Role Of Alpha-adrenoceptors Research Articles

Effects of the Alpha-1 Antagonist Prazosin on KOR Agonist-Induced Reinstatement of Alcohol Seeking.

BackgroundStress is associated with relapse to alcohol seeking during abstinence, but the processes underlying this relationship are poorly understood. Noradrenaline is a key transmitter in stress responses and in stress-induced drug seeking. The alpha-1 adrenoceptor antagonist prazosin has been investigated as a treatment for alcoholism and for chronic stress disorders that are frequently comorbid with alcoholism. In rats, we previously showed that prazosin blocks reinstatement of alcohol seeking induced by footshock and yohimbine stressors and reduces yohimbine-induced brain activation. The role of alpha-1 adrenoceptors in reinstatement induced by other stressors is not known. Our most recent work is on the role of kappa opioid receptors in stress-induced reinstatement of alcohol seeking and have reported that the selective kappa opioid receptor agonist U50,488 induces reinstatement and neuronal activation in stress- and relapse-related brain regions. Here we determine the involvement of alpha-1 receptors in reinstatement and brain activation induced by U50,488.MethodsWe trained male Long-Evans rats to self-administer alcohol (12% w/v), extinguished alcohol-reinforced responding, and then determined the effects of prazosin (1 mg/kg) on U50,488 (2.5 mg/kg)-induced reinstatement and regional Fos expression.ResultsPrazosin blocked U50,488-induced reinstatement and decreased U50,488-induced Fos expression in the orbitofrontal cortex, nucleus accumbens core, ventral bed nucleus of the stria terminalis, central and basolateral amygdalar nuclei and ventral tegmental area.ConclusionsThese findings suggest that prazosin may reduce U50,488-induced relapse by inhibiting activity in 1 or more of these brain areas.

Role of Alpha 2-Adrenoceptors in Hemodynamic Instability in Rats under Cooling Challenge: Investigation by Spectral Analysis

Cooling causes hemodynamic instability manifested as changes in blood pressure variability and heart rate variability (BPV, HRV). We previously observed that increased sympathomyogenic responses to cooling indexed as very-low-frequency BPV (VLF BPV ) and low-frequency BPV (LF BPV ) were dependent on the evoked pressor effect in rats. As a follow-up, the present study was designed to explore whether the alpha 2-adrenoceptor (α2-ADR) is involved in such responses. Hemodynamic changes were telemectrically monitored throughout the experiments. Vehicle or yohimbine (YOH, 2.5 or 5.0 mg/kg) was administered with a latency (5 min, 30 min) before a cooling impact (CI, 4±2 o C). Plasma nitric oxide (NO) was measured in the presence and absence of the added hexamethonium. Spectral powers of high-frequency (HF, 0.6-3.0 Hz), low-frequency (LF, 0.2-0.6 Hz), and very-low-frequency (VLF, 0.02-0.2 Hz) BPV versus HRV were assessed. Our results generally showed 1) control cooling-induced pressor was significantly attenuated after YOH pretreatments, 2) Compared to control vehicle prior to CI initiation, YOH produced tachycardia and increased most frequency powers but reduced normalized HF HRV power (nHF HRV ), 3) In contrast, compared with control vehicle throughout the CI trial, YOH produced less pressor, more tachycardia, and increased nHF HRV but attenuated most other frequency powers. Furthermore, the dicrotic notch was undetectable and NO was increased in CI after YOH pretreatment; however, the increase in NO was diminished after hexamethonium addition. These findings substantialized the sympathomyogenic role for α2-ADR during the cooling-induced hemodynamic instability.

The role of alpha-2 adrenoceptors in the anticonvulsant effects of adenosine on pentylenetetrazole-induced seizure threshold in mice

Adenosine has anticonvulsant effects in various models of seizures. Alpha-2 adrenoceptors have also demonstrated different effects in different models of epilepsy. In this study, the role of alpha-2 adrenoceptors in the anticonvulsant effects of adenosine in mice was determined according to the method of intravenous pentylenetetrazole-induced seizure. In this study, N6-cyclohexyladenosine (CHA) (a selective A1 receptor agonist), clonidine (an alpha-2 adrenoceptors agonist), yohimbine (an alpha-2 adrenoceptors antagonist) and 8-cyclopentyl-1,3-dimethylxanthine (8-CPT) (a selective A1 receptor antagonist) were used. CHA at doses of 0.5, 1 and 2mg/kg significantly increased seizure threshold with the maximum anticonvulsant effect at 2mg/kg. Yohimbine (0.1, 1 and 10mg/kg), clonidine (0.1, 0.5, 1 and 2mg/kg) and 8-CPT (0.5, 1, 2 and 4mg/kg) had no effect on seizure by itself. Combination of yohimbine (10mg/kg) and CHA (0.25mg/kg) increased clonic seizure latency showing that yohimbine and CHA have an additive effect. Increasing the seizure threshold created by combining ineffective doses of yohimbine (10mg/kg) and CHA (0.25mg/kg) was completely inhibited by 8-CPT (4mg/kg) or clonidine (1 and 2mg/kg). Clonidine (0.5, 1 and 2mg/kg) inhibited the anticonvulsant effects of CHA (2mg/kg). Combination of 8-CPT (1mg/kg) and clonidine (0.5mg/kg) which completely inhibited the anticonvulsant effect of CHA (2mg/kg) indicates that 8-CPT and clonidine have an additive effect. In conclusion, adenosine and yohimbine exhibit an additive effect on the enhancement of the pentylenetetrazole-induced seizure threshold in mice, indicating the interaction of alpha-2 adrenoceptors and A1 adenosine receptors.

081 — (TRO0111) Role of alpha1-adrenoceptors in one injection-induced behavioral sensitization to morphine

081 — (TRO0111) Role of alpha1-adrenoceptors in one injection-induced behavioral sensitization to morphine

The antinociceptive effect of intrathecal tramadol in rats: the role of alpha 2-adrenoceptors in the spinal cord

The alpha 2 (α(2))-adrenoceptor is highly important in the antinociception of tramadol administered systemically and intrathecally. However, it is unclear whether tramadol at the spinal level exerts an antinociceptive effect by directly binding with α(2)-adrenoceptors in the spinal cord. This study was conducted to investigate the relationship between α(2)-adrenoceptors and the antinociception of tramadol at the spinal level. The rat formalin test was designed to determine whether the intrathecal α(2)-adrenoceptor antagonist yohimbine could reverse the antinociceptive effect of intrathecal tramadol. The binding affinity of tramadol for α(2)-adrenoceptors in the spinal cord was determined by radioligand binding assay using the labeled α(2)-adrenoceptor antagonist [(3)H]-yohimbine. The nociceptive test showed that intrathecal tramadol induced significant antinociception whereas pretreatment with intrathecal yohimbine partially reversed this antinociception. Scatchard analysis of the binding data showed [(3)H]-yohimbine had high affinity (K(d) = 1.79 nM: ) for the α(2)-adrenoceptor in the rat spinal cord, and that tramadol inhibited specific binding of [(3)H]-yohimbine with the spinal cord membranes with a high affinity constant (K(i) = 34.14 μM: ) and an IC50 of 68.25 μM: , which indicated that tramadol was much less potent than [(3)H]-yohimbine at binding with α(2)-adrenoceptors of the spinal cord. The results suggested that, with very weak binding affinity for α(2)-adrenoceptors, the antinociception of intrathecal tramadol is partially related to α(2)-adrenoceptors, and its intrathecal antinociception may mainly involve its indirect activation of α(2)-adrenoceptors in the spinal cord.

P.2.b.023 Role of alpha2-adrenoceptor in trazodone modulatory effect of 5-HT cortical levels

P.2.b.023 Role of alpha2-adrenoceptor in trazodone modulatory effect of 5-HT cortical levels

Role of alpha adrenoceptors and nitric oxide on cardiovascular responses in acute and chronic hypertension

The contribution of α-adrenoceptors and nitric oxide (NO) on the alterations of sympathetically mediated cardiovascular responses after acute (AcH) and chronic (ChH) hypertension was evaluated in pithed aortic coarcted hypertensive rats. Pressor and tachycardia response produced by electrical stimulation of preganglionic sympathetic fibers or exogenous noradrenaline (NA) were recorded in the absence and presence of prazosin (α(1)-antagonist), rauwolscine (α(2)-antagonist), or N (G)-nitro-L-arginine methyl ester (L-NAME; an inhibitor of NO synthase). Compared with age-matched sham-operated rats (Nt), the pressor response produced by electrical stimulation or NA was smaller in AcH rats and larger in ChH rats. Prazosin caused a decrease of pressor response elicited by electrical stimulation or NA in all groups. However, this effect was higher in ChH. Rauwolscine produced a similar increase of sympathetically mediated pressor response in Nt and AcH rats. Nevertheless, this antagonist did not affect the sympathetically mediated pressor response in ChH rats. In addition, rauwolscine did not affect the NA-induced pressor response in all groups. The pressor response elicited by L-NAME was larger in all groups compared without L-NAME and in presence of L-arginine. Moreover, L-NAME in the presence of NA increased sympathetically mediated pressor response is in all groups, compared without it or in the presence of L-arginine. Compared with Nt, basally produced NO in aortic rings was increased in AcH but decreased in ChH. Collectively, our data suggest that decreased cardiovascular reactivity in AcH is due to an increase in basally produced NO. In ChH, enhanced cardiovascular response appears to be associated with a decrease in produced NO and an increase in released NA from sympathetic nerves.

Alpha 2-adrenoceptor- and D2-dopamine receptor-mediated analgesic response of B-HT 920.

The involvement of D2-dopamine receptors in the antinociceptive action of B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-(4H) thiazolo-(4,5d)-azepine) has been investigated in mice. B-HT 920 (0.1-2.0 mg kg-1) and apomorphine (0.1-2.0 mg kg-1) produced a dose-dependent increase in tail flick latency. Analgesia induced by apomorphine was blocked by the D2-antagonist, haloperidol (1 mg kg-1) but not by the opioid antagonist, naloxone (1 mg kg-1). The antinociceptive action of B-HT 920 was potentiated by the D1-agonist SKF 38393 (5 mg kg-1), an action antagonized by haloperidol. The selective alpha 2-adrenoceptor blocking drug yohimbine (1 mg kg-1) and naloxone (1 mg kg-1) blocked the antinociceptive action of B-HT 920 (1 mg kg-1). Haloperidol, however, failed to modify the B-HT 920-induced increase in tail flick latency. B-HT 920 and apomorphine reversed reserpine (2 mg kg-1) 4 h-induced hyperalgesia. The reversing action of apomorphine was blocked by haloperidol but not by yohimbine. Thus, a role of alpha 2-adrenoceptors and D2-dopamine receptors is postulated in the antinociceptive action of B-HT 920.

The role of alpha-adrenoceptors in the regulation of pentylenetetrazol convulsions in mice.

The role of alpha-adrenoceptors in the regulation of pentylenetetrazol convulsions in mice.

Antidiuretic effect of bremazocine and U-50,488 in rats after α2-adrenoceptor blockade

The role of alpha 2-adrenoceptors and kappa-opioid receptors in urination was studied in rats. In water-loaded rats (40 mL kg-1 p.o.) the kappa-opioid agonist bremazocine (0.05 0.2 mg kg-1 i.p.) induced a dose-related diuretic response in the second hour after administration, but had no effect in the first hour. When rats were pretreated with the alpha 2-adrenoceptor antagonist idazoxan (1 mg kg-1 s.c.), bremazocine induced a dose-related antidiuretic response in the first hour; thereafter the rats showed an increase of urination similar to that with bremazocine alone. The antidiuretic effect of bremazocine was dependent on the dose of idazoxan with maximal response after 1-3 mg kg-1. Similar results were obtained with bremazocine in the presence of yohimbine (1 mg kg-1 s.c.). The antidiuretic profile of bremazocine after idazoxan was shared by U-50,488 (2.5-10 mg kg-1 i.p.), although this compound alone at the high dose reduces urine output in the first hour. The antidiuresis induced by bremazocine in the presence of idazoxan in water-loaded rats was completely antagonized by 10 but not 2 mg kg-1 i.p. of the opioid antagonist naloxone. Thus, kappa-opioid agonists, in addition to their diuretic effect, also produce an antidiuretic response which may be mediated by alpha 2-adrenoceptors.

The role of alpha adrenoceptors in the vascular and estradiol secretory responses to stimulation of the superior ovarian nerve

Electrical stimulation of the superior ovarian nerve in rats reduces both the plasma flow rate of ovarian venous blood (ovarian blood flow) and the ovarian estradiol secretion rate. Here, we examined the possible roles of alpha-adrenoceptors in these processes. The reduction of the plasma flow rate was blocked by an alpha 1- (prazosin), but not by an alpha 2- (yohimbine) adrenoceptor blocker. In contrast, the reduction of the estradiol secretion rate was blocked by yohimbine but not by prazosin. We conclude that ovarian vascular and estradiol secretory responses to superior ovarian nerve activation are mediated by alpha 1- and alpha 2-adrenoceptors, respectively.

In vitro and in vivo analysis of the role of Alpha-2 adrenoceptors in the regulation of gastric motility in the rat

In vitro and in vivo analysis of the role of Alpha-2 adrenoceptors in the regulation of gastric motility in the rat

Role of alpha adrenoceptors in the nucleus accumbens in the control of accumbal noradrenaline efflux: a microdialysis study with freely moving rats

Microdialysis technique was used to study the effects of the locally applied alpha adrenoceptor agonist phenylephrine and antagonist phentolamine on the basal noradrenaline efflux as well as on the noradrenaline uptake inhibitor desipramine-elicited noradrenaline efflux in the nucleus accumbens (NAc) of freely moving rats. Tetrodotoxin reduced basal noradrenaline efflux by 72%, whereas desipramine increased it by 204%. Phenylephrine reduced the basal noradrenaline efflux by 32% and phentolamine blocked this effect. Phentolamine elevated the basal noradrenaline efflux by 150% and phenylephrine counteracted this effect. The desipramine-elicited noradrenaline efflux was not affected by phenylephrine, but enhanced by phentolamine. Desipramine counteracted the effects of phenylephrine and potentiated those of phentolamine. These results indicate that the accumbal noradrenaline efflux is under inhibitory control of alpha adrenoceptors that are suggested to be presynaptically located on adrenergic nerve terminals in the NAc. Furthermore, this study suggests that the conformational state of alpha adrenoceptors varies across the available amount of noradrenaline. The clinical impact of these data is discussed.

Role of Alpha-2 Adrenoceptors in Regulation of Giant Migrating Contractions and Defecation in Conscious Dogs

The aim was to investigate the effects of alpha(2)-adrenoceptor antagonist yohimbine on colonic motility and defecation. The effects of yohimbine (0.5, 1.0, and 3.0 mg/kg) on colonic motility and defecation were studied in neurally intact dogs (N=6), dogs with extrinsic denervation of the ileocolon (N=4), and dogs with enterically isolated ileocolnic loops (N=5) equipped with strain gauge force transducers on the ileocolon. The effects of yohimbine on colonic motility and defecation were also studied in the presence of various antagonists (atropine, hexamethonium, ondansetron, FK224, and naloxone). Yohimbine evoked giant migrating contractions and defecation in a dose-independent manner in neurally intact dogs. These stimulatory effects of yohimbine were abolished by atropine and hexamethonium. In dogs with extrinsic denervation, yohimbine induced giant migrating contractions in the colon but did not stimulate defecation. In dogs with ileocolonic loops, yohimbine induced colonic motor complexes but not giant migrating contractions in the enterically isolated colon. These results indicate that alpha(2)-adrenoceptors in the peripheral nervous system regulate giant migrating contractions by controlling the release of acetylcholine, while those in the central nervous system must be important in the regulation of defecation.

The role of alpha 2-adrenoceptors in the local peripheral antinociception by carbamazepine in a rat model of inflammatory mechanical hyperalgesia

The anticonvulsant carbamazepine was recently shown to possess local peripheral antinociceptive properties. In this study, we investigated whether alpha2-adrenergic receptors are involved in the local peripheral antihyperalgesic effects of carbamazepine and determined the type of interaction between carbamazepine and clonidine, an alpha2-adrenoceptor agonist. Intraplantar (i.pl.) coadministration of either carbamazepine (100-1000 nmol/paw) or clonidine (1.9-3.7 nmol/paw) with the proinflammatory compound concanavalin A (Con A; 0.8 mg/paw) caused a significant dose- and time-dependent reduction of the difference between the forces exerted by a rat's hind paws in a modified paw-pressure test. The coadministration of 260 and 520 nmol/paw (i.pl.) yohimbine, an alpha2-adrenoceptor antagonist, with carbamazepine, significantly depressed the local antihyperalgesic effect in a dose- and time-dependent manner whereas yohimbine by itself did not have any effect. The administration of a mixture of carbamazepine and clonidine at fixed dose fractions (1/4, 1/2 and 3/4) of ED50 caused a significant and dose-dependent reduction of Con A-induced hyperalgesia. Isobolographic analysis revealed an additive interaction. These results suggest that alpha2-adrenoceptors play a role in the local peripheral antihyperalgesic effects of carbamazepine and that local peripheral coadministration of carbamazepine with clonidine results in an additive antihyperalgesic effect.

Alpha-adrenoceptors are a common denominator in the pathophysiology of erectile function and BPH/LUTS - implications for clinical practice

A literature search of PubMed documented publications and abstracts from proceedings of scientific meetings was made to review the available data on benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) and erectile dysfunction (ED) with a special focus on the role of alpha-adrenoceptors as critical mediators of pathophysiology. The reader is introduced to clinical results on the therapeutic potential of alpha-blockers alone and in combination with phosphodiesterase type 5 (PDE-5) inhibitors in the treatment of ED associated with LUTS/BPH. Epidemiological studies clearly show that an association exists between ED and LUTS/BPH. The severity of LUTS is correlated with the risk for ED. A significant number of LUTS/BPH patients are nonresponsive to the common ED treatment with PDE-5 inhibitors. As smooth muscle contractility is regulated by adrenoceptors in the corpus cavernosum, prostate and detrusor, the alpha-adrenoceptor system may be considered a common pathophysiological mediator in the development of ED and LUTS/BPH. Blockade of alpha-adrenoceptors for the treatment of BPH/LUTS may have the potential of improving sexual function. Conversely, PDE-5 inhibitors may exhibit positive effects in LUTS patients. Pilot studies on combination regimens of alpha-adrenoceptor antagonists and PDE-5 inhibitors have yielded encouraging results in LUTS patients with persistent ED. On the basis of pharmacological and clinical evidence, it is established that the alpha-adrenoceptor system plays an important role in the pathophysiology of ED and LUTS secondary to BPH. Larger trials on the combination of alpha-adrenoceptor antagonists with PDE-5 inhibitors are necessary to develop an integrated treatment approach for BPH/LUTS patients with comorbid ED.

Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats

Alpha-2 adrenoceptors are known to be involved in stress-induced reinstatement of heroin and cocaine seeking in laboratory animals. Here, we studied the involvement of these receptors in stress-induced reinstatement of alcohol seeking by using an agonist (lofexidine) and an antagonist (yohimbine) of these receptors, which inhibit and activate, respectively, noradrenaline transmission. We also tested the effect of lofexidine and yohimbine on alcohol self-administration. Lofexidine is used clinically for treating opiate withdrawal symptoms and yohimbine induces stress-like responses in humans and non-humans. Rats were trained to self-administer alcohol (12% w/v, 1 h/day) and after extinction of the alcohol-reinforced behavior, they were tested for the effect of lofexidine (0, 0.05 and 0.1 mg/kg, IP) on reinstatement of alcohol seeking induced by intermittent footshock stress (10 min, 0.8 mA) or for the effect of yohimbine (0, 1.25 and 2.5 mg/kg, IP) on reinstatement of alcohol seeking. Other rats were trained to self-administer alcohol, and after stable responding, the effects of lofexidine and yohimbine on alcohol self-administration were determined. Pretreatment with lofexidine (0.05 mg/kg and 0.1 mg/kg) attenuated stress-induced reinstatement of alcohol seeking and also decreased alcohol self-administration. In contrast, yohimbine pretreatment potently reinstated alcohol seeking after extinction and also induced a profound increase in alcohol self-administration. Results indicate that activation of alpha-2 adrencoceptors is involved in both stress-induced reinstatement of alcohol seeking and alcohol self-administration. To the degree that the present results are relevant to human alcoholism, alpha-2 adrencoceptor agonists should be considered in the treatment of alcohol dependence.

Activation of alpha 1-adrenoceptors is not essential for the mediation of ischaemic preconditioning in rat heart.

1. The aim of the present study was to clarify the role of alpha1-adrenoceptors in the mechanism of ischaemic preconditioning (IP). 2. Rat isolated perfused hearts were either non- preconditioned, preconditioned with 5 min ischaemia or treated for 5 min with alpha1-adrenoceptor agonists (50 micromol/L phenylephrine; 0.1, 0.5 and 1 micromol/L methoxamine) before being subjected to 45 min of sustained ischaemia followed by 60 min reperfusion. 3. Within each of the above protocols, hearts were divided into groups to which alpha1-adrenoceptor antagonists (prazosin, 5'-methyl urapidil and chloroethylclonidine (CEC)) were administered. Functional recovery and infarct size were used as indices of the effects of ischaemia. Ischaemic contracture characteristics and maximal diastolic pressure during reflow were also assessed. 4. Blockade of alpha(1)-adrenoceptors with prazosin or the subtype-selective antagonists 5'-methyl urapidil and CEC did not abolish the protective effect of IP with respect to both functional recovery and infarct size reduction. 5. Protection afforded by phenylephrine was attenuated in hearts treated with prazosin or the alpha(1B)-adrenoceptor- selective antagonist CEC, but not in those treated with the alpha(1A)-adrenoceptor-selective antagonist 5'-methyl urapidil. 6. Treatment with low concentrations of methoxamine, considered to be alpha(1A)-adrenoceptor selective, did not confer any protection to the ischaemic myocardium. 7. A close relationship between accelerated ischaemic contracture and enhanced cardioprotection was observed. 8. The results suggest that alpha1-adrenoceptor stimulation mimics IP, but it is not an essential component in the mechanism behind the protective effect of IP in rat heart. In addition, the present study demonstrates that stimulation of the alpha(1B)- but not the alpha(1A)-adrenoceptor subtype is responsible for the catecholamine-induced protection of ischaemic myocardium in rat.

Alpha-Adrenoceptors and Acute Migraine Therapy.

In contrast to the well-established role of serotonin (5-hydroxytryptamine; 5-HT) 5-HT(1B) receptors in mediating constriction within the carotid vascular bed of dogs and pigs, the role of alpha-adrenoceptors and their subtypes has not been as well understood. Using experimental animal models and alpha(1)-adrenoceptor and alpha(2)-adrenoceptor agonists (phenylephrine and BHT-933, respectively) and antagonists (prazosin and rauwolscine, respectively), it was recently shown that activation of either receptor produces a cranioselective vasoconstriction. Subsequently, investigations employing relatively selective antagonists at alpha(1)- (alpha(1A), alpha(1B), alpha(1D)) and alpha(2)- (alpha(2A), alpha(2B), alpha(2C)) adrenoceptor subtypes revealed that specific receptors mediate carotid vasoconstrictor responses. Since alpha(1B)-adrenoceptors and alpha(2C)-adrenoceptors do not seem to play an important role in the cardiovascular regulation, it is suggested that selective agonists at these receptors may provide a promising novel avenue for the development of acute antimigraine drugs. (c) 2002 Prous Science. All rights reserved.

Mechanisms whereby glucose deprivation triggers metabolic preconditioning in the isolated rat heart.

Transient glucose deprivation of the heart [GLU (-)] confers a preconditioning-like protection against subsequent ischemic/reperfusion (I/R). The mechanisms involved remain unclear. We hypothesized that GLU (-) would induce the classic ischemic preconditioning activated signaling cascade. Potential metabolic consequences and putative cell signaling events induced by transient glucose deprivation were evaluated as candidate mediators of this cardioprotection. Isolated glucose-perfused rat hearts were subjected to 30 min global ischemia followed by 30 min reperfusion (index I/R). Cardiac contractile recovery following I/R was used as the functional end-point in these studies. Metabolic preconditioning was stimulated by 15 min GLU (-) followed by 10 min glucose repletion prior to the index I/R. The potential metabolic consequences of GLU (-) were evaluated by using excess octanoate (11 mM OCT Hi) or 11 mM 2-deoxy-D-glucose (2-DG) in place of GLU (-) and by combining GLU (-) with fuels known to inhibit glycolysis supply (20 mM pyruvate or 1 mM octanoate, OCT Lo). The roles of alpha-adrenoceptors, beta-adrenoceptors, adenosine receptors, protein kinase C (PKC) and mitochondrial K(ATP) channels were investigated using inhibitors prazosin (10 microM), propranolol (10 microM), 8-(p-sulfophenyl) theophylline, (SPT 100 microM), chelerythrine (CHEL 10 microM) and 5-hydroxydecanoate (5 HD 100 microM) respectively. GLU (-) increased mechanical recovery (59.8 +/- 4.0 vs. 32.3 +/- 4.7%; p < 0.01). Protection was abolished by pyruvate 26.6 +/- 3.1; SPT 36.6 +/- 3.0; CHEL 35 +/- 4.8 or 5 HD 23.8 +/- 3.3%. In a separate set of experiments, the specificity of SPT in this model was tested by preconditioning with adenosine (100 microM) (34.7 +/- 4 vs. control 16.8 +/- 1.3%, p = 0.01) and blocking this protection with the same dose of SPT (16.3 +/- 1 .5%) used in the GLU (-) studies. Protection was unaltered by prazosin (50.2 +/- 3.3%), propranolol (55.5 +/- 4.0%), or OCT Lo (50.2 +/- 2.5%). Protection was not mimicked by OCT Hi (35.6 +/- 3.8%) or 2-DG (34 +/- 4.3%). Transient glucose deprivation does not seem to achieve preconditioning-like cardioprotection by decreased glycolysis. Rather, the signal system may involve enhanced adenosine release, PKC, and activation of the mitochondrial K(ATP) channel.