Propranolol Pretreatment Research Articles

Cellular mechanism of adrenalin stimulated chloride secretion via beta‐adrenoceptor in T84 cells

In the present study, the intracellular regulatory pathways involved in the adrenalin-stimulated chloride secretion across T84 cells were investigated. Biphasic characteristics were observed in the Isc response to the basolateral addition of adrenalin (0.25 nM-100 microM). The biphasic response was almost abolished by removing ambient Cl(-). Chloride secretion was found to depend on the activities of basolaterally located Na+-K+-2Cl(-) cotransporters and K+ channels. The alpha-adrenoceptor antagonist phentolamine did not have any effect on either phase of adrenalin-induced Isc, while after pretreatment of the beta-adrenoceptor antagonist propranolol, the adrenalin-induced Isc was substantially abolished, suggesting the biphasic response may be mediated by the beta-adrenoceptor. Under whole cell patch-clamp conditions, T84 cells responded to adrenalin with a rise in inward current. The current, which exhibited a linear I-V relationship and time- and voltage-independent characteristics, was inhibited by the chloride channel blocker DPC and the reverse potential was close to the equilibrium potential for Cl(-) (0 mV), implying that the current was Cl(-) selective. When preloaded with a Ca2+-chelating agent, BAPTA/AM did not affect the Isc response to adrenalin, whereas the Isc was destroyed by pretreating the cells with an adenyl cyclase inhibitor, MDL12330A. These observations were further supported by the intracellular [cAMP] measurement experiment, indicating that adrenalin induced chloride secretion could be mediated by a beta-adrenoceptor only involving cAMP as an intracellular second messenger.

Effect of propranolol on mepivacaine serum concentrations in dental practice

The objective of this study was to determine the effect of propranolol pretreatment on mepivacaine serum concentrations in dental patients. In a double blind, randomized, 2-way crossover study, 10 patients ingested 30 mg propranolol or placebo, 2 hours before local anesthesia for dental scaling. Each subject received a single dose of 51 mg mepivacaine for posterior superior alveolar nerve block. Mepivacaine in venous serum was measured for up to 1 hour, after 5, 15, 30, 45, and 60 minutes from injection. Serum concentrations of mepivacaine were determined by gas chromatography. Blood pressure and heart rate were measured before and after propranolol or placebo and after each sampling. Peak serum concentrations of mepivacaine, C(max) (1.214 +/- 0.746 microg/mL(-1)), were significantly increased by propranolol (2.249 +/- 1.559 microg/mL(-1), P < .05). Propranolol pretreatment reduced blood pressure and heart rate. Although propranolol pretreatment increased almost doublefold mepivacaine serum concentrations and reduced blood pressure and heart rate, mepivacaine can be used safely in dental patients taking propranolol for short-duration interventions.

Effect of propranolol on the splanchnic and peripheral renin angiotensin system in cirrhotic patients

To evaluate the effect of beta-blockade on angiotensins in the splanchnic and peripheral circulation of cirrhotic patients and also to compare hemodynamic parameters during liver transplantation according to propranolol pre-treatment or not. Patients were allocated into two groups: outpatients with advanced liver disease(LD) and during liver transplantation(LT). Both groups were subdivided according to treatment with propranolol or not. Plasma was collected through peripheral venipuncture to determine plasma renin activity(PRA), Angiotensin(Ang) I, Ang II, and Ang-(1-7) levels by radioimmunoassay in LD group. During liver transplantation, hemodynamic parameters were determined and blood samples were obtained from the portal vein to measure renin angiotensin system(RAS) components. PRA, Ang I, Ang II and Ang-(1-7) were significantly lower in the portal vein and periphery in all subgroups treated with propranolol as compared to non-treated. The relationships between Ang-(1-7) and Ang I levels and between Ang II and Ang I were significantly increased in LD group receiving propranolol. The ratio between Ang-(1-7) and Ang II remained unchanged in splanchnic and peripheral circulation in patients under beta-blockade, whereas the relationship between Ang II and Ang I was significantly increased in splanchnic circulation of LT patients treated with propranolol. During liver transplantation, cardiac output and index as well systemic vascular resistance and index were reduced in propranolol-treated subgroup. In LD group, propranolol treatment reduced RAS mediators, but did not change the ratio between Ang-(1-7) and Ang II in splanchnic and peripheral circulation. Furthermore, the modification of hemodynamic parameters in propranolol treated patients was not associated with changes in the angiotensin ratio.

Reversing the alpha-Adrenergic Mediated Fetal Gene Program Reverses Cardiomyocyte Dysfunction

Background: Previously we found that abrogating activator protein-1 (AP-1) in neonatal rat ventricular myocytes subjected to pathologic stimuli resulted in reversal of the pathologic/fetal gene profile while maintaining agonist-induced myocyte hypertrophy. We now extend these observations to the adult rat cardiomyocyte (ARVM) and further investigate if reversing the gene program towards a physiologic profile in a pathologic model results in improved myocyte function. Methods and Results: Hypertrophy was induced in cultured ARVMs using norepinephrine with propranolol pretreatment or with phenylephrine.

Effect of propranolol on secretin-induced gastrin release and secretin-induced tachycardia in patients with the Zollinger-Ellison syndrome

The mechanism for secretin-induced gastrin release in the Zollinger-Ellison syndrome is uncertain. We evaluated whether the stimulatory effect of intravenous secretin on gastrin release was partly mediated through a beta-adrenergic stimulatory mechanism. Serum gastrin concentrations and heart rate were monitored in six patients with the Zollinger-Ellison syndrome. Secretin (2 clinical units/kg) increased mean serum gastrin concentrations from 1558 pg/ml basally to a peak of 3683 pg/ml (136% above baseline). This increase was not altered by pretreatment with 2 mg of propranolol intravenously, a dose which in previous studies blocked terbutaline-induced gastrin release. Secretin increased heart rate by 14 beats/min (20% above base-line) and this also was not altered by propranolol pretreatment. Thus, the stimulatory effects of secretin on gastrinoma cells and the heart do not appear to be mediated by beta-adrenergic receptors.

REVERSING THE FETAL GENE PROGRAM IN THE SETTING OF PATHOLOGIC STIMULI IMPROVES CARDIOMYOCYTE FUNCTION.

Background Previously we found that abrogating activator protein 1 (AP-1) in neonatal rat ventricular myocytes subjected to pathologic stimuli resulted in reversal of the pathologic/fetal gene profile while maintaining agonist-induced myocyte hypertrophy. We now extend these observations to the adult rat cardiomyocyte (ARVM) and further investigate if reversing the gene program toward a physiologic profile in a pathologic model results in improved myocyte function. Methods and Results Hypertrophy was induced in cultured ARVMs using norepinephrine with propranolol pretreatment. Induction of the pathologic gene profile was observed, ie, expression of beta-myosin heavy chain (betaMHC), and atrial/brain natriuretic peptides (ANP/BNP) was increased, whereas expression for the alpha-myosin heavy chain (alphaMHC) and sarcoplasmic reticulum Ca2+-ATPase (SERCA) genes was repressed. As with the neonatal cardiomyocyte experiments, the role of AP-1 in the hypertrophic phenotype was evaluated with the use of an adenoviral construct expressing a dominant negative mutant of the c-Fos proto-oncogene (AdAFos). Although AdAFos infection did not change the myocyte growth response, it resulted in the reversal of the gene profile to alpha-adrenergic stimulation, ie, up-regulation of alphaMHC/SERCA and repression of betaMHC and ANP/BNP. Translation of both MHC and SERCA proteins corresponded with their gene expression. Further, ARVM infected with Ad-AFos showed improved myocyte shortening, a surrogate marker for contractile function. Conclusion Abrogation of AP-1 transcription factor in the setting of alpha-adrenergic stimulation results in improved cardiomyocyte function.

Protective effect of endogenous β-adrenergic tone on lung fluid balance in acute bacterial pneumonia in mice

Some investigators have reported that endogenous beta-adrenoceptor tone can provide protection against acute lung injury. Therefore, we tested the effects of beta-adrenoceptor inhibition in mice with acute Escherichia coli pneumonia. Mice were pretreated with propranolol or saline and then intratracheally instilled with live E. coli (10(7) colony-forming units). Hemodynamics, arterial blood gases, plasma catecholamines, extravascular lung water, lung permeability to protein, bacterial counts, and alveolar fluid clearance were measured. Acute E. coli pneumonia was established after 4 h with histological evidence of acute pulmonary inflammation, arterial hypoxemia, a threefold increase in lung vascular permeability, and a 30% increase in extravascular lung water as an increase in plasma catecholamine levels. beta-Adrenoceptor inhibition resulted in a marked increase in extravascular lung water that was explained by both an increase in lung vascular permeability and a reduction in net alveolar fluid clearance. The increase in extravascular lung water with propranolol pretreatment was not explained by an increase in systemic or vascular pressures. The increase in lung vascular permeability was explained in part by anti-inflammatory effects of beta-adrenoceptor stimulation because plasma macrophage inflammatory protein-2 levels were higher in the propranolol pretreatment group compared with controls. The decrease in alveolar fluid clearance with propranolol was explained by a decrease in catecholamine-stimulated fluid clearance. Together, these results indicate that endogenous beta-adrenoceptor tone has a protective effect in limiting accumulation of extravascular lung water in acute severe E. coli pneumonia in mice by two mechanisms: 1) reducing lung vascular injury and 2) upregulating the resolution of alveolar edema.

Central β-adrenoceptors mediate phasic and sustained components of hemodynamic responses to acute behavioral stress

Startle elicits a pattern of cardiovascular responses that is consistent within individual rats but varies between rats. We examined the hypothesis that central β-adrenoceptors mediate differences in the hemodynamic responses to stress. Conscious rats exposed to cold water (1 cm deep, 1 min) had an initial phasic (startle) response (first 5 s) that varied considerably between rats. We designated those rats with an initial increase in cardiac output (CO) and systemic vascular resistance (SVR) as mixed responders while those with only an increase in SVR were vascular responders. Propranolol pretreatment (3 μg, icv) made the phasic changes in CO more negative, whereas isoproterenol (3 μg) made the CO response more positive in mixed responders and attenuated the increases in arterial pressure and SVR in vascular responders. Metoprolol (30 μg, icv) depressed the change in CO due to startle in mixed responders by decreasing heart rate. ICI 188,551 (25 μg, icv) did not alter the responses to startle but depressed the heart rate and CO responses and enhanced the pressor and SVR responses to sustained stress (1 min exposure to cold water). The results suggest that startle elicits hemodynamic responses that are primarily dependent on β 1-adrenoceptors but responses to sustained stress are dependent on β 2-adrenoceptors in the CNS.

Effects of propranolol on symptom and endocrine responses to pentagastrin

Intravenous injections of CCK-B agonists, such as pentagastrin, produce symptoms of panic and potent activation of the human hypothalamic–pituitary–adrenal (HPA) axis. It is unclear whether these psychological and endocrine effects are mediated by similar or independent processes. Independence is supported by prior evidence that β-adrenergic receptor blockade attenuates cardiovascular and symptom but not vasopressin responses to CCK-4. To further explore associations between somatic, emotional and endocrine responses to CCK-B agents, and potential β-adrenergic mediating mechanisms, symptom and endocrine responses to pentagastrin were examined after propranolol pre-treatment. Cardiovascular, symptom, and endocrine (ACTH, cortisol, epinephrine) responses to pentagastrin were measured in 16 healthy adult subjects randomly assigned to receive propranolol or placebo pre-treatment. Propranolol significantly blocked the normal cardiac acceleration produced by pentagastrin, but did not reduce panic symptom or anxiety effects. It delayed and perhaps enhanced the cortisol response. No relationship between HPA and symptom responses following pentagastrin could be detected, though pre-pentagastrin cortisol was inversely related to post-injection panic symptom intensity. Endocrine, cardiovascular and symptom responses to pentagastrin appear to be separately mediated, as they did not change in concert in response to propranolol pre-treatment, nor were they correlated with one another. The results are consistent with the presence of inhibitory β-adrenergic mediation of the HPA axis in humans. They support the hypothesis that the HPA response to pentagastrin is not secondary to the psychological stress of its side effects.

Changes underlying arrhythmia in the transgenic heart overexpressing Refsum disease gene-associated protein

Previously, we identified a novel neuron-specific protein (PAHX-AP1) that binds to Refsum disease gene product (PAHX), and we developed transgenic (TG) mice that overexpress heart-targeted PAHX-AP1. These mice have atrial tachycardia and increased susceptibility to aconitine-induced arrhythmia. This study was undertaken to elucidate the possible changes in ion channels underlying the susceptibility to arrhythmia in these mice. RT-PCR analyses revealed that the cardiac expression of adrenergic β 1-receptor ( ADRB1) was markedly lower, whereas voltage-gated potassium channel expression ( Kv2.1) was higher in PAHX-AP1 TG mice compared with non-TG mice. However, the expression of voltage-sensitive sodium and calcium channels, and muscarinic receptor was not significantly different. Propranolol pretreatment, a non-specific β-adrenoceptor antagonist, blocked aconitine-induced arrhythmia in non-TG mice, but not in PAHX-AP1 TG mice. Our results indicate that, in the PAHX-AP1 TG heart, the modulation of voltage-gated potassium channel and ADRB1 expression seem to be important in the electrophysiological changes associated with altered ion channel functions, but ADRB1 is not involved in the greater susceptibility to aconitine-induced arrhythmia.

Muscarinic cholinergic and beta-adrenergic contribution to hindquarters vasodilation and cardiac responses to cocaine.

Cocaine produces a pressor response associated with an initial hindquarters vasoconstriction followed by a prolonged vasodilation in conscious rats. Propranolol pretreatment prevented the vasodilation and enhanced the pressor response, whereas atropine methylbromide pretreatment reduced the increase in systemic vascular resistance. We studied the role of selective muscarinic and beta-adrenoceptor antagonists on responses to cocaine in rats with an increase in systemic vascular resistance to cocaine (vascular responders). Arterial blood pressure and ascending aortic and distal descending aortic blood flow using pulsed Doppler flowmetry were measured. In conscious rats, cocaine (5 mg/kg i.v.) elicited consistent pressor responses but variable systemic and hindquarters vascular resistance responses that were directly correlated, suggesting that skeletal muscle resistance responses comprise an important component of systemic vascular resistance. ICI 118551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)-amino]-2-butanol] (0.5 mg/kg i.v.) pretreatment prevented the hindquarters vasodilation, enhancing the increase in systemic vascular resistance and the pressor response while further depressing the cardiac output response, similar to the effects of propranolol. Atenolol (1 mg/kg) pretreatment attenuated the stroke volume and cardiac output responses while enhancing the increase in systemic vascular resistance without affecting the hindquarters responses. In contrast, M2 antagonist methoctramine (0.3 mg/kg) pretreatment had similar effects as atropine in reducing the decrease in cardiac output by reducing the increase in systemic vascular resistance, whereas the M1 antagonist pirenzipine (0.02 mg/kg) did not alter responses. Therefore, the cocaine-induced pressor response is ameliorated by beta2-adrenoceptor mediated skeletal muscle vasodilation, whereas the decrease in cardiac output and the increase in systemic vascular resistance are dependent on M2-cholinoceptor activation.

Acute cold/restraint stress inhibits host resistance to Listeria monocytogenes via β1-adrenergic receptors

We previously reported that acute cold/restraint stress (ACRS) significantly inhibits host resistance to Listeria monocytogenes ( LM) in BALB/c mice and that the sympathetic nervous system plays a major role in this inhibition. Here, we have further investigated the involvement of adrenergic receptor (ADR) subtypes. β-ADR antagonist propranolol, but not α-ADR antagonist phentolamine significantly enhanced host resistance of ACRS mice. Pro-inflammatory cytokine (IL-6, IL-1β, and TNFα) and IFNγ levels positively correlated with the LM levels in all groups of mice. Furthermore, β1-ADR antagonist atenolol but not β2-ADR antagonist ICI118,551 significantly decreased LM burden in ACRS mice. In addition, SCID mice on the same genetic background (BALB/c), which have no adaptive immune potential, were used to assess the immune responses targeted by ACRS. ACRS-induced suppression of host resistance was not observed in SCID mice, and propranolol pretreatment provided no further improvement of host resistance, indicating that ACRS mainly affects adaptive immunity, which is less critical in mice with greater innate than adaptive immunity. In summary, the data suggest that ACRS inhibition of host resistance to LM is mediated through β1-ADR stimulation, which appears to directly or indirectly modify activation of T cells or subsequent T cell functions involved in adaptive immunity, thus inhibiting overall host resistance. Interestingly, with heightened innate immunity and the absence of adaptive immunity, as observed in the SCID mice, ACRS does not affect host resistance, which emphasizes the importance of innate immunity in defense against bacterial infection.

Peripheral 5-HT 2A-receptor-mediated formation of an inhibitor of atrial natriuretic peptide binding involves inflammation

A peripheral 5-HT 2A receptor-mediated hemodynamic change prompted formation of indole-2,3-dione, an endogenous inhibitor of atrial natriuretic peptide (ANP) receptor binding and G protein-mediated intracellular signaling (IC 50: 0.4 μM). This effect was significantly suppressed by dexamethasone, indomethacin and the 5-HT 2 receptor antagonists, ketanserin or ritanserin. 5-HT 2A receptor-mediated acute hemodynamic change was not modified significantly by indomethacin, prazosin or propranolol pretreatment. A tyrosine hydroxylase inhibitor, α-methyl- p-tyrosine, but not a dopamine β hydroxylase inhibitor, diethyldithiocarbamate, abolished the 5-HT 2A receptor-mediated increase in indole-2,3-dione. Exogenous indole-2,3-dione induced a significant increase in plasma catecholamine levels and decrease in urine volume. A 5-HT 2A receptor-mediated decrease in capillary flow may have caused an inflammatory process and peripheral sympathetic activation via ANP signaling inhibition. 3,4-dihydroxyphenylalanine (DOPA)/dopamine may contribute to the progression of inflammation or the generation of a precursor of indole-2,3-dione. The observation that indole-2,3-dione abolished angiotensin AT 1 receptor-mediated NADPH activation in both human umbilical vein endothelial cells and smooth muscle cells at 20 μM may suggest that sulfhydryl-reactive indole-2,3-dione could influence mitochondrial function and cellular redox states via flavoenzyme inhibition and/or regulation of dehydrogenase–oxidase conversion.

Spasmolytic effects of three harmala alkaloids on guinea-pig isolated trachea.

The present study examined and compared the spasmolytic effects of 3 harmala alkaloids, harmine, harman, and harmaline, on carbachol-, histamine-, and KCl-induced contractions of guinea-pig isolated tracheal preparations. All 3 compounds relaxed the tracheal preparations contracted by these spasmogens with similar or different EC50 values, harmine being the most potent one. The cumulative concentration-response curves of all 3 compounds for carbachol-induced contraction were shifted to the right by propranolol (1 microM) pretreatment, indicating the involvement of the activation on the beta-adrenoceptors. All 3 compounds shifted the concentration-response curves of carbachol to the right in a parallel manner with the pA2 values comparable with their relaxation EC50 values, indicating a competitive antagonism at the muscarinic receptors. Receptor binding assays indicated that all 3 compounds interacted with lung muscarinic receptors (Ki = 11-13 microM), histamine H1 receptors (Ki = 27-107 microM), and beta2-adrenoceptors (Ki = 20-51 microM). Therefore, in addition to their actions on receptor-linked and voltage-dependent Ca2+ channels as reported in other types of smooth muscle, the present study suggests that the actions on muscarinic receptors, histamine H1 receptors, and beta2-adrenoceptors are also involved in their spasmolytic effects on airway smooth muscles.

Spasmolytic Effects of Three Harmala Alkaloids onGuinea‐Pig Isolated Trachea

Abstract: The present study examined and compared the spasmolytic effects of 3 harmala alkaloids, harmine, harman, and harmaline, on carbachol‐, histamine‐, and KCl‐induced contractions of guinea‐pig isolated tracheal preparations. All 3 compounds relaxed the tracheal preparations contracted by these spasmogens with similar or different EC50 values, harmine being the most potent one. The cumulative concentration‐response curves of all 3 compounds for carbachol‐induced contraction were shifted to the right by propranolol (1 μM) pretreatment, indicating the involvement of the activation on the β‐adrenoceptors. All 3 compounds shifted the concentration‐response curves of carbachol to the right in a parallel manner with the pA2 values comparable with their relaxation EC50 values, indicating a competitive antagonism at the muscarinic receptors. Receptor binding assays indicated that all 3 compounds interacted with lung muscarinic receptors (Ki=11–13 μM), histamine H1 receptors (Ki=27–107 μM), and β2‐adrenoceptors (Ki=20–51 μM). Therefore, in addition to their actions on receptor‐linked and voltage‐dependent Ca2+ channels as reported in other types of smooth muscle, the present study suggests that the actions on muscarinic receptors, histamine H1 receptors, and β2‐adrenoceptors are also involved in their spasmolytic effects on airway smooth muscles.

Is endotracheal adrenaline deleterious because of the beta adrenergic effect?

IV adrenaline increases coronary and cerebral perfusion pressures during cardiopulmonary resuscitation. We recently showed that endotracheal adrenaline can decrease blood pressure (BP), a detrimental effect presumably mediated by the beta 2-adrenergic receptor unopposed by alpha-adrenergic vasoconstriction. This prospective, randomized, laboratory comparison of endotracheal adrenaline (0.05 mg/kg diluted with normal saline to 10 mL total volume) with or without nonselective beta-blocker (propranolol) pretreatment was conducted in an attempt to clarify the mechanism of this BP decrease. Five mongrel dogs were given 0.05 mg/kg endotracheal adrenaline (diluted) or 0.05 mg/kg endotracheal adrenaline followed by an IV propranolol (0.1 mg/kg) pretreatment. Each dog served as its own control (10 mL of normal saline administered endotracheally) and received each regimen at least one week apart. Endotracheal adrenaline given after the propranolol pretreatment produced an increase in systolic, diastolic, and mean arterial BPs, from 165/110 mm Hg (mean 128 mm Hg) to 177.5/125 mm Hg (mean 142.5 mm Hg), respectively, as opposed to the hypotensive effect of isolated endotracheal adrenaline (P < 0.03). Thus, endotracheal adrenaline was associated with predominantly beta-adrenergic-mediated effects, causing hypotension via peripheral vasodilatation unopposed by alpha-adrenergic vasoconstriction. The search for the optimal dose of endotracheal adrenaline should be aimed at achieving the higher alpha-adrenergic vasoconstrictive threshold.

Central corticotropin releasing factor (CRF) and adrenergic receptors mediate hemodynamic responses to cocaine

Cocaine administration evokes cardiovascular responses that are variable in rats such that the pressor response is attributable to either a large increase in systemic vascular resistance and a decrease in cardiac output (vascular responders) or a smaller increase in systemic vascular resistance and no change or an increase in cardiac output (mixed responders). This study was designed to determine the role of central corticotropin releasing factor (CRF) and adrenergic receptors in mediating specific hemodynamic response patterns. Rats were instrumented for ascending aortic blood flow determination (cardiac output) using a pulsed Doppler system, arterial pressure measurement and for intravenous and intracerebroventricular (icv) administration of drugs. After characterizing the hemodynamic response pattern in individual rats to cocaine (5 mg/kg, i.v., 4–6 trials), selective receptor antagonists were administered icv 10 min before cocaine (5 mg/kg, i.v.). Pretreatment with the CRF antagonist α-helical CRF 9–41 (10 μg/5 μl, icv) prevented the decrease in cardiac output in vascular responders without altering hemodynamic responses to cocaine in mixed responders. Astressin (5 μg/5 μl, icv) exerted a similar effect in vascular responders. The α 2 receptor antagonist, yohimbine (3 μg/μl, icv) also prevented the decrease in cardiac output in vascular responders. Lower doses of α-helical CRF 9–41 (1 and 3 μg) were ineffective whereas higher doses of either CRF antagonist were lethal within 24 h. In contrast, propranolol (3 or 30 μg, icv) pretreatment enhanced the cocaine-induced decrease in cardiac output and increase in systemic vascular resistance noted in vascular responders and resulted in a decrease in cardiac output in mixed responders. We conclude that CRF and adrenoceptors in the CNS play an important role in determining the hemodynamic response pattern to cocaine. Furthermore, central β-adrenoceptors may be responsible for the reported effects of intravenous propranolol on cocaine-induced responses.

Inability of propranolol to prevent alcohol-induced reductions in cardiac protein synthesis in vivo

Rats were acutely injected with alcohol (75 mmol/kg body weight) and at the end of 2.5 h changes in cardiac synthesis rates were assessed with a ‘flooding dose’ of l-[4- 3H]phenylalanine. The results showed that acute alcohol dosage reduced the fractional rates of cardiac protein synthesis ( k S, %/day). This effect was also seen when data were expressed relative to either RNA (i.e. k RNA, mg protein/day/mg RNA) or DNA (i.e. k DNA, mg protein/day/mg DNA). Both left and right ventricles responded similarly to ethanol. However, propranolol pre-treatment (at doses of 17 and 170 μmol/kg body weight; i.p.) did not prevent these effect of ethanol in either the left or right ventricle. Indeed, there was evidence that propranolol per se perturbed cardiac protein synthesis in vivo in control (i.e. without ethanol) rats particularly in the right ventricle. In conclusion, the results suggest that alcohol is cardiotoxic to the myocardium, which may cause its effects on protein synthesis independently of β-receptors and/or xanthine oxidase inhibition.

Beta adrenoceptor regulation of macrophage arginase activity

Background: Arginase, which metabolizes L-arginine within the urea cycle, is essential for production of polyamines and affects production of nitric oxide by depletion of L -arginine, the common substrate for both arginase and nitric oxide synthase. Having shown that trauma increases splenic macrophage arginase activity, we seek to define the mechanisms for this. RAW macrophage arginase activity and expression are increased by 8-bromo-cAMP in vitro. We hypothesize that since catecholamines increase cAMP, trauma-induced splenic arginase activity may be mediated by post-injury catecholamine release. Methods: RAW 264.7 macrophage arginase activity was measured in vitro in response to 4 catecholamines with or without propranolol or lipopolysaccharide (LPS). C57BL/6 mice underwent laparotomy as a model of moderate trauma after propranolol treatment, with and without intraperitoneal Escherichia coli LPS administration as a simulated pro-inflammatory stimulus. Results: Macrophage arginase activity increased in vitro in response to catecholamines or LPS ( P < .05). Propranolol pretreatment blocked macrophage arginase activity induced by epinephrine (10 μmol/L) in vitro ( P < .05). Trauma or LPS alone increased splenic arginase activity in vivo ( P < .05). Propranolol did not alter LPS-induced splenic arginase activity but did significantly reduce trauma-induced splenic arginase activity ( P < .05). Conclusions: Catecholamines alone increase macrophage arginase activity through β-adrenoceptor activation. Increased splenic arginase activity induced by moderate trauma is decreased by β-adrenoceptor blockade, suggesting that trauma-induced arginase activity is partly mediated by endogenous catecholamines. (Surgery 2000;127:412-8.)

Impaired atrial M(2)-cholinoceptor function in obesity-related hypertension.

The aim of this study was to investigate the activity of the parasympathetic limb of the baroreflex arch in a canine model of obesity-related hypertension. Twelve male beagle dogs were randomized into 2 groups. Six dogs were fed with normal canine food and 6 were submitted to a 10-week high-fat diet (HFD). We have evaluated the consequences of HFD on heart rate (HR) and blood pressure (BP) circadian cycles and methylscopolamine dose-response curves. Binding of [(3)H]-AF-DX 384 and adenylyl cyclase activity were investigated to determine the density and functionality of M(2)-cholinoceptors on right atrial membranes from control and HFD dogs. HFD induced a significant increase in body weight (15+/-1 vs 12+/-1 kg), systolic BP (161+/-5 vs 145+/-4 mm Hg), diastolic BP (92+/-3 vs 79+/-2 mm Hg), and HR (96+/-4 vs 81+/-3 bpm). Circadian rhythms of HR and BP observed in the baseline period were abolished after 9 weeks of HFD. After propranolol (1 mg/kg) pretreatment, the dose of methylscopolamine able to induce 50% maximum tachycardia was significantly increased after 9 weeks of HFD (7.4+/-0.3 vs 4.7+/-0.1 microg/kg). In the control group, the experimental period failed to modify these parameters. The numbers of M(2)-cholinoceptors measured in right atrial membranes were significantly lower in HFD than in control groups (54+/-6 vs 27+/-6 fmol/mg protein). The ability of carbachol to inhibit isoproterenol-stimulated adenylyl cyclase activity was significantly lower in HFD than in control groups (IC(50)=47+/-12 vs 6.4+/-1.4 micromol/L). However, the basal activity of adenylyl cyclase was unchanged by HFD. HFD decreases M(2)-cholinoceptor number and function in cardiomyocytes. This could explain the abolition of circadian rhythm of HR and the changes in chronotropic effect brought about by methylscopolamine.