Propranolol-treated Group Research Articles

Propranolol Reduces Cardiac Index But does not Adversely Affect Peripheral Perfusion in Severely Burned Children.

The aim of this study was to quantify the effect of propranolol on hemodynamic parameters assessed using the PiCCO system in burned children. We analyzed hemodynamic data from patients who were randomized to receive either propranolol (4 mg/kg/day) or placebo (control), which was initiated as a prospective randomized controlled trial. Endpoints were cardiac index (CI), percent predicted heart rate (%HR), mean arterial pressure (MAP), percent predicted stroke volume (%SV), rate pressure product (RPP), cardiac work (CW), systemic vascular resistance index (SVRI), extravascular lung water index (EVLWI), arterial blood gases, events of lactic acidosis, and mortality. Mixed multiple linear regressions were applied, and a 95% level of confidence was assumed. One hundred twenty-one burned children (control: n = 62, propranolol: n = 59) were analyzed. Groups were comparable in demographics, EVLWI, SVRI, %SV, arterial blood gases, Denver 2 postinjury organ failure score, incidence of lactic acidosis, or mortality. Percent predicted HR, MAP, CI, CW, and RPP were significantly reduced in the propranolol-treated group (P <0.01). Propranolol significantly reduces cardiogenic stress by reducing CI and MAP in children with severe burn injury. However, peripheral oxygen delivery was not reduced and events of lactic acidosis as well as organ dysfunction was not higher in propranolol treated patients.

Propranolol sensitizes thyroid cancer cells to cytotoxic effect of vemurafenib.

Treatment options for advanced metastatic or progressive thyroid cancers are limited. Although targeted therapy specifically inhibiting intracellular kinase signaling pathways has markedly changed the therapeutic landscape, side-effects and resistance of single agent targeted therapy often leads to termination of the treatment. The objective of the present study was to identify the antitumor property of the non-selective β-adrenergic receptor antagonist propranolol for thyroid cancers. Human thyroid cancer cell lines 8505C, K1, BCPAP and BHP27 were used in the present study. Broad β-blocker propranolol and β2-specific antagonist ICI118551, but not β1-specific antagonist atenolol, inhibited the growth of 8505C and K1 cells. Propranolol treatment inhibited growth and induced apoptosis of 8505C cells invitro and invivo, which are closely associated with decreased expressions of cyclinD1 and anti-apoptotic Bcl-2. Expression of hexokinase2 (HK2) and glucose transporter1 (GLUT1) also decreased following propranolol intervention. 18F-FDG PET/CT imaging of the 8505C xenografts validated shrinkage of the tumors in the propranolol-treated group when compared to the phosphate‑buffered saline treated group. Finally, we found that propranolol can amplify the cytotoxicity of vemurafenib and sensitize thyroid cancer cells to cytotoxic effect of vemurafenib. Our present results suggest that propranolol has potential activity against thyroid cancers and investigation of the combination with targeted molecular therapy for progressive thyroid cancers could be beneficial.

Propranolol versus captopril in the treatment of infantile hemangioma (IH): A randomized controlled trial

Renin-angiotensin system components have been demonstrated in the biology of infantile hemangioma (IH). Captopril, an angiotensin-converting enzyme inhibitor, is proposed as a therapeutic alternative to oral propranolol. We sought to compare the benefit of propranolol and captopril in the treatment of IH, and to assess angiotensin-converting enzyme gene polymorphism in patients with IH and in control subjects. Thirty patients with IH and 35 healthy control subjects were enrolled in this study. Patients were randomly assigned to treatment with either propranolol or captopril. Assessment was done clinically and by measurement of serum vascular endothelial growth factor and angiotensin II in patients and control subjects. Angiotensin-converting enzyme gene polymorphism was also studied. Clinical improvement was significantly better and faster in the patients treated with propranolol. Both groups showed reduced vascular endothelial growth factor and angiotensin II levels posttreatment, with a significantly higher percentage reduction in the propranolol-treated group. Cardiac side effects were reported only in the captopril-treated group. Baseline vascular endothelial growth factor level was significantly higher, and baseline angiotensin II level was significantly lower, in patients than control subjects. We studied a relatively small number of patients and control subjects. Propranolol shows greater benefit than captopril in the treatment of IH.

Reactivating addiction-related memories under propranolol to reduce craving: A pilot randomized controlled trial

BackgroundThe reconsolidation blocker propranolol abolishes alcohol and drug-seeking behavior in rodents and attenuates conditioned emotional responses to drug-cues in humans in experimental settings. This suggests a role for its use in the treatment of substance dependence. In this translational pilot study, we explored the feasibility and efficacy of this procedure as an adjunct treatment for addiction. We hypothesized that guided addiction-related memory reactivation under propranolol would significantly attenuate tonic craving, a central element in relapse following addiction treatment. MethodsSeventeen treatment-seeking adults diagnosed with substance dependence were randomized to receive double-blind propranolol (n = 9) or placebo (n = 8) on six occasions prior to reading a personalized script detailing a drug-using experience. The primary outcome measure was self-reported craving intensity. ResultsAfter controlling for baseline craving scores, intent-to-treat analysis revealed a time by group interaction, F(1, 14) = 5.68, p = .03, η2 = 0.29; craving was reduced in the propranolol-treated group (Cohen's d = 1.40, p < .05) but not in the placebo group (d = 0.06, n.s.). LimitationsThe usual limitations related to small sample size and the lack of a follow-up apply here. ConclusionDrug-related memory reactivation under propranolol can subsequently reduce craving among substance-dependent individuals. Considering the relapse rate among individuals treated for substance dependence, our study highlights the feasibility of, and need for, more comprehensive trials of this treatment approach.

Effects of repeated propranolol administration in a rat model of surgically induced endometriosis

ObjectivesTo determine whether propranolol has an inhibitory effect on the angiogenesis of endometriosis in an experimental rat model or not. Study designThis was an experimental animal model study. Twenty-four female Wistar albino rats (200–250g) were used to create a model for surgical induction of endometriosis. Two rats died during the surgeries. The rats were randomly divided into treatment (n=11) and control groups (n=10), which were treated with daily intraperitoneal propranolol (10mg/kg) and saline (2mL), respectively. Study duration was 8 weeks. The volumes and histopathological findings of the implants, and immunochemistry for vascular endothelial growth factor (VEGF), metalloproteinase (MMP)-2, and MMP-9 were evaluated. ResultsViable endometriotic implants were created in all animals. In the propranolol-treated group, the mean implant volume significantly decreased after treatment (142.5 vs. 32.1mm3, respectively; p=0.008), while the mean implant volume significantly increased in the control group (141.0 vs. 174.2mm3, respectively; p=0.009). There were also significant reductions in VEGF immunoreactivity scores and both stroma and epithelium MMP-2 and MMP-9 immunoreactivity scores in the propranolol-treated group compared with the control group (p<0.005 for all scores). ConclusionsPropranolol may suppress endometrial tissue by its antiangiogenic activity through inhibitory actions on VEGF, MMP-2, and MMP-9. Therefore, propranolol is a promising candidate drug for effective treatment of patients with endometriosis, which needs to be confirmed with further studies.

Propranolol impairs the closure of pressure ulcers in mice

Aimsβ-Adrenoceptors modulate acute wound healing; however, few studies have shown the effects of β-adrenoceptor blockade on chronic wounds. Therefore, this study investigated the effect of β1-/β2-adrenoceptor blockade in wound healing of pressure ulcers. Main methodsMale mice were daily treated with propranolol (β1-/β2-adrenoceptor antagonist) until euthanasia. One day after the beginning of treatment, two cycles of ischemia–reperfusion by external application of two magnetic plates were performed in skin to induce pressure ulcer formation. Key findingsPropranolol administration reduced keratinocyte migration, transforming growth factor-β protein expression, re-epithelialization, and necrotic tissue loss. Neutrophil number and neutrophil elastase protein expression were increased in propranolol-treated group when compared with control group. Propranolol administration delayed macrophage mobilization and metalloproteinase-12 protein expression and reduced monocyte chemoattractant protein-1 protein expression. Myofibroblastic differentiation, angiogenesis, and wound closure were delayed in the propranolol-treated animals. Propranolol administration increased neo-epidermis thickness, reduced collagen deposition, and enhanced tenascin-C expression resulting in the formation of an immature and disorganized collagenous scar. Significanceβ1-/β2-Adrenoceptor blockade delays wound healing of ischemia–reperfusion skin injury through the impairment of the re-epithelialization and necrotic tissue loss which compromise wound inflammation, dermal reconstruction, and scar formation.

Propranolol Inhibits Glucose Metabolism and 18F-FDG Uptake of Breast Cancer Through Posttranscriptional Downregulation of Hexokinase-2

The advancement of breast cancer therapy is limited by the biologic behaviors of cancer cells, such as metastasis and recurrence. β-adrenoceptors (ADRB) are reported to be associated with the biologic behaviors of breast cancer and may influence glucose metabolism. Here, we sought to investigate the relationship between the activation of ADRB and the expression of glucose transporter (GLUT)-1 and hexokinase (HK)-2 and to clarify the impact of ADRB on (18)F-FDG PET imaging in breast cancer. ADRB1/2 expression in 4T1, MDA-MB-231, and MCF-7 breast cancer cell lines was detected by Western blotting and immunofluorescence. ADRB-dependent regulation of GLUT-1 and HK-2 was determined by in vitro pharmacologic intervention. 4T1 breast cancer cells were treated with phosphate-buffered saline, isoproterenol, or propranolol, and the transcription and expression of GLUT-1 and HK-2 were measured by quantitative real-time polymerase chain reaction (RT-PCR) and Western blotting, respectively. ADRB1/2 was, respectively, blocked by small-interfering RNA to investigate the direct relationship between ADRB1/2 and HK-2. To evaluate the impact of ADRB on (18)F-FDG PET imaging, BALB/c mice bearing 4T1 tumors were injected with phosphate-buffered saline, isoproterenol, or propranolol, and (18)F-FDG PET imaging was performed. The tumor-to-nontumor (T/NT) values of tumors and brown adipose tissue were calculated by defining the liver as a reference. The in vivo expression of GLUT-1 and HK-2 was observed by immunohistochemical analysis and Western blotting. MDA-MB-231, MCF-7, and 4T1 breast cancer cells were positive for ADRB1/2 expression. The protein expression and posttranscriptional level of HK-2 were significantly decreased by treatment with propranolol in vitro, whereas GLUT-1 expression was not significantly altered by pharmacologic intervention. The expression of HK-2 could be reduced in ADRB2-blocked 4T1 cells. Mice in the propranolol-treated group exhibited lower T/NT values for the tumors and brown adipose tissue than the control group. Immunohistochemical analysis and Western blotting revealed reduced HK-2 expression in the tumors of propranolol-treated mice. The expression of HK-2 was regulated by the activation of ADRB2 in 4T1 breast cancer cells primarily at the posttranscriptional level. Additionally, propranolol prevented glucose metabolism and (18)F-FDG PET imaging of 4T1 breast cancer tumors.

Propranolol improves cutaneous wound healing in streptozotocin-induced diabetic rats

Sympathetic nerve failure has been proposed as a contributing factor in impaired cutaneous wound healing in diabetes mellitus. Nevertheless, no studies have shown whether β-adrenoceptor blockade through β-blocker (e.g., propranolol) administration may alter healing of diabetic cutaneous lesions. This study evaluated macro- and microscopically the effects of propranolol administration on cutaneous wound healing in streptozotocin-induced diabetic rats. Acute diabetes was induced by a single intraperitoneal injection of streptozotocin 14 days before wounding. Animals were treated with propranolol (50 mg/kg) dissolved in drinking water; controls received water only. Administration of β-receptor antagonist began 1 day before wounding and was continued daily until euthanasia. A full-thickness excisional lesion (1 cm 2) was created. The wound area was measured weekly and the animals were killed 14 days after wounding. Lesions and adjacent skin were formalin-fixed and paraffin-embedded. Sections were stained with hematoxylin-eosin, Sirius red, and toluidine blue, and immunostained for CD-68, alpha-smooth muscle actin and proliferating cell nuclear antigen. The wound area was significantly smaller in the propranolol-treated group than in the control group 7 and 14 days after wounding. Inflammatory cell numbers and metalloproteinase-9 levels were reduced in the propranolol-treated group compared to the control group 14 days after wounding. Cell proliferation, mast cell number, collagen deposition, blood vessel density, and nitric oxide levels were increased in the propranolol-treated group compared to the control group 14 days after wounding. Propranolol administration improves cutaneous wound healing of hyperglycemic diabetic rats by reducing the local inflammatory response and improving subsequent phases of the repair process.

Low-Dose Propranolol Improves Cutaneous Wound Healing of Burn-Injured Rats

Severe burns stimulate a hypermetabolic response that causes systemic complications. Propranolol, a nonselective beta-blocker, reduces this response and increases survival. Nevertheless, few studies have shown the effects of propranolol on healing of severe burns. This study evaluated macroscopically and microscopically the effects of the administration of propranolol (low-dose) on cutaneous wound healing of burn-injured rats. A third-degree burn (10 percent total body surface area) was created in female Wistar rats. Beginning 1 week after burning, animals were treated daily with propranolol (n = 5) (6 mg/kg) dissolved in water until they were euthanized, whereas rats in the control group (n = 5) received only water. Wound area was measured weekly and animals were euthanized 63 days after burning. Lesions and adjacent skin were fixed in formalin and embedded in paraffin. Sections were stained with hematoxylin and eosin, Sirius red, and toluidine blue, and immunostained for CD68, alpha-smooth muscle actin, and proliferating cell nuclear antigen. The wound area was greater in the control group than in the propranolol-treated group 21, 53, and 63 days after burning. All propranolol-treated animals presented more than 70 percent of reepithelialized wound area 63 days after burning, whereas control animals did not. The number of inflammatory cells and blood vessel density were greater in the control group than in the propranolol-treated group 63 days after burning. Cellular proliferation, myofibroblast density, collagen deposition, and active matrix metalloproteinase-2 levels were reduced in the control group compared with the propranolol-treated group 63 days after burning. Administration of (low-dose) propranolol improves healing of burned rats, reducing the local inflammatory response and improving subsequent healing phases.

Dexmedetomidine, Diazepam, and Propranolol in the Treatment of Ethanol Withdrawal Symptoms in the Rat

In this study, the effects of dexmedetomidine, a selective alpha 2-adrenoceptor agonist, on ethanol withdrawal symptoms, were compared with those of diazepam and propranolol. The rats were given highly intoxicating doses of ethanol for 4 days. After the intoxication period, rats were divided into four equal groups: a dexmedetomidine-treated group (30 micrograms/kg, sc), a diazepam-treated group (2 mg/kg, sc), a propranolol-treated group (5 mg/kg, sc), and a control group with no medication. Medication was given in the withdrawal phase-2, 8, 14, and 20 hr after the onset of the withdrawal symptoms. The severity of the ethanol withdrawal symptoms (rigidity, tremor, irritability, and hypoactivity) was observed up to 33 hr after the onset of the ethanol withdrawal symptoms. Both dexmedetomidine and diazepam significantly relieved tremor compared with the control group. Diazepam reduced irritability significantly, compared with the control group. When measured as the sum score of the three most specific withdrawal signs (rigidity, tremor, and irritability), dexmedetomidine and diazepam significantly relieved the ethanol withdrawal reaction. Propranolol attenuated tremor, but was inefficient against other withdrawal symptoms. Dexmedetomidine may thus represent a new effective drug in the treatment of the ethanol withdrawal syndrome.

Role of central nicotinic and beta-adrenergic receptors in the onset and further development of tail-tremor induced by repeated nicotine administration to rats.

The effects of nicotinic and beta-adrenergic receptor antagonists on tail-tremor induced by repeated nicotine administration were investigated in rats. The daily administration of nicotine (0.5 mg/kg/day, s.c.) for 8 days resulted in an augmentation of tail-tremor. However, repeated administration of dimethyl phenyl piperazinium iodide (1 mg/kg/day, s.c.) for 8 days did not cause tail-tremor. Mecamylamine (0.5 mg/kg, i.p), administered before the nicotine injection on each day, abolished the tail-tremor. After discontinuation of the mecamylamine treatment, nicotine injections caused tail-tremor augmentation. Propranolol (20 mg/kg, i.p.), administered before the nicotine on each day, suppressed the appearance of tail-tremor. After the discontinuation of propranolol treatment, the degree of tail-tremor induced by a single injection of nicotine on day 9 was much greater in the propranolol-treated group than in the saline-treated control group. Neither carteolol (20 mg/kg, i.p.) nor metoprolol (20 mg/kg, i.p.) treatment showed such effects. Intraspinal injection of 6-hydroxydopamine markedly enhanced the tail-tremor induced on the first day of nicotine injection. This effect became more intense on subsequent administration of nicotine. The enhanced tail-tremor following 6-hydroxydopamine treatment was abolished by mecamylamine (0.5 and 1 mg/kg, i.p.), and was suppressed by propranolol (5-20 mg/kg, s.c.) in a dose-dependent manner. These results suggest that central nicotinic receptors are essential for the onset and for the further development of tail-tremor induced by the repeated administration of nicotine, and that beta 2-adrenoceptors are associated with the tremor mechanism. Moreover, spinal noradrenergic mechanisms may be involved in the manifestation of this phenomenon.

β-blocker therapy for prophylaxis of initial variceal hemorrhage: Has its time come?

In a double-blind randomized trial, the hemodynamic events following the administration of propranolol (n = 51) or a placebo (n = 51) were prospectively studied in cirrhotic patients with esophageal varices. The hepatic venous pressure gradient, heart rate, and variceal size were determined at the baseline and 3, 12, and 24 months after the beginning of therapy. Baseline values were similar in both groups. At 3 months, the hepatic venous pressure gradient decreased significantly in propranolol-treated patients (from 18.1 ± 4.2 to 15.7 ± 3.4 mm Hg; P &lt; 0.05) but not in patients receiving the placebo (19.6 ± 6.8 to 17.5 ± 5.3 mm Hg; NS). At subsequent time intervals this gradient decreased significantly from the baseline value in both groups. Heart rate decreased significantly in the propranolol-treated group at all times (P &lt; 0.001). Variceal hemorrhage occurred in 13 patients (11 placebo-, 2 propranolol-treated; P &lt; 0.01), all of whom had a hepatic venous pressure gradient &gt; 12 mm Hg. In 21 patients (14 propranolol-, 7 placebo-treated) the hepatic venous pressure gradient decreased to ≤12 mm Hg; none of them bled from esophageal varices, and their mortality rate also decreased. Because most of the bleeding events occurred during the first year (10 placebo-, 1 propranololtreated; P &lt; 0.01), propranolol seems to have its protective effect during the period associated with the largest reduction in the hepatic venous pressure gradient. Because a reduction in the hepatic venous pressure gradient to &lt; 12 mm Hg protects from variceal bleeding and increases the rate of survival, this should be the aim of the pharmacological therapy of portal hypertension.

Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage

In a double-blind randomized trial, the hemodynamic events following the administration of propranolol (n = 51) or a placebo (n = 51) were prospectively studied in cirrhotic patients with esophageal varices. The hepatic venous pressure gradient, heart rate, and variceal size were determined at the baseline and 3, 12, and 24 months after the beginning of therapy. Baseline values were similar in both groups. At 3 months, the hepatic venous pressure gradient decreased significantly in propranolol-treated patients (from 18.1 ± 4.2 to 15.7 ± 3.4 mm Hg; P < 0.05) but not in patients receiving the placebo (19.6 ± 6.8 to 17.5 ± 5.3 mm Hg; NS). At subsequent time intervals this gradient decreased significantly from the baseline value in both groups. Heart rate decreased significantly in the propranolol-treated group at all times (P < 0.001). Variceal hemorrhage occurred in 13 patients (11 placebo-, 2 propranolol-treated; P < 0.01), all of whom had a hepatic venous pressure gradient > 12 mm Hg. In 21 patients (14 propranolol-, 7 placebo-treated) the hepatic venous pressure gradient decreased to ≤ 12 mm Hg; none of them bled from esophageal varices, and their mortality rate also decreased. Because most of the bleeding events occurred during the first year (10 placebo-, 1 propranolol-treated; P < 0.01), propranolol seems to have its protective effect during the period associated with the largest reduction in the hepatic venous pressure gradient. Because a reduction in the hepatic venous pressure gradient to <12 mm Hg protects from variceal bleeding and increases the rate of survival, this should be the aim of the pharmacological therapy of portal hypertension.

Chronic Propranolol Treatment Promotes Left Ventricular Dilation Without Altering Systolic Function After Large Myocardial Infarction in Rats

In rats with chronic myocardial infarction (MI), we have examined the effects of prolonged beta-adrenergic blockade with propranolol on left ventricular (LV) performance, weight, and volumes. Sham-operated rats and rats with large MI (greater than 30%) were evaluated. Four groups of rats were studied: control, sham-operated (n = 12); control, MI (n = 12); propranolol (500 mg/L of drinking water)-treated, sham-operated (n = 10); and propranolol treated, MI (n = 10). Treatment was started 3 weeks after coronary ligation. After 5-6 weeks, LV, systemic arterial, and right atrial pressures in addition to aortic blood flow before and during volume loading were measured. LV pressure-volume relations were measured ex vivo. The rats with chronic MI demonstrated expected decreases in LV systolic performance and increased LV end-diastolic and right atrial pressures. Propranolol had no independent effect on LV systolic pressure, LV end-diastolic pressure, resting cardiac index, stressed cardiac index during volume loading, peak developed aortic pressure during aortic occlusion, or ejection fraction index in either sham-operated or infarcted rats; however, heart rate was decreased. LV weight/body weight was 2.17 +/- 0.04 mg/g in control sham-operated rats, which was not different from the propranolol-treated sham-operated rats (2.09 +/- 0.04 mg/g). The LV weight/body weight was increased (p less than 0.01) to 2.21 +/- 0.08 mg/g in the propranolol-treated MI group from 1.94 +/- 0.06 mg/g in the control MI group. The LV pressure-volume relation was not altered by propranolol in the sham-operated rats but was shifted to the right by MI.(ABSTRACT TRUNCATED AT 250 WORDS)

Isradipine vs Propranolol in Hydrochlorothiazide-Treated Hypertensives

A randomized, parallel, controlled study was conducted to evaluate the safety and efficacy of isradipine, 2.5 to 10 mg orally twice a day, compared with propranolol hydrochloride, 60 to 240 mg orally twice a day, in 78 hypertensives whose supine diastolic blood pressure was greater than 95 mm Hg while receiving 50 mg/d or more of hydrochlorothiazide. Isradipine or propranolol was titrated during a 10-week double-blind phase to achieve a supine diastolic blood pressure below 90 mm Hg while a fixed dose of hydrochlorothiazide was maintained. Supine diastolic blood pressure was reduced by 10 mm Hg in 88% of the isradipine/hydrochlorothiazide-treated and 83% of the propranolol/hydrochlorothiazide-treated groups and to less than 90 mm Hg in 55% of the isradipine/hydrochlorothiazide-treated and 69% of the propranolol/hydrochlorothiazide-treated patients. There was no significant difference in supine blood pressure reduction between either group, but there was a 3-to 4-beats per minute increase in supine heart rate in isradipine-treated patients and an expected 15- to 20-beats per minute decrease in heart rate in propranolol-treated patients. Five of 7 patients in the isradipine-treated group and 8 of 9 patients in the propranolol-treated group discontinued the therapy because of adverse reactions or treatment failure. Using Fisher's Exact Test, we found no significant difference in the relative frequency of individual adverse reactions between groups, although the absolute adverse reaction frequency was significantly higher with isradipine. This study demonstrates the effectiveness and safety of supplemental isradipine in the treatment of hypertension not controlled by hydrochlorothiazide alone.

Indirect Effect of Catecholamines on Development of Insulin Resistance in Skeletal Muscle From Diabetic Rats

The role of an increased sympathetic activation in the development of insulin resistance in diabetic skeletal muscle was investigated. Epitrochlearis muscles from rats with streptozocin-induced diabetes and from controls were incubated in vitro for 0.5-12.0 h. Diabetes decreased maximal insulin-stimulated (20 mU/ml) glucose transport capacity by 60% (P less than .001), but this decreased insulin responsiveness returned to normal on in vitro incubation (3.79 +/- 0.59 before vs. 8.92 +/- 0.64 mumol.ml-1.h-1 after 12 h of incubation). The reversal of decreased insulin responsiveness in diabetic muscles did not require the presence of insulin and was not affected by the presence of 5.0 x 10(-8) M of epinephrine. However, it was possible to partially prevent the development of insulin resistance with regard to glucose transport by treating the rats with the beta-adrenergic antagonist propranolol (0.5 mg/kg) every 12 h during the entire 72-h period in which the animals were kept diabetic (insulin responsiveness was 3.16 +/- 0.40 mumol.ml-1.h-1 for saline-injected group vs. 5.55 +/- 0.46 mumol.ml-1.h-1 for propranolol-treated group). This effect was not present after a single injection of the drug 2 h before the experiment or when propranolol treatment was withdrawn 12 h before the experiment. The beta-adrenergic blockade markedly reduced the plasma concentration of free fatty acids (0.5 +/- 0.01 mumol/ml for propranolol-treated rats vs. 1.1 +/- 0.1 mumol/ml for saline-treated rats; P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of adrenomedullectomy and propranolol treatment on the response of gonadotrophins to chronic stress in male rats

In order to study the involvement of the adrenal medulla in stress-induced inhibition of gonadotrophin secretion, we measured plasma concentrations of LH, FSH and corticosterone in adult male rats subjected to chronic restraint after surgical ablation of the adrenal medulla. In intact animals, chronic restraint (6 h daily over 4 days) induced a significant (P less than 0.05) decrease in plasma concentrations of LH, whereas plasma concentrations of corticosterone showed the expected significant (P less than 0.01) increase. Adrenomedullectomy did not significantly modify basal plasma concentrations of LH or corticosterone. In these rats, there was no significant decrease of LH after stress, while the increase in corticosterone was as significant as in sham-operated animals (P less than 0.01). In order to confirm the role of adrenomedullary catecholamines in stress-induced gonadotrophin inhibition another group of rats was treated s.c. with the beta-adrenergic blocker propranolol (2 mg/kg twice daily). These rats showed an attenuated inhibition of LH during stress similar to that observed in adrenomedullectomized rats. Levels of FSH were significantly reduced after stress in the saline-treated group, while there were no differences between stressed or unstressed rats in the propranolol-treated group. These results may be considered as evidence that medullary catecholamines, acting through beta-receptors, are factors involved in gonadotrophin inhibition during chronic stress.

Changes of the Degree of Hypertrophy in Hypertrophic Obstructive Cardiomyopathy under Medical and Surgical Treatment

The aim of our study was to establish the extent to which therapy of hypertrophic obstructive cardiomyopathy (HOCM) can influence the degree of hypertrophy. By means of two-dimensionally guided M-mode echocardiography, 120 patients with HOCM (age range 4-72 years, mean age 41 years) were observed over an average period of 49 +/- 41 months. Depending on the respective therapy, we formed four patient groups: group 1: 13 patients without any therapy (follow-up period 31 +/- 30 months); group 2: 27 patients receiving propranolol (follow-up period 47 +/- 34 months); group 3: 50 patients receiving verapamil (follow-up period 39 +/- 27 months), and group 4: 30 patients with myectomy (follow-up period 34 +/- 32 months). In group 4, as expected, the thickness of the interventricular septum (IVS) decreased postoperatively (from 24.2 +/- 4.5 to 19.8 +/- 6.7 mm, p less than 0.05), and the left ventricular posterior wall (LVPW) thickness also decreased later postoperatively (from 13.0 +/- 2.6 to 11.9 +/- 2.3 mm, p less than 0.05). The left ventricular diameters increased. In groups 2 and 3 treated with pharmacotherapy as in the untreated patients of group 1, on average there was no change in IVS and LVPW thickness nor in the left ventricular diameters (with the exception of increasing left ventricular end-diastolic diameter in the propranolol-treated group). In contrast to group 1, in occasional cases there were substantial decreases of IVS thickness (11% of the patients in group 2, 13% in group 3) or LVPW thickness (13% of the patients in group 2, 12% in group 3).(ABSTRACT TRUNCATED AT 250 WORDS)

Early intervention with propranolol after acute myocardial infarction: serial left ventricular function determined by M-mode and cross-sectional echocardiography

Fifty patients (mean age 48.6 ± 9.4 years) with uncomplicated acute myocardial infarction were randomly assigned to propranolol therapy ( n = 25) or placebo ( n = 25) in a double-blind manner within 24 hours of their presentation with acute symptoms. M-mode and cross-sectional echocardiography were performed at one week and three months to evaluate the left ventricular function. A comparison of the two groups revealed that the group receiving propranolol had higher left ventricular ejection fraction (69% vs 52%, P < 0.001), fractional shortening (32% vs 24%, P < 0.01), lower mitral E-point septal separation (6 mm vs 14 mm, P < 0.001) and wall motion abnormality score (2.5 vs 6.0, P < 0.001) than the group receiving placebo therapy. At three months there was further significant improvement in wall motion abnormality score (1.1 vs 2.5, P < 0.001) in the propranolol-treated group as compared to the placebo group, whereas the other parameters remained unchanged. We conclude that the left ventricular function detected by M-mode and cross-sectional echocardiography showed significant improvement in patients with acute myocardial infarction after early intervention with propranolol. This is possibly due to a reduction in the size of infarction.

Acute hemodynamic effects of pindolol and propranolol in patients with dilated cardiomyopathy: Relevance of intrinsic sympathomimetic activity

The administration of beta-blocking agents to patients with poor left ventricular (LV) function may result in clinical and hemodynamic deterioration. The beta antagonist pindolol has intrinsic sympathomimetic activity (ISA) and therefore may be better tolerated. To test this hypothesis 30 patients with a precatheterization diagnosis of dilated cardiomyopathy were randomly assigned to three groups to receive intravenous injections of placebo, propranolol, or pindolol. The baseline jection fraction and hemodynamics were similar for all groups. For propranolol 1 mg, 2 mg, 3 mg, and 4 mg doses were given 5 minutes apart until a maximum dose of 10 mg was reached, until a 25% reduction in the heart rate or mean arterial pressure occurred, or until clinical deterioration developed. For pindolol 0.1 mg, 0.2 mg, 0.3 mg, and 0.4 mg boluses were used with the same end points. Baseline hemodynamics were measured and repeated 15 minutes after the last dose of each drug was administered. The mean number of doses given was similar for both groups: 3.3 doses for the propranolol group and 3.4 for the pindolol group. Compared to propranolol, pindolol caused less of a reduction in heart rate, cardiac output. cardiac index, stroke volume index, and stroke work index and less of an increase in the mean right atrial pressure, mean pulmonary arterial pressure, mean pulmonary capillary wedge pressure, left ventriculs end-diastolic pressure, and pulmonary vascular resistance; there was a decrease in systemic vascular resistance. These differences were statistically significant for changes in heart rate, right atrial pressure, cardiac index, and systemic vascular resistance. Although no patients in the pindolol-treated group had clinical deterioration, four in the propranolol-treated group required tomporary intravenous inotropic support. Based on these data we conclude that pindolol as compared to propranolol is better tolerated acutely when given to patients with markedly reduced LV function. It is likely that the ISA of pindolol accounts for this effect. Therefore patients with severely reduced LV function who require beta blockade acutely may better tolerate pindolol or other beta-blocking agents that possess ISA than those that do not. Whether or not these same findings can be extrapolated to the chronic administration of beta blockade in patients with reduced LV function remains unknown and will require further investigation.