Effects Of Alpha-adrenoceptor Agonists Research Articles

α‐Adrenoceptor agonists for the treatment of vasovagal syncope: a meta‐analysis of worldwide published data

The present study was aimed at evaluating present randomized controlled trials (RCTs) regarding the effect of alpha-adrenoceptor agonists on vasovagal syncope (VVS). According to inclusion and exclusion criteria, articles were selected from medical electronic databases. RCTs were then assessed based on the Juni assessment, and meta-analysis was completed using the Review Manager 4.2 software. Indication to further evaluate effects was the recurrence of syncope during follow-up treatment or a response in the head-up tilt test (HUT) after treatment. The results were stated as odd ratio (OR), with a 95% confidence interval (CI) and a p < 0.05 significant level. In total, six RCTs were selected. Funnel plot analysis showed possible publication bias. Meta-analysis of the six RCTs, including all 165 patients in the treatment group and 164 patients in the control group, indicated that alpha-adrenoceptor agonists were more effective than placebos in treating VVS (OR = 0.21, 95% CI: 0.06-0.77, p = 0.02). The further, weighted independent t-test disclosed that the weighted mean percentage of responders for midodrine (76.3%+/- 7.7%) was significantly higher than that for etilefrine (65.5%+/- 15.4%) (t = 5.863, p < 0.001). The currently published RCTs support that alpha-adrenoceptor agonists might be effective for VVS. Midodrine can be regarded as a better choice compared with etilefrine.

Effects of α2-adrenoceptor agonists on tetrodotoxin-resistant Na+ channels in rat dorsal root ganglion neurons*

When intrathecally or epidurally administered, alpha2-adrenoceptor agonists produce potent antinociception by affecting the activity of primary afferent fibres and spinal cord neurons. Recent reports have indicated that in dorsal root ganglion neurons, tetrodotoxin-resistant Na+ channels play important roles in the conduction of nociceptive sensation. We therefore investigated the effects of alpha2-adrenoceptor agonists on tetrodotoxin-resistant Na+ currents. Using the whole-cell patch-clamp technique, we recorded tetrodotoxin-resistant Na+ currents from rat dorsal root ganglion neurons. Both clonidine and dexmedetomidine reduced the peak amplitude of the tetrodotoxin-resistant Na+ current concentration- and use-dependently. The concentration required for a half-maximal effect was significantly lower for dexmedetomidine (58.0 +/- 10.2 micromol) than for clonidine (257.2 +/- 30.9 micromol) at holding potential -70 mV. The current inhibitions induced by these agonists were not prevented by 1 micromol yohimbine, an alpha2-adrenoceptor antagonist. Both clonidine and dexmedetomidine shifted the inactivation curve for the tetrodotoxin-resistant Na+ current in the hyperpolarizing direction. The combinations clonidine with lidocaine and dexmedetomidine with lidocaine produced an additive blockade-type interaction on the tetrodotoxin-resistant Na+ current. The results suggest that a direct inhibition of tetrodotoxin-resistant Na+ channels may contribute to the antinociceptive effects of clonidine and dexmedetomidine when used as additives to regional anaesthesia.

Pertussis toxin converts hyperpolarizations caused by alpha(2)-adrenoceptor agonists containing an imidazoline moiety into depolarizations in MIN 6 cells.

Several alpha(2)-adrenoceptor agonists containing an imidazoline moiety inhibit insulin secretion when applied to beta cells. In the present study we investigated such imidazolines in regard to membrane potential effects in MIN 6 cells. We confirmed the inhibition of insulin release as reported in previous studies and showed an additional hyperpolarizing activity of the imidazolines using bisoxonol for membrane potential measurements. Pertussis toxin pre-incubation of MIN 6 cells converted the inhibitory imidazoline activity with regard to insulin release into a stimulatory effect. In addition, the marked hyperpolarization caused by the alpha-adrenoceptor agonists containing an imidazoline moiety was converted into a depolarizing effect after pertussis toxin pre-incubation. Adrenaline, an alpha-adrenoceptor agonist lacking an imidazoline moiety, also inhibited insulin release and hyperpolarized MIN 6 cells. Pertussis toxin pre-incubation led only to a loss of the inhibitory adrenaline effect and of the hyperpolarization but not to the stimulatory effects observed with the imidazolines. Thus a stimulatory effect of alpha-adrenoceptor agonists containing an imidazoline moiety was demasked by PTX in this study. It remains to be clarified to which extent a blockade of K(ATP) channels is responsible for this effect.

Effect of Alpha-Adrenoceptor Agonists and Antagonists on Imipramine-Induced Antinociception in the Rat Formalin Test

In this study, the effect of central administration of the α-adrenoceptor agents on the antinociception induced by imipramine in the formalin test has been investigated. Intraperitoneal (IP) administration of different doses of imipramine (10–80 mg/kg) and intracerebroventricular (ICV) administration of the α₂-adrenoceptor agonist clonidine (0.05–0.8 µg/rat) elicited a dose-dependent antinociception in the both phases of the test. Furthermore, different doses of clonidine (0.05–0.2 µg/rat) increased the antinociception induced by imipramine (10 and 20 mg/kg). The α₂-adrenoceptor antagonist yohimbine (2 µg/rat, ICV) reduced the response of a low dose imipramine (10 mg/kg, IP) plus different doses of clonidine (0.05, 0.1 and 0.2 µg/rat, ICV), but did not alter the response induced by higher doses of imipramine (20 and 40 mg/kg) alone or in combination with clonidine. Yohimbine by itself elicited no effect. The α₁-adrenoceptor agonist phenylephrine (0.07–1.5 µg/rat) induced antinociception in both phases of the formalin test, but did not alter the imipramine-induced antinociception. The α₁-adrenoceptor antagonist prazosin neither elicited antinociception nor altered the imipramine response. Yohimbine (2 µg/ rat, ICV) in combination with prazosin (0.5 µg/rat, ICV) caused more inhibition of the response of imipramine or imipramine plus clonidine. Therefore, it is concluded that α₂-adrenoceptor mechanism may be involved in the imipramine-induced antinociception.

Peculiarities of adrenergic regulation of smooth muscles in rabbit pulmonary arteries.

Muscle tension recording was used to study adrenergic contractile reactions of pulmonary artery smooth muscles in rabbits. Stimulation of alpha-adrenoceptors induced contraction of pulmonary artery smooth muscle cells. Endothelium partially inhibited the contractile effect of alpha-adrenoceptor agonists. Activation of smooth muscle beta-adrenoceptors in pulmonary arteries produced a dual dose-dependent effect (relaxation at agonist concentrations of 10 nM-1 muM and contraction at concentrations above 10 muM). The contractile effect of beta-adrenoceptor activation in smooth muscle cells is a specific feature of pulmonary arteries probably related to peculiarities of cAMP-signaling in these cells.

The effects of alpha2-adrenoceptor agonists on circulation and respiration

In December 1999, the United States Food and Drug Administration approved dexmedetomidine, the active isomer of medetomidine, a veterinary anaesthetic, for use in the ICU. Dexmedetomidine is far more potent and selective as an α2-agonist than clonidine, and it is the first of its class in the USA to be available for intravenous administration to critically ill patients. The clinical approval of dexmedetomidine stimulated this review of the applications of α2-adrenergic agonists in the critically ill to modulate adrenergic output, to provide sedation and to limit narcotic analgesic use in this challenging group of patients. This chapter focuses on the salient features of the effects of α2-adrenergic agonists on cardiovascular and respiratory function, commenting on the special aspects of the dynamic state of critical illness. The bulk of this review is devoted to a discussion of pertinent human trials of dexmedetomidine. The remainder of the chapter briefly addresses the effects of epidural clonidine administration and the comparative circulatory effects of two other α2-adrenergic agents, mivazerol and tizanidine.

Role of Alpha-1 Adrenoceptor Subtypes Mediating Constriction of the Rabbit Ear Thermoregulatory Microvasculature

An acute in vivo preparation of the microvasculature of the rabbit ear was used to evaluate the functional role of alpha1 (alpha1)-adrenoceptor subtypes in thermoregulatory microcirculation. The effect of alpha1-adrenoceptor subtype blockade on phenylephrine-induced vasoconstriction was assessed with the alpha1A, alpha1B, and alpha1D-adrenoceptor-selective antagonists 5-methyl-urapidil (10(-8) M), chloroethylclonidine (10(-5) M), and 8-[2-[4(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol[4.5]deca ne-7,9-dione dihydrochloride (BMY7378) (10(-6) M), respectively. The results demonstrated that pretreatment of the ear microvasculature with 5-methyl-urapidil or BMY7378 shifted the phenylephrine concentration-response curve rightward and significantly changed the log of the phenylephrine concentration, causing half-maximum stimulation (EC50) in arterioles (p < 0.05). BMY7378 shifted the phenylephrine concentration-response curve of the arteriovenous anastomoses about 100-fold rightward (p < 0.05). All three alpha1-adrenoceptor antagonists eliminated the vasoconstrictive effects of phenylephrine on venules. The results indicate that the ear microvasculature has a heterogenous distribution of alpha1-adrenoceptor subtypes. The alpha1A and alpha1D-adrenoceptor subtypes appear to have a greater influence on constrictive function in arterioles, whereas the alpha1D-adrenoceptor is the dominant constrictor of arteriovenous anastomoses. In general, the alpha1-adrenoceptor does not play a major vasoconstrictor role in venules. Chloroethylclonidine, an irreversible alpha1B-adrenoceptor antagonist, induced contractile responses in the ear microvasculature, probably due to its alpha2-adrenoceptor agonist effects. This study extended our understanding of the adrenergic receptor control mechanisms of a cutaneous thermoregulatory end organ characterized by two parallel perfusion circuits providing nutritional and thermoregulatory functions.

Role of alpha-1 adrenoceptor subtypes mediating constriction of the rabbit ear thermoregulatory microvasculature.

An acute in vivo preparation of the microvasculature of the rabbit ear was used to evaluate the functional role of alpha1 (alpha1)-adrenoceptor subtypes in thermoregulatory microcirculation. The effect of alpha1-adrenoceptor subtype blockade on phenylephrine-induced vasoconstriction was assessed with the alpha1A, alpha1B, and alpha1D-adrenoceptor-selective antagonists 5-methyl-urapidil (10(-8) M), chloroethylclonidine (10(-5) M), and 8-[2-[4(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol[4.5]deca ne-7,9-dione dihydrochloride (BMY7378) (10(-6) M), respectively. The results demonstrated that pretreatment of the ear microvasculature with 5-methyl-urapidil or BMY7378 shifted the phenylephrine concentration-response curve rightward and significantly changed the log of the phenylephrine concentration, causing half-maximum stimulation (EC50) in arterioles (p < 0.05). BMY7378 shifted the phenylephrine concentration-response curve of the arteriovenous anastomoses about 100-fold rightward (p < 0.05). All three alpha1-adrenoceptor antagonists eliminated the vasoconstrictive effects of phenylephrine on venules. The results indicate that the ear microvasculature has a heterogenous distribution of alpha1-adrenoceptor subtypes. The alpha1A and alpha1D-adrenoceptor subtypes appear to have a greater influence on constrictive function in arterioles, whereas the alpha1D-adrenoceptor is the dominant constrictor of arteriovenous anastomoses. In general, the alpha1-adrenoceptor does not play a major vasoconstrictor role in venules. Chloroethylclonidine, an irreversible alpha1B-adrenoceptor antagonist, induced contractile responses in the ear microvasculature, probably due to its alpha2-adrenoceptor agonist effects. This study extended our understanding of the adrenergic receptor control mechanisms of a cutaneous thermoregulatory end organ characterized by two parallel perfusion circuits providing nutritional and thermoregulatory functions.

Role of alpha2C-adrenoceptor subtype in spatial working memory as revealed by mice with targeted disruption of the alpha2C-adrenoceptor gene.

The role of the alpha2C-adrenoceptor subtype in mediating the beneficial effect of alpha2-adrenoceptor agonists on spatial working memory was studied in adult mice with targeted inactivation of the alpha2C-receptor gene (KO) and their wild-type controls (WT). A delayed alternation task was run in a T-maze with mixed delays varying from 20 s to 120 s. Dexmedetomidine, a specific but subtype nonselective alpha2-adrenoceptor agonist, dose-dependently decreased the total number of errors. The effect was strongest at the dose of 5 microg/kg (s.c.), and was observed similarly in KO and WT mice. KO mice performed inferior to WT mice due to a higher number of perseverative errors. Dexmedetomidine slowed initiation of the motor response in the start phase at lower doses in WT mice than in KO mice but no such difference was observed in the return phase of the task, suggesting involvement of alpha2C-adrenoceptors in the cognitive aspect of response preparation or in response sequence initiation. According to these findings, enhancement of spatial working memory is best achieved with alpha2-adrenoceptor agonists which have neither agonistic nor antagonistic effects at the alpha2C-adrenoceptor subtype.

Potentiation of barbiturate-induced alterations in presynaptic noradrenergic function in rat frontal cortex by imidazol(in)e alpha2-adrenoceptor agonists.

1. In order to resolve the extent to which presynaptic noradrenergic mechanisms contribute to the anaesthetic-sparing effects of alpha2-adrenoceptor agonists in vivo microdialysis was used to investigate the combined effects of sodium pentobarbitone and imidazol(in)e alpha2-adrenoceptor agonists on extracellular levels of noradrenaline (NA) in the rat frontal cortex. 2. Dialysate levels of NA were markedly reduced by the addition of TTX (2 microM) or by the removal of calcium in the perfusate. These data imply that dialysate NA levels are ultimately dependent on exocytotic release mechanisms from afferent coeruleo-cortical neurones. 3. Systemic administration of sodium pentobarbitone (85 mg kg(-1), i.p.) induced general anaesthesia and reduced NA levels by 92% after 30 min. The restoration of basal levels 90 min later was closely associated with a return of the corneal blink reflex. 4. Basal NA levels in conscious animals were not affected by an intravenous infusion of equally radioactive solutions of either imidazoline (clonidine) or imidazole (mivazerol) alpha2-adrenoceptor agonists. The dose rate employed for each compound was 2 microg kg(-1) h(-1) over 2 h. 5. The co-administration of intravenous clonidine or mivazerol, each at 2 microg kg(-1) h(-1) for 2 h, with sodium pentobarbitone (85 mg kg(-1), i.p.), produced a marked and prolonged reduction in NA efflux. After 2 h, NA levels remained suppressed by 95% (clonidine) and 80% (mivazerol) and animals remained deeply anaesthetized. 6. The accumulation of tritium in brain tissue was 42-73% lower across all brain regions examined after [3H]-mivazerol administration than after [3H]-clonidine administration. Sodium pentobarbitone did not alter the accumulation of tritium in brain tissue after the administration of either alpha2-adrenoceptor agonist. 7. These data demonstrate that alpha2-adrenoceptor agonists potentiate the inhibitory effects of sodium pentobarbitone on extracellular levels of NA in the frontal cortex. Further studies will be necessary to establish a causal role of noradrenergic mechanisms in the potentiation of anaesthesia by selective alpha2-adrenoceptor agonists.

Nasal vasoconstriction and decongestant effects of nitric oxide synthase inhibition in the pig.

The effects of systemic administration of the nitric oxide synthase inhibitor N omega-nitro-L-arginine on the vasculature of the pig nasal mucosa were compared with the effects of alpha-adrenoceptor agonists and of sympathetic nerve stimulation. A novel in vivo pig model was used in which standard measurements of nasal mucosal blood flow were complemented with measurements of nasal cavity volume using an acoustic rhinometer. The vasodilatory effects of capsaicin, substance P. acetylcholine, vasoactive intestinal polypeptide and nitroprusside, before and after nitric oxide synthase inhibition, were also investigated. N omega-nitro-L-arginine evoked a marked, slowly developing, long-lasting reduction in nasal vascular conductance with a parallel increase in nasal cavity volume (by approximately 30%) comparable in magnitude with the response upon alpha-adrenoceptor stimulation. L-Arginine partly reversed the N omega-nitro-L-arginine-evoked vasoconstriction, although nasal cavity volume was unaffected. Nasal vasodilation and decrease in nasal cavity volume resulting from capsaicin-evoked activation of sensory nerves were unaltered after administration of N omega-nitro-L-arginine. Nitric oxide synthase inhibition did not attenuate the vasodilator responses evoked by either substance P. acetylcholine, vasoactive intestinal polypeptide or nitroprusside. The present data suggest that nitric oxide synthase activity is of importance both for basal nasal vascular conductance and nasal cavity volume in the pig in vivo. In contrast, nitric oxide synthase inhibition does not reduce the vascular effects of a variety of vasodilating agents, including capsaicin, acetylcholine and substance P.

Alpha 2-Adrenoreceptor-mediated inhibition of acetylcholine-induced noradrenaline release from rat sympathetic neurons: an action at voltage-gated Ca2+ channels.

[3H]Noradrenaline release was studied in cultured sympathetic neurons derived from superior cervical ganglia of neonatal rats. Acetylcholine elicited a concentration- and time-dependent increase in 3H outflow which was half-maximal at about 300 microM and within 5 s. The overflow induced by 10 s exposure to 300 micro A acetylcholine was reduced by the nicotinic antagonist hexamethonium, but increased by the muscarinic antagonist atropine. Cd2+ (300 microM) prevented the overflow evoked by electrical field stimulation, but reduced acetylcholine-induced overflow by less than 50%. Removal of extracellular Ca2+ abolished stimulation-evoked tritium overflow irrespective of the stimulus. The selective alpha2-adrenoceptor agonist UK 14,304 inhibited acetylcholine-evoked overflow to a significantly smaller extent (approximately 25% maximal inhibition) than electrically induced overflow ( > or = 45% maximal inhibition). These inhibitory effects were antagonized by the alpha2-adrenoceptor antagonist yohimbine. Noradrenaline (0.1 microM) reduced acetylcholine-evoked overflow to the same extent as did UK 14,304 (0.1 microM). UK 14,304 had no effect when 3H overflow was evoked by acetylcholine in the presence of 300 microM Cd2+. Currents through nicotinic acetylcholine receptors and voltage-activated Ca2+ currents were studied with the whole-cell variant of teh patch-clamp technique. UK 14,304 reduced nicotinic acetylcholine receptor currents and voltage-activated Ca2+ currents with similar potency and efficacy. Yohimbine, however, antagonized only the inhibition of voltage-activated Ca2+ currents, but not the effects of UK 14,304 on nicotinic receptor currents. Furthermore, yohimbine per se reduced currents through nicotinic receptors. Noradrenaline (10 microM) inhibited voltage-dependent Ca2+ currents just as did UK 14,304 (10 microM), but failed to reduce currents through nicotinic acetylcholine receptor channels. Cd2+ (300 microM) abolished voltage-activated Ca2+ currents and reduced nicotinic acetylcholine receptor currents by 65%. These results indicate that acetylcholine evokes noradrenaline release from rat sympathetic neurons by activation of nicotinic receptors and restricts this release via muscarinic receptors. The acetylcholine-induced transmitter release is based on two mechanisms, one involving and the other one bypassing voltage-dependent Ca2+ channels. alpha2-Adrenoceptor activation reduces voltage-activated Ca2+ currents and effects exclusively the component of acetylcholine-induced release which involves voltage-dependent Ca2+ channels. These results support the hypothesis that voltage-activated Ca2+ channels are the sole site of autoinhibitory alpha2-adrenergic effects on transmitter release from rat sympathetic neurons. The inhibitory effects of alpha2-adrenoceptor agonists and antagonists on currents through nicotinic acetylcholine receptors are not mediated by an alpha2-adrenoceptor.

The role of α2‐adrenoceptors in the vasculature of the rat tail

1. The effects of alpha 2-adrenoceptor agonists and antagonists on rat tail skin temperature (tts), an indicator of local cutaneous blood flow, were studied in conscious and anaesthetized rats and in the isolated, Krebs perfused, vascular bed of the rat tail. 2. In conscious rats, at an ambient temperature of 18.5-20 degrees C, tts was 21.0 +/- 0.2 degrees C and core (rectal) temperature (tc) was 38.2 +/- 0.04 degrees C (n = 126). The alpha 2-adrenoceptor antagonist, delequamine (RS-15385-197; 1 mg kg-1, s.c., n = 6), produced a rapid elevation in tts to 29.1 +/- 0.7 degrees C (P < 0.001 vs. saline-treated control group), attained 10 min after injection. tc fell slightly, by 1.0 +/- 0.1 degrees C. The tts response was dose-related over the dose-range tested (0.01-1 mg kg-1, s.c.), with an ED50 of 17 micrograms kg-1, s.c. (n = 6 per dose). 3. The maximum increases in tts in response to a dose of 1 mg kg-1, s.c. of alpha 2-adrenoceptor antagonists were as follows (n = 6 per drug): delequamine (+9.6 +/- 0.8 degrees C) > yohimbine (+9.0 +/- 1.0 degrees C) > WY-26703 (+7.9 +/- 1.3 degrees C) > piperoxan (+5.6 +/- 1.7 degrees C) > idazoxan (+4.6 +/- 1.3 degrees C) > imiloxan (+4.1 +/- 1.3 degrees C) > SKF 104078 (+2.0 +/- 1.9 degrees C) > BDF-6143 (+1.3 +/- 0.8 degrees C). 4. Prazosin (0.3 mg kg-1, s.c.), hydralazine (10 mg kg-1, s.c.) and nifedipine (3 mg kg-1, s.c.) did not increase tts, whereas propranolol (10 mg kg-1, s.c.) evoked a small increase in tts (+2.9 +/- 1.0 degrees C). Pentolinium (2-10 mg kg-1, s.c.) elicited a dose-related increase in tts, which was elevated by 4.4 +/- 1.3 degrees C after a dose of 10 mg kg-1; tc was reduced in a dose-related manner. Drug vehicles (1 ml kg-1, s.c.) had no effect on tts or tc. 5. In anaesthetized rats, idazoxan (300 microg, i.v.) produced a rapid increase in tts which was detectable 2 min after beginning the injection, reaching a peak after 7 min. When the same dose was administered i.c.v., tts also rose, but more slowly. The peak response (+ 3.6 +/- 0.70C, n = 5) was significantly smaller than when idazoxan was administered intravenously (+ 6.3 +/- 1.2 C, n = 5), which suggests that the increase in tts following systemic administration of M2-adrenoceptor antagonists is not due to a central effect. The change in tts was not secondary to changes in blood pressure.6. In the isolated, Krebs perfused, tail vascular bed of the rat, at an ambient temperature of 20-21C,under constant flow conditions (3.5-4.0 ml min-1; n = 4), baseline perfusion pressure was 57 +/- 4 mmHg.5-Hydroxytryptamine (5-HT; 70-150 nM) increased perfusion pressure by 56+/- 9 mmHg. The alpha2-adrenoceptor agonist, UK-14,304 (10 nmol), elicited a further increase in perfusion pressure by27.5 +/- 15 mmHg but had no effect in the absence of 5-HT; this response to UK-14,304 was abolished by rauwolscine (1 microM).7. Under constant pressure conditions (-100 mmHg; n = 9), baseline mean perfusion flow was 2.1 +/- 0.2 ml min-1, and mean tail skin temperature was 31.6 +/- 0.6C. 5-HT (119 +/- 28 nM) decreased tts.by 3.3 +/- 2.0 C and reduced flow by 1.2 +/- 0.3 ml min-1. UK-14,304 (10 nmol) further reduced tts by 3.0 +/- 0.3 C without significant effect on flow; this effect was also abolished by 1 microM rauwolscine.8. We conclude that post-junctional M2-adrenoceptors in the vasculature of the rat tail have a major vasoconstrictor role, controlling both the flow and distribution of blood within the tail and thereby thermoregulatory heat loss from its surface.

Modulation of respiratory rhythm by alpha 2-adrenoceptors in awake and anesthetized goats

The purpose of this study was to examine the effects of alpha 2-adrenoceptor agonists in the control of breathing with goats that were either awake (n = 7) or anesthetized and artificially ventilated (n = 11). Awake goats infused intravenously with either of the alpha 2-agonists clonidine (1.0-6.0 micrograms/kg) or guanabenz (15.0-63.0 micrograms/kg) exhibited two distinct ventilatory patterns. One pattern was characterized by tachypnea in which respiratory frequency and minute ventilation increased to approximately 50% above control values. A second ventilatory pattern consisted of slow breathing with reductions of respiratory frequency and minute ventilation and highly variable expiratory duration intervals. These two patterns were unaffected by bilateral carotid body denervation. In anesthetized goats, alpha 2-agonists also caused an arrhythmia in phrenic nerve activity that was similar to the slow breathing pattern seen in awake goats. Respiratory disturbances were abolished by the selective alpha 2-receptor antagonist SKF-86466 (100-500 micrograms/kg), indicating that the effects are mediated by alpha 2-receptors. The results suggest that stimulation of alpha 2-adrenoceptors generally has an inhibitory effect on breathing in goats. The disruption of ventilation with clonidine or guanabenz suggests that alpha 2-adrenoceptors may play an important role in the control of central respiratory rhythm.

Functional evidence that alpha 2A-adrenoceptors are responsible for antilipolysis in human abdominal fat cells.

The effects of alpha 2-adrenoceptor agonists (dexmedetomidine, oxymetazoline), alone or in combination with various alpha-adrenoceptor subtype-selective antagonists (CH-38083, idazoxan, WB4101, BRL44408, ARC-239, prazosin), on noradrenaline- and isoprenaline-induced lipolysis were investigated in human isolated abdominal subcutaneous fat cells. The rank order of potency of antagonists in preventing dexmedetomidine- and oxymetazoline-evoked suppression of isoprenaline-induced lipolysis was (pA2-values): CH-38083 (7.69 and 7.48) congruent to idazoxan (7.5 and 7.41) > BRL44408 (7.23 and 7.19) congruent to WB4101 (7.13 and 7.12) > prazosin (5.18 and 5.17) > ARC-239 (4.72, 4.9). While CH-38083 and idazoxan, non-subtype selective alpha 2-adrenoceptor antagonists and BRL44408, a selective alpha 2A-adrenoceptor antagonist as well as WB4101 potentiated the lipolytic effect of noradrenaline, ARC-239, the selective alpha 2B-adrenoceptor antagonist failed to affect it. In addition since the alpha 2A-adrenoceptor selective agonist, oxymetazoline concentration dependently inhibited the lipolytic effect of isoprenaline, and WB4101 and BRL44408 (alpha 2A-adrenoceptor antagonists) antagonised the effect of oxymetazoline in a competitive manner, it is concluded that the alpha 2A-adrenoceptor subtype is involved in antilipolysis. In addition, functional evidence was obtained that there is an interaction between alpha 2A- and beta-adrenoceptors located on the cell surface of adipocytes, through which locally released noradrenaline and/or circulating circulating adrenaline influence lipolysis.

Effect of alpha 2-adrenoceptor agonists on gastric pepsin and acid secretion in the rat.

1. The purpose of the present study was to analyze the effects of the alpha 2-adrenoceptor agonists clonidine, guanabenz, detomidine and medetomidine on pepsin secretion in conscious rats provided with gastric chronic fistula and to compare this with acid secretion. 2. Basal interdigestive gastric secretion, which is mainly neurally driven in the rat, and the secretion directly stimulated by the two main stimulants of chief cells, cholecystokinin octapeptide (CCK8) and methacholine, were studied. 3. Basal secretion of pepsin and acid was inhibited by all four drugs with comparable EC50S. 4. CCK-stimulated pepsin and acid secretion was less sensitive than basal pepsin and acid secretion to alpha 2-adrenoceptor inhibition. 5. Methacholine-stimulated pepsin and acid secretion was not changed by clonidine and guanabenz; methacholine-stimulated acid was even marginally increased by clonidine. 6. These results do not favour the presence of alpha 2-receptors on chief cells in the rat stomach. They rather suggest that pepsin inhibition by alpha 2-adrenoceptor agonists is indirect and due to central or peripheral inhibition of the discharge of nerve fibres activating pepsin secretion.

Pertussis toxin abolishes the inhibition of Ca2+ currents and of noradrenaline release via alpha 2-adrenoceptors in chick sympathetic neurons.

Effects of alpha 2-adrenoceptor agonists on whole-cell Ca2+ currents and 3H-noradrenaline release were investigated by applying the patch-clamp technique and electrical field stimulation to cultured embryonic chick sympathetic neurons. A 24-h exposure of the sympathetic neurons to pertussis toxin (100 ng/ml) abolished both the alpha 2-adrenoceptor-mediated inhibition of Ca2+ currents and the modulation of noradrenaline release caused by noradrenaline (1 mumol/l; in the presence of 10 mumol/l cocaine) or the alpha 2-adrenoceptor agonists 5-bromo-6-(2-imidazolin-2- ylamino)quinoxaline (UK 14,304, 10 mumol/l) and clonidine (10 mumol/l). These results suggest that the alpha 2-autoreceptor-mediated inhibition of noradrenaline release from chick sympathetic neurons operates through the modulation of Ca2+ channels via pertussis-toxin-sensitive GTP-binding-proteins.

Pharmacology of saccadic eye movements in man

The effects of alpha 2-adrenoceptor agonists and antagonists on saccadic eye movements were studied in normal volunteers using the agonist clonidine and the antagonist idazoxan. Changes in blood pressure, heart rate, and several psychological self-ratings were also recorded. Clonidine produced marked slowing of peak saccade velocity, acceleration and deceleration, with deceleration affected more than acceleration, but had no effect on saccade error or latency measurements. In contrast, most saccade parameters were not altered by idazoxan, although fatigue effects were eliminated. Blood pressure, heart rate, and self ratings of alertness were increased by idazoxan and reduced by clonidine, with opposite effects noted on sedation self-ratings. There were no correlations between the clonidine-induced changes in saccade parameters and changes in self-ratings. Although the slowing of some saccade parameters by clonidine may imply that alpha 2-adrenoceptors are involved in control of saccades, it may also be due to sedation. Although alpha 2-adrenoceptor antagonists may abolish fatigue effects, they cannot increase them over baseline values.

Modulation of 5-hydroxytryptamine release by presynaptic inhibitory ?2-adrenoceptors in the human cerebral cortex

Slices and synaptosomes from human cerebral cortex (which had to be removed to reach deeply located tumours) and, for comparison, synaptosomes from guinea-pig and rat cerebral cortex were preincubated with [3H]5-hydroxytryptamine and superfused with physiological salt solution containing an inhibitor of 5-hydroxytryptamine uptake. The effects of alpha-adrenoceptor agonists and antagonists on the electrically (slices) or potassium-evoked (synaptosomes) tritium overflow were studied. In human cerebral cortical slices, the electrically-evoked [3H] overflow was inhibited by noradrenaline (pIC25 value: 6.35); the non-selective alpha-adrenoceptor antagonist phentolamine, at a concentration of 0.32 mumol/l, strongly antagonized the inhibitory effect of noradrenaline (apparent pA2 value: 8.19) but did not affect the evoked overflow by itself. In synaptosomes from humans, guinea-pigs and rats, noradrenaline also inhibited the K(+)-evoked [3H] overflow in a concentration dependent manner; the alpha 2-adrenoceptor clonidine (1 mumol/l), but not the alpha 1-adrenoceptor agonist methoxamine (1 mumol/l), mimicked the effects of noradrenaline; the effect of noradrenaline (0.3 mumol/l) was abolished by the alpha 2-adrenoceptor antagonist idazoxan (0.5 mumol/l), but not by the alpha 1-adrenoceptor antagonist prazosin (1 mumol/l). It is concluded that release-inhibiting adrenoceptors of the alpha 2-subtype exist on 5-hydroxytryptamine terminals innervating the cerebral cortex in human and guinea-pig brain.

Modulation of vasopressin antidiuretic action by renal alpha 2-adrenoceptors

It has been almost 40 years since the diuretic effect of alpha-adrenoceptor agonists was first demonstrated. Two possible mechanisms were proposed: inhibition of vasopressin secretion and antagonism of the cellular hydrosmotic actions of vasopressin. The debate could not be settled then for the lack of appropriate experimental models and pharmacological tools. Advances made in adrenoceptor pharmacology in the 1970s such as 1) subdivision of alpha-adrenoceptors into alpha 1- and alpha 2-subtypes; 2) development of selective agonists and antagonists; and 3) localization of both adrenoceptor subtypes in the kidney, including the proximal and collecting tubules, stimulated new research. With regard to renal adrenoceptors, selective alpha 2-agonists have been shown to induce diuresis in dogs and rats. Whereas in the dog the increase in urine flow results mostly from an increase in osmolal clearance, in the rat the diuresis results in large part from an increase in the excretion of solute-free water. In vitro studies on isolated collecting tubules from rats and rabbits (none from dogs) have shown that alpha 2-agonists inhibit vasopressin-induced adenosine 3',5'-cyclic monophosphate formation and that this effect is mediated by the inhibitory guanine nucleotide regulatory protein and abolished by pertussis toxin treatment. In vivo evidence in support of such a mechanism was presented from conscious Brattleboro homozygous rats in which a selective alpha 2-agonist inhibited the antidiuretic effect of exogenous vasopressin, and this effect was abolished by pertussis toxin. The physiological importance of renal alpha 2-adrenoceptors was identified by use of adrenal medullectomized rats and the alpha 2-antagonist, yohimbine.(ABSTRACT TRUNCATED AT 250 WORDS)