Adrenergic Receptor Mechanisms Research Articles

Evaluation of antinociceptive activity of Ritchiea longipedicellata (Capparaceae) leaf extract in mice

ABSTRACTThe antinociceptive effect of ethanolic extracts of Ritchiea longipedicellata (Capparaceae) leaves was evaluated in acetic acid, formalin, tail immersion, and hot plate models. Motor effect was assessed with rota-rod and open field tests. The effect of receptor antagonists was examined in the formalin test. The extract (50, 100, or 200 mg.kg−1, p.o.) showed dose dependent inhibition of writhing with percent inhibition of 36.88%, 46.29%, and 52.48%, respectively. There was a reduction in the time spent in paw-licking in both the early and late phases of formalin test. The extract increased the withdrawal latency of the mice in tail immersion test, but failed to show an effect beyond 60 min of hotplate test. The extract impaired the mice motor performance function in the rota-rod and open field tests. The effect of the extract in formalin test was only reversed by yohimbine in the late phase. The results suggested that R. longipedicellata leaf extracts exerted antinociceptive effects which may partly involve α2 adrenergic receptor mechanism.

Oxidative burst and Dectin-1-triggered phagocytosis affected by norepinephrine and endocannabinoids: implications for fungal clearance under stress.

A prolonged stress burden is known to hamper the efficiency of both the innate and the adaptive immune systems and to attenuate the stress responses by the catecholaminergic and endocannabinoid (EC) systems. Key mechanisms of innate immunity are the eradication of pathogens through phagocytosis and the respiratory burst. We tested the concentration-dependent, spontaneous and stimulated (via TNFα and N-formylmethionine-leucyl-phenylalanine) release of reactive oxygen species (ROS) by human polymorphonuclear leukocytes (PMNs) in vitro in response to norepinephrine (NE) and AM1241, a pharmacological ligand for the EC receptor CB2. We evaluated phagocytosis of Dectin-1 ligating zymosan particles and tested the cytokine response against Candida antigen in an in vitro cytokine release assay. Increasing concentrations of NE did not affect phagocytosis, yet stimulated ROS release was attenuated gradually reaching maximum suppression at 500 nM. Adrenergic receptor (AR) mechanisms using non-AR-selective (labetalol) as well as specific α-(prazosin) and β-(propranolol) receptor antagonists were tested. Results show that only labetalol and propranolol were able to recuperate cytotoxicity in the presence of NE, evidencing a β-receptor-mediated effect. The CB2 agonist, AM1241, inhibited phagocytosis at 10 µM and spontaneous peroxide release by PMNs. Use of the inverse CB2 receptor agonist SR144528 led to partial recuperation of ROS production, confirming the functional role of CB2. Additionally, AM1241 delayed early activation of monocytes and induced suppression of IL-2 and IL-6 levels in response to Candida via lower activity of mammalian target of rapamycin (mTOR). These findings provide new insights into key mechanisms of innate immunity under stressful conditions where ligands to the sympatho-adrenergic and EC system are released.

Application of genomics to breakthroughs in the cosmetic treatment of skin ageing and discoloration

The use of global gene expression profiling, also known as transcriptomics or genomics, provides a means to identify key pathways affected in ageing skin that can be improved with appropriate cosmetic compounds. Aspects of skin ageing that can be addressed include matrix production, barrier, lipid synthesis, antioxidant capacity and hyperpigmentation. Gene expression profiling together with in vitro human skin cell cultures for compound screening and verification have led to the identification of cosmetic compounds and an understanding of the biological effects of compounds such as niacinamide, Pal-KTTKS, hexamidine, retinyl propionate and sodium dehydroacetate. In addition, understanding of the decreased antioxidant capacity of aged skin has led to the identification of new antiageing ingredients, olive-derived fatty acid ethoxylates, which have been shown to restore antioxidant enzymes in skin keratinocytes and fibroblasts. Gene expression profiling of age spots has also provided an understanding of the role of undecylenoyl phenylalanine in reducing melanin production by an adrenergic receptor mechanism in melanocytes. The use of these compounds in cosmetic formulations for skin care can aid improvements in the appearance of aged skin, including the improved appearance of fine lines, wrinkles and age spots.

In vitro effects of 2-hydroxyestradiol-17β on ovarian follicular steroid secretion in the catfish Heteropneustes fossilis and identification of the receptor and signaling mechanisms

Ovarian pieces containing postvitellogenic follicles were incubated in vitro with different concentrations of the catecholestrogen 2-hydroxyestradiol-17β (2-OHE 2) to evaluate its effects on steroid production and germinal vesicle breakdown (GVBD) in the catfish Heteropneustes fossilis. The incubation with 2-OHE 2 induced a shift in steroidogenic pattern: the C 19 and C 18 steroids testosterone (T) and estradiol-17β (E 2), respectively were significantly decreased with a concomitant significant increase in the C 21 steroids progesterone (P 4), 17-hydroxyprogesterone (17-OHP), 17,20β-dihydroxy-4-pregnen-3-one (17,20β-DP), 17,20α-dihydroxy-4-pregnen-3-one (17,20α-DP) and cortisol (F). Concomitantly, the catecholestrogen induced dose-dependently GVBD response, the first sign of meiosis resumption. The co- and pre-incubations of the ovarian pieces with 2-OHE 2, and adrenergic (phentolamine, α-blocker and propranolol, β-blocker) or estrogen (tamoxifen) receptor blockers resulted in inhibition of the stimulatory effect of the catecholestrogen on C 21 steroids and reversed the inhibition of testosterone and E 2. The α-blocker was more effective than the β-blocker. Our results suggest that 2-OHE 2 appears to employ both adrenergic (α-type) and estrogen receptor mechanisms in mediating the effects. The co- or pre-incubation of ovarian pieces with IBMX (a cAMP elevating drug), H89 (a protein kinase A inhibitor), and PD098059 (a MAP kinase kinase inhibitor) significantly inhibited the stimulatory effect of 2-OHE 2 on the C 21 steroids. The effect of chelerythrine (a protein kinase C inhibitor), on the other hand, varied with the incubation condition. In the co-incubation, the steroids showed varied effects: 17,20β-DP, testosterone and E 2 were elevated, and P 4 and 17-OHP were decreased. In the pre-incubation set up, all the steroids were inhibited except E 2. The inhibition by the blockers was higher in the pre-incubation groups. Taken together, the data suggest the involvement cAMP–protein kinase A, protein kinase C and MAP kinase pathways in the modulation of the steroidogenic activity.

EFFECT OF PRONETHALOL ON SOME INHIBITORY ACTIONS OF CATECHOLAMINES.

Abstract On the blood pressure of the pithed rat isoprenaline produced a vasodepressor, noradrenaline a pressor, and adrenaline a biphasic response consisting of a rise followed by a fall in the pressure. The magnitude of the responses to increasing doses of adrenaline was not proportional to the doses. An intravenous injection of pronethalol (nethalide) hydrochloride (1 mg./kg.) changed the responses to adrenaline into purely pressor, well-graded responses; they were also increased. The responses to isoprenaline after pronethalol were reduced, but those to noradrenaline remained usually unaltered. Similar results were obtained in anaesthetised rats, rabbits and guinea-pigs, but the augmentation of the pressor effect of adrenaline was not so marked as in pithed rats. The vasodepressor action of dopamine in rabbits and guinea-pigs was not blocked by pronethalol (2·5 to 10 mg./kg.). The inhibitory actions of adrenaline, noradrenaline and isoprenaline on the isolated rat uterus and rabbit colon were not consistently antagonised by concentrations of pronethalol up to 1·0 μg./ml. In experiments on the rabbit duodenum and ileum, pronethalol, 0·2 to 1·0 μg./ml., reduced the relaxations produced by all three catecholamines. These results are discussed in relation to Ahlquist's theory of a dual adrenergic receptor mechanism.

Lactate fuels the human brain during exercise

The human brain releases a small amount of lactate at rest, and even an increase in arterial blood lactate during anesthesia does not provoke a net cerebral lactate uptake. However, during cerebral activation associated with exercise involving a marked increase in plasma lactate, the brain takes up lactate in proportion to the arterial concentration. Cerebral lactate uptake, together with glucose uptake, is larger than the uptake accounted for by the concomitant O(2) uptake, as reflected by the decrease in cerebral metabolic ratio (CMR) [the cerebral molar uptake ratio O(2)/(glucose+(1/2) lactate)] from a resting value of 6 to <2. The CMR also decreases when plasma lactate is not increased, as during prolonged exercise, cerebral activation associated with mental activity, or exposure to a stressful situation. The CMR decrease is prevented with combined beta(1)- and beta(2)-adrenergic receptor blockade but not with beta(1)-adrenergic blockade alone. Also, CMR decreases in response to epinephrine, suggesting that a beta(2)-adrenergic receptor mechanism enhances glucose and perhaps lactate transport across the blood-brain barrier. The pattern of CMR decrease under various forms of brain activation suggests that lactate may partially replace glucose as a substrate for oxidation. Thus, the notion of the human brain as an obligatory glucose consumer is not without exceptions.

Role of Selective α and β Adrenergic Receptor Mechanisms in Rat Jejunal Longitudinal Muscle Contractility

Gut motility is modulated by adrenergic mechanisms. The aim of our study was to examine mechanisms of selective adrenergic receptors in rat jejunum. Spontaneous contractile activity of longitudinal muscle strips from rat jejunum was measured in 5-ml tissue chambers. Dose–responses (six doses, 10−7–3 × 10−5M) to norepinephrine (NE, nonspecific), phenylephrine (PH, α1), clonidine (C, α2), prenalterol (PR, β1), ritodrine (RI, β2), and ZD7714 (ZD, β3) were evaluated with and without tetrodotoxin (TTX, nerve blocker). NE(3 × 10−5M) inhibited 74 ± 5% (mean ± SEM) of spontaneous activity. This was the maximum effect. The same dose of RI(β2), PH(α1), or ZD(β3) resulted in an inhibition of only 56 ± 5, 43 ± 4, 33 ± 6, respectively. The calculated concentration to induce 50% inhibition (EC50) of ZD(β3) was similar to NE, whereas higher concentrations of PH(α1) or RI(β2) were required. C(α2) and PR(β1) had no effect. TTX changed exclusively the EC50 of RI from 4.4±0.2 to 2.7 ± 0.8% (p < 0.04). Contractility was inhibited by NE (nonspecific). PH(α1), RI(β2), and ZD(β3) mimic the effect of NE. TTX reduced the inhibition by RI. Our results suggest that muscular α1, β2, and β3 receptor mechanisms mediate adrenergic inhibition of contractility in rat jejunum. β2 mechanisms seem to involve also neural pathways.

Minimum Essentials for Problem‐Based Learning in Physiological Pedagogy (the Jos Experience)

Problem-based learning (PBL) is an instructional method that challenges students to “learn to learn,” working cooperatively in groups to seek solutions to real world problems. These problems are used to engage students’ curiosity and initiate learning the subject matter. PBL prepares students to think critically and analytically, and to find and use appropriate learning resources. Objectives For pre-clinical students to acquire an extensive, integrated knowledge base of physiology that is readily recalled and applied to the analysis and care of patient problems; To foster the development of effective and efficient problem-solving/clinical reasoning skills, self-directed learning/team skills and sound clinical skills. In our university medical, pharmacy and medical laboratory science students are taught human physiology using a clinically-oriented course-unit system to adequately prepare them for their clinical years. Out of a normal class of 204 students 70% prefer PBL because it fosters “student-centred” learning. Minimum essentials for PBL in physiological education include: Students’ familiarity with informational technology, Creating personal mnemonics, Availability of self-test simulators of patient problems and clinical vignettes adapted for physiology trainees, Integrated-learning applying knowledge of anatomy, biochemistry, psychology, epidemiology, etc in addition to physiology, Ability to manage time and prioritise tasks. Finally, it is more interesting to highlight first how beta-blockers and diuretics lower blood pressure in man compared to stressing the adrenergic receptor and angiotensin-aldosterone mechanisms alone.

α- and β-adrenergic receptor mechanisms in spontaneous contractile activity of rat ileal longitudinal smooth muscle

Gastrointestinal motility is influenced by adrenergic modulation. Our aim was to identify specific subtypes of adrenergic receptors involved in inhibitory mechanisms that modulate gut smooth muscle contractile activity. Muscle strips of rat ileal longitudinal muscle were evaluated for spontaneous contractile activity and for equimolar dose-responses (10(-7) to 3 x 10(-5) M) to the adrenergic agents norepinephrine (nonselective agonist), phenylephrine (alpha(1)-agonist), clonidine (alpha(2)-agonist), prenalterol (beta(1)-agonist), ritodrine (beta(2)-agonist), and ZD7114 (beta(3)-agonist) in the presence and absence of tetrodotoxin (nonselective nerve blocker). Norepinephrine (3 x 10(-5) M) inhibited 65 +/- 6% (mean +/- SEM) of spontaneous contractile activity. The same molar dose of ritodrine, phenylephrine, or ZD7114 resulted in less inhibition (46 +/- 7%, 31 +/- 5%, and 39 +/- 3%, respectively; P < 0.05). The calculated molar concentration of ZD7114 needed to induce 50% inhibition was similar to that of norepinephrine, whereas higher concentrations of phenylephrine or ritodrine were required. Clonidine and prenalterol had no effect on contractile activity. Blockade of intramural neural transmission by tetrodotoxin affected the responses to ritodrine and phenylephrine (but not to norepinephrine or ZD7114), suggesting that these agents exert part of their effects via neurally mediated enteric pathways. Our results suggest that adrenergic modulation of contractile activity in the rat ileum is mediated primarily by muscular beta(3)-, beta(2)-, and alpha(1)-receptor mechanisms; the latter two also involve neural pathways.

Role of A and B adrenergic receptor mechanisms in rat jejunal longitudinal muscle contractility

Role of A and B adrenergic receptor mechanisms in rat jejunal longitudinal muscle contractility

A third life for burimamide. Discovery and characterization of a novel class of non-opioid analgesics derived from histamine antagonists.

Burimamide, a histamine (HA) derivative with both H2- and H3-blocking properties, induces antinociception when injected into the rodent CNS. Several related compounds share this property, and structure-activity studies have shown that this new class of analgesics is distinct from known HA antagonists. The prototype, named improgan, shows a preclinical profile of a highly effective analgesic, with activity against thermal, mechanical and inflammatory nociception after doses that do not alter motor balance or locomotor activity. Improgen analgesia is not blocked by opioid antagonists and is observed in opioid receptor knock-out mice. Unlike morphine, improgan does not induce tolerance after daily dosing. Extensive in vitro pharmacology studies have excluded known histaminergic, opioid, serotonergic, GABAergic and adrenergic receptor mechanisms, as well as 50 other sites of action. The improgan-like analgesic activity of some HA congeners suggests an analgesic action on a novel HA receptor, but further studies are required to substantiate this. Studies in progress are characterizing the sites and mechanisms of action of improgan, and developing brain-penetrating derivatives that could be useful for clinical pain.

Responsiveness to alpha- and beta-adrenergic receptor agonists. Effects of race in borderline hypertensive compared to normotensive men.

The responsiveness of alpha- and beta-adrenergic receptors was assessed in 13 black and 13 white borderline hypertensive and normotensive men, matched for age and body mass. White borderline hypertensives showed significantly decreased responsiveness of cardiac beta-adrenergic receptors and vascular beta 2-adrenergic receptors to intravenous isoproterenol. In contrast, black borderline hypertensives showed no evidence of decreased beta-adrenergic receptor responsiveness. Vascular alpha 1-adrenergic receptor responsiveness, assessed by pressor response to phenylephrine, was unrelated to blood pressure, but was significantly greater in black than in white men. These preliminary observations suggest that there may be racial differences in adrenergic receptor mechanisms involved in the pathogenesis of hypertension.

Alpha-Adrenergic Receptor Responsiveness in Vascular Smooth Muscle of Canine Bone

In an ex vivo canine tibial preparation, an alpha-1-adrenergic antagonist (prazosin, 212 ng.ml-1.minute-1) markedly attenuated the effect of high intraluminal doses (greater than 0.5 mg) of norepinephrine but was less effective at lower doses. An alpha-2-adrenergic antagonist (rauwolscine, 198 ng/ml/minute) was more effective than prazosin in blocking the vascular smooth muscle contraction evoked by low doses of norepinephrine (greater than 0.125 mg). Cirazoline, an alpha-1-adrenergic agonist, had a potent contractile effect on smooth muscle at high concentrations (5 x 10(-6) M), whereas the alpha-2-adrenergic agonist UK14304 was more effective at low concentrations (1 x 10(-7) M). Thus, in the vascular smooth muscle of canine tibia there is a mixed population of postjunctional alpha-1 and alpha-2-adrenergic receptors that exhibits a dose-dependent responsiveness. Adrenergic receptor mechanisms may contribute to alterations in bone blood flow. This may be relevant to impaired reperfusion after microvascular bone transfer. Furthermore, adrenergic receptor mechanisms may help explain variations in bone blood flow related to systemic, regional humoral, or metabolic factors.

High density of beta 2-adrenoceptors in a human keratinocyte cell line with complete epidermal differentiation capacity (HaCaT).

A non-tumorigenic keratinocyte cell line with complete epidermal differentiation capacity (HaCaT) was used in radioligand binding experiments to determine the number of beta-adrenoceptors. Intact cells were saturated with 3H-labelled (-)CGP-12177 (CGP), a hydrophilic non-selective beta-adrenergic antagonist as radioligand. In order to investigate the beta-adrenergic subtype selectivity, displacement experiments were performed with different antagonists and agonists. Binding of CGP to keratinocytes has been shown to be reversible and saturable and to have high affinity (Bmax = 114.0 +/- 8.8 fmol/10(7) cells with 6866 receptors/cell, KD = 0.095 +/- 0.017 nmol/l; n = 11). Beta-adrenergic antagonists inhibited binding yielding monophasic displacement curves. IC50-values (nmol/l) were: propranolol (non-selective) 1.68; CGP-12177 (non-selective) 1.08; ICI 118,551 (beta 2-selective) 2.92; bisoprolol (beta 1-selective) 1230; and CGP-20712 (beta 1-selective) 24,980. Agonists displaced CGP in the order isoprenaline greater than adrenaline greater than noradrenaline. We conclude that HaCaT cells express a high density of beta2-adrenoceptors providing a good model system to study adrenergic receptor mechanisms under reproducible experimental conditions in keratinocytes.

Regional changes in adrenergic receptor status during hypocaloric intake do not predict changes in adipocyte size or body shape

The anatomic distribution of fat is related to the risk for obesity-associated morbidity. Among individuals with equal degrees of relative adiposity, those with an upper-body preponderance of fat distribution (android) have higher rates of diabetes, stroke, ischemic heart disease, and early death than those with preferential deposition of adipose tissue in lower portions of the body (hips, thighs, buttocks; gynecoid. There are well-documented anatomic site-related differences in the relative activities of the adrenergic receptors ( β 1 → lipolysis; α 2 → antilipolysis) that control lipolysis. We assessed modifications of the status of α 2- and β 1-adrenergic receptor and subreceptor function in small fragments of adipose tissue obtained by needle biopsy from the gluteal and abdominal subcutaneous regions of five android, seven gynecoid, and six uniformly obese women during a period of weight maintenance (4 weeks) (T1), and after 15% weight loss on an 840 kcal/d diet (T2). Measurements of body shape and adipocyte size were made and related to changes in the metabolism of these adipocytes. The waist-to-hip ratio (WHR) was used to define these three types of regional distribution of fat in these obese subjects: android = WHR >0.86; gynecoid = WHR ≤ 0.76; uniform = WHR > 0.76 ≤ 0.86. WHR was not significantly altered by weight loss in any of the three groups. Although significant effects of time and/or anatomic site on in vitro responses to isoproterenol, norepinephrine, clonidine, forskolin, and dibutyryl cAMP were found, these did not correlate with intra-individual changes in anthropometry or adipocyte size. Thus, the mobilization of lipid from specific subcutaneous anatomic sites during long-term restriction of caloric intake does not appear to be related to alterations in the functional status of the adrenergic receptor or subreceptor mechanisms studied. The precise mechanisms by which the body regulates fat mobilization under these circumstances remain unknown.

Parasympathetic effects on in vivo rat heart can be regulated through an alpha 1-adrenergic receptor.

A prejunctional mechanism involving an alpha 1-adrenergic receptor may exert control on the release of acetylcholine from parasympathetic nerve endings in the heart. To test this hypothesis in vivo, rats were prepared for electrical stimulation of the vagus nerves. Blood pressures and heart rates were monitored, and the animals were treated with alpha-agonists and alpha-antagonists. The alpha 1-selective agonist phenylephrine significantly attenuated vagally induced bradycardia in a dose-dependent fashion (ED50 = 19 micrograms/kg). This is consistent with the hypothesis that there is alpha-adrenergic inhibition of ACh release. In contrast, the alpha 2-selective agonist, BHT-920, caused no change in heart rate during vagal stimulation. The effects of phenylephrine to raise heart rate and blood pressure during vagal stimulation were blocked by the alpha 1-selective antagonist prazosin (ID50 approximately 1 microgram/kg) but not by the alpha 2-selective antagonists yohimbine and rauwolscine. This further supports an alpha 1 assignment to the prejunctional adrenergic receptor mechanism, which can regulate the release of acetylcholine from cardiac parasympathetic neurons.

Osmoregulatory actions of angiotensin II are independent of adrenergic receptor mechanisms in the duck, Anas platyrhynchos

1. Intravenous infusion of a physiological dose of fowl angiotensin II (ANG II) in salt-loaded ducks raised systemic arterial blood pressure, inhibited nasal salt gland fluid and solute secretion, and stimulated renal-cloacal urine production. 2. Beta-adrenergic receptor blockade by propranolol lowered arterial pressure but did not prevent the effects of ANG II on salt and water excretion. 3. Alpha-adrenergic receptor blockade by prazosin decreased both arterial pressure and plasma glucose levels, but it did not impair the osmoregulatory actions of ANG II. 4. These observations indicate that redistribution by ANG II of salt and water excretion is independent of adrenergic receptor mechanisms and therefore does not depend on the sympathomirnetic activity of the hormone.

Regulation of melanotropin release from the pars intermedia of the amphibian Xenopus laevis: Evaluation of the involvement of serotonergic, cholinergic, or adrenergic receptor mechanisms

Melanophore-stimulating hormone (MSH) release from the pars intermedia of the pituitary gland is probably regulated by multiple factors of hypothalamic origin. We have examined a number of potential regulatory factors for their effects on MSH release from the amphibian Xenopus laevis. Serotonin and acetylcholine have no effect on MSH release. Both adrenaline and noradrenaline inhibit release of MSH in a dose-dependent manner. Studies with specific receptor agonists and antagonists reveal that these neurotransmitters exert their in vitro effects primarily through a dopamine D-2 receptor, although and α-adrenergic receptor could not be excluded. We further conclude that the pars intermedia of X. laevis lacks a β-adrenergic receptor for the regulation of MSH secretion from the pars intermedia. In mammals, this receptor activates the adenylate cyclase system. Our studies reveal that despite the lack of β-adrenergic receptors, cyclic-AMP is likely an intracellular factor involved in the stimulation of MSH release.

Adrenergic receptors: Possible mechanism of inverse regulation of α- and β-receptors

Many physiologic and pathologic conditions, including bronchial asthma, are associated with inverse changes in α- and β-receptor-mediated responses in various tissues. The direction of the change elicited by a given stimulus is tissue specific, as exemplified by the actions of thyroid hormones: In the rat heart, hypothyroidism reduces β- and increases α-receptor responses, whereas in the rat liver it has the opposite effects. A similar increase in β- and decrease in α-receptor responses in the rat liver is triggered by a number of different conditions, including glucocorticoid deficiency, that appear to represent lower levels of cellular differentiation. Among these, incubation of isolated hepatocytes in a serum-free buffer triggers the conversion of the receptor response in vitro within 4 hours, without parallel changes in the density or affinity of receptor binding sites. This change can be acutely reversed by an endogenous inhibitor of membrane phospholipase A 2, or accelerated by an activator of phospholipase A 2, suggesting that changes in the activity of this enzyme are involved in the conversion of the hepatic adrenoceptor response. The glucocorticoid-induced increase in β-receptors in cultured human lung adenocarcinoma cells also appears to be mediated indirectly through the induction of an endogenous inhibitor (lipomodulin) of membrane phospholipase A 2. The possible relevance of altered membrane phospholipid metabolism in the pathomechanism of asthma and in the associated glucocorticoid-sensitive changes in adrenergic receptor mechanisms is discussed.

Identification of receptor mechanism mediating epinephrine-induced arrhythmias during halothane anesthesia in the dog.

The adrenergic receptor mechanism by which halothane sensitizes the myocardium to the ventricular arrhythmogenic properties of catecholamines is unknown. The new generation of selective adrenergic receptor antagonists have been used to determine which receptor blockade causes the greater increase in the dose of epinephrine needed to achieve a threshold for ventricular arrhythmias. Dogs anesthetized with 1.2 MAC halothane had an arrhythmogenic dose of epinephrine (ADE) of 2.2 micrograms X kg X min-1 that significantly increased (P less than 0.01) to 27 micrograms X kg-1 X min-1 after alpha 1 blockade with prazosin. beta 1 blockade with metoprolol also significantly increased the ADE to 12 micrograms X kg-1 X min-1 (P less than 0.05) but was less than the effect noted after prazosin treatment (P less than 0.05). The dramatic increase in the threshold for arrhythmias noted after prazosin could not be ascribed solely to its hemodynamic properties because treatment with sodium nitroprusside did not change the ADE (2.7 micrograms X kg-1 X min-1) significantly; yet nitroprusside treatment resulted in a similar drop in mean arterial pressure (59 mmHg) to that of prazosin treatment (51 mmHg) when compared with the control group. Thus postsynaptic myocardial alpha 1 adrenergic receptors mediate most of the sensitization by halothane to the ventricular arrhythmogenic effects of catecholamines, while a lesser contribution is conferred by the beta 1 adrenoceptors. These results have implications for the treatment and identification of patients particularly at risk from halothane-epinephrine interactions.