X indening oral liquid improves cardiac function of rats with chronic cardiac failure via TGF-ß1/Smad3 and p38 MAPK pathway.

OBJECTIVE: Xindening oral liquid (Xin) is a widely used traditional Chinese medicine for the treatment of chronic heart failure (CHF). However, the exact mechanisms related to its therapeutic effects against CHF remain unclear. In the present study, we investigate the effects of Xin on cardiac function in CHF rats and the possible mechanisms involved. METHODS: Transverse aortic constriction (TAC) was conducted to induce a CHF rat model in this study. Sixty male Wistar rats were randomly assigned to six groups 28 days after TAC: sham; CHF model; Xin at concentrations of 5 ml/kg, 10 mL/kg, and 20 mL/kg; and QiLi 0.6 g/kg. After four weeks, the rats were treated with Xin (5, 10, or 20 mL/kg/d) for six weeks consecutively. At the end of the study, the cardiac function, heart weight index (HWI) and left ventricular mass index (LVMI), serum level of LDH, B-type natriuretic peptide (BNP), cTnI and CK-MB, and collagen volume fraction were studied. The expression of transforming growth factor-ß1 (TGF-ß1), drosophila mothers against decapentaplegic protein 3 (Smad3), and p38 mitogen activated protein kinase (p38 MAPK) were detected. RESULTS: The results showed that Xin treatment significantly improved cardiac function but decreased the serum level of LDH, BNP, cTnI, and CKMB of CHF rats. In addition, it reduced the HWI, LVMI, and collagen volume fraction compared with the model group. Xin treatment significantly improved cardiac function and attenuated cardiac fibrosis by suppressing the p38 MAPK and TGF-ß1/Smad3 signaling pathway in CHF rats. CONCLUSION: These results suggested that Xin might be a promising complementary treatment for CHF. More detailed experimental studies will be carried out in our subsequent research.

Effects of adrenergic receptor blockers on adrenaline and nicotine-induced hyperglycaemia in the rat.

Studies in fasted, anaesthetized rats have shown that adrenaline and nicotine-induced hyperglycaemia is mediated via activation of beta-adrenoceptors. The hyperglycaemic response to nicotine is different from that of adrenaline in that, unlike adrenaline hyperglycaemia, nicotine hyperglycaemia is characterized by a long latent period, delayed attainment of peak of response and sustained hyperglycaemia throughout the 120 minutes post-injection observation. Comparison with previous studies in dogs showed that different receptors are involved in nicotine hyperglycaemia in fasted dogs and fasted rats.

Surgical treatment of constrictive pericarditis due to practolol. A case report.

We report a case of constrictive pericarditis presenting as a late complication of Practolol therapy associated with polyserositis. The patient had a successful result following pericardectomy. This is the first documented case of surgical treatment for Practolol induced constrictive pericarditis.

The correlation between CK MB curve type and the clinical course of recent myocardial infarction.

In 265 patients with acute myocardial infarction (MI) for whom the 72-hour CK MB curve was obtained, three types of a curve were found: with a single and early 16 h peak value (type A), with a single late 16 h peak value (type B), and with a double peak (type C). Type A of the CK MB curve was found in 32% of patients with acute MI, type B in 55% and type C in 13%. There were no significant differences of CK MB max between the type groups. Infarct size differed significantly between groups (A-29 +/- 19, B-35 +/- 22, C-53 +/- 30 g Eq CK MB). In-hospital mortality also differed significantly particularly between type C (31%) and type A groups (5%). Nitroglycerin or practolol given intravenously during the first 48 hours changed the CK MB curve mainly by decreasing CK MB max as compared to controls treated conventionally. There was no effect of treatment with either nitroglycerin or practolol on the clinical course in patients with type A CK MB curve. There is a good correlation between the CK MB curve type and the clinical course of MI. Nitroglycerin or practolol decreased the infarct size only in patients with either B or C type of CK MB curve, having no influence in patients with a mild form of acute MI (type A).

Electrocardiographic changes during microlaryngoscopy in practolol-pretreated patients under balanced anaesthesia.

Electrocardiographic (ECG) changes were studied in 82 adult patients with a mean age of 49 years undergoing microlaryngoscopy. The patients were pretreated with practolol 0.15 mg/kg i.v. 5 min before induction of anaesthesia with thiopental. Anaesthesia was maintained with nitrous oxide in oxygen, fentanyl and suxamethonium-infusion. ECG changes occurred in 49% of the patients before anaesthesia and procedure. Pre-existing ECG changes increased or new changes occurred in 39% of the patients during intubation and in 38% during the procedure. The most common preanaesthetic ECG changes were flat or negative T-wave (18%), sinus tachycardia (13%), ischaemic S-T segment depression (8.5%) and intraventricular conduction disturbance (8.5%). ECG changes during intubation were sinus tachycardia (16%), ventricular ectopic beats (12%), supraventricular ectopic beats (10%) and ischaemic S-T segment depression (10%). The most common changes during microlaryngoscopy were supraventricular ectopic beats (16%), T-wave flattening or inversion (15%), ischaemic S-T segment depression (11%) and sinus bradycardia (10%). In all patients ECG changes disappeared without any special treatment. Unlike our earlier identical study without practolol pretreatment, neither sinus tachycardia nor junctional rhythm occurred during microlaryngoscopy in the present study. The results suggest that practolol pretreatment before microlaryngoscopy is especially useful when sinus tachycardia and junctional rhythm should be avoided.

Some new positive inotropic agents.

In the search for new effective positive inotropic agents for the treatment of congestive heart failure (CHF), interest has focused mainly on two groups of agents namely adrenoceptor agonists and drugs inhibiting phosphodiesterase. Common for drugs belonging to both groups is that their positive inotropic effects seem to involve an increase in the intracellular concentration of cyclic AMP. Drugs acting by stimulation of beta 1- and/or beta 2-adrenoceptors (e.g. dopamine, dobutamine, prenalterol, pirbuterol, salbutamol, terbutaline, fenoterol) have initial beneficial effects, but seem to be ineffective for long-term treatment. This has been suggested to be due to desensitization of the beta-adrenoceptors, and means, if this effect can be definitely established, that beta-adrenoceptor stimulation should be restricted to the acute treatment of CHF. Among drugs inhibiting phosphodiesterase, sulmazole, amrinone, milrinone, and fenoximone all have been shown to improve cardiac performance in patients with CHF during short-term treatment. However, results of long-term treatment with most of these drugs seem less encouraging. It has been suggested that these drugs may not be an effective approach to treatment of patients with CHF, since even if it is possible to achieve short-term gains, the long-term effects on the myocardium may be detrimental. Their ultimate place in the treatment of CHF remains to be established.

Curve-fitting in pharmacokinetics--a comparison between gamma- and biexponential fits.

Seven sets of plasma concentration-time data were fitted to both a conventional biexponential equation and a gamma equation. The values of clearance (CL) and mean residence time (MRT) were calculated from the fitted parameters and compared with the values calculated by the trapezoid rule. Both the biexponential and gamma equations provided adequate fits to the data. The values of CL and MRT calculated from the biexponential fits correlated very closely with the values calculated by the trapezoid rule, but there were large discrepancies between the values calculated from the gamma fits and the trapezoid rule. The biexponential model appears to be less sensitive to scatter in the data.

Hemodynamic response to oral prenalterol in dilated decompensated cardiomyopathy as a result of cardiac and vascular effects.

The initial antifailure efficacy of beta-adrenergic agonists is generally lost during prolonged treatment. The reasons are not fully understood. In 11 patients with advanced cardiac decompensation due to dilated cardiomyopathy, prenalterol, a selective beta 1 adrenergic agonist, improved the left ventricular contractility after acute intravenous and during prolonged oral administration. However, after periods of treatment ranging from 2 to 18 weeks, blood pressure and systemic vascular resistance were raised in each patient. These changes resulted in an increase of the left ventricular afterload which was such as to overwhelm the effects of the enhanced contractility, and to extinguish the initial improvement of the cardiac function and of the clinical condition. Stimulation of the presynaptical beta-receptors facilitating norepinephrine release or of the renin secretion by this beta 1 agonist, may be the causes of the systemic vasoconstriction and of the loss of effectiveness in the long run.

[Chronic therapy of congestive cardiomyopathy: effects of prenalterol and digoxin]. / Chronische Therapie der kongestiven Kardiomyopathie: Wirkungen von Prenalterol und Digoxin.

UNLABELLED: Prenalterol (P), a partial adrenergic agonist with functional beta 1-specificity, has been shown to have inotropic effects when given orally and thus represents a potential substitute or adjunct to conventional digitalis therapy (D) in the long-term management of congestive cardiomyopathy (COCM). A direct comparison between both drugs has not been reported. In a blind controlled trial, 15 patients with COCM (NYHA II-III) with sinus rhythm and a left ventricular ejection fraction (LV-EF) of 34.5 +/- 2.6% received consecutively D (0.25-0.5 mg/d), placebo (PLAC), P (slow releases = SR) (80 mg/d SR) and both drugs combined in respective doses. After 4 weeks of therapy with each drug, effects were assessed by gated blood pool scintigraphy at rest (R) and during graded bicycle exercise (EX), systolic time intervals (STI), Holter monitoring and a clinical score. Plasma levels of both drugs and of catecholamines and lactate were also determined. Compared to PLAC, LV-EF was not significantly altered by D at R (34.5 +/- 2.6 vs. 31.9 +/- 2.3%, p = ns), but a shortening of the QS2-interval could be demonstrated (533 +/- 7 vs. 550 +/- 6 msec, p less than 0.05). In contrast, during EX an improvement of LV-EF was observed (34.5 +/- 3 vs. 31.3 +/- 2.8%, p less than 0.05). P alone showed no significant alterations in LV-EF and STI, along with a lack of symptomatic improvement. The addition of D (D + P) resulted in improved left ventricular performance both at R (LV-EF 37.9 +/- 3.3 vs. 31.9 +/- 2.3%, p less than 0.01, QS2 530 +/- 8 vs. 550 +/- 6 msec, p less than 0.01) and during EX (LV-EF 35.3 +/- 2.5 vs. 31.1 +/- 2.8%). Values between D and D + P were not significantly different. No drug or combination improved maximal working capacity. CONCLUSIONS: Beneficial effects of chronic treatment with D could be demonstrated in patients with COCM, particularly during EX. Further studies are needed to determine why the acute effects of P are not fully sustained during long-term therapy.

Decrease in beta-receptor density explaining the development of pindolol- and prenalterol-tolerance in orthostatic hypotension.

A 58-year-old woman with diabetic autonomic dysfunction was well treated for orthostatic hypotension with pindolol. After eight months however, symptoms recurred in spite of continued treatment with pindolol. Addition of prenalterol, a beta-blocking agent with very high intrinsic sympathomimetic activity, had a marked clinical effect on her orthostatic hypotension. Before treatment with prenalterol, stroke volume and left ventricular enddiastolic volume markedly decreased during tilt, as demonstrated by radionuclide angiography. After short-term prenalterol treatment, the orthostatic decreases of stroke volume and left ventricular end-diastolic volume were less pronounced. During continued prenalterol treatment, both symptoms and haemodynamic changes recurred in the erect position. Beta-receptor density in her lymphocytes decreased from elevated levels before prenalterol to subnormal levels, when the clinical effect had disappeared. The data suggest that the tolerance development to prenalterol may be explained by the decrease in beta-adrenergic receptor density.

Immediate central hemodynamic effects of five different beta-adrenoceptor-blocking agents, acebutolol, atenolol, pindolol, practolol, and propranolol, in patients with ischemic heart disease.

The hemodynamic effects of acebutolol were studied in six patients with ischemic heart disease. The changes in heart rate, cardiac output, and arterial blood pressure were determined after intravenous administration of six increasing doses of acebutolol to a cumulative dose of 0.64 mg/kg. After the sixth dose of acebutolol, cardiac output and heart rate were reduced 15% and 8%, respectively. Pulmonary artery pressure was increased by 4 mm Hg. Arterial blood pressure was not changed significantly. The effects of graded doses of acebutolol on heart rate and cardiac output were compared with earlier obtained results after atenolol (0.19 mg/kg), pindolol (0.025 mg/kg), practolol (0.64 mg/kg), and propranolol (0.19 mg/kg). The effects of increasing doses of acebutolol and practolol were very similar and significantly different from the effects of the other three drugs in spite having been administered at equipotent doses. The hemodynamic effects of acebutolol support the hypothesis that the hemodynamic response to beta-adrenoceptor antagonist drugs at rest is determined primarily by the degree of intrinsic sympathomimetic activity, whereas beta-1 selectivity does not modify the central hemodynamic response.

Alpha and beta-blockade and beta-stimulation in Raynaud's syndrome: a double-blind, placebo controlled, single dose study.

We examined in a double blind fashion and placebo controlled the effects of some alpha and beta adrenergic receptor agonists and antagonists on the recovery of finger skin temperature 12 min after finger cooling (5 min waterbath for both hands) in twelve patients with Raynaud's syndrome. A favourable effect was established on phenoxybenzamine 20 mg as compared to placebo. A significant but rather small effect on orciprenaline 10 mg. The beta-agonists prenalterol (10 mg) and terbutaline (5 mg) did not influence the recovery of finger skin temperature. The beneficial effect of phenoxybenzamine 20 mg was not influenced by the addition of beta-agonists (prenalterol 10 mg or terbutaline 5 mg) or a beta-blocker (propranolol 40 mg). The beta-agonists terbutaline and orciprenaline caused a fall in diastolic pressure and an increase in heart rate. These effects presumably were connected with one collapse and three near-collapses. On alpha- and beta-blocker (phenoxybenzamine and propranolol) a decrease in systolic pressure appeared, whereas diastolic pressure did not significantly differ from the placebo value. While physical exercise is considered to exacerbate the hypotensive effect of alpha-blockers, a fall in blood pressure during physical exercise could not be established in our experiments after the addition of propranolol to the alpha-blocker phenoxybenzamine. Our results suggest that an alpha-blocker is a good choice in Raynaud's syndrome, whereas the addition of a beta-blocker may have some advantages.

Are the clinical benefits of oral prenalterol in ischaemic heart failure due to beta blockade? A six month randomised double blind comparison with placebo.

The clinical effects of the oral beta 1 partial agonist, prenalterol, were investigated in 37 patients (29 male, eight female; mean age 57 years) with chronic ischaemic left ventricular failure using a placebo controlled randomised double blind protocol over six months. All patients were limited by dyspnoea (New York Heart Association class III) despite treatment with digoxin and diuretics. Twenty eight patients completed the protocol. Moderate clinical improvement was seen in the prenalterol group, whereas there was little change in the placebo group. Bicycle exercise capacity increased over six months in the prenalterol and placebo groups but only achieved statistical significance for prenalterol when compared with baseline values. Maximum exercise heart rate was significantly reduced in the prenalterol group compared with placebo. Radionuclide left ventricular ejection fraction at rest and during exercise and cardiothoracic ratio showed no significant improvement in either group over six months. Prenalterol was well tolerated and produced no increase in frequency of angina or ventricular arrhythmias. Prenalterol produced clinical benefits and improved exercise tolerance while reducing exercise heart rate. A moderate placebo response was noted. The apparent beta blocking effect of prenalterol may be as important as the beta 1 agonist effect in producing these benefits. Prenalterol has, however, been withdrawn because of side effects in animals.

The possible role of the ancillary properties of beta adrenoceptor antagonists in the management of angina pectoris.

Beta adrenoceptor antagonists are effective in the symptomatic management of angina pectoris. This paper examines critically the possible influence of the ancillary properties of beta 1 selectivity, partial agonism and membrane-stabilizing action on the response in anginal patients. The response is categorized according to experimental, pharmacological and clinical endpoints, placing emphasis on the possible errors which may arise from extrapolation from the former to the latter. It is concluded: That selective beta adrenoceptor antagonism confers limited, but tangible advantages over non-selective antagonists in regard to patients with reversible airways obstruction, and also in the metabolic and haemodynamic response to acute hypoglycaemia. Cardioselectivity does not influence the central haemodynamic response to exercise, but lessens adrenaline-mediated hypertensive responses to smoking and hypoglycaemia. Non-selective partial agonists cause less reduction in resting ventricular function, but their effects on cardiac output during exercise are indistinguishable from full antagonists. Membrane stabilizing properties have a marked influence on the tolerability of these agents in terms of unwanted, nonspecific central nervous system symptoms. Unresolved questions relate to the influence of partial agonism on fatigue, metabolic responses, especially blood lipids and glucose, and the possibility of lesser efficacy in angina compared to full antagonists.

[Positive inotropic agents. Generalities and classification]. / Les inotropes positifs. Généralités et classification.

The aim of inotropic therapy is to increase the force of myocardial fibre shortening by improving the availability of calcium to the contractile proteins. Digitalis remains the most widely used drug, but its positive inotropic effects are weak and the therapeutic index is low. Dobutamine is the most useful catecholamine because the most cardioselective and it induces the least increase in myocardial oxygen consumption. There are three groups of new inotropic agents: sympathomimetics: pirbuterol and prenalterol are effective in the short term but tolerance is usually observed within a few weeks. Salbutamol and terbutaline have only been assessed in acute studies, phosphodiesterase inhibitors (MDL 17043, MDL 19025) are powerful inotropic agents in the short and medium term. ARL 115 has mainly been studied by parenteral administration, Amrinone has a largely unknown mode of action, but is a very effective positive inotropic drug; its side-effects limit it as age. However, its derivative, milrinone, seems to be more inotropic and less toxic. The new inotropic drugs currently under assessment are active in the short term but their long-term efficacy and side-effects are still little known. The ideal inotropic agent remains to be discovered.