A blinded, randomized, controlled trial of three doses of high-dose insulin in poison-induced cardiogenic shock.

BACKGROUND: High dose insulin (HDI) has proven superior to glucagon and catecholamines in the treatment of poison-induced cardiogenic shock (PICS) in previous animal studies. Standard recommendations for dosing of insulin vary and the optimal dose of HDI in PICS has not been established. Our hypothesis was a dose of 10 U/kg/hr of HDI would be superior to 1 U/kg/hr with cardiac output (CO) as our primary outcome measure in pigs with propranolol-induced PICS. METHODS: This was a blinded, prospective, randomized trial with 4 arms consisting of 4 pigs in each arm. The arms were as follows: placebo (P), 1 U/kg/hr (HDI-1), 5 U/kg/hr (HDI-5), and 10 U/kg/hr (HDI-10). Cardiogenic shock was induced with a bolus of 0.5 mg/kg of propranolol followed by an infusion of 0.25 mg/kg/min until the point of toxicity, defined as 0.75 x (HR x MAP) was reached. At this point the propranolol infusion was decreased to 0.125 mg/kg/min and a 20 mL/kg bolus of normal saline (NS) was administered. The protocol was continued for 6 hours or until the animals died. RESULTS: 2 pigs died in the P arm, 1 pig died each in the HDI-1 and HDI-5 arms, and all pigs lived in the HDI-10 arm. There was a statistically significant difference in dose by time interaction on CO of 1.13 L/min over the 6 hr study period (p = < 0.001). There was also a statistically significant difference in dose by time interaction on MAP, HR, and systemic vascular resistance (SVR). No statistically significant difference was found between any of the arms regarding glucose utilization. CONCLUSION: HDI was statistically and clinically significantly superior to placebo in this propranolol model of PICS. Furthermore a dose response over time was found where CO increased corresponding to increases in doses of HDI.

Nitric oxide induced sinusoidal relaxation after a propranolol priming dose in the perfused rat liver reduces propranolol availability on subsequent dosing.

1. The present study sought to explain the mechanism leading to reduced availability of propranolol when given after a priming dose in the single-pass perfused rat liver. 2. Extracellular sucrose space (as a measure of sinusoidal relaxation) in perfused rat liver before and after propranolol or propranolol and N(G)-nitro-L-arginine methyl ester (L-NAME; nitric oxide (NO) synthase inhibitor) treatment were examined. The results showed that propranolol induces sinusoidal relaxation in the perfused liver and this effect could be abolished by NO synthase inhibitor L-NAME. 3. Two bolus injections of propranolol were given to the isolated perfused rat liver and outflow concentration-time profiles of intact propranolol were determined. A two-phase physiologically based organ pharmacokinetic model was applied to estimate hepatocellular influx, efflux, binding, ion-trapping and metabolic elimination pharmacokinetic parameters for propranolol. The recovery of propranolol in the second injection was approximately 54% of that in the first injection. The permeability-surface area product, the binding and the intrinsic clearance all increased significantly after prior exposure of the rat liver to the first bolus of propranolol (P < 0.05). 4. Based on the findings of the present study, we propose that the most likely explanation for the reduced availability of a second propranolol dose (after administration of a priming dose) in the perfused liver is a consequence of the NO-mediated sinusoidal relaxation effect of propranolol, arising from the priming dose. This observation supports the view that the pharmacokinetics of some drugs might be altered by the pharmacodynamic effects of the same drug given earlier in the perfused liver.

Increased tracheal responsiveness to beta-adrenergic agonist and antagonist in ovalbumin-sensitized guinea pigs.

Despite the controversy of bronchial responsiveness to beta2-agonist drugs in asthma, in a previous study we have shown increased responsiveness of asthmatic tracheobronchial tree to isoprenaline. Therefore, in the present study, tracheal responsiveness to isoprenaline and also beta-adrenergic receptor blockade were studied in sensitized guinea pigs. An experimental model of asthma was induced in guinea pigs by sensitization of animals with injection and inhalation of ovalbumin (OA). The responses of tracheal chains of sensitized and control animals to cumulative concentrations of isoprenaline (I) in the absence and presence of 10 nmol/l propranolol were measured, and the effective concentration of I causing 50% of maximum response (EC50 I) was obtained. The propranolol blockade (CR - 1) was calculated by: (post-propranolol EC50 I/EC50 I) - 1. Tracheal responses of sensitized and control animals to cumulative concentrations of methacholine (M) were also measured and EC50 M were obtained. The tracheal responses of sensitized guinea pig to isoprenaline was significantly higher than that of the control animals (EC50 I for sensitized and control animals were 0.24 +/- 0.04 and 0.58 +/- 0.07 micromol/l, respectively; p < 0.001). The beta-adrenergic receptor blockade by propranolol (CR - 1) was also significantly higher in sensitized guinea pigs than that of the control animals (p < 0.001). The results of this study indicate an increased tracheal response to beta-adrenergic-stimulating drug and enhancement of beta-adrenergic blockade by propranolol in the sensitized guinea pig.

Inhibition of (-)-propranolol hydrochloride by its enantiomer in white mice--a placebo-controlled randomized study.

BACKGROUND: A previous pilot study was performed to see if toxicity of (S)-(-)-propranolol hydrochloride may be inhibited by a potentized preparation of its enantiomer. The present study is based on the hypothesis that the toxic effects of an optical isomer, may be counteracted or reversed by the administration of a potentized preparation of one of its stereoisomers, and in particular the enantiomer. METHODS: 508 ICR conventional mice were used. 254 mice were administered (R)-(+)-propranolol HCl homeopathic potency prior to and during the experiment, and the other 254 were administered indistinguishable placebo. On the day of the experiment mice were anesthetized with intraperitoneal Rometar. Once sedated the mice were administered the LD50 dose of (-)-propranolol HCl intraperitoneally. RESULTS: The end point for statistical analysis was the difference in survival between the placebo and treatment mice. The odds ratio for survival of treatment mice relative to placebo mice was 1.52. The hypothesis of equal survival proportions gave a chi-square of 5.0429 (1 degree of freedom), which has a p-value of 0.0247. The analysis was then adjusted for mouse weight and intraperitoneal (-)-propranolol dosage using a logistic regression (LR) model. The LR treatment odds ratio was 1.51 and the LR treatment chi-square was 4.8112 (1 degree of freedom), which has a p-value of 0.0283. Consequently, we reject the null hypothesis of no treatment effect on survival. Eleven percent more treatment mice survived than placebo mice. CONCLUSION: We conclude that the toxicity of intraperitoneal (-)-propranolol HCl, may be counteracted by administration of a potency of its enantiomer, in ICR conventional mice which have survived preceding intraperitoneal Rometar injection, and pre-dosing with (+)-propranolol HCl homeopathic potency.

Inhibition of (-)-propranolol hydrochloride by its enantiomer in white mice.

BACKGROUND: This study is based on the hypothesis, that the toxic or physiological effects of an optical isomer may be counteracted or reversed by the administration of a potentized preparation of one of its stereoisomers. In the present study the enantiomer was used. METHODS: 154 ICR conventional mice were used. 77 mice were administered (R)-(+)-propranolol HCl homeopathic potency prior to and during the experiment, and the other 77 were administered indistinguishable placebo. On the day of the experiment the mice were sedated with intraperitoneal Rometar. Once sedated they were injected intraperitoneally with the LD50 dose of (S)-(-)-propranolol HCl. RESULTS: The end point for statistical analysis was the difference in survival between the placebo and treatment mice. The odds ratio for survival of treatment mice relative to placebo mice was 1.64. The hypothesis of equal survival proportions gave a chi-square of 2.0916 (1 degree of freedom), which has a p-value of 0.1481. The analysis was then adjusted for mouse weight and intraperitoneal (-)-propranolol dosage using a logistic regression (LR) model. The LR treatment odds ratio was 2.017 and the LR treatment chi-square was 2.8864 (1 degree of freedom), which has a p-value of 0.0893. Consequently we accept the null hypothesis of no treatment effect on survival. The odds ratio estimates show that the treatment mice are 2.02 times more likely to survive than placebo mice, but this was not statistically significant with p = 0.089. Nine percent more treatment mice survived than placebo mice. The investigators accustomed to handling rodents noted that mouse recovery seemed substantially faster in the treatment mice than in the placebo mice.

Limited effect of systemic beta-blockade on sympathetic outflow.

Central beta-adrenoreceptors may augment sympathetic outflow. We tested the hypothesis that beta-blockade attenuates central sympathetic outflow by inhibiting central adrenoreceptors. We studied 18 healthy controls (4 female, 14 male; age, 26+/-6 years, body mass index, 23+/-3 kg/m(2)). ECG, brachial, and finger arterial blood pressure, muscle sympathetic nerve activity, and respiration were measured continuously before and during complete beta-blockade. Subjects received a total intravenous dose of 0.21 mg/kg of propranolol in 15 minutes. Spontaneous baroreflex slopes were calculated using the sequence technique (BRSup, BRSdown). The sympathetic baroreflex slope was determined at baseline using phenylephrine and sodium nitroprusside infusions. The subjects underwent cold pressor testing before and during beta-blockade. The R-R interval increased from 861+/-119 ms at baseline to 952+/-141 ms during beta-blockade (P<0.01). Blood pressure was 117+/-9/65+/-8 mm Hg at baseline and 117+/-10/67+/-8 mm Hg during beta-Blockade (P=NS). beta-Blockade did not affect baroreflex sensitivity (BRSup: 21+/-10 versus 28+/-11 ms/mmHg, P<0.1; BRSdown: 17+/-8 versus 20+/-8 ms/mmHg, P=NS). Muscle sympathetic nerve activity increased significantly during beta-blockade (number of bursts/100 beats: 32+/-9 versus 40+/-14, P<0.05), compared with baseline. However, the operating points of the parasympathetic and sympathetic baroreflex during beta-blockade were on the baroreflex curves obtained at baseline. beta-Blockade blunted the heart rate response to cold pressor testing; blood pressure and muscle sympathetic nerve activity responses were similar. Our study demonstrates that propranolol does not cause an acute decrease in sympathetic activity in normotensive young subjects. This, observation is not consistent with an important tonic stimulatory effect of beta-adrenoreceptors in the brain.

Effect of thromboxane synthase inhibitor, CS-518, on propranolol-induced bronchoconstriction in guinea pigs.

Beta-adrenoreceptor antagonists, such as propranolol, can provoke severe bronchoconstriction in asthmatic subjects. Recently we developed an animal model of propranolol-induced bronchoconstriction and investigated the involvement of chemical mediators in this reaction. The purpose of this study was to elucidate the role of thromboxane A2 in the development of propranolol-induced bronchoconstriction after allergic bronchoconstriction. Passively sensitized guinea pigs were anesthetized and treated with diphenhydramine hydrochloride and were then artificially ventilated. Propranolol at a concentration of 10 mg/ml was inhaled 20 min after an aerosolized antigen challenge. A potent and selective thromboxane A2 synthase inhibitor, CS-518, in doses of 0.01, 0.1 and 1 mg/kg and vehicle were administered intravenously 15 min after the antigen challenge. Another study was performed in naive guinea pigs; ascending doses of methacholine (12.5, 25, 50, 100 and 200 microg/ml) were inhaled for 20 sec at 5-min intervals, 10 min after intravenous administration of CS-518. Propranolol inhaled 20 min after the antigen challenge caused bronchoconstriction in sensitized guinea pigs. CS-518 administered 15 min after the antigen challenge significantly inhibited propranolol-induced bronchoconstriction in a dose-dependent manner, while CS-518 did not influence the dose-dependent response to inhaled methacholine in naive guinea pigs. We conclude that thromboxane A2 contributes to the development of propranolol-induced bronchoconstriction following allergic reaction in our guinea pig model.

Attenuation of propranolol-induced bronchoconstriction by frusemide.

BACKGROUND: Inhaled propranolol causes bronchoconstriction in asthmatic subjects by an indirect mechanism which remains unclear. Inhaled frusemide has been shown to attenuate a number of indirectly acting bronchoconstrictor challenges. The aim of this study was to investigate whether frusemide could protect against propranolol-induced bronchoconstriction in patients with stable mild asthma. METHODS: Twelve asthmatic subjects were studied on three separate days. At the first visit subjects inhaled increasing doubling concentrations of propranolol (0.25-32 mg/ml), breathing tidally from a jet nebuliser. The provocative concentration of propranolol causing a 20% reduction in FEV1 (PC20FEV1 propranolol) was determined from the log concentration-response curve for each subject. At the following visits nebulised frusemide (4 ml x 10 mg/ml) or placebo (isotonic saline) was administered in a randomised, double blind, crossover fashion. FEV1 was measured immediately before and five minutes after drug administration. Individual PC20FEV1 propranolol was then administered and FEV1 was recorded at five minute intervals for 15 minutes. Residual bronchoconstriction was reversed with nebulised salbutamol. RESULTS: Frusemide had no acute bronchodilator effect but significantly reduced the maximum fall in FEV1 due to propranolol: mean fall 18.2% after placebo and 11.8% after frusemide. The median difference in maximum % fall in FEV1 within individuals between study days was 3.6% (95% CI 1.2 to 11.7). CONCLUSIONS: Frusemide attenuates propranolol-induced bronchoconstriction, a property shared with sodium cromoglycate. Both drugs block other indirect challenges and the present study lends further support to the suggestion that frusemide and cromoglycate share a similar mechanism of action in the airways.

Inhibitory avoidance impairments induced by intra-amygdala propranolol are reversed by glutamate but not glucose.

Both systemic and central injections of glucose can enhance memory. For example, glucose reverses impairments on inhibitory avoidance resulting from intra-amygdala injections of morphine. The present experiment investigated the ability of glucose to reverse memory impairments resulting from intra-amygdala injections of propranolol, a beta-noradrenergic antagonist. Pretraining administration of 10 microg propranolol significantly reduced inhibitory avoidance retention latencies but had no effect on performance in a spontaneous alternation task. Coadministration of glucose into the amygdala at 3 doses (1.5, 3.0, and 6.0 microg) did not reverse the propranolol-induced inhibitory avoidance deficits. However, coadministration of 2.5 microg of glutamate with the propranolol did reverse these deficits. The ability of glucose to reverse impairments following intra-amygdala injections of morphine but not propranolol may reflect the neurotransmitter system or systems through which glucose exerts its effects.

Characteristics of vagal reflex-mediated tracheal response induced by bronchoconstriction in guinea pigs.

The reflex tracheal response induced by bronchoconstriction was investigated using a newly devised tracheo-bronchi preparation in anesthetized guinea pigs. Tracheal constriction and subsequent dilatation were observed in response to bronchoconstriction induced by the inhalation of 0.001-0.01% histamine and 0.003-0.03% acetylcholine. These tracheal responses were abolished by cervical vagotomy or treatment of the tracheal site with 1% tetrodotoxin. Tracheal constriction and dilatation were significantly inhibited by 0.1% atropine and 1% propranolol, respectively. When high tracheal tone was induced by 0.01% serotonin, the residual tracheal dilatation observed in the presence of propranolol was enhanced, while dilatation was completely inhibited by 1% hexamethonium. Dilatation was also suppressed by 1% N omega-nitro-L-arginine methyl ester (L-NAME) and 1% methylene blue. The tracheal constriction produced by bronchoconstriction was significantly enhanced by propranolol 2 mg/kg, i.v. and L-NAME 10 mg/kg, i.v. These results demonstrate that a vagally mediated reflex tracheal response (constriction followed by dilatation) is induced by bronchoconstriction in anesthetized guinea pigs. Cholinergic nerves may mediate the constriction, and adrenergic and nonadrenergic noncholinergic (NANC) inhibitory nerves may mediate the dilatation. Furthermore, NO may be involved in the NANC reflex tracheal dilatation.

Beta-receptor blockade by propranolol modifies the effect of the inhibitory, endogenous epidermal pentapeptide on epidermal cell flux at the G2-M transition but not at the G1-S transition.

The mitosis inhibitory pentapeptide, pGlu-Glu-Asp-Ser-GlyOH (EPP), which was isolated from mouse epidermis extracts, belongs to a group of growth inhibitory peptides that all have pyroglutamyl at the N-terminal end. Earlier experiments with crude or partially purified skin extracts have shown that the inhibitory effect could be enhanced by beta-receptor agonists and by dibutyryl cAMP, and that beta-receptor blockade could neutralise it. We now show that treatment with the beta receptor blocker propranolol before or after EPP treatment of hairless mice significantly modifies the effect of EPP on mouse epidermal cell proliferation, as estimated by using a metaphase-arrest technique (Colcemid) to estimate the G2-M cell flux. The interaction between propranolol and EPP is complex; only the EPP-induced inhibition of the G2-M cell flux was modified by beta-receptor blockade, while the late (18-21 h) inhibition of the mitotic rate was unaltered. Propranolol alone was followed by a dose-related and transient increase in the epidermal mitotic rate. The phosphodiesterase inhibitor caffeine had no effect on its own on epidermal cell proliferation but counter-acted the late (18-21 h) EPP-induced inhibition.

Milrinone versus glucagon: comparative hemodynamic effects in canine propranolol poisoning.

Glucagon has been reported to be one of the most effective treatments for severe beta-blocker poisoning. Recently, amrinone was suggested as an alternative therapeutic choice for beta-blocker poisoning. Milrinone, a derivative of amrinone, acts independently of beta-adrenoceptors and increases cyclic AMP. Therefore milrinone may also be effective in the treatment of beta-blocker poisoning. In the present study, we compared the effect of glucagon and milrinone in treating severe beta-blocker poisoning. Following the administration of 10 mg/kg propranolol i.v. over 10 min, heart rate, cardiac output, mean arterial pressure, stroke volume, and end tidal CO2 were depressed, while central venous pressure, and pulmonary capillary wedge pressure increased significantly (p < 0.05). Following the administration of saline (Group S, N = 3), glucagon 20 micrograms/kg (Group G, N = 5), and milrinone 300 micrograms/kg (Group M, N = 5), hemodynamic parameters were observed for 30 min. In group M, mean arterial pressure, cardiac output and stroke volume recovered to their baseline values, while central venous pressure and pulmonary capillary wedge pressure decreased. Although there were no significant differences between groups G and M, the heart rate, central venous pressure and pulmonary capillary wedge pressure, mean arterial pressure and stroke volume did not return to baseline values in group G. Milrinone administration produced a significant hemodynamic improvement without increasing the heart rate in the canine model of severe heart failure caused by propranolol. In the glucagon treatment group, central venous pressure and pulmonary capillary wedge pressure improved less than the milrinone group. Although more data are needed before a clinical recommendation, milrinone might be an effective drug to treat beta-blocker poisoning.

Substrate stereoselectivity and enantiomer/enantiomer interaction in propranolol metabolism in rat liver microsomes.

The substrate stereoselectivity and enantiomer/enantiomer interaction of (S)- and (R)- propranolol for the formation of their metabolites were investigated in rat liver microsomal fractions. The enantiomers of primary metabolites of propranolol, 4-, 5-, 7-hydroxy- and N-desisopropyl-propranolol were separated and assayed by an HPLC method employing a chiral ovomucoid column. Regioselective substrate stereoselectivity (R < S for 4- and 5-hydroxylations; R > S for 7-hydroxylation; R = S for N-desisopropylation) was observed in the formation of propranolol metabolites when the individual enantiomers or a racemic mixture of propranolol were used as substrates. Concentration-dependent metabolic inhibition of propranolol enantiomers by their optical isomers was also observed. In addition, the inhibition of propranolol 4-, 5- and 7-hydroxylations between the enantiomers showed a typical competitive nature. These findings suggested that the propranolol enantiomers competed for the same enzyme, probably a cytochrome P450 isozyme in the CYP2D subfamily.

Kinetic analysis of mutual metabolic inhibition of lidocaine and propranolol in rat liver microsomes.

The metabolic interaction between lidocaine (LD) and propranolol (PL) was analysed kinetically in rat liver microsomes. Employing a very short incubation time of 30 sec, we demonstrated that PL competitively inhibited liver microsomal 3-hydroxylation of LD, but did not affect either the formation of monoethylglycinexylidide or methylhydroxylidocaine from LD in PL concentrations up to 1 microM. On the other hand, LD competitively inhibited PL 4-, 5- and 7-hydroxylations, but the inhibition type of LD for PL N-desisopropylation could not be clarified. Comparison of the kinetic data for liver microsomes from Wistar and Dark Agouti rats indicated that among the primary metabolic pathways of LD, the Vmax value for 3-hydroxylation was markedly less in female Dark Agouti rats. The results suggest that LD 3-hydroxylation and PL ring hydroxylations are mediated by the same isozyme(s) belonging to the CYP2D subfamily.

Clearance by the liver in cirrhosis. I. Relationship between propranolol metabolism in vitro and its extraction by the perfused liver in the rat.

To delineate the factors responsible for impaired clearance in cirrhosis, we examined propranolol disposition in rats with carbon tetrachloride-induced cirrhosis and compared it with that in control animals, rats treated with chlorpromazine (an inhibitor of propranolol metabolism) and rats with acute liver injury. We measured the extraction ratio of propranolol by the isolated perfused liver and related it to estimates of propranolol drug-metabolizing enzyme activity in homogenates of the same livers. In control animals, drug-metabolizing enzyme activity (measured as the ratio Vmax/Km) averaged 5,319 +/- 1,193 ml/min; the extraction ratio in the perfused liver was close to 1.0 (0.97 +/- 0.01). Important decreases of microsomal enzyme activity were observed in rats treated with chlorpromazine (30 +/- 27 ml/min, p < 0.001) and in rats with acute liver injury (724 +/- 401 ml/min, p < 0.001), accounting for the decrease in the hepatic extraction ratio by the perfused liver (0.33 +/- 0.09 and 0.71 +/- 0.04, respectively, p < 0.01). In cirrhotic livers, enzyme activity was not significantly different from that of controls (3,592 +/- 1,857 ml/min) and could not account for the observed decrease in extraction (0.66 +/- 0.14, p < 0.01). The extraction of antipyrine by the isolated perfused liver was also measured as an index of microsomal enzyme activity and related to propranolol extraction. Antipyrine extraction was decreased by 90% in acute liver injury, compared with 33% in cirrhosis, suggesting a much greater reduction of microsomal enzyme activity in the former group.(ABSTRACT TRUNCATED AT 250 WORDS)

[Methodologic approaches to evaluation of interaction of anti-anginal agents in their combined use in patients with exercise-induced angina]. / Metodicheskie podkhody k otsenke vzaimodeistviia antianginalnykh preparatov pri ikh kombinirovannom primenenii u bolnykh so stenokardiei napriazheniia.

The paper shows methodological approaches to assessing the interaction (antagonism and synergism) of antianginal agents in their combination used in 15 patients with stable angina. Each patient underwent paired bicycle ergometry with placebo, isosorbide dinitrate, 10 mg (ID), nifedipine, 20 mg (N), propranolol, 40 mg (P), and a combination of the drugs: ID, 10 mg, +P, 40 mg; N, 20 mg, +P, 40 mg; ID, 10 mg+N, 20 mg. The results were processed by two-dimensional dispersion analysis. Based on the findings, it was concluded that the interaction of drugs in all combinations was statistically insignificant in patients. At the same time the developed individual criteria for assessing the interaction allowed patients both with synergic and antagonistic interaction of antianginal drugs to be revealed.

Are 5-HT receptors or beta-adrenoceptors involved in idazoxan-induced food and water intake?

Idazoxan (10 mg/kg, i.p.) produces an unexpected increase in food intake in freely-feeding rats which has been linked to its high affinity for non-adrenoceptor idazoxan binding sites. In this study, a dose-related antagonism of idazoxan-induced food intake by the beta-adrenoceptor antagonist (-)-propranolol (5-20 mg/kg, i.p.), which also blocks 5-HT1 (5-hydroxytryptamine1) receptors has been demonstrated. (+)-Propranolol (10, 20 mg/kg, i.p.) did not attenuate idazoxan-induced feeding. (-)-Propranolol (10 mg/kg, i.p.) but not the (+)-enantiomer (10 mg/kg, i.p.) also significantly inhibited the food intake, induced by the 5-HT1A agonist 8-OH-DPAT (0.25 mg/kg, i.p.). Idazoxan-induced feeding was not altered by the selective beta-adrenoceptor antagonists betaxolol (beta 1; 5 mg/kg, i.p.) and ICI 118,551 (beta 2; 5 mg/kg, i.p.) but was potentiated by the 5-HT receptor antagonist metergoline (5 mg/kg, i.p.). The anomalous findings with metergoline may reflect its action at different sub-types of 5-HT receptor. The water intake induced by idazoxan and the peripherally-active alpha 2-adrenoceptor antagonist L-659,066 was also blocked in a stereoselective manner by propranolol (10 mg/kg) but not significantly by either metergoline (5 mg/kg, i.p.), the beta 1-adrenoceptor antagonist betaxolol (5 mg/kg, i.p.) nor by the beta 2-adrenoceptor antagonist ICI 118,551 (5 mg/kg, i.p.). These results suggest that the food intake induced by idazoxan (and perhaps mediated by non-adrenoceptor idazoxan binding sites) may involve the 5-HT system, although further studies, using antagonists acting selectively at the different sub-types of 5-HT receptor, are required to confirm this.(ABSTRACT TRUNCATED AT 250 WORDS)

[Elimination of the atherogenic effect of beta blocker propranolol by papaverine]. / Ustranenie aterogennogo éffekta beta-blokatora propranolola c pomoshch'iu papaverina.

Recently, the ability of beta-blockers to stimulate proliferative activity and induce lipid accumulation in cultured human aortic intimal cells has been demonstrated. Moreover, the addition of calcium antagonists completely blocked the increase in proliferative activity and abolished cholesterol accumulation caused by propranolol. In this study blood serum of rabbits treated with 20 mg of propranolol induced 2-fold cholesterol accumulation in mouse peritoneal macrophages. Papaverin did not influence this effect. In case of simultaneous administration of propranolol and papaverin rabbit serum did not exhibit the ability to accumulate intracellular lipids. Propranolol substantially stimulated the formation of myointimal thickening and neutral lipid accumulation in denuded rabbit aorta. Papaverin completely blocked the propranolol-produced atherogenic changes. The data suggest that in vitro and in vivo atherogenic effects of beta-blockers may be prevented by papaverin.

Heterogeneous interference of nicardipine, verapamil, and diltiazem with forearm arteriolar responsiveness to adrenergic stimulation in hypertensive patients.

The interference of intraarterial nicardipine, verapamil, and diltiazem with the forearm vascular response to graded exogenous norepinephrine was evaluated in hypertensive patients. Nicardipine antagonized the vasoconstrictor effect of norepinephrine in a dose-dependent manner, whereas verapamil was ineffective, suggesting that functional alpha-adrenergic antagonism may participate in the vasodilatory and possibly the antihypertensive effect. Nicardipine also blunted the vasoconstriction to lower-body negative pressure and the action of angiotensin II administered intraarterially. Despite a comparable increase in basal forearm flow, verapamil was less potent than nicardipine in inhibiting vasoconstriction after both stimuli. Therefore nicardipine suppressed preferentially regional vascular reactivity, probably by blockade of the influx of extracellular calcium in response to receptor activation, because both alpha-adrenergic and angiotensin II receptor-mediated vasoconstrictor responses were attenuated. At variance with both nicardipine and verapamil was potentiation of the responses to norepinephrine after the administration of diltiazem. Because intraarterial propranolol abolished that potentiating action and the local vasodilatation to isoproterenol was clearly reduced, diltiazem probably interfered also with beta-adrenergic receptor-mediated vasorelaxing mechanisms in human forearm arterioles. The data further stress the heterogeneity of calcium channel blockers in humans.

Methylprednisolone prevents propranolol-induced airway hyperreactivity in the Basenji-greyhound dog.

To determine if corticosteroids would prevent beta-adrenergic-antagonist-induced increases in airway reactivity, we evaluated the ability of chronic methylprednisolone administration to prevent propranolol-induced airway hypereactivity to methacholine aerosol in the basenji-greyhound (BG) dog model of asthma. Initial studies included the measurement of lung resistance (RL) and dynamic compliance (Cdyn) with and without propranolol pretreatment in 5 BG and 5 mongrel dogs. A single dose of propranolol (2 mg/kg) did not significantly alter airway reactivity in the mongrels. The dose of methacholine needed to increase RL by 200% (ED200RL) was 0.20 +/- 0.05 mg/ml (mean +/- standard error of the mean [SEM]) in untreated and 0.18 +/- 0.04 mg/ml in propranolol-treated mongrels. In contrast, propranol significantly increased methacholine-reactivity in the BGs. The ED200RL for methacholine was 0.17 +/- 0.03 mg/ml in untreated and 0.05 +/- 0.02 mg/ml (P less than 0.05) in propranolol-treated BG dogs. Following the initial studies, the 5 BG dogs were given methylprednisolone (2 mg.kg-1.day-1) for 4 weeks, after which time propranolol no longer increased methylacholine reactivity in the BGs. The ED200RL was 0.16 +/- 0.03 mg/ml after 4 weeks of methylprednisolone and 0.22 +/- 0.06 mg/ml after propranolol administration in the BGs given 4 weeks of methylprednisolone treatment. The attenuation of propranolol-induced bronchoconstriction by corticosteroids may be a clinically useful intervention in asthmatic patients receiving beta-adrenergic antagonists in the perioperative period. However, further studies are needed to define the effective dose and duration of corticosteroid therapy that is needed.