Α2-adrenoreceptor Agonist Research Articles

Effects of lofexidine, an alpha 2-adrenoreceptor agonist, on ocular blood flow and ion transport of rabbit iris-ciliary body.

The effect of topical unilateral application of lofexidine, an alpha 2-agonist, on ocular regional blood flow was tested in anesthetized rabbits using radiolabeled microspheres. A significant reduction in blood flow was found only in the ciliary body of the treated eye at 1 hr after lofexidine treatment. However, the IOP of both eyes was decreased significantly at 30 and 60 min post lofexidine treatment. Yohimbine (i.v.) blocked this IOP lowering effect, but only partially prevented the blood flow response. In addition, no significant difference was found in either basal or amphotericin-B stimulated short-circuit current or potential difference of the isolated rabbit iris-ciliary body after 30 minutes of lofexidine treatment. These observations suggest that the IOP lowering effect of lofexidine appears to be mediated by alpha 2-receptors but unrelated to the reduction in the ocular blood flow and net electrogenic ion transport.

Prejunctional α2-adrenoreceptors modulate the stimulated release of noradrenaline in isolated follicle strips from bovine ovaries

1 Strips from the follicle wall of bovine ovaries were incubated in Krebs-Ringer solution containing 3H-noradrenaline for measurement of transmitter liberation during electrical field stimulation (5 Hz frequency, 1 ms pulse duration, 10 V between the electrodes). The effects of noradrenaline as well as selective α-adrenoreceptor agonists and antagonists were studied on the electrically induced efflux of radioactivity. 2 Noradrenaline (1 μM) inhibited the stimulated release of radioactivity. The α2-adrenoreceptor agonist, oxymetazoline, significantly reduced the release of radioactivity in concentrations as low as 0.01 μM. The α1-adrenoreceptor agonist, phenylephrine (0.01–1 μm), was without significant effect. 3 Phentolamine (0.01–1 μm) and the selective α2-adrenoreceptor antagonist, idazoxan (0.01–1 μm) significantly enhanced the electrically evoked release. The α1-adrenoreceptor antagonist, prazosin (0.01–1 μm), was without effect. Idazoxan (0.1 μm) reversed the inhibitory effect of oxymetazoline (0.1 μm). 4 It is concluded that administration of noradrenaline or the α2-adrenoreceptor agonists reduces the release of labelled noradrenaline by acting on prejunctional α2-adrenoreceptors in the noradrenergic nerves distributed in the wall of the bovine ovarian follicle. This is one of several prejunctional receptor mechanisms that modulate the activity of the sympathetic nerves innervating the smooth musculature of the follicle wall.

Effects of activating spinal α-adrenoreceptors on sympathetic nerve activity in the rat

The effects of several α-adrenoreceptor agonists and antagonists administered intrathecally at T 10 level on renal sympathetic nerve activity (RSNA) were examined, in chloralose-urethane anaesthetised rats. Intrathecal noradrenaline (NA, 0.5–500 μg) produced one of 3 responses depending on dose, an inhibition of RSNA at low doses, an excitation of RSNA at high doses, or a biphasic effect. Intrathecal adrenaline (5–200 μg) was inhibitory in the main but some doses elicited poorly repeatable brief excitation followed by prolonged inhibition. Intrathecal methoxamine (ME; 2.5 ng-25 μg) caused a dose-dependent increase in RSNA (mean maximum response 27 ± 0.5%). The excitatory effects of NA and ME were blocked (72% ± 12%) by pretreatment with intrathecal prazosin (PRA, 20–200 ng) but not by yohimbine (YOH, 200 ng). Intrathecal guanabenz (GUA 3–15 μg) caused a dose-dependent inhibitory effect on RSNA (mean maximum 32% ± 5%). The inhibitory effects of NA, adrenaline and GUA were blocked by pretreatment with intrathecal YOH (200 ng-2 μg). Intrathecal PRA (200 ng) had no effect on the inhibitory effects of NA and GUA. Intravenous administration of each of the adrenoreceptor agonists (apart from adrenaline), at similar doses to those given intrathecally, in most cases had no significant effect on RSNA; in a few cases the opposite effects to those produced by intrathecal administration were seen.

Potentiation of in vivo thermogenesis in rat brown adipose tissue by stimulation of alpha 1-adrenoreceptors is associated with increased release of cyclic AMP.

Release of cyclic AMP (cAMP) from the interscapular brown adipose tissue (IBAT) of barbital-anesthetized, cold-acclimated rats given activators and inhibitors of brown adipose tissue (BAT) thermogenesis was assessed by measuring IBAT blood flow (microsphere method) and the arteriovenous difference in plasma cAMP across the tissue. The release was taken as an index of the generation of cAMP in the IBAT. During thermogenesis induced by infusion of graded doses of noradrenaline (NA), release of cAMP increased from no significant release without NA to 68 pmol/min at a NA dose that effected maximal thermogenesis. The alpha-adrenoreceptor antagonist dihydroergotoxin inhibited NA-induced BAT thermogenesis and markedly reduced the release of cAMP. The alpha 1-adrenoreceptor agonist phenylephrine potentiated the in vivo thermogenic response of BAT to isoproterenol or to a suboptimal dose of NA and enhanced the release of cAMP elicited by these catecholamines. But given alone, phenylephrine or dihydroergotoxin had very little or no effect on thermogenesis and cAMP release. These results suggest that stimulation of the alpha 1-adrenoreceptors on BAT adipocytes potentiates the thermogenic response originating from stimulation of the adenylate cyclase-coupled beta 1-adrenoreceptors by increasing, in some indirect way, the generation of cAMP, the intracellular messenger for activation of thermogenesis. However, in the absence of proof that adipocytes are the principal source of the cAMP released from IBAT, during catecholamine-induced thermogenesis, this explanation for the effect of alpha 1-adrenoreceptor stimulation on thermogenesis remains tentative.

New developments in alpha-adrenoreceptor drugs for the treatment of hypertension.

The alpha 1- and alpha 2-adrenoreceptor types are defined in terms of the selective binding of radioligands and their displacement from membrane preparations by a range of agonists and antagonists. Their distribution is described in brain, kidney, heart, and peripheral blood vessels. A group of centrally acting clonidine-like drugs are classified in terms of their selectivity for the alpha 2-adrenoreceptors, and it is suggested that differences between alpha-adrenoreceptors in various tissues may allow development of highly selective alpha 2-adrenoreceptor agonists for specific tissue sites such as the juxtaglomerular cells and brainstem nuclei controlling blood pressure. It is further suggested that the aim of treatment with such compounds is to modulate adrenergic activity while retaining normal homeostatic mechanisms. For this purpose, competitive agonists and antagonists are preferable to compounds which bind irreversibly to the receptor.

Is There a Mast Cell-Noradrenergic Nerve Interaction in the Bovine Splenic Vein?

Release of neurotransmitter from noradrenergic nerve terminals can be modulated by a variety of endogenous and exogenous compounds which act as agonists or antagonists at receptors located on the presynaptic membrane of the terminal.For example, noradrenaline acts as an α-adrenoreceptor agonist to decrease further release. This effect can be reversed by drugs such as phentolamine which blocks the α-adrenoreceptor to increase the outflow of transmitter. Actually, the α-receptor mediated overflow after exposure to an antagonist is one of the most studied mechanisms in transmitter regulation. However, we have been confronted with an exception to the rule of noradrenaline overflow after phentolamine (Fig. 1). In this study isolated bovine splenic vein strips were preincubated in tritiated noradrenaline and mounted in a superfusion apparatus. Oxygenated Tyrodes medium (pH 7.4) containing 10-6M cocaine and 10-4M normetanephrine was used during superfusion.

Presence of postsynaptic alpha 2-adrenoreceptors of predominantly extrasynaptic location in the vascular smooth muscle of the dog hind limb.

1. In the autoperfused hind limb of the dog prazosin (10 microgram/kg intravenously) markedly antagonized responses to lumbar sympathetic stimulation, whereas responses to injected noradrenaline were largely unaffected. 2. In beta-adrenoreceptor- and ganglion-blocked animals, the hind limb pressor responses to phenylephrine were antagonized to a greater degree by prazosin than responses to injected noradrenaline. 3. Rauwolscine, a selective alpha 2-adrenoreceptor-blocking agent, antagonized responses to the alpha 2-adrenoreceptor agonist guanabenz, but not those to phenylephrine. 4. Hind limb pressor responses to noradrenaline were significantly inhibited by rauwolscine and further reduced by prazosin. 5. These results demonstrate that in this vascular bed alpha 1- and alpha 2-adrenoreceptors are located postsynaptically. Furthermore the results suggest that neuronally released noradrenaline acts mainly upon alpha 1-adrenoreceptors, whereas exogenous noradrenaline acts upon alpha 1- and alpha 2-adrenoreceptors. 6. It is suggested that this selectivity of prazosin in blocking the vasoconstriction to neuronally-released noradrenaline may in part explain the effectiveness of this drug as an antihypertensive agent.

Effect of the alpha-adrenoreceptor agonist LD 3098 (cirazoline) on the magnitude of end-organ responses induced by nerve stimulation and exogenous noradrenaline in a variety of sympathetically innervated animal tissues.

1. Previous studies have shown that LD 3098 (cirazoline), a potent directly acting α-adrenoreceptor agonist, failed to antagonize heart rate increases induced by ansa subclavia stimulation in anaesthetized dogs. However, in the isolated perfused cat spleen LD 3098 inhibited transmitter release elicited by nerve stimulation and behaved as a preferential presynaptic α-adrenoreceptor agonist. 2. LD 3098 (0·01–10 μmol/l) increased the twitch response of the isolated rat vas deferens to field stimulation. However, preincubation of the tissue with prazosin (0·1 μmol/l) unmasked a presynaptic inhibitory effect of LD 3098, which was antagonized by yohimbine. 3. LD 3098 was a full agonist in isolated dog saphenous veins and in low concentrations (0·01 μmol/l) shifted the concentration—response curves to noradrenaline, potasium (K+) and prostaglandin F2α (PGF2α) to the left without changing the maximum response. Furthermore the potentiating effect of LD 3098 on PGF2α responses was antagonized by prazosin (0·1 μmol/l). 4. It is concluded that LD 3098 produces a non-specific sensitization of vascular smooth muscle by acting on postsynaptic α-adrenoreceptors. 5. This increase in end-organ sensitivity might explain why LD 3098 appears as an α-adrenoreceptor agonist with preferential affinity for postsynaptic receptors when end-organ responses to nerve stimulation are measured and yet it is a preferential presynaptic agonist in 3H-labelled transmitter-release studies. Such findings further emphasize the need for caution when assessing presynaptic activity indirectly via end-organ response to nerve stimulation.

Catecholamine receptors on locus coeruleus neurons: Pharmacological characterization

There is evidence that the noradrenergic neurons of the locus coeruleus (LC) possess α-adrenoreceptors in the vicinity of their cell bodies. To further characterize this receptor, we studied the responses of LC neurons to a series of catecholamine agonist and antagonist drugs using the techniques of single-unit recording and microiontophoresis. The spontaneous firing of LC neurons was inhibited by microiontophoretic application of norepinephrine, epinephrine, the α-adrenoreceptor agonist clonidine and the β-agonist isoproterenol. These inhibitions were blocked by the α-adrenergic antagonist piperoxane but not by the β-antagonist sotalol. In addition these cells were strongly inhibited by dopamine or α-methylnorepinephrine, but only weakly inhibited by phenylephrine or the dopamine agonist apomorphine. The dopamine antagonist trifluoperazine was ineffective in blocking the inhibitions of LC neurons by both dopamine and norepinephrine. The rank order of potencies of agonist drugs in inhibiting LC neurons was clonidine > > α-methylnorepinephrine ⩾ epinephrine = norepinephrine > > phenylephrine. In this respect the LC α-receptor is similar to ‘presynaptic’ or ‘ α 2’ receptors or peripheral sympathetic nerves and differs from the classical postsynaptic α-receptor. The noradrenergic neurons of the LC thus appear to possess catecholamine receptors on or near their cell bodies which have pharmacological characteristics of ‘presynaptic’ α-adrenergic receptors. The LC receptors are distinct from central dopamine receptors and from norepinephrine receptors areas of the brain receiving their noradrenergic iput fom the LC.