Fat cell adrenergic receptors and the control of white and brown fat cell function

Five adrenoceptor subtypes are involved in the adrenergic regulation of white and brown fat cell function. The effects on cAMP production and cAMP-related cellular responses are mediated through the control of adenylyl cyclase activity by the stimulatory beta 1-, beta 2-, and beta 3-adrenergic receptors and the inhibitory alpha 2-adrenoceptors. Activation of alpha 1-adrenoceptors stimulates phosphoinositidase C activity leading to inositol 1,4,5-triphosphate and diacylglycerol formation with a consequent mobilization of intracellular Ca2+ stores and protein kinase C activation which trigger cell responsiveness. The balance between the various adrenoceptor subtypes is the point of regulation that determines the final effect of physiological amines on adipocytes in vitro and in vivo. Large species-specific differences exist in brown and white fat cell adrenoceptor distribution and in their relative importance in the control of the fat cell. Functional beta 3-adrenoceptors coexist with beta 1- and beta 2-adrenoceptors in a number of fat cells; they are weakly active in guinea pig, primate, and human fat cells. Physiological hormones and transmitters operate, in fact, through differential recruitment of all these multiple alpha- and beta-adrenoceptors on the basis of their relative affinity for the different subtypes. The affinity of the beta 3-adrenoceptor for catecholamines is less than that of the classical beta 1- and beta 2-adrenoceptors. Conversely, epinephrine and norepinephrine have a higher affinity for the alpha 2-adrenoceptors than for beta 1-, 2-, or 3-adrenoceptors. Antagonistic actions exist between alpha 2- and beta-adrenoceptor-mediated effects in white fat cells while positive cooperation has been revealed between alpha 1- and beta-adrenoceptors in brown fat cells. Homologous down-regulation of beta 1- and beta 2-adrenoceptors is observed after administration of physiological amines and beta-agonists. Conversely, beta 3- and alpha 2-adrenoceptors are much more resistant to agonist-induced desensitization and down-regulation. Heterologous regulation of beta-adrenoceptors was reported with glucocorticoids while sex-steroid hormones were shown to regulate alpha 2-adrenoceptor expression (androgens) and to alter adenylyl cyclase activity (estrogens).     

In situ assessment of the role of the beta 1-, beta 2- and beta 3-adrenoceptors in the control of lipolysis and nutritive blood flow in human subcutaneous adipose tissue

1. The involvement of beta 1-, beta 2- and beta 3-adrenoceptors in the control of lipolysis and nutritive blood flow was investigated in abdominal subcutaneous adipose tissue of healthy young adults by use of an in situ microdialysis technique. 2. Dialysis probes were infused either with isoprenaline (non-selective beta-adrenoceptor agonist), CGP 12,177 (selective beta 3-adrenoceptor agonist having beta 1-/beta 2-antagonist properties), dobutamine (selective beta 1-adrenoceptor agonist) or terbutaline (selective beta 2-adrenoceptor agonist). The recovery of each probe used for perfusion was calculated by an in vivo calibration method. The local blood flow was estimated through the measurement of the escape of ethanol infused simultaneously with the drugs included in the probe. 3. Isoprenaline infusion at 0.01 microM had a weak effect while higher concentrations of isoprenaline (0.1 and 1 microM) caused a rapid, sustained and concentration-dependent increase of glycerol outflow; the maximum increase was 306 +/- 34% with 1 microM. Isoprenaline also increased the nutritive blood flow in adipose tissue; a significant effect appeared at 0.1 microM isoprenaline and was greater at 1 microM. 4. CGP 12,177 (10 and 100 microM) increased the glycerol concentration in the dialysate (128 +/- 8 and 149 +/- 12%, respectively) and nutritive blood flow. Terbutaline and dobutamine (100 microM) both provoked rapid and similar increases in glycerol outflow (252 +/- 18 and 249 +/- 18%, respectively). Both, terbutaline and dobutamine increased nutritive blood flow. 5. It is concluded that beta 1- and beta 2-adrenoceptor subtypes are both mainly involved in the mobilization of lipids and in the control of nutritive blood flow. beta 3-Adrenoceptors play a weaker role in the control of lipolysis and nutritive blood flow in human subcutaneous abdominal adipose tissue.     

Beta-adrenergic signal transduction in the failing and hypertrophied myocardium

A strong sympathetic activation has been observed in heart failure and is the cause of beta-adrenergic desensitization in this condition. On the receptor level there is downregulation of beta1-adrenergic receptors and uncoupling of beta2-adrenoceptors. The latter mechanism has been related to an increased activity and gene expression of beta-adrenoceptor kinase in failing myocardium, leading to phosphorylation and uncoupling of receptors. beta3-Adrenoceptors mediate negative inotropic effects, but alterations in these receptors are not known. In addition, an increase in inhibitory G protein alpha subunits (Gi alpha) has been suggested to be causally linked to adenylyl cyclase desensitization in heart failure. In contrast, the catalytic subunit of adenylyl cyclase, stimulatory G protein alpha and betagamma subunits, have been observed to be unchanged. Recent evidence shows that increases in Gi alpha also depress adenylyl cyclase in compensated cardiac hypertrophy both in monogenic and polygenic and in secondary hypertension. These increases of Gi alpha can suppress adenylyl cyclase in the absence of beta-adrenergic receptor downregulation. Since cardiac hypertrophy in pressure overload is a strong predictor of cardiac failure, these observations indicate that adenylyl cyclase desensitization by Gi alpha may be a pathophysiologically relevant mechanism contributing to the progression from compensated cardiac hypertrophy to heart failure.     

Diminished responsiveness of Gs-coupled receptors in severely failing human hearts: no difference in dilated versus ischemic cardiomyopathy

In end-stage heart failure, cardiac beta-adrenoceptors are decreased and cardiac Gi protein is increased. We assessed beta-adrenoceptors, G proteins, and effects of several beta-adrenoceptor agonists, histamine, and 5-HT on adenylyl cyclase activity in right and left atria and left ventricles and on left ventricular contractility in six potential heart transplant donors (nonfailing hearts; NFHs) and in nine patients with end-stage dilated cardiomyopathy (DCM) and 11 patients with end-stage ischemic cardiomyopathy (ICM) to establish whether the functional responsiveness of all cardiac Gs-coupled receptors is reduced. Beta-adrenoceptors were reduced in all three tissues; in DCM, beta1-adrenoceptors were more markedly downregulated; in ICM, both beta1- and beta2-adrenoceptors were diminished. In all three tissues, isoprenaline-, terbutaline-, histamine- and 5-HT-induced adenylyl cyclase activation was reduced similarly in DCM and ICM. Moreover, in DCM and ICM, guanosine triphosphate (GTP)- (involving Gs and Gi) activated adenylyl cyclase was significantly diminished, whereas NaF-activated (involving only Gs) and Mn2+-activated (acting at the catalytic unit of the enzyme) adenylyl cyclase was unaltered. Left ventricular positive inotropic responses to beta1- (noradrenaline, dopamine, and dobutamine), beta2- (terbutaline), and beta1- and beta2-adrenoceptors (isoprenaline, adrenaline, and epinine), as well as H2-receptor (histamine) stimulation were significantly reduced. The extent of reduction was not different for each agonist in ICM and DCM. We conclude that in DCM and ICM, functional responsiveness of all cardiac Gs-coupled receptors is similarly reduced.     

Comparison of the attenuating effects of four beta-adrenoceptor agonists on rat isolated uterus and aorta

1. The ability of four beta-adrenoceptor agonists to attenuate oxytocin (0.2, 2 and 20 nmol/L) or KCl (20, 40 and 80 mmol/L)-induced contractions of the uterus (n = 5-8 for each agonist) and the KCl (18 mmol/L)-induced contractions of the aorta (n = 9 for each agonist) from rats, pretreated with oestradiol has been compared. 2. Isoprenaline, salbutamol, terbutaline and procaterol (0.1-10 mumol/L) attenuated the contractions of the uterus and the aorta. All four agonists had similar attenuating potencies on the uterus. 3. Procaterol caused the same maximal attenuation (33%) on the aorta as the other beta-adrenoceptor agonists and is thus acting as a full beta 2-adrenoceptor agonist under these experimental conditions. Isoprenaline and procaterol were much more potent than salbutamol and terbutaline in attenuating the aorta responses. 4. This study showed that isoprenaline and procaterol were potent attenuants on both the uterus and aorta whereas salbutamol and terbutaline were potent uterine but only modest aorta attenuants. This preliminary study indicates that the responsiveness of uterine and vascular tissue to certain beta 2-adrenoceptors differs.     

Beta 2-agonist treatment reduces beta 2-sensitivity in alveolar macrophages despite corticosteroid treatment

Alveolar macrophage beta 2-adrenoceptor sensitivity and bronchodilator responses to inhaled terbutaline were investigated before and after 2 wk of oral treatment with terbutaline 7.5 mg twice a day in healthy volunteers. The influence of corticosteroid treatment was examined by giving 10 subjects budesonide 400 micrograms twice a day by inhalation throughout the treatment period, and by giving 10 subjects 40 mg prednisolone and 10 subjects placebo orally 12 h before the second examination. Terbutaline treatment elicited marked attenuation (approximately 75% reductions) of isoprenaline-induced cyclic AMP accumulation in the alveolar macrophages. Responses to prostaglandin E1 were not influenced by treatment, suggesting homologous beta-adrenoceptor desensitization. Corticosteroid administration failed to either prevent (budesonide) or reverse (prednisolone) this desensitization. Bronchodilator responses to terbutaline were not altered by treatment in either group. We conclude that the beta 2-adrenoceptor sensitivity of human alveolar macrophages is markedly and selectively depressed by beta 2-agonist treatment and that corticosteroid treatment, contrary to previous hypotheses, fails to influence this phenomenon. Studies on the mechanisms involved are needed. The importance of alveolar macrophages in asthma is unclear, but the present data in humans are of interest in relation to possible effects of continuous beta 2-agonist treatment on inflammatory mechanisms in the airways.     

Chronotropic effects of optical isomers of ephedrine and methylephedrine in the isolated rat right atria and in vitro assessment of direct and indirect actions on beta 1-adrenoceptors

Effects of optical isomers of ephedrine (EPH) and methylephedrine (MEP) on the spontaneous beating rate of isolated right atrium of normal and reserpinized rat were investigated to assess direct and indirect actions on beta 1-adrenoceptors. l-EPH (3 x 10(-7) - 3 x 10(-5) M) and d-EPH (10(-6) - 10(-4) M) markedly increased beating rate of rat right atrium. l-MEP (10(-5) - 3 x 10(-4) M) showed slight increase in heart rate. The potency of positive chronotropic effect is l-EPH > d-EPH "l-MEP. l-EPH was about 3 times as potent as d-EPH. In addition, d-MEP (3 x 10(-5) - 3 x 10(-4) M) caused a decrease in heart rate. Positive chronotropic effects of EPH isomers and l-MEP were attenuated by pretreatment with atenolol ( a selective beta 1-adrenoceptor antagonist) or reserpine treatment (8 mg/kg, s.c.). In reserpinized atria, the maximal increase by d-EPH was quite small, and l-MEP decreased heart rate. On the other hand, d-MEP, at 3 x 10(-4) M, did not show antagonist activity against the positive chronotropic effect of isoprenaline (10(-10) - 10(-5) M). These results suggest that l-EPH, d-EPH and l-MEP have beta 1-adrenoceptor agonist activity, while d-MEP is suggested to have only low or no affinity for beta 1-adrenoceptors. The relatively weak activity of l-MEP is believed to be mainly mediated by released noradrenaline. It is also suggested that d-EPH has very potent noradrenaline-releasing activity.     

The effect of ketotifen on nitric oxide synthase activity

1. We studied the effect of ketotifen, a second generation H1-receptor antagonist on nitric oxide synthase (NOS) activity in colonic mucosa and in renal tissues, and on rat renal haemodynamics in vivo. 2. Ketotifen (100 micrograms ml-1) increased human colonic NOS activity from 3.7 +/- 0.6 to 14.5 +/- 1.3 nmol g-1 min-1 (P < 0.005, ANOVA). In rat renal cortical and medullary tissues ketotifen increased NOS activity by 55% and 86%, respectively (P < 0.001). The stimulation of NOS activity was attenuated by NADPH deletion and by the addition of N omega nitro-L-arginine methyl ester (L-NAME) or aminoguanidine, but not by [Ca2+] deprivation. NOS activity was unaffected by two other H1-antagonists, diphenhydramine and astemizole, or by the structurally related cyproheptadine. Renal cortical NOS activity was also significantly stimulated 90 min after intravenous administration of ketotifen to anaesthetized rats. 3. Ketotifen administration to anaesthetized rats induced modest declines in blood pressure and reduced total renal, cortical and outer medullary vascular resistance. This is in contrast to diphenhydramine, which did not induce renal vasodilatation. 4. We conclude that ketotifen stimulates NOS activity by mechanisms other than H1-receptor antagonism. The association of this effect with therapeutic characteristics of ketotifen and the clinical implications of these findings are yet to be defined.     

Endometrial connexin expression in the mare and pig: evidence for the suppression of cell-cell communication in uterine luminal epithelium

AIMS: To study the dose-response effects of intravenous terbutaline on the cardiovascular and respiratory autonomic nervous regulation. METHODS: The study followed a randomized, placebo-controlled crossover design in six healthy adult volunteers. The terbutaline dose ranged from 10 to 30 microg min(-1) We continuously measured electrocardiogram, finger systolic arterial pressure (SAP) and flow-volume spirometry in supine and upright positions at baseline and during 3 h drug infusion. The periodic variability components of R-R intervals (time between successive heart beats) and SAP in relation to respiration were assessed using spectral analysis techniques. The regularity of the time series was assessed by approximate entropy (ApEn) and the convolutedness by fractal dimension (FD). RESULTS: Terbutaline dose-dependently decreased total variability of R-R intervals, low frequency (LF) variability of R-R intervals (10 s waves), high frequency (HF) variability of R-R intervals (respiratory variability), total variability of SAP, HF variability of SAP, baroreflex sensitivity, plasma potassium concentration, approximate entropy of R-R interval and of SAP as well as fractal dimension of R-R interval. Terbutaline dose-dependently increased heart rate, LF/HF ratios of R-R intervals and of SAP, LF variability of SAP, minute ventilation and plasma terbutaline concentration. CONCLUSIONS: Terbutaline infusion decreases parasympathetic cardiovascular reactivity, baroreflex sensitivity, dimensionality of heart rate and plasma potassium concentration; it increases sympathetic dominance in cardiovascular autonomic balance, minute ventilation, and the regularity of heart rate and blood pressure time series.     

Systolic time intervals during isometric exercise in supine position should be corrected also for arterial pressure

In this paper we have studied the relationship between the systolic time intervals (STI) and the heart rate (HR) and systolic arterial pressure (SAP) in a group of 24 healthy subjects at three different effort levels during an isometric exercise in supine position and in basal conditions. We observed a decrease of the non corrected STI values during the exercise. Then we corrected STI using the regression equations obtained by plotting STI values versus the corresponding HR values at rest and during the exercise. We showed an increase of corrected left ventricular ejection time (LVET) during the whole exercise, and an increase of corrected total electromechanical systole (QS2c) at 50% effort level and then a return to the basal values. We also derived the multiple regression equations correlating QS2 and LVET with HR and SAP. Notwithstanding these equations show a significant positive correlation between the two STI considered and SAP only at the maximum effort, we corrected LVET and QS2 values by these equations assuming that the relationship between these parameters exists also in basal conditions and during the remaining stages of the exercise. By this correction we found a decrease of LVETc and QS2c in accordance with hemodynamic data reported by other authors. We may conclude that it seems useful to correct the STI obtained during isometric exercise in supine position both for HR and SAP.     

Regulation of beta-adrenoceptors in the guinea-pig sinoatrial node

This study examined the changes of beta-adrenoceptors in the guinea-pig sinoatrial nodal region following 7 day (-)-isoprenaline (400 micrograms/kg/h s.c.) infusion and the relationship between beta-adrenoceptor desensitization and receptor down-regulation. Changes in beta 1- and beta 2-adrenoceptor density were measured using quantitative autoradiography and function in organ bath studies. (-)-Isoprenaline treatment produced a marked decrease in total (from 57.5 to 33.9 fmol/mg protein), beta 1- (from 49.4 to 32.8 fmol/mg protein), and beta 2-adrenoceptor density (from 8.1 to 1.05 fmol/mg protein) in the sinoatrial node. In adjacent right atrium, treatment produced no change in total (39.5 and 36.7 fmol/mg protein) or beta 1-adrenoceptors (35.9 and 36.4 fmol/mg protein) but did decrease beta 2-adrenoceptors (from 3.7 to 0.3 fmol/mg protein). Chronotropic effects were measured in spontaneously beating right atrium. Procaterol, a selective beta 2-adrenoceptor agonist, caused a biphasic chronotropic response in control right atria, the first part of which was abolished in the tissue from treated animals. The maximum increase in right atrial rate to RO363, a beta 1-adrenoceptor selective partial agonist, was reduced from 114 bpm in control to 43 bpm in treated animals. In electrically driven right atrium with the sinoatrial node removed procaterol failed to produce a positive inotropic response via beta 2-adrenoceptors, but the maximum response to RO363 was reduced from 0.75 g in the control tissue to 0.12 g in the treated tissue. This study showed that changes in beta 2-adrenoceptor density following 7 day (-)-isoprenaline infusion are compatible with reduced functional responsiveness in the SA node. The reduction of beta 1-adrenoceptor number in the SA node was also compatible with the reduced chronotropic response in this tissue. However the lack of effect on beta 1-adrenoceptor density in the right atrium was not consistent with the decrease in beta 1-adrenoceptor mediated inotropic response in this tissue. This suggests that beta-adrenoceptor desensitization is not always associated with receptor down-regulation but depends also on the changes in the cell signalling system beyond the level of the receptor which differ according to the cardiac location.     

Antiallergic action of betotastine besilate (TAU-284) in animal models: A comparison with ketotifen

The effects of betotastine besilate (betotastine: TAU-284), a novel antiallergic drug, on homologous passive cutaneous anaphylaxis (PCA), mediator-induced cutaneous reaction, antigen-induced asthmatic responses and platelet-activating factor (PAF)-induced airway eosinophilia in several animal models, were compared to ketotifen. Betotastine (0.1 mg/kg, p.o.) and ketotifen (1 mg/kg, p.o.) inhibited both rat PCA and histamine-induced cutaneous reaction, whereas they showed little effect on serotonin-induced cutaneous reaction. Betotastine (0.3 mg/kg, p.o.) and ketotifen (1 mg/kg, p.o. ) significantly inhibited antigen-induced bronchoconstriction in guinea pigs which had been passively sensitized with guinea pig IgE antibody. In actively sensitized guinea pigs, the immediate and late phase increase in airway resistance (Rrs) were observed within 5 min and between 4 and 7 h after the aeroantigen challenge. Betotastine (1 mg/kg, p.o.) inhibited both responses. Ketotifen (1 mg/kg, p.o.) inhibited the immediate phase response, but did not affect the late phase response. Exposure of guinea pigs to aerosolized PAF increased the number of eosinophils in bronchoalveolar lavage fluid 24 h after the stimulation. Betotastine (3-10 mg/kg, p.o.) dose-dependently inhibited PAF-induced accumulation of eosinophils in the bronchoalveolar cavity. In contrast, cetirizine (10 mg/kg, p.o.) showed a tendency to inhibit eosinophil accumulation, and ketotifen (10 mg/kg, p.o.) and terfenadine (10 mg/kg, p.o.) did not have any affect. These results indicate that betotastine could be useful in the treatment of allergic disease such as bronchial asthma.     

Opposite modulation of noradrenaline and ATP release in guinea-pig vas deferens through prejunctional beta-adrenoceptors: evidence for the beta 2 subtype

Activation of prejunctional beta-adrenoceptors has been suggested to increase the release of noradrenaline but to decrease the neural release of ATP in the guinea-pig vas deferens. Experiments were carried out to determine the subtype of beta-adrenoceptor involved. In [3H]-noradrenaline-preincubated tissues superfused with medium containing prazosin and suramin, isoprenaline (1-100 nM), salbutamol (0.01-1 microM) and terbutaline (0.1-10 microM) increased the overflow of tritium but reduced the overflow of ATP elicited by electrical stimulation (210 pulses/7 Hz). The effects of isoprenaline were blocked by the beta 2-selective antagonist 1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3- [(1-methylethyl)amino]-2-butanol (ICI 118,551; 100 nM). In prazosin- and suramin-free medium, isoprenaline (100 nM) did not change the overflow of ATP elicited by exogenous noradrenaline (10 microM). Isoprenaline (1-100 nM), salbutamol (0.01-1 microM) and terbutaline (0.1-10 microM) reduced the initial twitch contraction elicited by electrical stimulation (210 pulses/7 Hz) in prazosin- and suramin-free medium as well as the isolated purinergic neurogenic contraction obtained by exposure to prazosin. They increased or tended to increase the secondary sustained concentration elicited by electrical stimulation in prazosin- and suramin-free medium as well as the isolated adrenergic neurogenic contraction obtained in the presence of suramin. The inhibition by isoprenaline of the isolated purinergic contraction was attenuated by ICI 118,551 (100 nM) but not by the beta 1-selective antagonist 1-[2-((3-carbamoyl- 4-hydroxy)phenoxy)ethylamino]-3-[4-(1-methyl-4- trifluoromethyl-2-imidazolyl)phenoxy]-2-propanol (CGP 20712A; 100 nM). The results confirm the opposite beta-adrenoceptor-mediated modulation of noradrenaline and neural ATP release in the guinea-pig vas deferens. They show that the prejunctional beta-adrenoceptor is of the beta 2-subtype.     

Effects of ketotifen on symptoms and on bronchial mucosa in patients with atopic asthma

Ketotifen is marketed throughout the world as an antiallergy drug, but whether it affects infiltration of inflammatory cells into airway mucosa is not known. We studied the effects of ketotifen on symptoms, pulmonary function, and airway inflammation in 25 patients with atopic asthma. Patients took ketotifen (1 mg twice daily) or a matching placebo for 8 weeks in a double-blind, parallel-group study. Data recorded on diary cards were used for 2 weeks before treatment began, and they were used for the last 2 weeks of treatment to study asthma symptoms, use of beta 2-agonists, and peak expiratory flow (PEF). Pulmonary function tests, bronchial responsiveness to methacholine, and fiberoptic bronchoscopy were performed before and after treatment. Biopsy specimens were obtained by bronchoscopy. Specimens were stained immunohistochemically with monoclonal antibodies against stored eosinophil cationic protein (EG1), the secreted form of eosinophil cationic protein (EG2), mast-cell tryptase (AA1), neutrophil elastase (NP57), CD3, CD4, CD8, and CD25. The numbers of positively stained cells in the lamina propria were counted. Compared with the placebo, the ketotifen-treated group exhibited significant improvement of asthma symptoms (P < 0.05) and bronchial responsiveness (P < 0.05). This was accompanied by a reduction of EG2+ eosinophils (P < 0.05), CD3+ T cells (P < 0.001), CD4+ T cells (P < 0.01), and CD25+ activated T cells (P < 0.01) in the bronchial mucosa. These results suggested that the beneficial effects of ketotifen in bronchial asthma may result from consequent inhibition of activated eosinophils and T-cell recruitment into the airway. Moreover, ketotifen may relieve allergic inflammation in bronchial asthma.     

Specific and long-lasting suppression of rat adjuvant arthritis by low-dose Mycobacterium butyricum

The thyrotropin-releasing hormone (TRH) analog, RX 77368, (p-Glu-His-(3,3'-dimethyl)-Pro-NH2) injected intracisternally (i.c.) at low doses increases gastric mucosal blood flow through vagal cholinergic and calcitonin gene-related peptide dependent pathways. The influence of the mast cell stabilizer, ketotifen, on i.c. injection of RX 77368 (1.5 ng)-induced changes in gastric mucosal blood flow (hydrogen gas-clearance technique), gastric acid secretion and mean arterial pressure was studied in urethane-anesthetized rats. RX 77368 increased gastric blood flow by 131% and systemic arterial pressure by 11 mm Hg and decreased gastric mucosal vascular resistance by 54% whereas acid secretion was not altered within the 30 min period post injection. Ketotifen had no effect on these basal parameters but abolished i.c. RX 77368-induced increased gastric mucosal blood flow and decreased gastric vascular resistance. These data suggest that mast cells may be part of the peripheral mechanisms involved in vagal gastric hyperemia induced by TRH analog injected i.c. at a low dose.     

Effects of the administration of acebutolol in patients with chronic angina of effort

12 patients suffering from chronic coronary insufficiency with signs of ischemia in the ECG, were treated orally with 200 mg of acebutolol t.i.d. for a period of 3 weeks. The following parameters were examined at the beginning of the therapy as well as at the end of every week: number of stenocardiac attacks, characteristics of pain, nitroglycerin consumption, B.P., H.R., respiratory rate, ECG, maximal exercise test, PEP, LVET, PEP/LVET at rest and immediately after effort. The treatment with acebutolol was effective inducing an improvement of subjective symptoms (reduction of stenocardiac crises, intensity and duration of angor, trinitrin pearls consumption) and an increase of effort tolerance. The utility of the therapy was also proved by the reduction of the systolic pressure and by the following decrease of hemodynamic overload and, therefore, of the heart muscle's work. This positive effect is due to the reduction of the myocardial oxygen consumption, modulated among others by the bradycardiac action of the drug. The cardioselectivity of acebutolol avoided to cause peripherical disorders usually observed with other non selective beta blocking drugs.     

Selective ETA receptor blockade prevents left ventricular remodeling and deterioration of cardiac function in experimental heart failure

BACKGROUND: Left ventricular (LV) dilation, which is a predictor of survival in humans with chronic heart failure (CHF), is limited by a mixed endothelin ETA-ETB antagonist. Whether selective ETA receptor blockade influences LV dilation is unknown. We determined, in a rat model of CHF, the effects of the ETA receptor blocker LU 135,252 on LV remodeling. METHODS AND RESULTS: Rats were subjected to coronary artery ligation and treated for ten weeks with placebo or LU 135,252 (LU), at a dose of 10 or 30 mg kg-1 day-1. Systolic blood pressure and heart rate (plethysmography) were determined in conscious animals before and after four and ten weeks of treatment. At these time points, cardiac output and LV dimensions were measured in anesthetized rats by transthoracic echocardiography. LV hemodynamics were determined in anesthetized rats after ten weeks. Pressor responses to ET-1 (1 nmol/kg, i.v.) and sarafotoxin S6c (0.3 ng/kg, i.v.) were measured, to assess the efficacy of ET receptor antagonism and the lack of blockade of ETB receptor blockade, respectively. The pressor response to ET-1 was significantly reduced by LU (% change in systolic blood pressure: sham: 9 +/- 1; CHF: 5 +/- 1; CHF LU: 0 +/- 3 and -4 +/- 2% for the low and high dose, respectively). LU did not affect the response to sarafotoxin (CHF: -37 +/- 3; CHF LU: -29 +/- 3 and -28 +/- 2% for the low and high dose, respectively). Both doses of LU decreased systolic blood pressure, but only the high dose of LU reduced heart rate. Furthermore, LU restored cardiac output dose-dependently throughout the study. Both doses of LU limited LV dilatation and deterioration of LV fractional shortening to the same extent. After ten weeks, LU normalized LV end-diastolic- and central venous pressures, but did not affect LV dP/dtmax or dP/dtmin. LU did not prevent the development of cardiac hypertrophy, but reduced LV collagen density. CONCLUSIONS: In this rat model, the selective ETA receptor blocker LU, at the dose of 30 mg kg-1 day-1, reduced blood pressure and heart rate, limited progressive left ventricular remodeling and improved cardiac hemodynamics and function. These effects of LU might have important clinical relevance in the treatment of heart failure.     

Caffeine enhances the physiological response to occupational stress in medical students.

Tested caffeine (3.3 mg/kg) against a placebo in 20 male medical students (aged 19–31 yrs) during periods of low (no exams) vs high (final exams) work stress. On each of 8 test days, heart rate and blood pressure were measured at baseline and over a 40-min postdrug interval; immediately afterward, blood was drawn to test plasma cortisol and serum lipid concentrations. Exams increased heart rate and systolic blood pressure. Caffeine decreased heart rate and increased systolic blood pressure, diastolic blood pressure, plasma cortisol levels, and serum cholesterol levels. Caffeine effects were additive with those of exams, and together they increased the number of Ss showing systolic blood pressures in the borderline hypertensive range. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hemodynamic determinants of the time-course of fall in canine left ventricular pressure

The hemodynamic determinants of the time-course of fall in isovolumic left ventricular pressure were assessed in isolated canine left ventricular preparations. Pressure fall was studied in isovolumic beats or during prolonged isovolumic diastole after ejection. Pressure fall was studied in isovolumic relaxation for isovolumic and ejecting beats (r less than or equal to 0.98) and was therefore characterized by a time constant, T. Higher heart rates shortened T slightly from 52.6 +/- 4.5 ms at 110/min to 48.2 +/- 6.0 ms at 160/min (P less than 0.01, n = 8). Higher ventricular volumes under isovolumic conditions resulted in higher peak left ventricular pressure but no significant change in T. T did shorten from 67.1 +/- 5.0 ms in isovolumic beats to 45.8 +/- 2.9 ms in the ejecting beats (P less than 0.001, n = 14). In the ejecting beats, peak systolic pressure was lower, and end-systolic volume smaller. To differentiate the effects of systolic shortening during ejection from those of lower systolic pressure and smaller end-systolic volume, beats with large end-diastolic volumes were compared to beats with smaller end-diastolic volumes. The beats with smaller end-diastolic volumes exhibited less shortening but similar end-systolic volumes and peak systolic pressure. T again shortened to a greater extent in the beats with greater systolic shortening. Calcium chloride and acetylstrophanthidin resulted in no significant change in T, but norepinephrine, which accelerates active relaxation, resulted in a significant shortening of T (65.6 +/- 13.4 vs. 46.3 +/- 7.0 ms, P less than 0.02). During recovery from ischemia, T increased significantly from 59.3 +/- 9.6 to 76.8 +/- 13.1 ms when compared with the preischemic control beat (P less than 0.05). Thus, the present studies show that the time-course of isovolumic pressure fall subsequent to maximum negative dP/dt is exponential, independent of systolic stress and end-systolic fiber length, and minimally dependent on heart rate. T may be an index of the activity of the active cardiac relaxing system and appears dependent on systolic fiber shortening.     

The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle

Beta1- and beta2-adrenoceptors in heart muscle cells mediate the catecholamine-induced increase in the force and frequency of cardiac contraction. Recently, in addition, we demonstrated the functional expression of beta3-adrenoceptors in the human heart. Their stimulation, in marked contrast with that of beta1- and beta2-adrenoceptors, induces a decrease in contractility through presently unknown mechanisms. In the present study, we examined the role of a nitric oxide (NO) synthase pathway in mediating the beta3-adrenoceptor effect on the contractility of human endomyocardial biopsies. The negative inotropic effects of a beta3-adrenoceptor agonist, BRL 37344, and also of norepinephrine in the presence of alpha- and beta1-2-blockade were inhibited both by a nonspecific blocker of NO, methylene blue, and two NO synthase (NOS) inhibitors, L-N-monomethyl-arginine and L-nitroarginine-methyl ester. The effect of the NOS inhibitors was reversed by an excess of L-arginine, the natural substrate of NOS, but not by D-arginine. Moreover, the effects of the beta3-adrenoceptor agonist on contractility were associated with parallel increases in the production of NO and intracellular cGMP, which were also inhibited by NOS inhibitors. Immunohistochemical staining of human ventricular biopsies showed the expression of the endothelial constitutive (eNOS), but not the inducible (iNOS) isoform of NOS in both ventricular myocytes and endothelial cells. These results demonstrate that beta3-adrenoceptor stimulation decreases cardiac contractility through activation of an NOS pathway. Changes in the expression of this pathway may alter the balance between positive and negative inotropic effects of catecholamines on the heart potentially leading to myocardial dysfunction.