Chronic Propranolol Treatment 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.

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.

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.

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.

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.

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.

Differential effects of chronic propranolol treatment on the phenotypic profile of thymocytes from immature and adult rats

To elucidate a putative role of β-adrenoceptors in the modulation of intrathymic T-cell maturation, the expression of major differentiational antigens (CD4/CD8 and TCRαβ) on the thymocytes from both immature (aged 21 day at the beginning of the treatment) and adult (aged 75 days at the beginning of treatment) male rats subjected to a 15-day-long propranolol treatment (0.40 mg/100 g/day, s.c.) was analyzed by two- and one-color flow cytometry, respectively. Rats of matched age injected with saline served as controls. The propranolol treatment in immature but not adult rats caused a significant reduction in both the relative thymus weight and total thymocyte yield. In addition, a significant increase in the percentage of CD4+8+ double-positive cells, with a proportional decrease in the relative proportion of CD4+8− single positive cells, was found in immature rats. In contrast, a slight but significant decrease in the percentage of CD4+8+ cells with a parallel increase in the relative proportion of CD4+8− cells was found in adult rats. In both groups of rats, the percentage of TCRαβtotal thymocytes was increased: in immature rats this was due to an increase in the percentage of TCRαβlow thymocytes, while in the adult rats it reflected a rise in the relative proportion of TCRαβhigh cells. In conclusion, the study revealed that propranolol treatment in both immature and adult rats alters the relative proportion of CD4+8+ and CD4+8− thymocytes, but in opposite fashion, and the data suggest that this treatment affects distinct fractions within the population of CD4+8+ thymocytes with respect to expression of TCRαβ. The results also indicate that, regardless of rat sexual maturity, the development of thymocytes towards CD4−8+ T-cells is relatively insensitive to long-lasting β-adrenoceptor blockade.

Effects of propranolol treatment on left ventricular function and intracellular calcium regulation in rats with postinfarction heart failure.

1. Chronic treatment with beta-adrenergic blocking agents can improve survival in patients with heart failure. The mechanisms underlying the beneficial effects and whether these effects are generalizable to ischaemic heart failure are unresolved. 2. We performed echocardiographic-Doppler examinations in rats (n=28) 1 and 6 weeks after myocardial infarction (MI) or sham surgery. Rats were randomized to no treatment or propranolol (500 mg/l in drinking water) after the first echocardiogram. Isometric contractions and intracellular Ca transients were recorded simultaneously in noninfarcted left ventricular (LV) papillary muscles. 3. Untreated MI rats had significant LV dilatation (10.6+/-0.4* vs 8.9+/(-0.3) mm, MI vs control), impaired systolic function (fractional shortening=11+/-2* vs 38+/-2%), and a restrictive LV diastolic filling pattern. MI rats receiving propranolol had similar LV chamber sizes (10.6+/(-0.5) mm) and systolic function (13+/(-2%). The propranolol treated animals had higher LV end-diastolic pressures (27+/-2* vs 20+/(-3 mmHg) and a more restricted LV diastolic filling pattern (increased ratio of early to late filling velocities and more rapid E wave deceleration rate). Contractility of papillary muscles from untreated MI rats was depressed (1.6+/(-0.3) vs 2.4+/(0.5 g mm(-2). In addition, Ca transients were prolonged and the inotropic response to isoproterenol was blunted. Propranolol treatment did not improve force development (1.6+/(-0.3 g mm(-2) or the duration of Ca transients during isoproterenol stimulation. 4. Chronic propranolol treatment in rats with postinfarction heart failure did not improve LV remodeling or systolic function. LV diastolic pressures and filling patterns were worsened by propranolol. Treatment also did not produce appreciable improvement in contractility, intracellular Ca regulation or beta-adrenergic responsiveness in the noninfarcted myocardium.

Duplex‐Doppler evaluation of the effects of propranolol and isosorbide‐5‐mononitrate on portal flow and splanchnic arterial circulation in cirrhosis

A decrease in portal flow is an important pharmacological effect of drugs used for the prophylaxis of variceal bleeding. To assess the acute and chronic effects of propranolol, and the effect of the acute addition of isosorbide-5-mononitrate, on splanchnic circulation. Measurements of portal blood flow volume (PBFV) and of Doppler ultrasound pulsatility index of the superior mesenteric, femoral and interlobar renal arteries were performed in 10 cirrhotic patients with varices at baseline, 90 min after propranolol or placebo, after 30 days of chronic propranolol treatment and 45 min after the addition of isosorbide-5-mononitrate. The mean PBFV was significantly lower at all times than at baseline, with the greatest mean percentage decrease achieved after the addition of isosorbide-5-mononitrate (> or = 20% in all patients). Acute changes, however, did not predict the chronic effects in many patients. Isosorbide-5-mononitrate significantly increased the mesenteric and femoral pulsatility indices, whereas no significant change was observed in the kidney. Propranolol significantly decreases PBFV, but chronic effects cannot be reliably predicted by the acute change. All patients achieved a decrease in PBFV of > or = 20% after the acute addition of isosorbide-5-mononitrate to chronic propranolol treatment.

Effects of beta-adrenergic blockade on papillary muscle function and the beta-adrenergic receptor system in noninfarcted myocardium in compensated ischemic left ventricular dysfunction.

beta-Adrenergic receptor blockade has been reported to improve hemodynamics and beta-adrenergic receptor-adenylate cyclase function in idiopathic dilated cardiomyopathy. The purpose of this study was to determine the effects of beta-adrenergic receptor blockade on the beta-adrenergic receptor system and myocardial function in a model of compensated ischemic heart failure. We examined the effects of propranolol treatment on the beta-adrenergic receptor-adenylate cyclase system and isolated papillary muscle isometric function in noninfarcted left ventricular myocardium in rats after coronary artery ligation. In untreated rats with large myocardial infarction (MI), developed tension (DT) (3.0 +/- 0.7 versus 5.1 +/- 1.1 g/mm2), peak rate of tension rise (+dT/dt) (40.3 +/- 9.5 versus 71.2 +/- 12.0 g/mm2/sec), and peak rate of tension fall (-dT/dt) (24.4 +/- 5.0 versus 38.2 +/- 6.0 g/mm2/sec) were decreased (p < 0.05). In addition, DT, +dT/dt, and -dT/dt of untreated MI rats demonstrated an impaired response to isoproterenol stimulation compared with controls. beta-Adrenergic receptor density (Bmax) measured by [125I]iodocyanopindolol (ICYP) binding was decreased 23% after infarction (9.3 +/- 0.6 versus 12.0 +/- 1.8 fmol/mg protein [prot]) (p < 0.05); however, the dissociation constant (Kd) for ICYP was not changed (24.1 +/- 5.7 versus 33.2 +/- 12.1 pM). Adenylate cyclase activity in the presence of 10(-2) M MgCl2 was reduced (p < 0.05) in MI rats (30.3 +/- 10.8 versus 45.9 +/- 12.5 pmol cAMP/min/mg prot). Maximal isoproterenol (52.5 +/- 7.3 versus 79.9 +/- 10.0 pmol cAMP/min/mg prot), guanyl-5'-imidodiphosphate (GppNHp) (95 +/- 8 versus 141 +/- 25 pmol cAMP/min/mg prot) and forskolin (503 +/- 76 versus 753 +/- 157 pmol cAMP/min/mg prot) stimulation of adenylate cyclase was also decreased (p < 0.05). In addition, manganese-stimulated adenylate cyclase activity was depressed (p < 0.05) in MI rats compared with controls (23.5 +/- 2.8 versus 52.1 +/- 9.0 pmol cAMP/min/mg prot). Chronic propranolol treatment in MI rats improved DT (4.1 +/- 0.9 versus 3.0 +/- 0.7 g/mm2) and +dT/dt (54.4 +/- 11.3 versus 40.5 +/- 9.5 g/mm2/sec) (p < 0.05); however, isoproterenol-stimulated isometric function remained impaired. Propranolol treatment normalized Bmax (11.9 +/- 1.7 versus 9.3 +/- 0.6 fmol/mg prot) (p < 0.05), whereas adenylate cyclase activity remained depressed. After large MI in rats, there is impaired papillary muscle function with decreased beta-adrenergic receptors and adenylate cyclase activity in the noninfarcted myocardium. Propranolol treatment improved basal isometric muscle function and beta-adrenergic receptor density in rats after myocardial infarction but did not improve adenylate cyclase activity or isoproterenol-stimulated muscle function. These data suggest that there is a primary defect in adenylate cyclase function that persists despite upregulation of receptors with propranolol treatment.

Increased activity of the GABAergic system in selected brain areas after chronic propranolol treatment in spontaneously hypertensive rats

The influence of chronically administered propranolol on the functional state of the γ-aminobutyric acid-ergic (GABAergic) system in spontaneously hypertensive rats was studied and compared with the effect of dihydralazine. GABA content, synthesis and turnover rate in selected brain areas were assessed. Hypotensive activity of propranolol and dihydralazine after injection of GABA antagonist pictrotoxin was examined in acute experiment. Prolonged administration of propranolol increased GABA content, synthesis and turnover rate in the hypothalamus and the pons-medulla. After chronic injections of dihydralazine there was no change in GABA indices. Antihypertensive activity of dihydralazine in picrotoxin-treated animals remained unchanged. On the contrary, picrotoxin suppressed the propranolol-induced decrease in blood pressure. Our results indicate that propranolol increases GABAergic system activity. Therefore, we conclude that down-regulation of the GABAergic system in hypertension may be compensated by the regulatory action of propranolol.

Propranolol reduces rat dopamine-β-hydroxylase activity and catecholamine levels

Propranolol treatment (1 mg/kg i.p. twice daily for 8 days) reduced atrial dopamine-β-hydroxylase (DβH) activity by 60.5% and lung DβH activity by 53.5% but did not alter ventricle DβH activity. Propranolol also significantly reduced atrial noradrenaline (NA) by 66.3%, adrenaline (A) by 40%, dopamine (DA) by 72.4% and lung NA by 46.6% but did not change plasma or cardiac ventricle catecholamines. The addition of propranolol (10 −6 M) to cardiac and lung tissue homogenates in vitro did not inhibit tissue DβH activities. The results suggest that chronic propranolol treatment inhibits NA synthesis and support the hypothesis of a centrally induced inhibition of sympathetic activity caused by β-adrenoceptor blockade.

The Effect of Chronic Atropine or Propranolol Treatment on Salivary Composition and Caries in Rats. G. WATSON*, S, PEARSON, J. FALANY, D. CULP, L. TABAK, and W. BOWEN (Cariology Center, University of Rochester)

The Effect of Chronic Atropine or Propranolol Treatment on Salivary Composition and Caries in Rats. G. WATSON*, S, PEARSON, J. FALANY, D. CULP, L. TABAK, and W. BOWEN (Cariology Center, University of Rochester)

Agonist-induced Ca 2+ mobilization in the rat submandibular gland during aging and subsequent to chronic propranolol treatment

The effects of age and chronic propranolol treatment on the agonist-induced rise in intracellular free Ca 2+ ([Ca 2+] i), an index for the coupling of receptor-second messenger generation, was studied using a dispersed rat submandibular gland preparation. Muscarinic stimulation (10 μm carbachol) caused a rapid ( T 1 2 < 2 s ) and dramatic (∼ 4.5-fold) rise in [Ca 2+] i followed by a lower sustained increase (∼ 3-fold) in [Ca 2+] i as measured directly with the Ca 2+-sensitivie fluorescent probe, fura-2. The magnitude and the rate of increase of the initial rise in [Ca 2+ i and the level of the sustained increase in [Ca 2+] i were not different between 2- and 21-month-old rats. Stimulation in a Ca 2+-free medium reduced the initial agonist-induced increase in [Ca 2+] i by ∼ 35–40%, while the sustained increase was abolished by the removal of extracellular Ca 2+ from cells in both young and old rats. Chronic treatment for 30 days with 20 mg/kg propranolol, a β-adrenergic antagonist, did not significantly alter the ability of dispersed submandibular cells in old rats to mobilize Ca 2+ during agonist stimulation or influence the in vivo stimulated gland output. These results suggest that the agonist-induced rise in [Ca 2+] i is not altered by aging or by chronic treatment of aged rats with propranolol and, therefore, receptor-second messenger coupling remains intact.