Scholar J F Waterfall J F Waterfall Wyeth Laboratories, Huntercombe Lane South, Taplow, Maidenhead, Berks, UK Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 30, Issue 1, September 1978, Pages 516–517, https://doi.org/10.1111/j.2042-7158.1978.tb13308.x Published: 12 April 2011 Article history Received: 01 February 1978 Published: 12 April 2011

Effect of prazosin and guanfacine on stress-induced reinstatement of alcohol and food seeking in rats

Relapse to alcohol use during abstinence or maladaptive eating habits during dieting is often provoked by stress. The anxiogenic drug yohimbine, which causes stress-like responses in humans and non-humans, reliably reinstates alcohol and food seeking in a rat relapse model. Yohimibine is a prototypical alpha-2 adrenoceptor antagonist, but results from studies on noradrenaline's role in yohimbine-induced reinstatement of drug and food seeking are inconclusive. Here, we further addressed this issue by studying the effect of the alpha-1 adrenoceptor antagonist prazosin and the alpha-2 adrenoceptor agonist guanfacine on yohimbine-induced reinstatement. In exp. 1, we trained rats to self-administer alcohol (12% w/v, 1 h/day), and after extinction of alcohol-reinforced lever pressing, we tested prazosin's (0.5, 1.0, and 2.0 mg/kg, i.p.) or guanfacine's (0.125, 0.25, and 0.5 mg/kg, i.p.) effect on yohimbine (1.25 mg/kg, i.p.)-induced reinstatement; we also examined prazosin's effect on intermittent-footshock-stress-induced reinstatement. In exp. 2, we trained food-restricted rats to self-administer 45 mg food pellets and first examined prazosin's or guanfacine's effects on food-reinforced responding, and then, after extinction of lever presses, on yohimbine-induced reinstatement. Prazosin (0.5-2.0 mg/kg) blocked yohimbine-induced reinstatement of food and alcohol seeking, as well as footshock-induced reinstatement of alcohol seeking. Guanfacine attenuated yohimbine-induced reinstatement of alcohol seeking at the highest dose (0.5 mg/kg), but its effect on yohimbine-induced reinstatement of food seeking was not significant. Neither prazosin nor guanfacine affected high-rate food-reinforced responding. Results demonstrate an important role of postsynaptic alpha-1 adrenoceptors in stress-induced reinstatement of alcohol and food seeking.

ChemInform Abstract: Synthesis and Pharmacological Characterization of Some Benzazepinone Derivatives.

A series of some benzazepinone derivatives were prepared. The compounds were evaluated for inotropic, chronotropic and calcium antagonist properties. For the compounds bearing well-known alpha-blocking fragments, the antagonist potency at postsynaptic alpha-adrenoceptors was assessed. The new compounds were less effective as bradycardic agents and calcium antagonists but show remarkable negative inotropic activity.

Guanfacine Potentiates the Activation of Prefrontal Cortex Evoked by Warning Signals

Warning signals evoke an alert state of readiness that prepares for a rapid response by priming a thalamo-frontal-striatal network that includes the dorsolateral prefrontal cortex (DLPFC). Animal models indicate that noradrenergic input is essential for this stimulus-driven activation of DLPFC, but the precise mechanisms involved have not been determined. We tested the role that postsynaptic alpha(2A) adrenoceptors play in the activation of DLPFC evoked by warning cues using a placebo-controlled challenge with the alpha(2A) agonist guanfacine. Sixteen healthy young adults were scanned twice with event-related functional magnetic resonance imaging (fMRI), while performing a simple cued reaction time (RT) task following administration of a single dose of oral guanfacine (1 mg) and placebo in counterbalanced order. The RT task temporally segregates the neural effects of warning cues and motor responses and minimizes mnemonic demands. Warning cues produced a marked reduction in RT accompanied by significant activation in a distributed thalamo-frontal-striatal network, including bilateral DLPFC. Guanfacine selectively increased the cue-evoked activation of the left DLPFC and right anterior cerebellum, although this increase was not accompanied by further reductions in RT. The effects of guanfacine on DLPFC activation were specifically associated with the warning cue and were not seen for visual- or target-related activation. Guanfacine produced marked increases in the cue-evoked activation of DLPFC that correspond to the well-described actions of postsynaptic alpha(2) adrenoceptor stimulation. The current procedures provide an opportunity to test postsynaptic alpha(2A) adrenoceptor function in the prefrontal cortex in the pathophysiology of several psychiatric disorders.

Accumbal noradrenaline that contributes to the alpha-adrenoceptor-mediated release of dopamine from reserpine-sensitive storage vesicles in the nucleus accumbens is derived from alpha-methyl-para-tyrosine-sensitive pools

Alpha-adrenoceptors in the nucleus accumbens are known to inhibit accumbal dopamine release from reserpine-sensitive pools. The aim of this study was to test our previously reported hypothesis that accumbal noradrenaline that controls the dopamine release from these storage vesicles is derived from alpha-methyl-para-tyrosine-sensitive pools. The sensitivity of accumbal alpha-adrenoceptors to noradrenergic agents depends on the amount of noradrenaline that is available in the synapse. In case the synaptic noradrenaline levels decrease, the conformation of alpha-adrenoceptors changes into a state that makes these receptors more sensitive to its agonists. The effects of alpha-methyl-para-tyrosine, respectively reserpine, on the alpha-adrenoceptor-agonist-induced changes of accumbal dopamine release were investigated. Alpha-methyl-para-tyrosine, but not reserpine, made accumbal postsynaptic alpha-adrenoceptors more sensitive to phenylephrine. These results indicate that noradrenaline that inhibits the release of dopamine from reserpine-sensitive storage vesicles, via stimulation of accumbal postsynaptic alpha-adrenoceptors, is derived from alpha-methyl-para-tyrosine-sensitive pools. The clinical impact of these data is discussed.

Postsynaptic Alpha 2-Adrenoceptors Mediate Melanosome Aggregation in Melanophores of the White-Spotted Rabbitfish (Siganus canaliculatus)

The present investigation was undertaken to study the nature of neuro-melanophore junction in the white-spotted rabbit fish Siganus canaliculatus. In vitro experiments using split fin preparation indicated that melanophores of S. canaliculatus are highly responsive to potassium ions and adrenergic agonists. Potassium ions and the adrenergic agonists induced prompt melanosome aggregation that could be competitively blocked by yohimbine (alpha-2 specific adrenergic antagonist) and phentolamine (non-specific alpha adrenergic antagonist). The melanophore responses to repeated potassium stimulation (up to 20 stimuli) did not show any sign of fatigue. However, statistically significant enhancement was observed in responses to potassium that followed the first five stimulations. Adrenergic agonists acted in a time and concentration-dependent manner and their relative potency had the following rank order: clonidine (alpha-2 specific agonist) > norepinephrine (non-specific adrenergic agonist) > phenylephrine (alpha-1 specific agonist) > methoxamine (alpha-1-specific agonist). Yohimbine exerted a more potent inhibiting effect on norepinephrine induced melanosome aggregation compared to phentolamine. Prazosine (alpha-1 specific antagonist) had no effect on such aggregation. Chemically denervated melanophores displayed hypersensitivity to alpha-adrenergic agonists but were refractive to potassium ion stimulation. The refractivity of denervated melanophores to potassium indicates the effect of potassium ion is not direct on melanophores but it is rather through depolarization effect of potassium on the neuro-melanophore peripheral sympathetic fibers and hence release of norepinephrine. In denervated melanophores, similar to intact melanophores, only phentolamine and yohimbine but not prazosine, significantly inhibited melanosome aggregation effect of norepinephrine, indicating that norepinephrine effect is through postsynaptic alpha-2 adrenoceptors. The present data demonstrate that the nature of melanophore innervation in this teleost is adrenergic and neuro-melanophore signals mediating melanosome aggregation are transmitted through alpha-2 postsynaptic adrenoceptors.

Functional subtypes of renal α1-adrenoceptor in diabetic and non-diabetic 2K1C Goldblatt renovascular hypertension

This study investigates the subtypes of the alpha1-adrenoceptor mediating the adrenergically-induced renal vasoconstrictor responses in streptozotocin-induced diabetic and non-diabetic 2-kidney one clip (2K1C) Goldblatt hypertensive rats. The renal blood flow responses to renal nerve stimulation, noradrenaline, phenylephrine, and methoxamine were measured in the absence and presence of nitrendipine, 5-methylurapidil, chloroethylclonidine and BMY 7378. The renal vasoconstrictor responses were markedly attenuated by nitrendipine and 5- methylurapidil in the diabetic rats (all P< 0.05). In the non-diabetic rats, these responses were markedly attenuated by nitrendipine, 5-methylurapidil, and BMY 7378 (all P< 0.05). In both experimental groups, chloroethylclonidine markedly accentuated the renal vasoconstrictions caused by all the adrenergic stimuli (all P< 0.05). These observations indicate that alpha 1A-adrenoceptor subtypes play a major role in mediating adrenergically-induced renal vasoconstriction in the diabetic 2K1C Goldblatt hypertensive rats. In the non-diabetic 2K1C Goldblatt hypertensive rats, contributions of alpha 1A and alpha 1D-adrenoceptor subtypes were proposed. Apart from post-synaptic alpha 1-adrenoceptors, both in the diabetic and non-diabetic 2K1C Goldblatt hypertensive rats, the potential involvement of presynaptic alpha 1- adrenoceptors is also suggested.

Intermittent Hypoxia Induces Early Functional Cardiovascular Remodeling in Mice

Intermittent hypoxia, a hallmark of sleep apnea, is a major factor for hypertension and impaired vasoreactivity. To examine the temporal occurrence of these two outcomes in order to provide insight into mechanisms and early cardiovascular disease identification. Functional and structural cardiovascular alterations were assessed in C57BL6 mice exposed to intermittent hypoxia (21-4% Fi(O(2)), 30-s cycle, 8 h/d) or air for up to 35 days. Blood pressure, heart rate, and urinary catecholamines were measured at Days 1 and 14. Hindquarter vasoreactivity was assessed at Days 14 and 35, including vasoconstriction to norepinephrine, endothelium-, and non-endothelium-dependent vasodilation. Aorta, heart, and hindquarter skeletal muscles were immunostained for vascular markers PECAM-1 and collagen IV. Hemodynamic alterations occurred from Day 1, characterized by blood pressure surges with bradytachyarrhythmia driven by cyclic hypoxia. At Day 14, blood pressure at normoxia was elevated, with predominant diastolic increase. With hypoxia, vasopressive catecholamines were elevated, blood pressure surged with a lower hypoxic threshold, whereas heart rate fluctuations decreased. Histologic alterations started from Day 14, with decreased endothelial PECAM-1 expression in descending aorta and left heart. Impaired peripheral vasoreactivity occurred at Day 35, including hypervasoconstriction to norepinephrine secondary to sympathetic hyperactivity, without changes in pre- and postsynaptic alpha-adrenoceptors or in endothelium- and non-endothelium-dependent vasodilation. Intermittent hypoxia induces sequential cardiovascular events suggesting increased chemoreflex and depressed baroreflex, resulting in sympathoadrenal hyperactivity, early hemodynamic alterations with proximal histologic remodeling, and delayed changes in peripheral vasoreactivity. Such early alterations before overt cardiovascular disease strengthen the need for identifying at-risk individuals for systematic treatment.

Effects of Low and High Plasma Concentrations of Dexmedetomidine on Myocardial Perfusion and Cardiac Function in Healthy Male Subjects

Dexmedetomidine, a selective alpha2-adrenoceptor agonist, has counteracting effects on the cardiovascular system. It mediates sympatholysis by activating alpha2 adrenoceptors in the central and peripheral nervous system, and vasoconstriction and vasorelaxation by activating postsynaptic alpha2 adrenoceptors in blood vessels. The goal of this study was to determine the effects of therapeutic and high concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy subjects. The authors studied 12 healthy young men. Myocardial blood flow (assessed with positron emission tomography), myocardial function (by echocardiography), and hemodynamic data were collected before and during low (measured mean plasma concentration, 0.5 ng/ml) and high (5 ng/ml) plasma concentrations of dexmedetomidine. The low concentration of dexmedetomidine reduced myocardial perfusion (mean difference, -27% from baseline [95% confidence interval, -31 to -23%], P < 0.001) in parallel with a reduction in myocardial oxygen demand (estimated by the rate-pressure product (-23% [-28 to -18%], P < 0.001). The high dexmedetomidine plasma concentration did not further attenuate myocardial perfusion (-3% [-12 to +6%] from low dexmedetomidine, P > 0.05; -29% [-39 to -18%] from baseline, P < 0.001) or statistically significantly affect the rate-pressure product (+5% [0 to +10%], P > 0.05). Systolic myocardial function was attenuated by sympatholysis during the low infusion rate and was further attenuated by a combination of the sustained sympatholysis and increased afterload during the high infusion rate. In healthy subjects, plasma concentrations of dexmedetomidine that significantly exceed the recommended therapeutic level do not seriously attenuate myocardial perfusion below the level that is observed with usual therapeutic concentrations and do not induce evident myocardial ischemia.