Chronic Propranolol Research Articles

Rats with Postinfarction Heart Failure: Effects of Propranolol Therapy on Intracellular Calcium Regulation and Left Ventricular Function

Patients with heart failure may live longer if they receive chronic treatment with beta-adrenergic blocking medications. Unresolved are the mechanisms underlying the beneficial effects and if they may be applied to ischemic heart failure. Rats (n = 28) underwent echocardiographic-Doppler exams one and six weeks following a simulated operation or myocardial infarction (MI). After the first echocardiography, rats were randomized to either no therapy or 500 mg/l of propranolol in their drinking water. The noninfected left ventricular (LV) papillary muscles were used to record isometric contractions and intracellular Ca transients simultaneously. Untreated MI rats had a restrictive LV diastolic filling pattern, decreased systolic function (13% ± 2%), and significant LV dilatation (10.6 ± 0.4 mm vs. 8.9 ± 0.3 mm, MI vs. control). The LV chamber diameters of the propranolol-treated MI rats were 10.6 ± 0.5 mm, and systolic performance (13% ± 2%). Higher LV end-diastolic pressures (27 ± 2 mmHg vs. 20 ± 3 mmHg) and a more constrained LV diastolic filling pattern (increased ratio of early to late filling velocities and faster E wave deceleration rate) were seen in the propranolol-treated animals. Papillary muscle contractility in untreated MI rats was lower (1.6 ± 0.3 g mm²). Furthermore, the inotropic response to isoproterenol was attenuated, and Ca transients were extended. During isoproterenol stimulation, beta-adrenergic blocking administration had no effect on force development (1.6 ± 0.3 g mm²) or the length of Ca transients. Rats with postinfarction heart failure receiving chronic propranolol treatment did not have improvements in systolic function or LV remodeling. Propranolol exacerbated LV diastolic pressures and filling patterns. Additionally, there was no discernible improvement in intracellular contractility following treatment, Calcium control, or beta-adrenergic sensitivity in the myocardium that is not infarcted).

B-cell response to seasonal influenza vaccine in mice is amenable to pharmacological modulation through β-adrenoceptor

AimsGiven that deprivation of noradrenaline acting on lymphocytes through β-adrenoceptor influences antibody response, the effects of propranolol treatment beginning two days before immunization with quadrivalent inactivated influenza vaccine (QIV) on IgG response and underlying cellular molecular mechanism in mice were investigated. Main methodsTwenty-one days post-immunization the total QIV antigen-specific IgG titer and IgG subclass titers in sera were determined using ELISA. Additionally, the total counts of germinal centre (GC) B cells, T follicular helper (Tfh) and T follicular regulatory (Tfr) cells in draining lymph nodes (dLNs) and spleens, in vitro proliferation of interacting B cells and Th cells and IL-21 synthesis in Th cells in response to QIV antigens and/or mitogen were attested using flow cytometry analysis. In QIV antigen-stimulated dLN cell and splenocyte cultures were also measured concentrations of INF-γ and IL-4, cytokines upregulating IgG2a and IgG1 synthesis, respectively. Key findingsPropranolol decreased the total QIV antigen-specific IgG titer. This correlated with lower GC B cell count and the shift in Tfr/Tfh cell and Tfr/GC B cell ratio towards Tfr in propranolol-treated mice compared with controls. Consistently, QIV antigen-stimulated proliferation of B cells and Th cells from propranolol-treated mice in vitro was impaired. This correlated with the lower frequency of QIV antigen-specific IL-21-producing cells among Th cells. Additionally, in propranolol-treated mice, in accordance with the changes in INF-γ/IL-4 ratio in dLN cell/splenocyte cultures, serum IgG2a/IgG1 ratio was shifted towards IgG1 reflecting decreased IgG2a response. SignificanceThe study indicates that chronic propranolol treatment may impair response to QIV.

Chronic propranolol treatment moderately attenuated development of N-methyl-N-nitrosourea-induced mammary carcinoma in female rats.

The sympathetic nervous system participates in the development and progression of several cancer types and this effect is mediated mainly via β-adrenergic signaling. However, the potential of β-adrenergic signaling blockade to prevent cancer development after exposure to carcinogens has not been investigated, yet. Therefore, in our study, we determined the effect of the β-blocker propranolol on the development and progression of mammary cancer induced in female rats by administration of the chemical carcinogen N-methyl-N-nitrosourea (MNU). The propranolol treatment (20 mg/kg body weight) started 12 days after MNU administration and lasted 10 weeks. We found that both saline and propranolol treatment significantly increased gene expression of the catecholamine-synthesizing enzyme tyrosine hydroxylase, indicating that repeated injection of saline or propranolol-induced stress in these two groups. However, compared to the vehicle-treated group, propranolol slightly delayed the development and moderately reduced the incidence of mammary carcinoma in animals. To evaluate the mechanisms mediating the effect of propranolol on the development of MNU-induced cancer, we investigated several parameters of the tumor microenvironment and found that propranolol increased gene expression of Casp3. Our data indicate that propranolol treatment that starts after exposure to carcinogens might represent a new, useful approach for preventing the development of cancer, especially in stressed individuals. However, the potential efficiency of propranolol treatment for preventing cancer development and progression in individuals exposed to carcinogens needs further investigation.

\u03b2-Adrenoceptor blockade prevents carotid body hyperactivity and elevated vascular sympathetic nerve density induced by chronic intermittent hypoxia

Carotid body (CB) hyperactivity promotes hypertension in response to chronic intermittent hypoxia (CIH). The plasma concentration of adrenaline is reported to be elevated in CIH and our previous work suggests that adrenaline directly activates the CB. However, a role for chronic adrenergic stimulation in mediating CB hyperactivity is currently unknown. This study evaluated whether beta-blocker treatment with propranolol (Prop) prevented the development of CB hyperactivity, vascular sympathetic nerve growth and hypertension caused by CIH. Adult male Wistar rats were assigned into 1 of 4 groups: Control (N), N + Prop, CIH and CIH + Prop. The CIH paradigm consisted of 8 cycles h−1, 8 h day−1, for 3 weeks. Propranolol was administered via drinking water to achieve a dose of 40 mg kg−1 day−1. Immunohistochemistry revealed the presence of both β1 and β2-adrenoceptor subtypes on the CB type I cell. CIH caused a 2–3-fold elevation in basal CB single-fibre chemoafferent activity and this was prevented by chronic propranolol treatment. Chemoafferent responses to hypoxia and mitochondrial inhibitors were attenuated by propranolol, an effect that was greater in CIH animals. Propranolol decreased respiratory frequency in normoxia and hypoxia in N and CIH. Propranolol also abolished the CIH mediated increase in vascular sympathetic nerve density. Arterial blood pressure was reduced in propranolol groups during hypoxia. Propranolol exaggerated the fall in blood pressure in most (6/7) CIH animals during hypoxia, suggestive of reduced sympathetic tone. These findings therefore identify new roles for β-adrenergic stimulation in evoking CB hyperactivity, sympathetic vascular hyperinnervation and altered blood pressure control in response to CIH.

Propranolol Suppresses the T-Helper Cell Depletion-Related Immune Dysfunction in Cirrhotic Mice.

Bacterial translocation (BT) and splenomegaly contribute to cirrhosis-associated immune dysfunction (CAID) including T cell depletion, infection, and chronic inflammation. β-blockers have been reported to decrease BT and improve splenomegaly. This study explores the modulation of β1 and β2 adrenergic receptors (ADRB1/ADRB2) by propranolol treatment on the peripheral and splenic immune dysfunction of cirrhotic mice. In vivo experiments were performed in bile duct ligation (BDL)- and thioacetamide (TAA)-cirrhotic mice receiving two weeks of propranolol treatment. Acute effects of propranolol were evaluated in T-helper (Th) cells isolated from spleen of cirrhotic mice. Over-expression of β1 and β2 adrenergic receptors (ADRB1/ADRB2) in spleen and T lymphocytes was associated with high peripheral/splenic lipopolysaccharide binding protein levels. Moreover, a decrease in Th cells percentage, increase in Treg subset, and cytokines were accompanied by increased apoptosis, proliferation, and reduced white pulp hyperplasia in cirrhotic mice, which were counteracted by propranolol treatment. The Th-cell depletion, systemic inflammation, BT, and infection were improved by chronic propranolol treatment. Acute propranolol treatment inhibited apoptosis, Treg-conditioned differentiation, and promoted Th2-conditioned differentiation through ADRB-cyclic adenosine monophosphate (cAMP) signals in cirrhotic mice. In conclusion, suppression of ADRB1 and ADRB2 expressions in spleen and splenic T lymphocytes by acute and chronic propranolol treatment ameliorate systemic and splenic immune dysfunction in cirrhosis.

Regulator of G Protein Signaling 6 Protects the Heart from Ischemic Injury.

Gαi-coupled receptors play important roles in protecting the heart from ischemic injury. Regulator of G protein signaling (RGS) proteins suppress Gαi signaling by accelerating the GTPase activity of Gαi subunits. However, the roles of individual RGS proteins in modulating ischemic injury are unknown. In this study, we investigated the effect of RGS6 deletion on myocardial sensitivity to ischemic injury. Hearts from RGS6 knockout (RGS6-/-) and RGS6 wild-type (RGS6+/+) mice were subjected to 30 minutes of ischemia and 2 hours of reperfusion on a Langendorff heart apparatus. Infarcts in RGS6-/- hearts were significantly larger than infarcts in RGS6+/+ hearts. RGS6-/- hearts also exhibited increased phosphorylation of β2-adrenergic receptors and G protein-coupled receptor kinase 2 (GRK2). Mitochondrial GRK2 as well as caspase-3 cleavage were increased significantly in RGS6-/- hearts compared with RGS6+/+ hearts after ischemia. Chronic propranolol treatment of mice prevented the observed increases in ischemic injury and the GRK2 phosphorylation observed in RGS6-/- hearts. Our findings suggest that loss of RGS6 predisposes the ventricle to prodeath signaling through a β2AR-GRK2-dependent signaling mechanism, and they provide evidence for a protective role of RGS6 in the ischemic heart. Individuals expressing genetic polymorphisms that suppress the activity of RGS6 may be at increased risk of cardiac ischemic injury. Furthermore, the development of agents that increase RGS6 expression or activity might provide a novel strategy for the treatment of ischemic heart disease.

β2-Adrenoceptor involved in smoking-induced airway mucus hypersecretion through β-arrestin-dependent signaling.

Progression of chronic obstructive pulmonary disease is associated with small airway obstruction by accumulation of inflammatory mucous exudates. However, the mechanism of mucin hypersecretion after exposure to cigarette smoke (CS) is still not clear. In this study, we explored the contribution of β2-adrenoceptor (β2-AR) signaling to CS extract (CSE)-induced mucus hypersecretion in vitro and examined the effect of a β-blocker on airway mucin hypersecretion in vivo. NCI-H292 epithelial cell line was used to determine the contribution of β2-AR signaling to CSE-induced MUC5AC production by treatment with β2-AR antagonists propranolol and ICI118551 and β2-AR-targeted small interfering RNA. The effect of propranolol on airway mucus hypersecretion was examined in a rat model exposed to CS. MUC5AC expression was assayed by real-time PCR, immunohistochemistry and ELISA. β2-AR and its downstream signaling were detected by western blot analysis. We found that pretreating NCI-H292 cells with propranolol, ICI118551 for 30 min or β2AR–targeted siRNA for 48 h reduced MUC5AC mRNA and protein levels stimulated by CSE. However,inhibiting the classical β2AR–cAMP-PKA pathway didn’t attenuate CSE-induced MUC5AC production, while silencing β-arretin2 expression significantly decreased ERK and p38MAPK phosphorylation, thus reduced the CSE-stimulated MUC5AC production. In vivo, we found that administration of propranolol (25 mg kg−1d−1) for 28 days significantly attenuated the airway goblet cell metaplasia, mucus hypersecretion and MUC5AC expression of rats exposed to CS. From the study, β2-AR–β-arrestin2–ERK1/2 signaling was required for CS-induced airway MUC5AC expression. Chronic propranolol administration ameliorated airway mucus hypersecretion and MUC5AC expression in smoking rats. The exploration of these mechanisms may contribute to the optimization of β2-AR target therapy in chronic obstructive pulmonary disease.

Propranolol modulates the collateral vascular responsiveness to vasopressin via a Gα-mediated pathway in portal hypertensive rats

Gastro-oesophageal variceal haemorrhage is one of the most dreadful complications of portal hypertension and can be controlled with vasoconstrictors. Nevertheless, sympathetic tone abnormality and vascular hyporesponsiveness in portal hypertension may impede the haemostatic effects of vasoconstrictors. Propranolol, a β-blocker binding the G-protein-coupled adrenoceptor, is a portal hypotensive agent. However, whether propranolol influences the collateral vasoresponse is unknown. Portal hypertension was induced by PVL (portal vein ligation) in Sprague-Dawley rats. In an acute study with an in situ perfusion model, the collateral responsiveness to AVP (arginine vasopressin) was evaluated with vehicle, propranolol (10 μmol/l), propranolol plus suramin (100 μmol/l, a G(α) inhibitor) or suramin pre-incubation. G(α) mRNA expression in the splenorenal shunt, the most prominent intra-abdominal collateral vessel, was measured. In the chronic study, rats received DW (distilled water) or propranolol (10 mg x kg(-1) of body weight x day(-1)) for 9 days. Then the concentration-response relationship of AVP and G(α) mRNA expression were assessed. Propranolol pre-incubation elevated the perfusion pressure changes of collaterals in response to AVP, which was inhibited by suramin. The splenorenal shunt G(αq) and G(α11) mRNA expression were enhanced by propranolol. The group treated with propranolol plus suramin had a down-regulation of G(α11) as compared with the propranolol group. Chronic propranolol treatment reduced mean arterial pressure, PP (portal pressure) and the perfusion pressure changes of collaterals to AVP. G(αs) expression was up-regulated. In conclusion, propranolol pre-incubation enhanced the portal-systemic collateral AVP responsiveness in portal hypertensive rats, which was related to G(αq) and G(α11) up-regulation. In contrast, the attenuated AVP responsiveness by chronic propranolol treatment was related to G(αs) up-regulation. The G(α) signalling pathway may be a therapeutic target to control variceal bleeding and PP in portal hypertension.

Behavioral and Cellular Modulation of l-DOPA-Induced Dyskinesia by β-Adrenoceptor Blockade in the 6-Hydroxydopamine-Lesioned Rat

Chronic dopamine replacement therapy in Parkinson's disease (PD) leads to deleterious motor sequelae known as L-DOPA-induced dyskinesia (LID). No known therapeutic can eliminate LID, but preliminary evidence suggests that dl-1-isopropylamino-3-(1-naphthyloxy)-2-propanol [(±)propranolol], a nonselective β-adrenergic receptor (βAR) antagonist, may reduce LID. The present study used the rat unilateral 6-hydroxydopamine model of PD to characterize and localize the efficacy of (±)propranolol as an adjunct to therapy with L-DOPA. We first determined whether (±)propranolol was capable of reducing the development and expression of LID without impairing motor performance ON and OFF L-DOPA. Coincident to this investigation, we used reverse-transcription polymerase chain reaction techniques to analyze the effects of chronic (±)propranolol on markers of striatal activity known to be involved in LID. To determine whether (±)propranolol reduces LID through βAR blockade, we subsequently examined each enantiomer separately because only the (-)enantiomer has significant βAR affinity. We next investigated the effects of a localized striatal βAR blockade on LID by cannulating the region and microinfusing (±)propranolol before systemic L-DOPA injections. Results showed that a dose range of (±)propranolol reduced LID without deleteriously affecting motor activity. Pharmacologically, only (-)propranolol had anti-LID properties indicating βAR-specific effects. Aberrant striatal signaling associated with LID was normalized with (±)propranolol cotreatment, and intrastriatal (±)propranolol was acutely able to reduce LID. This research confirms previous work suggesting that (±)propranolol reduces LID through βAR antagonism and presents novel evidence indicating a potential striatal locus of pharmacological action.

Chronic treatment with propranolol does not alter sympathetic and cardiovagal baroreflex sensitivity in the Postural Orthostatic Tachycardia Syndrome

Patients with Postural Orthostatic Tachycardia Syndrome (POTS) have marked increases in heart rate (HR) during orthostasis, while β‐blocker is commonly used to reduce tachycardia. We tested the hypothesis that chronic β‐blocker treatment alters baroreflex sensitivity in POTS. Eighteen POTS patients (age 16–44) were treated with placebo (n=10) or propranolol (n=8, 80 mg qd) for 1 mo. Sympathetic baroreflex sensitivity was quantified by 1) linear correlation between muscle sympathetic nerve activity (MSNA) and stroke volume supine and during a graded upright tilt, and 2) relating sympathetic bursts to the fall of diastolic blood pressure (BP) during Valsalva (VAL). Cardiovagal baroreflex sensitivity was assessed during early phase II (decreasing BP) and phase IV (increasing BP) of VAL. Patients’ quality of life was evaluated using SF‐36 form. Propranolol decreased upright HR but had limited impacts on MSNA. Sympathetic baroreflex sensitivity remained unchanged after propranolol treatment [−1.04±0.40 bursts/min/mL pre vs −0.99±0.33 post, P=0.78; −0.97±0.30 bursts/20s/mmHg pre vs −1.01±0.33 post, P=0.69). Cardiovagal baroreflex sensitivity during decreasing BP (5.05±3.58 ms/mmHg pre vs 5.75±2.03 post, P=0.44) and during increasing BP (14.23±7.59 ms/mmHg vs 13.05±4.43; P=0.92) of VAL was comparable before and after propranolol treatment. Patients’ quality of life remained unchanged after treatment. Placebo had no effects on any variables measured. These results suggest that chronic propranolol treatment decreased tachycardia but did not alter baroreflex sensitivity in POTS patients. Patients’ quality of life was not improved by propranolol. More effective therapies to improve not only symptoms but also patients’ overall well‐being are needed.

Severe Hypoglycemia During Successful Treatment of Diffuse Hemangiomatosis with Propranolol

A 27-day-old male infant with diffuse hemangiomatosis of the skin and liver was treated with oral propranolol at a dosage of 2 mg/kg per day. Five months later skin and liver hemangiomas regressed almost completely. After 160 days of onset of propranolol, the patient presented with seizures on waking up. Laboratory examinations showed blood glucose of 15 mmol (n.v. 50-110) and increased ketone bodies. Propranolol was recommenced at a lower dosage the day after the crisis and then withdrawn when the baby was aged ten months. Hypoglycemia is the most frequent and insidious side effect of propranolol, mainly occurring in circumstances with diminished oral intake. Although the risk appears small, increased vigilance for hypoglycemia in children on chronic propranolol treatment who have decreased caloric intake for any reason seems prudent.

Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3

AimsClinical observations in patients with long QT syndrome carrying sodium channel mutations (LQT3) suggest that bradycardia caused by parasympathetic stimulation may provoke torsades de pointes (TdP). β-Adrenoceptor blockers appear less effective in LQT3 than in other forms of the disease.Methods and resultsWe studied effects of autonomic modulation on arrhythmias in vivo and in vitro and quantified sympathetic innervation by autoradiography in heterozygous mice with a knock-in deletion (ΔKPQ) in the Scn5a gene coding for the cardiac sodium channel and increased late sodium current (LQT3 mice). Cholinergic stimulation by carbachol provoked bigemini and TdP in freely roaming LQT3 mice. No arrhythmias were provoked by physical stress, mental stress, isoproterenol, or atropine. In isolated, beating hearts, carbachol did not prolong action potentials per se, but caused bradycardia and rate-dependent action potential prolongation. The muscarinic inhibitor AFDX116 prevented effects of carbachol on heart rate and arrhythmias. β-Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. β-Adrenoceptor density was reduced in LQT3 hearts. Acute β-adrenoceptor blockade by esmolol, propranolol or chronic propranolol in vivo did not suppress arrhythmias. Chronic flecainide pre-treatment prevented arrhythmias (all P < 0.05).ConclusionCholinergic stimulation provokes arrhythmias in this model of LQT3 by triggering bradycardia. β-Adrenoceptor density is reduced, and β-adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and β-adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.

Chronic propranolol treatment affects expression of adrenoceptors on peritoneal macrophages and their ability to produce hydrogen peroxide and nitric oxide

Using both immunocytochemical and flow cytometric analyses of rat peritoneal exudate cells constitutive expression of tyrosine hydroxylase and both β 2- and α 1- adrenoceptors on macrophages was revealed. Furthermore, according to the characteristic assemblage of tyrosine hydroxylase and adrenoceptor subtype expression different macrophage subsets were identified. In vitro treatment of macrophages with the non-selective α,β-adrenoceptor agonist arterenol and/or the β-adrenoceptor antagonist propranolol indicated that β-adrenoceptors potentiated nitric oxide (NO) production and suggested α-adrenoceptor-mediated suppression of hydrogen peroxide (H 2O 2) production. An increase in H 2O 2 production in the presence of the α 1-adrenoceptor antagonist ebrantil provided support for this. Chronic propranolol treatment in vivo led to increased NO and H 2O 2 production by peritoneal macrophages. Furthermore, this treatment resulted in opposing effects on the expression of β 2- and α 1-adrenoceptors on peritoneal macrophages (a stimulatory effect on β 2-adrenoceptors and a suppressive effect on α 1-adrenoceptors). In conclusion, a subset of resident peritoneal macrophages synthesizes catecholamines, which may exert differential effects on H 2O 2 and NO production via distinct adrenoceptors. Finally, chronic propranolol treatment affected adrenoceptor expression on peritoneal macrophages and altered their capacity to generate NO and H 2O 2.

Physiological and Reproductive Effects of Beta Adrenergic Receptor Antagonists in Daphnia magna

Although pharmaceuticals are increasingly found in surface waters, environmental levels of many of these compounds are not acutely toxic to model test organisms. Prior to conducting appropriate ecological risk assessments of pharmaceuticals, the mode of action-based biomarkers needs to be developed for non-target species. To evaluate toxicity of the beta-adrenergic blockers propranolol and metoprolol on non-target biota, we assessed standard ecotoxicological endpoints after 9 days of subchronic exposure in a transgenerational study with Daphnia magna. On day 9 of exposure, the lowest observed effects concentration (LOEC) for growth were 0.44 mg L(-1) for propranolol and 12 mg L(-1) for metoprolol. Total fecundity LOECs for the 9-day exposure were 0.11 mg L(-1) and 6 mg L(-1) for propranolol and metoprolol, respectively. In addition to typical ecotoxicological endpoints, we evaluated the utility of employing the physiological biomarkers of heart rate and metabolic rate following subchronic and acute exposures to propranolol and metoprolol. Propranolol and metoprolol LOECs for heart rate were 0.055 mg L(-1) and 3.1 mg L(-1), significantly lower than the LOECs for growth and reproduction. At these concentrations, heart rate was significantly lower than the control values for both compounds. Daphnia magna endpoint sensitivity to chronic propranolol and metoprolol exposure was mortality < growth < fecundity < heart rate. Second generation D. magna were less sensitive to both compounds. Responses of the physiological biomarkers heart rate and metabolic activity suggest that propranolol and metoprolol exerts sublethal toxicity to D. magna at lower concentrations than observed in the classical endpoints.

CHRONIC PROPRANOLOL TREATMENT CAUSES DESENSITIZATION OF THE STEROIDOGENIC RESPONSE IN TESTICULAR INTERSTITIAL CELLS BUT DOES NOT ALTER PROTEIN KINASE C

We investigated effects of chronic propranolol treatment on the secretory response of rat testicular interstitial cells (testosterone secretion) to subsequent in vitro stimulation with activators of protein kinase-C (PK-C) (L-propranolol, phorbol 12, 13-dibutyrate (PDBu), LHRH) or activators of protein kinase A (PK-A), (hCG or dibutyryl cAMP (dbcAMP)). We determined [3H]PDBu binding and PK-C activity in these cells. Treatment of rats with propranolol (Inderal 500 mg/L of water for 5 weeks) reduced by 48%, 50% and 29% the L-propranolol-, LHRH- or PDBu-induced testosterone secretion, respectively, when compared to cells from controls. This desensitization in testosterone secretion in vitro was also present when the testicular interstitial cells were stimulated with hCG or dbcAMP (secretion decreased by 65%/57%, respectively, when compared to cells from control rats). Challenging the cells originated from rats that received propranolol chronically with the addition in vitro of propranolol resulted in an additional reduction of the hCG/dbcAMP-stimulated testosterone secretion. Chronic propranolol-induced desensitization was not associated with a loss in [3H]PDBu binding or a decrease in PK-C activity. Chronic propranolol-induced desensitization can be uncoupled from down-regulation of protein kinase C. The effector responsible for the desensitization could be distal to the protein kinase C and protein kinase A.

Low doses of isosorbide mononitrate attenuate the postprandial increase in portal pressure in patients with cirrhosis

Postprandial hyperemia is associated with a significant increase in portal pressure in cirrhosis, which may contribute to progressive dilation and rupture of gastroesophageal varices. In cirrhosis, an insufficient hepatic production of nitric oxide (NO) may impair the expected hepatic vasodilatory response to increased blood flow, further exaggerating the postprandial increase in portal pressure. This study was aimed at investigating whether low doses of an oral NO donor might counteract the postprandial peak in portal pressure. Twenty-three portal hypertensive cirrhotics, 8 of them under propranolol therapy, were randomized to receive orally 5-isosorbide mononitrate (ISMN; 10 mg; n = 11) or placebo (n = 12) and a standard liquid meal 15 minutes later. Hepatic venous pressure gradient (HVPG), mean arterial pressure (MAP), and hepatic blood flow (HBF) were measured at baseline and 15, 30, and 45 minutes after a meal. ISMN significantly attenuated the postprandial increase in portal pressure as compared with placebo (peak HVPG increase: 2.4 ± 1.4 mm Hg vs. 5.2 ± 2.1 mm Hg, P = .002). Percentual increases in HBF were similar in both groups. MAP decreased slightly in ISMN group (−7.5% ± .5%; P < .01 vs. baseline). These effects were also observed in patients on chronic propranolol therapy. In conclusion, hepatic NO supplementation by low doses of ISMN effectively reduces the postprandial increase of portal pressure in cirrhosis, with only a mild effect on arterial pressure. The same was observed in patients receiving propranolol. Our results suggest that therapeutic strategies based on selective hepatic NO delivery may improve the treatment of portal hypertension. (H EPATOLOGY 2003;37:378-384.)

Effects of long-term propranolol and octreotide on postprandial hemodynamics in cirrhosis: A randomized, controlled trial

Postprandial increases in portal pressure may influence esophageal variceal rupture. The effects of chronic propranolol and octreotide (100 and 200 microg subcutaneously in a single dose) on postprandial hemodynamics were evaluated. FIRST STUDY: 36 cirrhotic patients were studied at baseline and 30 and 60 minutes after a standard meal and then treated with propranolol (139 +/- 9 mg/d during 39 +/- 2 days). SECOND STUDY: After baseline measurements, patients were randomized into 3 groups: (1) placebo, (2) octreotide (100 microg), or (3) octreotide (200 microg) (n = 12 for each group). Thirty minutes postinjection a new baseline was established and measurements were repeated 30 and 60 minutes after the meal. First study: Baseline portal pressure was 18.1 +/- 1.2 mm Hg, 30 and 60 minutes after the meal it was 21.5 +/- 0.8 mm Hg and 20.5 +/- 0.8 mm Hg, respectively (both P < 0.01 vs. baseline). Cardiac index (CI) was 4.5 +/- 0.2, 4.8 +/- 0.2, and 4.9 +/- 0.2 L x min(-1) x m(-2), respectively (both P < 0.05 vs. baseline). Peripheral vascular resistance was 1012 +/- 56, 902 +/- 51 (P = NS), and 884 +/- 49 dynes x sec x cm(-5) (P< 0.05 vs. baseline), respectively. Second study: Propranolol and placebo did not blunt postprandial increase in portal pressure. Octreotide (100 microg) partially ameliorated postprandial increase in portal pressure. Octreotide (200 microg) significantly enhanced the portal hypotensive effect of propranolol and blunted the postprandial increase in portal pressure. Octreotide blunts postprandial increase in portal pressure not prevented by long-term propranolol administration.

Effectiveness of low dose Captopril versus Propranolol therapy in infants with severe congestive failure due to left-to-right shunts

To evaluate the therapeutical effects of the angiotensin converting enzyme inhibitor Captopril to the beta-blocker Propranolol in infants with congestive failure due to pulmonary overcirculation, we retrospectively analysed clinical, neurohormonal and hemodynamic data in 22 infants, 11 of whom were treated with Captopril (Group 1), 11 with Propranolol (Group 2). Age, weight, number of palliative operations, plasma renin activities and pulmonary to systemic flow ratios (3.5 vs. 3.5) were not significantly different prior to Captopril or Propranolol therapy. If treatment with digoxin and diuretics did not succeed, the infants were additionally treated with Captopril (1 mg/kg) for a mean of 7.4 months, or with 1.9 mg/kg Propranolol for 9.2 months. Results: 1 mg/kg Captopril did not effectively suppress angiotensin converting enzyme in the steady state at trough level (92±52 vs. 87±50 nmol/min/ml). In the Propranolol group, the clinical heart failure score (2.6±1.5 vs. 7.4±2.5) and plasma renin activities (14±10 vs. 101±70 ng/ml/h) were significantly lower, compared to the Captopril group. Length of hospital stay (23±9 vs. 52±24 days) was lower and weight gain (126±38 vs. 86±84 g/week) was higher within 3 months after starting Propranolol therapy. Significantly lower left atrial pressures (6.2±2.2 vs. 13.4±9.2 mmHg) and lower endiastolic ventricular pressures (7.6±2.5 vs. 12.6±4.0 mmHg) during pre-operative cardiac catheterization indicated a better diastolic ventricular function under chronic Propranolol treatment. Conclusion: Although high dose Captopril was not evaluated in this study, when compared to patients on low Captopril dosages, infants who received Propranolol treatment showed improvement in heart failure scores, shorter lengths of hospital stay, lower plasma renin activities and better diastolic ventricular functions.

Chronic Propranolol Induces Deficits in Retention but Not Acquisition Performance in the Water Maze in Mice

Agents that alter adrenergic receptors, such as “beta-blockers,” also alter memory storage. However, reports suggest that beta-adrenergic receptor antagonists, such as propranolol, have conflicting behavioral effects with acute vs chronic dosing. This study was designed to evaluate the effects of chronic propranolol on retention for a spatial learning task. Adult male ICR mice were given daily injections of propranolol (2, 4, 8, or 12 mg/kg ip) or 0.9% NaCl for 15 days prior to, and during, trials in a Morris water maze. Mice received five massed acquisition (escape) trials in each of three daily sessions, followed by a single 60-s probe trial on the fourth day. The location of the submerged platform was constant for each animal over acquisition trials, but varied across animals; starting position varied across trials. A 5 (dose) × 3 (trial blocks) mixed factorial ANOVA for escape time yielded a significant trial blocks effect only (p < .001), showing performance improving over sessions. Time spent in the target quadrant on the probe trial was shorter under all doses of propranolol when compared to vehicle group (all p < .001), indicating poorer retention of prior platform location. This effect, however, was not dose-related. Swim speed was not significantly affected by propranolol. These data demonstrate that chronic dosing with propranolol can impair retention of spatial learning, which cannot be attributed to reduced arousal or motor function.

Beta-adrenergic receptor signaling: an acute compensatory adjustment-inappropriate for the chronic stress of heart failure? Insights from Gsalpha overexpression and other genetically engineered animal models.

Under normal physiological conditions, the heart must be able to increase its output 5-fold to supply the required blood flow to the coronary circulation and skeletal muscles during severe stress. This is normally met by ≈5-fold increases in myocardial contractility, ≈3-fold increases in heart rate, and additional increases in stroke volume.1 This increased load requires a commensurate increase in myocardial blood flow, because oxygen extraction across the heart is nearly complete, even under normal conditions. Accordingly, the design of the cardiovascular system evolved to conserve myocardial metabolic demand, and consequently coronary blood flow, at rest, but with considerable reserve that can be called on rapidly in times of stress. There is a host of compensatory adjustments, including changes in metabolic substrates and kinetics, as well as oxygen-carrying capacity, that may be recruited in response to stress. However, none is more important than the autonomic nervous system in general, and the sympathetic arm in particular, in terms of providing large, rapid changes in cardiac function. When this compensatory mechanism is unavailable, eg, after treatment with propranolol, the 3-fold increases in heart rate and 5-fold increases in myocardial contractility in response to exercise cannot be achieved.1 In this connection, it is recognized that heart failure is a state characterized by enhanced sympathetic tone, but when the failing myocardium is challenged by β-adrenergic stimulation in vivo or in vitro, the most frequent result is β-adrenergic downregulation or desensitization.2 3 4 5 An impairment of cardiac function leads to autocrine, paracrine, and neurohormonal adjustments, including a strong sympathetic component (Figure 1⇓); under acute conditions, these reflex adjustments are beneficial, as noted above. However, when the sympathetic nervous system is chronically and tonically stimulated, as occurs in the pathogenesis of heart failure, desensitization mechanisms are called into play, such that the …