Non-selective Beta-adrenoceptor Antagonist Research Articles

Cerebral non‐oxidative carbohydrate consumption in humans driven by adrenaline

During brain activation, the decrease in the ratio between cerebral oxygen and carbohydrate uptake (6 O(2)/(glucose + (1)/(2) lactate); the oxygen-carbohydrate index, OCI) is attenuated by the non-selective beta-adrenergic receptor antagonist propranolol, whereas OCI remains unaffected by the beta(1)-adrenergic receptor antagonist metroprolol. These observations suggest involvement of a beta(2)-adrenergic mechanism in non-oxidative metabolism for the brain. Therefore, we evaluated the effect of adrenaline (0.08 microg kg(-1) min(-1) i.v. for 15 min) and noradrenaline (0.5, 0.1 and 0.15 microg kg(-1) min(-1) i.v. for 20 min) on the arterial to internal jugular venous concentration differences (a-v diff) of O(2), glucose and lactate in healthy humans. Adrenaline (n = 10) increased the arterial concentrations of O(2), glucose and lactate (P < 0.05) and also increased the a-v diff for glucose from 0.6 +/- 0.1 to 0.8 +/- 0.2 mM (mean +/- s.d.; P < 0.05). The a-v diff for lactate shifted from a net cerebral release to an uptake and OCI was lowered from 5.1 +/- 1.5 to 3.6 +/- 0.4 (P < 0.05) indicating an 8-fold increase in the rate of non-oxidative carbohydrate uptake during adrenaline infusion (P < 0.01). Conversely, noradrenaline (n = 8) did not affect the OCI despite an increase in the a-v diff for glucose (P < 0.05). These results support that non-oxidative carbohydrate consumption for the brain is driven by a beta(2)-adrenergic mechanism, giving neurons an abundant provision of energy when plasma adrenaline increases.

Mechanisms involved in the pressor response to noradrenaline microinjection into the supraoptic nucleus of unanesthetized rats

We report on the cardiovascular effects of noradrenaline (NA) microinjection into the hypothalamic supraoptic nucleus (SON) as well as the central and peripheral mechanisms involved in their mediation. Microinjections of NA 1, 3, 10, 30 or 45 nmol/100 nL into the SON caused dose-related pressor and bradycardiac response in unanesthetized rats. The response to NA 10 nmol was blocked by SON pretreatment with 15 nmol of the alpha(2)-adrenoceptor antagonist RX821002 and not affected by pretreatment with equimolar dose of the selective alpha(1)-adrenoceptor antagonist WB4101, suggesting that local alpha(2)-adrenoceptors mediate these responses. Pretreatment of the SON with the nonselective beta-adrenoceptor antagonist propranolol 15 nmol did not affect the pressor response to NA microinjection of into the SON. Moreover, the microinjection of the 100 nmol of the selective alpha(1)-adrenoceptor agonist methoxamine (MET) into the SON did not cause cardiovascular response while the microinjection of the selective alpha(2)-adrenoceptor agonists BHT920 (BHT, 100 nmol) or clonidine (CLO, 5 nmol) caused pressor and bradycardiac responses, similar to that observed after the microinjection of NA. The pressor response to NA was potentiated by intravenous pretreatment with the ganglion blocker pentolinium and was blocked by intravenous pretreatment with the V(1)-vasopressin receptor antagonist dTyr(CH2)5(Me)AVP, suggesting an involvement of circulating vasopressin in this response. In conclusion, our results suggest that pressor responses caused by microinjections of NA into the SON involve activation of local alpha(2)-adrenoceptor receptors and are mediated by vasopressin release into circulation.

Dose–response effects of sotalol on cardiovascular function in conscious, freely moving cynomolgus monkeys

The non-selective beta-adrenoceptor antagonist, D,L-sotalol (sotalol) is commonly employed as a positive control during preclinical cardiovascular safety pharmacology testing, mainly because of its ability to prolong QT interval duration. However, no information appears in the literature, except in abstract form, regarding the dose-response effects of sotalol in unanesthetized monkeys. The current study was conducted to determine the dose- and plasma-response effects of orally administered sotalol on cardiovascular function in conscious non-human primates. Male cynomolgus monkeys were implanted with telemetry devices and the effects of sotalol hydrochloride (5, 10 and 30 mg kg(-1) of body weight, p.o.) on arterial blood pressure, heart rate, body temperature and electrocardiogram waveform were continuously monitored for 6 h after dosing. Blood was sampled for the measurement of plasma concentrations of sotalol. Sotalol dose dependently decreased heart rate and prolonged RR, PR, QT and corrected QT intervals, while having little or no effects on the QRS complex, arterial pressure or body temperature, over the dose range tested. When the data were related to plasma concentrations of sotalol, it was clear that the cardiovascular effects occurred in a similar pattern and to a comparable degree as those reported in human studies. The current study helps demonstrate the validity of utilizing telemetry-instrumented non-human primates for the cardiovascular safety pharmacology assessment of drugs prior to first-in-human testing, and its findings may serve as a reference source for the dose- and plasma-response effects of orally administered sotalol in conscious monkeys.

No Effect of 5-Day Treatment with Acetylsalicylic Acid (Aspirin) or the Beta-Blocker Propranolol (Inderal) on Free Cortisol Responses to Acute Psychosocial Stress: A Randomized Double-Blind, Placebo-Controlled Study

Background: The characterization of an individual’s hypothalamic-pituitary-adrenal axis stress response is a main research topic in neuropsychobiology since alterations have been causally linked to several disease states. Over the last years, several studies focused on the identification of sources of inter- and intraindividual variability, but there is still a paucity of experimental data on the effect of different pharmaceuticals on cortisol responses to acute psychological stress. Therefore, in this randomized double-blind placebo-controlled study, we investigated the effect of treatment with two popular and clinically used pharmaceuticals on stress-related cortisol responses, namely acetylsalicylic acid (aspirin), a known prostaglandin synthesis inhibitor, and the beta-blocker propranolol (Inderal), a nonselective beta-receptor antagonist. Methods: For 5 days, 73 healthy subjects (50 men, 23 women; mean age 47.3 ± 7.7 years) received either a daily oral dose of 100 mg aspirin, 80 mg propranolol (Inderal), aspirin + propranolol, or placebo. After treatment, subjects were confronted with the Trier Social Stress Test, a widely-used standardized psychosocial stress protocol. Cortisol responses were measured by six saliva samples taken before and after the stress exposure. Results: Subjects showed a significant cortisol increase after stress (p < 0.0001). The four treatment groups did not differ in their cortisol responses (group effect p > 0.44; interaction p > 0.97). Additionally, controlling for gender, age, smoking status, body mass index, mean arterial blood pressure or pre-stress cortisol levels yielded similar results in the total sample as well as in the male or female subgroups, respectively. Conclusion: Neither short-term treatment with aspirin nor propranolol altered the acute free cortisol response to psychological stress in healthy adults.

Both α1 and α2‐adrenoceptors mediate the cardiovascular responses to noradrenaline microinjected into the bed nucleus of the stria terminal of rats

We have previously shown that noradrenaline microinjected into the bed nucleus of stria terminalis (BST) elicited pressor and bradycardiac responses in unanaesthetized rats. In the present study, we investigated the subtype of adrenoceptors that mediates the cardiovascular response to noradrenaline microinjection into the BST. Cardiovascular responses following noradrenaline microinjection into the BST of male Wistar rats were studied before and after BST pretreatment with different doses of the selective alpha(1)-adrenoceptor antagonist WB4101, the alpha(2)-adrenoceptor antagonist RX821002, the combination of WB4101 and RX821002, the non-selective beta-adrenoceptor antagonist propranolol, the selective beta(1)-adrenoceptor antagonist CGP20712 or the selective beta(2)-adrenoceptor antagonist ICI118,551. Noradrenaline microinjected into the BST of unanaesthetized rats caused pressor and bradycardiac responses. Pretreatment of the BST with different doses of either WB4101 or RX821002 only partially reduced the response to noradrenaline. However, the response to noradrenaline was blocked when WB4101 and RX821002 were combined. Pretreatment with this combination also shifted the resulting dose-effect curve to the left, clearly showing a potentiating effect of this antagonist combination. Pretreatment with different doses of either propranolol or CGP20712 increased the cardiovascular responses to noradrenaline microinjected into the BST. Pretreatment with ICI118,551 did not affect cardiovascular responses to noradrenaline. The present results indicate that alpha(1) and alpha(2)-adrenoceptors mediate the cardiovascular responses to noradrenaline microinjected into the BST. In addition, they point to an inhibitory role played by the activation of local beta(1)-adrenoceptors in the cardiovascular response to noradrenaline microinjected into the BST.

Use of β-Adrenoceptor Antagonists in Older Patients with Chronic Obstructive Pulmonary Disease and Cardiovascular Co-Morbidity

The incidence of and mortality from both chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) increase with age. In addition, the average age of patients with COPD and CVD is also increasing as a result of improvements in both pharmacological and non-pharmacological treatments. Coronary artery disease is a compelling indication for beta-adrenoceptor antagonist use in a population in whom beta-adrenoceptor antagonism is often viewed as contraindicated. beta-Adrenoceptor antagonists have been proven to improve cardiovascular morbidity and mortality but have been under-utilized in patients with COPD with concomitant CVD because of a fear of bronchoconstriction and adverse effects, particularly in the elderly. The advanced age of patients with COPD and CVD, along with the sheer number of patients with these diseases, necessitates that clinicians understand the treatment of these co-morbidities using seemingly conflicting therapy in the form of beta-adrenoceptor agonists and antagonists. We review changes in the pharmacokinetics and pharmacodynamics of beta-adrenoceptor antagonists in the elderly, the role of beta-adrenoceptor antagonists in CVD and the literature regarding the safety and mortality benefits of beta-adrenoceptor antagonists in elderly patients with COPD and concomitant CVD. We conclude that cardioselective beta-adrenoceptor antagonists appear to be safe to use in elderly male patients with mild-to-moderate COPD who have a compelling indication for beta-adrenoceptor antagonist therapy. Data in female patients are very limited. Nonselective beta-adrenoceptor antagonists should be avoided in general, except in patients with heart failure who might benefit significantly from the use of carvedilol. beta-Adrenoceptor antagonists have been shown to improve mortality in older patients with coexisting CVD and COPD.

Protective effects of carvedilol on ischemia–reperfusion injury in rat epigastric island skin flaps

Carvedilol, a selective alpha-1 and nonselective beta-adrenoceptor antagonist and potent antioxidant, has been shown to provide a significant decrease in neutrophil-mediated tissue injury. Epigastric skin flaps were elevated in rats, rendered ischemic for 10 h, and subsequently reperfused for 12 h. Forty rats were divided into four equal experimental groups: 1—nonischemic group, 2—ischemic saline control group, 3—ischemic control group without any vehicle treatment, and 4—drug-administered ischemic group. The effects of carvedilol on flap necrosis, neutrophil infiltration, and levels of malondialdehyde and nitric oxide in the flap tissue and serum were examined. The authors found that neutrophil numbers were significantly higher in the saline and nontreated groups. Additionally, serum and tissue levels of malondialdehyde were lower in the carvedilol-treated group, and serum nitric oxide was highest in the carvedilol-treated group. Carvedilol-treated animals had significantly lower areas of necrosis compared with controls. We conclude that administration of carvedilol before ischemia and reperfusion can significantly reduce the extent of flap necrosis and flap neutrophil counts because of ischemia–reperfusion injury.

Verrucotoxin, a stonefish venom, modulates calcium channel activity in guinea‐pig ventricular myocytes

Stonefish (Synanceia genus) are commonly found in shallow waters of the Pacific and Indian Oceans. The venom of stonefish is stored in the dorsal fine spines and contains a proteinaceous toxin, verrucotoxin (VTX). The stings produced by the spines induce intense pain, respiratory weakness, damage to the cardiovascular system, convulsions and paralysis, sometimes leading to death. Although there are many studies on VTX, the mechanism(s) underlying the VTX-mediated cardiotoxicity is not yet fully understood. The aim of this study was to investigate the modulation of ion channels in cardiac tissue by VTX. The effects of VTX on changes in the voltage or current in guinea-pig ventricular myocytes were investigated using a patch clamp method. VTX (10 microg ml(-1)) prolonged the action potential duration by 2.5-fold. VTX increased L-type Ca(2+) currents (I (Ca(L))) in a concentration-dependent manner with a EC(50) value of 7 microg ml(-1) and a maximum increase of 3.1-fold. The non-selective beta-adrenoceptor antagonist, propranolol (1 microM) and the selective beta(1)-adrenoceptor antagonist, CGP20712A (10 microM) each abolished the effect of VTX (100 microg ml(-1)) on I (Ca(L)). Furthermore, the protein kinase A (PKA) antagonists H-89 (10 microM) and Rp-8-Br-cAMPS (30 microM) inhibited the effect of VTX on I (Ca(L)). VTX modulates Ca(2+) channel activity through the beta-adrenoceptor-cAMP-PKA pathway.

The effects and selectivity of β-adrenoceptor agonists in rat myometrium and urinary bladder

Recent evidence supports a role for beta(3)-adrenoceptors in human non-pregnant and pregnant myometrium. The present study was designed to characterize the pharmacology of beta-adrenoceptors involved in the function of non-pregnant rat myometrium by comparison of the activity of several beta-adrenoceptor agonists and antagonists in isolated rat uterus and urinary bladder. Contractions of myometrial and detrusor strips were induced by adding 1 nM oxytocin and 15 mM KCl respectively. Cumulative concentration-response curves to the selective beta(3)-adrenoceptor agonists, CL 316243 and BRL 37344 and the selective beta(2)-adrenoceptor agonist ritodrine were obtained in the presence and absence of the selective beta(2)-adrenoceptor antagonist ICI 118551 and the non-selective beta-adrenoceptor antagonist bupranolol. Both BRL 37344 (pD(2)=6.79+/-0.09) and ritodrine (pD(2)=6.89+/-0.19) produced potent inhibition of oxytocin-induced contractions in myometrial strips; CL 316243 was inactive at concentrations up to 10 microM. Concentration effect curves to both BRL 37344 and ritodrine were shifted (10 to 30-fold) to the right in the presence of ICI 118551 (10 nM). BRL 37344 (pD(2)=8.51+/-0.21) and CL 316243 (pD(2)=8.61+/-0.24) produced potent inhibition of detrusor strips, while ritodrine was almost 100-fold less potent (pD(2)=5.83+/-0.17). The response to all agonists was significantly attenuated by pretreatment with bupranolol (10 microM), but only ritodrine was affected by ICI 118551 (1 microM). These results demonstrate that relaxation of rat myometrium is mediated by beta(2)-adrenoceptors while, consistent with previous reports, the beta(3)-subtype is primarily responsible for relaxation of rat detrusor.

Carvedilol, a nonselective β-blocker, suppresses the production of tumor necrosis factor and tissue factor by inhibiting early growth response factor-1 expression in human monocytes in vitro

Tumor necrosis factor (TNF) and tissue factor (TF) produced by monocytes and macrophages have been shown to be among the aggravating factors for chronic heart failure (CHF), because they induce cardiac dysfunction and thrombotic complications, respectively. Carvedilol, a nonselective beta-adrenoceptor antagonist with alpha(1)- adrenoceptor blockade action, has been demonstrated to improve the outcome of patients with severe CHF, suggesting that carvedilol might inhibit the production of TNF and TF. In this study, this possibility is examined using isolated human monocytes stimulated with lipopolysaccharide (LPS) in vitro. Carvedilol (10 muM) significantly inhibited LPS-induced production of TNF and TF by monocytes, whereas prazosin (a selective alpha(1)-adrenoceptor antagonist), bisoprolol (a selective beta(1)-adrenoceptor antagonist), ICI-118,551 (a selective beta(2)-adrenoceptor antagonist), and arotinolol (a nonselective beta-adrenoceptor antagonist with alpha(1)-adrenoceptor blockade action) did not. Carvedilol inhibited both expression of early growth response factor-1 (Egr-1) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, but it did not inhibit activation of either nuclear factor-kappaB or activator protein-1 in monocytes stimulated with LPS. These results suggest that carvedilol inhibits LPS-induced production of TNF and TF by inhibiting activation of the ERK1/2-Egr-1 pathway independent of its adrenoceptor inhibitory activities in monocytes.

Ocular Carteolol

Ocular carteolol (Mikelan), Teoptic, Ocupress) is a nonselective beta-adrenoceptor antagonist with intrinsic sympathomimetic activity (ISA). Ocular carteolol effectively reduces intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) or ocular hypertension (OH). Twice-daily administration of standard carteolol has generally similar IOP-lowering efficacy to other ocular beta-adrenoceptor antagonists such as timolol, betaxolol and metipranolol in patients with OAG or OH. In addition, long-term treatment with carteolol has similar efficacy to timolol and betaxolol in terms of reducing IOP and maintaining visual fields in patients with newly diagnosed primary OAG (POAG). The new long-acting formulation of once-daily carteolol has equivalent efficacy to the standard formulation of carteolol administered twice daily in patients with OAG or OH. Both the standard and long-acting formulations of ocular carteolol are generally well tolerated in terms of topical adverse effects involving the eyes or systemic adverse effects involving the cardiovascular system. Thus, twice-daily carteolol is a well established option in the treatment of glaucoma and OH, and the new once-daily formulation of long-acting carteolol offers similar efficacy and tolerability with a potential for improved patient adherence.

Prevention of recurrent haemorrhage

Patients who survive a first bleeding episode of oesophageal varices have a high risk of rebleeding, which is associated with a high mortality rate. Prevention of a recurrent haemorrhage is therefore recommended. Patients who were not on a primary prophylaxis should be treated with non-selective beta-adrenoceptor antagonists, endoscopic band ligation or both. If beta-blockers are not tolerated or are contraindicated, patients should be treated with endoscopic band ligation. If these preventive strategies fail, transjugular intrahepatic portosystemic shunt (covered) or a small-diameter surgical shunt is indicated.

Enaminones and norepinephrine employ convergent mechanisms to depress excitatory synaptic transmission in the rat nucleus accumbens in vitro

We recently reported that anticonvulsant anilino enaminones depress excitatory postsynaptic currents (EPSCs) in the nucleus accumbens (NAc) indirectly via gamma-aminobutyric acid (GABA) acting on GABA(B) receptors [S.B. Kombian et al. (2005)Br. J. Pharmacol., 145, 945-953]. Norepinephrine (NE) and dopamine (DA), both known to be involved in seizure disorders, also depress EPSCs in this nucleus. The current study explored a possible interaction between enaminones and adrenergic and/or dopaminergic mechanisms that may contribute to their synaptic depression and anticonvulsant effect. Using whole-cell recording in rat forebrain slices containing the NAc, we show that NE-induced, but not DA-induced, EPSC depression occludes E139-induced EPSC depressant effect. UK14,304, a selective alpha(2) receptor agonist, mimicked the synaptic effect of NE and also occluded E139 effects. Phentolamine, a non-selective alpha-adrenergic antagonist that blocked NE-induced EPSC depression, also blocked the E139-induced EPSC depression. Furthermore, yohimbine, an alpha(2)-adrenoceptor antagonist, also blocked the E139-induced EPSC depression, while prazosin, a selective alpha(1)-adrenergic antagonist, and propranolol, a non-selective beta-adrenoceptor antagonist, did not block the E139 effect. Similar to the E139-induced EPSC depression, the NE-induced EPSC depression was also blocked by the GABA(B) receptor antagonist, CGP55845. By contrast, however, neither SCH23390 nor sulpiride, D1-like and D2-like DA receptor antagonists, respectively, blocked the E139-induced synaptic depression. These results suggest that NE and E139, but not DA, employ a similar mechanism to depress EPSCs in the NAc, and support the hypothesis that E139, like NE, may act on alpha(2)-adrenoceptors to cause the release of GABA, which then mediates synaptic depression via GABA(B) receptors.

The Primary Amine Metabolite of Sibutramine Stimulates Lipolysis in Adipocytes Isolated from Lean and Obese Mice and in Isolated Human Adipocytes

Sibutramine is a satiety-inducing serotonin-noradrenaline reuptake inhibitor that acts predominantly via its primary and secondary metabolites. This study investigates the possibility that sibutramine and/or its metabolites could act directly on white adipose tissue to increase lipolysis. Adipocytes were isolated by a collagenase digestion procedure from homozygous lean (+/+) and obese-diabetic OB/OB mice, and from lean nondiabetic human subjects. The lipolytic activity of adipocyte preparations was measured by the determination of glycerol release over a 2-hour incubation period. The primary amine metabolite of sibutramine M2, caused a concentration-dependent stimulation of glycerol release by murine lean and obese adipocytes (maximum increase by 157+/-22 and 245+/-16%, respectively, p<0.05). Neither sibutramine nor its secondary amine metabolite M1 had any effect on lipolytic activity. Preliminary studies indicated that M2-induced lipolysis was mediated via a beta-adrenergic action. The non-selective beta-adrenoceptor antagonist propranolol (10 (-6) M) strongly inhibited M2-stimulated lipolysis in lean and obese murine adipocytes. M2 similarly increased lipolysis by isolated human omental and subcutaneous adipocytes (maximum increase by 194+/-33 and 136+/-4%, respectively, p<0.05) with EC50 values of 12 nM and 3 nM, respectively. These results indicate that the sibutramine metabolite M2 can act directly on murine and human adipose tissue to increase lipolysis via a pathway involving beta-adrenoceptors.

Carvedilol preserves endothelial junctions and reduces myocardial no-reflow after acute myocardial infarction and reperfusion

Introduction Myocardial no-reflow, has been associated with alterations in endothelial junctions, which is regulated in part by endothelial dysfunction. Carvedilol is an alpha1 and nonselective beta-adrenergic receptor antagonist with antioxidative properties known to protect endothelial function. Therefore, we hypothesized that carvedilol might also have protective effects on myocardial no-reflow and endothelial junctions. Methods Thirty-two mini-swines were randomized into 4 study groups: 8 in control, 8 pretreated with carvedilol (1 mg/kg/d) for 3 days, 8 in propranolol (nonselective beta-adrenergic receptor antagonist)-pretreated for 3 days and 8 in sham-operated. Acute myocardial infarction and reperfusion model was created with 3 h occlusion of the left anterior descending coronary artery followed by 1 h reperfusion. Coronary ligation area (LA) and area of no-reflow were determined with both myocardial contrast echocardiography (MCE) in vivo and pathological means (Path). Myocardial vascular endothelial (VE)-cadherin, beta-catenin and gamma-catenin were assessed by immunoblot. Results Compared with the control group, carvedilol significantly improved ventricular function, increased coronary blood flow from 50.6 ± 3.1% to 72.1 ± 3.8% of the baseline at 1 h of reperfusion ( P < 0.01), decreased area of no-reflow (MCE: from 78.5 ± 4.5% to 24.9 ± 4.1%, Path: from 82.3 ± 1.9% to 25.8 ± 4.3% of LA respectively, all P < 0.01), reduced necrosis area from 98.5 ± 1.3% to 74.4 ± 4.7% of LA ( P < 0.05). The levels of VE-cadherin, β-catenin, and γ-catenin in the reflow myocardium were significantly greater in the carvedilol group (all P < 0.05). However, propranolol failed to significantly modify area of no-reflow, VE-cadherin, β-catenin and γ-catenin levels (all P > 0.05). Conclusion Pretreatment with carvedilol preserves endothelial junctions and reduces myocardial no-reflow after acute myocardial infarction and reperfusion. The beneficial effect of carvedilol was not due to its β-blocking action.

Carvedilol-induced antagonism of angiotensin II: a matter of α1-adrenoceptor blockade

To investigate whether renin-angiotensin system blockade might underlie the favorable metabolic effects of the nonselective beta + alpha1-adrenoceptor blocker carvedilol as compared with the selective beta1-adrenoceptor blocker metoprolol. Human coronary microarteries (HCMAs), obtained from 32 heart valve donors, were mounted in myographs. Angiotensin II and the alpha1-adrenoceptor agonist phenylephrine constricted HCMAs to maximally 63 +/- 10 and 46 +/- 15% of the contraction to 100 mmol/l K. Neither carvedilol, metoprolol, the nonselective beta-adrenoceptor antagonist propranolol, nor the alpha1-adrenoceptor antagonist prazosin affected the constrictor response to angiotensin II. alpha1-adrenoreceptors and beta-adrenoceptors are thus not involved in the direct constrictor effects of angiotensin II. When added to the organ bath at a subthreshold concentration, angiotensin II greatly amplified the response to phenylephrine. Both carvedilol and the angiotensin II type 1 (AT1) receptor antagonist irbesartan inhibited this angiotensin II-induced potentiation. Furthermore, carvedilol blocked the angiotensin II-induced amplification of phenylephrine-induced inositol phosphate accumulation in cardiomyocytes. AT1-alpha1-receptor crosstalk, involving inositol phosphates, sensitizes HCMAs to alpha1-adrenoceptor agonists. Our results suggest that, in the presence of an increased sympathetic tone, carvedilol provides AT1 receptor blockade via its alpha1-adrenoceptor blocking effects. This could explain the favorable effects of carvedilol versus metoprolol.

Positive inotropic and lusitropic effects mediated via the low‐affinity state of β1‐adrenoceptors in pithed rats

1 Activation by CGP 12177 and cyanopindolol of the human and rat low-affinity state of beta(1)-adrenoceptors increases frequency and contractile force and hastens relaxation in isolated cardiac tissues, and probably relaxes isolated vessels. In order to identify the positive inotropic, positive lusitropic and vasodilator effects of both agonists also in vivo, we have determined their effects on the left ventricular systolic pressure (LVSP), the rate of intraventricular pressure rise (+dP dt(-1)(max)) and decline (-dP dt(-1)(max)), the diastolic blood pressure (DBP) and the mesenteric blood flow (MBF) in pithed and vagotomized rats. 2 CGP 12177 (0.1-100 nmol kg(-1)) and cyanopindolol (1-1000 nmol kg(-1)) dose-dependently enhanced all cardiac parameters. The nonselective beta-adrenoceptor antagonist bupranolol 10 micromol kg(-1) diminished the CGP 12177 (100 nmol kg(-1))-stimulated increases in LVSP from 26.3+/-8.2 to 13.1+/-1.8 mmHg (P<0.05), +dP dt(-1)(max) from 5287+/-290 to 2439+/-296 mmHg s(-1) (P<0.001) and -dP dt(-1)(max) from -3836+/-301 to -2187+/-443 mmHg s(-1) (P<0.05), respectively. The beta(1)-adrenoceptor antagonist CGP 20712A 10 micromol kg(-1) (known to block the low-affinity state of beta(1)-adrenoceptors at high doses) inhibited increases in +/-dP dt(-1)(max) elicited by the highest dose of CGP 12177. 3 The highest doses of CGP 12177 and cyanopindolol increased DBP by about 10 mmHg and MBF by 1.4+/-0.3 and 0.6+/-0.3 ml min(-1), respectively. The vascular effects of CGP 12177 were not affected by bupranolol and CGP 20712A. 4 In conclusion, activation of the low-affinity state of beta(1)-adrenoceptors by CGP 12177 and cyanopindolol in pithed rats causes a positive inotropic and lusitropic effect. By contrast, the vascular effects of CGP 12177 and cyanopindolol are not mediated by these receptors and have only marginal influence under in vivo conditions.

Central and peripheral components of the pressor effect of anandamide in urethane‐anaesthetized rats

1. We wanted to search for the mechanism(s) responsible for the brief pressor response induced by anandamide in urethane-anaesthetized rats. 2. The anandamide-induced pressor effect was not modified by the antagonists of cannabinoid CB(1) and vanilloid TRPV(1) receptors, SR 141716A (3 micromol kg(-1)) and capsazepine (1 micromol kg(-1)), respectively, by bilateral vagotomy and by pithing. Replacement of urethane by pentobarbitone virtually abolished the pressor effect of anandamide, both in pithed and vagotomized and in 'intact' rats (i.e. not treated in this manner). 3. The pressor effect of anandamide was reduced by the nonselective TRPV family inhibitor ruthenium red (3 micromol kg(-1)) and by the blocker of L-type calcium channels nifedipine (1 micromol kg(-1)), both in pithed urethane-anaesthetized rats and in 'intact' urethane-anaesthetized rats. The nonselective beta-adrenoceptor antagonist propranolol (0.1 or 0.3 micromol kg(-1)) and the nonselective NMDA receptor antagonist MK-801 (1 micromol kg(-1)) diminished the anandamide-induced vasopressor response in 'intact' but not in pithed rats. The inhibitory effect of propranolol in 'intact' rats was mimicked by the beta(2)-adrenoceptor antagonist ICI 118551 (1 micromol kg(-1)), but not by the beta(1)-adrenoceptor antagonist CGP 20712 (1 micromol kg(-1)). 4. The present study revealed that two mechanisms may be responsible for the anandamide-induced pressor response in urethane-anaesthetized rats. The first involves the central nervous system (probably the medulla oblongata) and is sensitive to propranolol and MK-801. The second, which is located peripherally (most probably in blood vessels), is sensitive to nifedipine, ruthenium red and pentobarbitone and, hence, probably represents a Ca(2+)-dependent mode of action.

Involvement of CB1-receptors and β-adrenoceptors in the regional hemodynamic responses to lipopolysaccharide infusion in conscious rats

A possible involvement of endocannabinoids in a chronic model of endotoxemia was assessed by measuring the regional (renal, mesenteric, hindquarters) hemodynamic responses to continuous 24-h LPS infusion (150 microg.kg(-1).h(-1)) in conscious, male Sprague-Dawley rats, in the absence or presence of the cannabinoid (CB1) receptor antagonist AM-251 (3 mg/kg). AM-251 inhibited the tachycardic and hindquarters vasodilator effects of LPS, but did not influence the other hemodynamic changes. In subsequent experiments, it was shown that the tachycardic and hindquarters vasodilator effects of LPS were also inhibited by the nonselective beta-adrenoceptor antagonist propranolol. In addition, the late (at 24 h) hindquarters vasodilator effects of LPS were inhibited by the beta2-adrenoceptor antagonist ICI-118551. Against the background of our previous work showing beta-adrenoceptor involvement in the cardiovascular effects of exogenous cannabinoids, we conclude that AM-251 may have been inhibiting endocannabinoid-modulated, sympathoadrenal-mediated activation of vasodilator beta-adrenoceptors in LPS-infused rats rather than suppressing a direct vasodilator action of endocannabinoids.

Age-dependent morphometrical changes in the thymus of male propranolol-treated rats

In order to elucidate a putative role of neurally derived noradrenaline in the thymus development, and in maintenance of adult thymus structure, sexually immature male rats (21-day-old at the beginning of treatment) and young adult animals (75-day-old on the beginning of treatment) were treated with the non-selective beta-adrenoceptor antagonist propranolol (0.40 mg/100 g BW/day, s.c.) for 15 consecutive days, and their thymuses were analyzed stereologically. The effects of beta-adrenoceptor blockade were much more pronounced in sexually immature than in adult rats. In immature propranolol-treated rats the thymus size and volumes of both the main compartments (cortex and medulla) were significantly decreased reflecting, at least partly, a reduction in the overall number of thymocytes. Furthermore, in both the cortical subcompartments (outer and deep cortex) the mean diameter of thymocytes was increased. However, in adult rats exposed to propranolol treatment, only the volume of interlobular connective tissue was enlarged, whereas in the outer part of the cortex the mean thymocyte diameter was increased. These results indicate that the lack of sympathetic input (via beta-adrenoceptors) during the prepubertal period of development diminishes the normal thymus growth and/or accelerates the thymic involution that starts at puberty, immediately after its maximum size is reached, while it is less significant for the maintenance of the thymus size and structure in adults. Additionally, they suggest that distinct cell types, as well as thymocyte subsets, are sensitive to lack of beta-adrenoceptor-mediated influences in sexually immature and adult rats.