Beta-adrenoceptor Blockade Research Articles

<I>β</I>-adrenoreceptor blocking and antihypertensive activity of PP-24, a newly synthesized aryloxypropanolamine derivative

PP-24 is a newly synthesized putative beta-adrenoceptor antagonist. The objective of the study was to the evaluate beta-adrenoceptor blocking activity of PP-24 on isolated rat preparations: right atria, uterus and colon. Effects on the rat ECG and renal hypertension (induced by left renal artery ligation) were also investigated. Treatment with PP-24 (3 and 10 mg kg(-1)) for 7 days in rats with renal hypertension significantly reduced the mean atrial blood pressure. Single i.v. injections of isoprenaline (0.3, 1 and 3 microg kg(-1)) alone in normal anaesthetized rat caused hypotension and tachycardia, while PP-24 alone produced dose-dependent falls in mean aterial pressure and bradycardia. Pretreatment of anaesthetized rats with test compounds significantly blocked the hypotension response but not the tachycardia induced by isoprenaline (0.3, 1 and 3 microg kg(-1)). The pA(2) of PP-24 to beta(1)-, beta(2)- and beta(3)-adrenoceptors was 7.72 +/- 0.082, 7.40 +/- 0.082 and 6.39 +/- 0.16, respectively. The beta(1)/beta(2) selectivity ratio was 2.08, compared with 1.27 for propranolol and 39.17 for atenolol. It is concluded that PP-24 possesses beta-adrenoceptor blockade activity but with non-specific affinity for beta(1)- and beta(2)-adrenoceptor subtypes. The rank order of potency of the antagonists for beta(1)-adrenoceptors was atenolol > PP-24 > propranolol. The antihypertensive activity of PP-24 in rats with renal hypertension appears to be due to blockade of beta-adrenoceptors.

β-Adrenergic Blockade and Metabo-Chemoreflex Contributions to ExerciseCapacity

Exercise-induced dyspnea in patients with cardiopulmonary diseases may be related to sympathetic nervous system activation, with increased metabo- and/or chemosensitivities. Whether this mechanism plays a role in exercising normal subjects remains unclear. Muscle sympathetic nerve activity (MSNA), HR, ventilation (V(E)), O2 saturation (SpO2), and end-tidal PCO2 (PetCO2) were measured in 14 healthy young adults after 1 wk of beta1-receptor blockade with bisoprolol 5 mg x d(-1) versus placebo after a double-blind, placebo-controlled, randomized crossover design. The MSNA and the ventilatory responses to hyperoxic hypercapnia (7% CO2 in O2), DeltaV(E)/DeltaPetCO2, and isocapnic hypoxia (10% O2 in N2), DeltaV(E)/DeltaSpO2, and to an isometric muscle contraction followed by a local circulatory arrest (metaboreflex) were determined at rest followed by an incremental cardiopulmonary exercise test. Bisoprolol did not change the V(E) and MSNA responses to hypercapnia, hyperoxia, or isometric muscle contraction or ischemia. Bisoprolol decreased maximum O2 uptake (P < 0.05), workload (P < 0.05), and HR (P < 0.0001) and both V(E)/VO2 and V(E)/VCO2 slopes (P < 0.05). These results suggest that decreased aerobic exercise capacity after intake of beta-blockers is accompanied by decreased ventilation at any metabolic rate. However, this occurs without detectable change in the sympathetic nervous system tone or in metabo- or chemosensitivity and is therefore probably of hemodynamic origin.

Does adenosine A1 receptor stimulation causes beta adrenergic receptor blockade in amitriptyline-induced QRS prolongation?

Does adenosine A1 receptor stimulation causes beta adrenergic receptor blockade in amitriptyline-induced QRS prolongation?

Protective Effect of a GRK5 Polymorphismon Heart Failure and its Interaction with β-Adrenergic Receptor Antagonists

EVALUATION OF: Liggett SB, Cresci S, Kelly RJ et al.: A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. Nat. Med. 14, 510-517 (2008). beta-Adrenoceptor blockade therapy was developed for the treatment of hypertension but is now also a cornerstone in the treatment of heart failure. Based on the mechanisms of action and current knowledge of pathway signaling, Ligget et al. hypothesized that genetic variants within G-protein coupled receptor kinases might alter disease course and response to beta-adrenoceptor blockade therapy. Following a multistep approach, a common variant in GRK5 was identified as being important in vitro and in vivo (mouse model) in beta-adrenergic desensitization, and was epidemiologically related to survival and therapy response in African-Americans. Although such a variety of research approaches is appealing, owing to the large number of used methods readers remain puzzled on some issues because it is not possible to give all details of each individual study. Therefore, interpretation of the overwhelming amount of results is difficult. In an era of shifting emphasis from classic hypothesis driven pharmacogenetics to genome-wide association studies, this study shows that hypothesis driven translational research is still of high value, especially in phenotypes as investigated here.

Hawthorn (Crataegus monogyna Jacq.) extract exhibits atropine-sensitive activity in a cultured cardiomyocyte assay

Hawthorn (Crataegus spp.) plant extract is used as a herbal alternative medicine for the prevention and treatment of various cardiovascular diseases. Recently, it was shown that hawthorn extract preparations caused negative chronotropic effects in a cultured neonatal murine cardiomyocyte assay, independent of beta-adrenergic receptor blockade. The aim of this study was to further characterize the effect of hawthorn extract to decrease the contraction rate of cultured cardiomyocytes. To test the hypothesis that hawthorn is acting via muscarinic receptors, the effect of hawthorn extract on atrial versus ventricular cardiomyocytes in culture was evaluated. As would be expected for activation of muscarinic receptors, hawthorn extract had a greater effect in atrial cells. Atrial and/or ventricular cardiomyocytes were then treated with hawthorn extract in the presence of atropine or himbacine. Changes in the contraction rate of cultured cardiomyocytes revealed that both muscarinic antagonists significantly attenuated the negative chronotropic activity of hawthorn extract. Using quinuclidinyl benzilate, L-[benzylic-4,4'-(3)H] ([(3)H]-QNB) as a radioligand antagonist, the effect of a partially purified hawthorn extract fraction to inhibit muscarinic receptor binding was quantified. Hawthorn extract fraction 3 dose-dependently inhibited [(3)H]-QNB binding to mouse heart membranes. Taken together, these findings suggest that decreased contraction frequency by hawthorn extracts in neonatal murine cardiomyocytes may be mediated via muscarinic receptor activation.

The Effect of Long-Term β-Adrenergic Receptor Blockade on the Oxygen Delivery and Extraction Relationship in Patients With Coronary Artery Disease

We evaluated the effects of long-term beta-blocker treatment on the balance between oxygen delivery and extraction at peak oxygen uptake (VO2) and at target heart rate training (anaerobic threshold). Fifteen patients with coronary artery disease performed paired peak cardiopulmonary and submaximal exercise tests on a cycle ergometer with and without atenolol treatment. Thirty minutes following the submaximal tests, participants pedaled 10 minutes at a workload corresponding to that of the anaerobic threshold attained. Arterial oxygen was defined from echocardiography and venous oxygen content. At rest, stroke volume, heart rate, and cardiac output were lower (P < .05), whereas arteriovenous oxygen difference [(a - v)O2] was higher with the use of atenolol (P < .05). At peak exercise, heart rate, lactate, and systolic blood pressure were lower (P < .05), whereas (a - v)O2 was higher (P < .05) with the use of atenolol. At anaerobic threshold, stroke volume, heart rate, cardiac output, and systolic blood pressure were lower (P < .05), whereas (a - v)O2 was higher (P < .05) with the use of atenolol. Absolute VO2 and workload during maximal (P = .67 and P = .49, respectively) and submaximal (P = .13 and P = .44, respectively) exercises were similar between conditions. Results demonstrate that atenolol treatment in patients with coronary artery disease does not alter VO2 and workload at the anaerobic threshold and peak exercise because of an increase in oxygen extraction and stroke volume in the face of reduced heart rate. These findings indicate that with long-term beta-adrenergic receptor blockade, there is interplay between oxygen delivery and extraction, suggesting a link between cardiac hemodynamic responses and skeletal muscle metabolic adaptations.

A GRK5 polymorphism that inhibits β-adrenergic receptor signaling is protective in heart failure

Beta-adrenergic receptor (betaAR) blockade is a standard therapy for cardiac failure and ischemia. G protein-coupled receptor kinases (GRKs) desensitize betaARs, suggesting that genetic GRK variants might modify outcomes in these syndromes. Re-sequencing of GRK2 and GRK5 revealed a nonsynonymous polymorphism of GRK5, common in African Americans, in which leucine is substituted for glutamine at position 41. GRK5-Leu41 uncoupled isoproterenol-stimulated responses more effectively than did GRK5-Gln41 in transfected cells and transgenic mice, and, like pharmacological betaAR blockade, GRK5-Leu41 protected against experimental catecholamine-induced cardiomyopathy. Human association studies showed a pharmacogenomic interaction between GRK5-Leu41 and beta-blocker treatment, in which the presence of the GRK5-Leu41 polymorphism was associated with decreased mortality in African Americans with heart failure or cardiac ischemia. In 375 prospectively followed African-American subjects with heart failure, GRK5-Leu41 protected against death or cardiac transplantation. Enhanced betaAR desensitization of excessive catecholamine signaling by GRK5-Leu41 provides a 'genetic beta-blockade' that improves survival in African Americans with heart failure, suggesting a reason for conflicting results of beta-blocker clinical trials in this population.

Effect of acute beta 1 and beta 1/beta 2 receptor blockade on carbohydrate and lipid metabolism during exertion

The influence of acute beta 1-receptor blockade using 50 mg metoprolol or beta 1/beta 2-blockade using 40 mg propranolol resulted in an equipotent reduction of cardiac frequency and systolic blood pressure without influencing diastolic pressure in ten healthy probands. There was no reduction of maximal bicycle ergometric exercise by either beta-receptor blocking agent. Serum glucose levels did not change during metoprolol in comparison to pre-test values. In contrast, propranolol resulted in a significant decrease of glucose levels during maximal exercise and 5 minutes after end of exercise. Plasma lactate was moderately lowered by both beta-receptor blockers after 20 min constant exercising when compared to pre-medication. Both substances reduced the insulin level in a comparable way during the exercise test. Serum triglyceride concentrations did not alter significantly during exercise tests. Serum free fatty acid levels showed a decreasing tendency until maximal exercise; however, there was no significant difference between values obtained with metoprolol or propranolol and drug-free pre-test.

Therapy of Marfan Syndrome

Marfan syndrome is a common inherited disorder of connective tissue caused by deficiency of the matrix protein fibrillin-1. Effective surgical therapy for the most life-threatening manifestation, aortic root aneurysm, has led to a nearly normal lifespan for affected individuals who are appropriately recognized and treated. Traditional medical therapies, such as beta-adrenergic receptor blockade, are used to slow pathologic aortic growth and decrease the risk of aortic dissection by decreasing hemodynamic stress. New insights regarding the pathogenesis of Marfan syndrome have developed from investigation of murine models of this disorder. Fibrillin-1 deficiency is associated with excess signaling by transforming growth factor beta (TGFbeta). TGFbeta antagonists have shown great success in improving or preventing several manifestations of Marfan syndrome in these mice, including aortic aneurysm. These results highlight the potential for development of targeted therapies based on discovery of disease genes and interrogation of pathogenesis in murine models.

A Case of Malignant Pheochromocytoma with Holt-Oram Syndrome

A 23-year-old female patient with malignant pheochromocytoma was admitted to the Tokyo Women's Medical University. The patient had been clinically diagnosed with Holt-Oram syndrome at birth. Since she had complex congenital heart disease, chronic heart failure, and severe hypoxia, the risk surrounding surgery to remove the primary tumor was predicted to be very high, and subsequently, chemotherapy was performed. The patient was not able to continue chemotherapy due to adverse effects. However, for one year, both her hypertension and catecholamine-dependent symptoms were well controlled by an alpha-adrenergic and beta-adrenergic receptor blockade, although the patient did experience high plasma norepinephrine levels. To our knowledge, this is the first report of a patient with the combination of malignant pheochromocytoma and Holt-Oram syndrome. A correlation between chronic hypoxia and pheochromocytoma has been reported. This instructive case reminds us to consider the possibility of pheochromocytoma with congenital heart disease when these types of unexpected or unusual symptoms are encountered.

Stimulation of adipose tissue lipolysis following insulin-induced hypoglycaemia: evidence of increased beta-adrenoceptor-mediated lipolytic response in IDDM.

The adrenergic regulation of adipose tissue lipolysis in response to insulin-induced hypoglycaemia (intravenous infusion of soluble insulin 0.10 IU.kg body weight-1.h-1 until the arterial plasma glucose fell below 2.8 mmol/l) was investigated directly in vivo in 11 insulin-dependent diabetic (IDDM) patients and 12 control subjects, using microdialysis of the extracellular space of abdominal subcutaneous adipose tissue. The tissue glycerol level (lipolysis index) and the escape of ethanol from the perfusion medium (blood flow index) were continuously monitored. During insulin infusion the arterial glucose level was reduced in parallel and the hypoglycaemic nadir was almost identical in the two groups (diabetic patients 2.2 +/- 0.1 and control subjects 2.3 +/- 0.1 mmol/l). While the maximum response of plasma epinephrine to hypoglycaemia was 30% lower in diabetic patients than in the control subjects (p < 0.05), the glycerol levels in adipose tissue and in plasma, as well as in serum non-esterified fatty acids, increased twice as much in the former as in the latter group following hypoglycaemia (p < 0.01). Addition of the beta-adrenoceptor blocker propranolol (10(4) mol/l) to the tissue perfusate almost completely prevented the hypoglycaemia-induced increase in the adipose tissue glycerol level in both groups, whereas in situ perfusion with 10(-4) mol/l of the alpha-adrenoceptor blocker phentolamine resulted in an additional increase in the tissue glycerol levels; during alpha-blockade, the glycerol response to hypoglycaemia remained enhanced by threefold in the diabetic patients (p < 0.01). In both groups local adipose tissue blood flow increased transiently in a similar way after hypoglycaemia; the increase being inhibited by in situ beta-adrenoceptor blockade. We conclude that both alpha- and beta-adrenergic mechanisms regulate adipose tissue lipolysis in response to hypoglycaemia. In IDDM, lipolysis is markedly enhanced following hypoglycaemia, despite a reduced catecholamine secretory response, because of increased beta-adrenoceptor action in adipose tissue.

Is there still a role for treatment with β-adrenoceptor antagonists in post-myocardial infarction patients with well-preserved left ventricular systolic function?

The utility of beta-adrenoceptor antagonists post myocardial infarction was established in the pre-thrombolytic era. Evidence for improvement in long-term prognosis with metoprolol, timolol and propranolol in particular derives from reduction in event rates in patients who have had substantial left ventricular damage at the time of infarction and probably correlates largely with the more recently demonstrated salutary effects of this group of drugs in patients with chronic heart failure. In all other respects, evidence for beneficial effects of beta-adrenoceptor antagonists in peri-infarct and post-infarct therapeutics is equivocal. They appear to exert no major influence on outcomes in patients with unstable angina, nor do they markedly alter early clinical course in uncomplicated acute myocardial infarction, irrespective of other interventions. Furthermore, the limited available analyses suggest no discernible beneficial effect on long-term outcomes post-uncomplicated infarction. It is possible that in such patients, current recommendations for 'routine' long-term beta-adrenoceptor blockade can no longer be justified.

Update on inotropic therapy in the management of acute heart failure

The use of classic inotropic agents activating the beta-receptor-cyclic adenosine monophosphate (cAMP) pathway (ie, dobutamine or milrinone) should be restricted to a "rescue" therapy in patients with acute heart failure and signs of peripheral hypoperfusion (hypotension, renal dysfunction) that is refractory to volume replacement, diuretics, and vasodilators. This approach is largely supported by observations from clinical trials suggesting that both short-term treatment of acute heart failure without an essential requirement of inotropic support as well as long-term inotropic therapy in patients with severe chronic heart failure with classical inotropic agents can increase arrhythmia and mortality. Vice versa, beta-receptor blockade, whenever tolerated, improves survival in patients with severe stable heart failure, further supporting the concept that beta-receptor stimulation has adverse long-term effects. Positive inotropic therapy stimulating the beta-receptor-cAMP pathway should, therefore, be used with caution, given the potential harmful effects. Levosimendan, a novel calcium sensitizer, has recently attracted substantial clinical interest and may be superior to classical inotropes with respect to improving cardiac mechanical efficiency and avoiding adverse effects such as increasing myocardial oxygen uptake or cardiomyocyte death. Earlier clinical studies have suggested a beneficial effect on survival compared with dobutamine or placebo in patients with acute heart failure (LIDO , RUSSLAN , and CASINO trials). However, more recent data from two large clinical trials (SURVIVE and REVIVE trials) did not confirm these beneficial effects on mortality. Therefore, additional data are required with respect to the optimum dosing of levosimendan and patient selection to reach a definitive conclusion about the role of levosimendan in the management of patients with acute heart failure.

Abstract 373: A Novel Haplotype In The G(alpha)s Gene Alters Gene Expression And Responsiveness To Receptor Stimulation And Predicts Cardiac Performance In Humans

Background: Transgenic mice with cardiac Gαs overexpression exhibit enhanced inotropic and chronotropic responses to sympathetic stimulation, but develop cardiomyopathy with age. In contrast, chronic beta-adrenergic receptor blockade (beta-AR) mitigates cardiac dilation and depressed left ventricular function in these models. We tested the hypothesis that naturally occurring variants in regulatory regions of the human gene GNAS encoding Gαs result in altered Gαs expression and signal transduction properties in humans. Methods and results: Sequencing the promoter and intron 1 of GNAS revealed 11 single nucleotide polymorphisms resulting in three common haplotypes. In reporter assays haplotype *3 constructs exhibited significantly higher promoter activity compared to haplotype *1 and *2 constructs. In hearts from 54 patients under chronic beta-AR blockade scheduled for coronary artery bypass grafting (CABG) Gαs mRNA expression was more than 50% higher in homozygous *3 carriers (*3/*3) than in heterozygous (*3/−) and negative *3 (−/−) carriers (Gαs/Actin, 0.16±0.06 vs. 0.10±0.03 vs. 0.09±0.04; p=0.002). Consistent with increased Gαs expression, functional studies showed that *3/*3 carriers had higher basal activities of adenylyl cyclase (AC, 32.4±12.9 vs. 29.1±7.9 vs. 25.5±5.3 pmol/min/mg; p=0.019) and maximal isoproterenol-stimulated activities were markedly higher for the *3/*3 compared to *3/− and −/− carriers (79.3±29.7 vs. 66.7±16.2 vs. 57.3±11.1 pmol/min/mg; p=0.002). Direct AC stimulation with Forskolin was unaffected by GNAS haplotypes. Hemodynamic measurements in 137 bypass patients under chronic beta-AR blockade revealed a higher cardiac index (2.2±0.2 vs. 1.9±0.1 vs. 1.8±0.1 l min-1 m-2; p=0.025) in *3/*3 carriers. This was also in line with a lower NYHA functional class (1.8±0.2 vs. 2.2±0.1 vs. 2.3±0.1; p=0.040) and NT-proBNP levels (339±87 vs. 746±110 vs. 1365±259 pg/ml; p=0.002). Summary: Increased Gαs expression due to a functional haplotype results in altered signal transduction properties and may have salutary effects on cardiac performance in CABG patients under chronic beta-AR blockade. Our data therefore could help to translate results from transgenic mice to genotype-phenotype correlations in humans.

Antianginal Actions of Beta-Adrenoceptor Antagonists

Angina pectoris is usually the first clinical sign of underlying myocardial ischemia, which results from an imbalance between oxygen supply and oxygen demand in the heart. This report describes the pharmacology of beta-adrenoceptor antagonists as it relates to the treatment of angina. The beta-adrenoceptor antagonists are widely used in long-term maintenance therapy to prevent acute ischemic episodes in patients with chronic stable angina. Beta-adrenoceptor antagonists competitively inhibit the binding of endogenous catecholamines to beta1-adrenoceptors in the heart. Their anti-ischemic effects are due primarily to a reduction in myocardial oxygen demand. By decreasing heart rate, myocardial contractility and afterload, beta-adrenoceptor antagonists reduce myocardial workload and oxygen consumption at rest as well as during periods of exertion or stress. Predictable adverse effects include bradycardia and cardiac depression, both of which are a direct result of the blockade of cardiac beta1-adrenoceptors, but adverse effects related to the central nervous system (eg, lethargy, sleep disturbances, and depression) may also be bothersome to some patients. Beta-adrenoceptor antagonists must be used cautiously in patients with diabetes mellitus, peripheral vascular disease, heart failure, and asthma or other obstructive airway diseases. Beta-adrenoceptor antagonists may be used in combination with nitrates or calcium channel blockers, which takes advantage of the diverse mechanisms of action of drugs from each pharmacologic category. Moreover, concurrent use of beta-adrenoceptor antagonists may alleviate the reflex tachycardia that sometimes occurs with other antianginal agents.

Metabolism modulators in sepsis: Propranolol

Sepsis is accompanied by an enormous increase in catecholamine expression, leading to metabolism of lipids and glucose, changes in cardiovascular output, immunomodulatory effects, and changes in protein metabolism, all of which push the body into a catabolic state. Deleterious beta-adrenoceptor controlled responses to stress and sepsis are well documented; therefore, it would seem appropriate to use propranolol under such circumstances. There are arguments both for and against the use of beta-adrenoceptor blockade during episodes of stress and infection. The definition of sepsis itself is a clinical one in most cases. There are guidelines concerning the diagnosis of sepsis (systemic inflammatory response syndrome [SIRS] in the presence of significant infection). However, when the cause of SIRS is not infection, for example, in burn patients, is it not possible, and indeed preferable, to tackle the stress response in a more aggressive fashion? The effects of SIRS on the body are myriad and have been defined and illustrated in many fine reviews. The effects of sepsis on the body, as well, have been discussed in the world literature and are beyond the scope of this article. In this article we attempt to demonstrate the effects of sepsis (SIRS plus infection) on whole body metabolism, outline the mediators of these changes, and then show the ability of propranolol to attenuate the changes seen.

Beta-Adrenergic Receptor Blockade Attenuates the Exercise-Induced Suppression of TNF-Alpha in Response to Lipopolysaccharide in Rats

Stressful exercise has been found to reduce the proinflammatory cytokine response to lipopolysaccharide (LPS). In this study, we aimed to determine whether receptor antagonists for corticosterone or catecholamines would increase the LPS-induced tumor necrosis factor-α (TNF-α) response after exhaustive exercise. Female F344 rats were randomly assigned to one of five groups: control (vehicle), RU-486 (glucocorticoid receptor antagonist, 30 mg/kg)-, propranolol [nonselective β-adrenergic receptor (AR) blockade, 30 mg/kg]-, atenolol (β₁-AR blockade, 30 mg/kg)-, or ICI 118551 (β₂-AR blockade, 30 mg/kg)-treated groups. Each antagonist was given intraperitoneally 30 min prior to exercise or control period. Exercised rats ran until exhaustion on a treadmill at gradually increasing speeds, from 10 to 36 m/min at 15% grade. Immediately postexercise or control period all rats were injected with LPS (1 mg/kg, i.v.). Plasma TNF-α was reduced by prior exercise to approximately 10% of that of sedentary controls (p < 0.01). Plasma TNF-α concentration in exercised RU-486-treated rats was significantly different than that of nonexercised rats (19.2%, p < 0.01) and not different from exercised rats. However, pretreatment of rats with the nonselective β-AR blocker propranolol almost completely reversed the exercise-induced suppression of plasma TNF-α in response to LPS. β₁-AR pretreatment almost completely attenuated the exercise-induced suppression of LPS-induced plasma TNF-α while β₂-antagonism had a partial effect. These results indicate that exercise-induced catecholamines, acting through β-ARs (especially the β₁-AR), are responsible for the exercise-induced suppression of plasma TNF-α after LPS administration.

The beta‐adrenoceptor antagonist propranolol counteracts anti‐inflammatory effects of isoflurane in rat endotoxemia

Recent studies suggest that volatile anaesthetics have anti-inflammatory and preconditioning properties and that beta-adrenoceptors are involved in the signalling pathways for these effects. Concurrently, the blockade of beta-adrenoceptors has been shown to augment the release of inflammatory mediators in response to pro-inflammatory stimuli. We therefore aimed to investigate whether the beta-adrenoceptor antagonist propranolol might modulate the anti-inflammatory effects of isoflurane on the systemic and pulmonary release of pro-inflammatory cytokines in endotoxemic rats. Forty anaesthetized and ventilated Sprague-Dawley rats were randomly treated as follows. Lipopolysaccharide (LPS) only (n = 8), endotoxemia with LPS [5 mg/kg, intravenously (i.v.)]. LPS-isoflurane (n = 8): endotoxemia and continuous inhalation of 1 minimum alveolar concentration (MAC) of isoflurane. LPS-isoflurane-propranolol (n = 8): administration of propranolol (3 mg/kg) before continuous inhalation of isoflurane and induction of endotoxemia. LPS-propranolol (n = 8): administration of propranolol (3 mg/kg) before endotoxemia without inhalation of isoflurane. Sham (n = 8): control-group only with surgical preparation. After 4 h of endotoxemia, levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-10 (IL-10) in plasma and bronchoalveolar fluid (BALF) were analysed. Release of nitric oxide (NO) and amount of inducible nitric oxide synthase (iNOS) protein in alveolar macrophages was measured by Griess assay or determined by Western Blotting, respectively. Inhalation of isoflurane reduced the release of TNF-alpha (P < 0.05) and IL-1beta (P < 0.05) in plasma and IL-1beta (P < 0.05) in BALF. Co-administration of propranolol significantly inhibited these effects. During inhalation of isoflurane, the increased release of NO and iNOS protein from alveolar macrophages was also completely inhibited by propranolol. Our results indicate for the first time, that blockade of beta-adrenoceptors counteracts the anti-inflammatory effects of isoflurane in endotoxemic rats.

ACTIVATION OF PERIPHERAL CHEMORECEPTORS CAUSES POSITIVE INOTROPIC EFFECTS IN A WORKING HEART–BRAINSTEM PREPARATION OF THE RAT

1. The aim of the present study was to evaluate the effects of peripheral chemoreceptor activation on myocardial contractility in an anaesthetic-free decerebrated rat preparation. 2. In the decerebrated and retrogradely perfused working heart-brainstem preparation, we recorded phrenic nerve activity, left ventricular (LV) pressure (microtip Millar catheter), LV dP/dT, heart rate and aortic perfusion pressure before and after activating peripheral chemoreceptors with bolus intra-arterial injections of KCN. 3. Without cardiac pacing, chemoreflex activation caused falls in heart rate (-108 +/- 21 b.p.m.) and complex polyphasic changes in LV pressure and LV dP/dT. If the heart was paced, chemoreflex activation caused significant rises in LP pressure (+16 +/- 3 mmHg) and LV dP/dt (+778 +/- 93 mmHg/s). These positive inotropic effects were significantly and substantially attenuated by beta-adrenoceptor blockade with atenolol. In all instances, chemoreflex activation elicited potent tachypnoeic responses. 4. In conclusion, activation of peripheral chemoreceptors in non-anaesthetized rats evokes a positive inotropic response that is sympathetically mediated. This observation may be relevant for the evaluation of neurally induced effects of acute hypoxia on the ventricular myocardium.

Preserving Cardiac Output With Beta-Adrenergic Receptor Blockade and Inhibiting the Bezold-Jarisch Reflex During Resuscitation From Hemorrhage

Successful fluid resuscitation after severe hemorrhage may be limited by activation of the Bezold-Jarisch reflex. We postulated that pharmacologic inhibition of this reflex would restore cardiovascular hemodynamics more effectively than would volume repletion alone during resuscitation for hemorrhagic shock. We measured mean arterial pressure (MAP), heart rate (HR), and cardiac output (CO) during fluid resuscitation after hemorrhaging laboratory rats until their CO had decreased by 90% to 95%. To block distinct components of the Bezold-Jarisch reflex, animals received capsazepine, yohimbine, or propranolol before iso-osmotic volume repletion. Hemorrhage decreased MAP and CO; despite an initial tachycardia, HR fell significantly in response to this large volume blood loss. The degree of hemorrhage-induced bradycardia mediated by the Bezold-Jarisch reflex predicted resuscitation MAP. Capsazepine-treated animals had greater resuscitation-induced increases in MAP (values in mm Hg +/- SEM), 130 +/- 12, when compared with the saline-only animals, 90 +/- 7 (p = 0.004). The capsazepine group also had a greater increase in systemic vascular resistance over baseline values during resuscitation (86% +/- 19%) compared with vehicle-treated animals (26% +/- 14%, p = 0.02). Capsazepine had no effect on cardiac dynamics. On the other hand, yohimbine increased HR and diminished CO, and propranolol dramatically increased stroke volume by 30%. Inhibition of the Bezold-Jarisch reflex may aid fluid resuscitation after hemorrhage only if stroke volume is restored. Beta-adrenergic receptor antagonists such as propranolol may prove the most salutary of these agents in enhancing fluid resuscitation in patients with severe hemorrhage.