Non-selective Β-adrenoceptor Blocker Research Articles

Pharmacological characterization of alpha adrenoceptor-mediated motor responses in the rat colon.

Inhibitory neuromuscular transmission in the gastrointestinal tract is mediated by intrinsic nitrergic and purinergic neurons. Purines activate G protein-coupled receptor P2Y1 receptors, increasing intracellular Ca2+ that activates small conductance calcium-activated potassium (SKCa) channels. Little is known about the effect of adrenergic receptor activation on intestinal smooth muscle. In vascular tissue, stimulation of α-adrenoceptors causes smooth muscle contraction, while their effect on intestinal tissue is poorly understood. This study aimed to pharmacologically characterize the effect of α-adrenoceptor activation in the rat colon, which shares similar inhibitory pathways to the human colon. Muscle bath experiments were performed with the rat proximal, mid, and distal colon oriented both circularly and longitudinally. The α1-adrenoceptor agonist phenylephrine (PE) (10-8-10-5 M) evoked concentration-dependent relaxations of the intestinal smooth muscle from all regions and orientations. However, in the mid-circular colon at low PE concentrations, a contraction sensitive to 10-5 M phentolamine (non-selective α-adrenoceptor blocker), the neural blocker tetrodotoxin (TTX; 10-6 M), and atropine (10-6 M) was recorded. PE-induced relaxations were insensitive to TTX (10-6 M) and the nonselective β-adrenoceptor blocker propranolol (10-6 M). In contrast, PE-induced relaxations were blocked by phentolamine (10-5 M), prazosin (10-6 M) (α1-adrenoceptor blocker), and RS17053 (10-6 M) (α1A-blocker), but not by yohimbine (10-6 M) (α2-adrenoceptor blocker). Apamin (10-6 M), a SKCa channel blocker, abolished PE-induced relaxations. Contractile responses in the circular muscle of the mid colon could be attributed to α-adrenoceptors located on enteric cholinergic neurons. Stimulation of α1A-adrenoreceptors activates SKCa channels to cause smooth muscle relaxation, which constitutes a signaling pathway that shares similarities with P2Y1 receptors.

Urinary Excretion of Nadolol as a Possible In Vivo Probe for Drug Interactions Involving P-Glycoprotein.

Nadolol is a hydrophilic and nonselective β-adrenoceptor blocker with a bioavailability of 30%, relatively longer half-life, negligible metabolism, and predominant renal excretion. Previous studies have reported that nadolol is a substrate of P-glycoprotein, and the coadministration with itraconazole, a typical P-glycoprotein inhibitor, results in elevated plasma concentrations and cumulative urinary excretion of nadolol. In this study, we assessed whether measurements of urinary-excreted nadolol can be an alternative method of plasma pharmacokinetics for P-glycoprotein-mediated drug interactions in humans. We reanalyzed the pooled data set of plasma concentration and urinary excretion of nadolol from our previous clinical studies in a total of 32 healthy Japanese adults. The area under the plasma concentration-time curve from 0 to infinity (AUC0-∞ ) of nadolol in individual subjects was significantly correlated with the maximum plasma concentration (r = 0.80, P < .01) and the cumulative amount excreted into urine (Ae ) at 4 (r = 0.51, P = .01), 8 (r = 0.63, P < .01), 24 (r = 0.75, P < .01), and 48 (r = 0.77, P < .01) hours. Significant correlations were also observed between the AUC and Ae during the same respective periods. In the drug interactions of nadolol with itraconazole, rifampicin, a well-known P-glycoprotein inducer, or grapefruit juice, there were significant correlations between the differences in AUC0-48 and those in Ae, 0-48 from the controls in individual subjects. These results suggest that the measurements of urinary excretion of nadolol can be employed as a sensitive and reliable alternative to plasma pharmacokinetics for the evaluation of P-glycoprotein-mediated drug interactions.

Effects of Propranolol on Growth, Lipids and Energy Metabolism and Oxidative Stress Response of Phaeodactylum tricornutum.

Simple SummaryIn the past two decades, increasing attention has been directed to investigate the incidence and consequences of pharmaceuticals in the aquatic environment. Propranolol is a non-selective β-adrenoceptor blocker used in large quantities worldwide to treat cardiovascular conditions. Diatoms (model organism) exposed to this compound showed evident signs of oxidative stress, a significant reduction of the autotrophic O2 production and an increase in the heterotrophic mitochondrial respiration. Additionally, diatoms exposed to propranolol showed a consumption of its storage lipids. In ecological terms this will have cascading impacts in the marine trophic webs, where these organisms are key elements, through a reduction of the water column oxygenation and essential fatty acid availability to the heterotrophic organisms that depend on these primary producers. In ecotoxicological terms, diatoms photochemical and fatty acid traits showed to be potential good biomarkers for toxicity assessment of diatoms exposed to this widespread pharmaceutical compound.Present demographic trends suggest a rise in the contributions of human pharmaceuticals into coastal ecosystems, underpinning an increasing demand to evaluate the ecotoxicological effects and implications of drug residues in marine risk assessments. Propranolol, a non-selective β-adrenoceptor blocker, is used worldwide to treat high blood pressure conditions and other related cardiovascular conditions. Although diatoms lack β-adrenoceptors, this microalgal group presents receptor-like kinases and proteins with a functional analogy to the animal receptors and that can be targeted by propranolol. In the present work, the authors evaluated the effect of this non-selective β-adrenoceptor blocker in diatom cells using P. tricornutum as a model organism, to evaluate the potential effect of this compound in cell physiology (growth, lipids and energy metabolism and oxidative stress) and its potential relevance for marine ecosystems. Propranolol exposure leads to a significant reduction in diatom cell growth, more evident in the highest concentrations tested. This is likely due to the observed impairment of the main primary photochemistry processes and the enhancement of the mitochondrial respiratory activity. More specifically, propranolol decreased the energy transduction from photosystem II (PSII) to the electron transport chain, leading to an increase in oxidative stress levels. Cells exposed to propranolol also exhibited high-dissipated energy flux, indicating that this excessive energy is efficiently diverted, to some extent, from the photosystems, acting to prevent irreversible photoinhibition. As energy production is impaired at the PSII donor side, preventing energy production through the electron transport chain, diatoms appear to be consuming storage lipids as an energy backup system, to maintain essential cellular functions. This consumption will be attained by an increase in respiratory activity. Considering the primary oxygen production and consumption pathways, propranolol showed a significant reduction of the autotrophic O2 production and an increase in the heterotrophic mitochondrial respiration. Both mechanisms can have negative effects on marine trophic webs, due to a decrease in the energetic input from marine primary producers and a simultaneous oxygen production decrease for heterotrophic species. In ecotoxicological terms, bio-optical and fatty acid data appear as highly efficient tools for ecotoxicity assessment, with an overall high degree of classification when these traits are used to build a toxicological profile, instead of individually assessed.

The investigations of propranolol by HPLC method suitable for a chemical-toxicological analysis

Topicality. Therapeutic monitoring when using propranolol hydrochloride, analysis of the drug in dosage forms and biological objects, identification and quantitative determination of the drug during intoxication are carried out using sensitive and selective methods. Among the modern methods of analysis for creating a database of parameters of identification and quantitative determination of analytes arrays in biological objects HPLC method is one of the most suitable methods with high sensitivity and selectivity.Propranolol hydrochloride (anaprilin) - (±)1-isopropylamino-3-(1-naphthyloxy) -2-propanol hydrochloride – non-selective β-adrenoceptor blocker, which is characterized by antianginal, antihypertensive and antiarrhythmic effects and is used for treatment of coronary heart disease, heart rhythm disorders and some forms of hypertension. The previously developed HPLC methods of propranolol analysis are based on the application of various chromatographic conditions (mobile phase composition, isocratic or gradient elution, detecting at one or several wavelengths, selection of sensitive and selective detector) due to individual properties of a substance. Taking into account the possibility of complex treatment of diseases of the cardiovascular system with the use of different drugs, the analysis by a unified HPLC methodology is an actual task of the study.The purpose of this work is identification and quantitative determination of propranolol hydrochloride by a unified HPLC methodology, which allows obtaining reliable and reproducible research results that are suitable for drug analysis in biological objects.Materials and methods of research. Chromatography of the investigated substance was performed on a microcolonial liquid chromatograph "Milichrome A-02" ("EcoNova", Novosibirsk, Russia) in an reverse-phase variant using a metal column with a nonpolar sorbent Prontosil 120-5C 18 AQ, 5 μm. For elution of the drug were used a mixture of solvents - acetonitrile with 0,2 M solution of lithium perchlorate in 0,005 M solution of acid perchloric. The linear gradient from eluent A (5% acetonitrile and 95% buffer solution) to eluent B (100% acetonitrile) for 40 minutes created conditions for the exit from the column of all component parts of the sample as narrow zones. The flow rate of the mobile phase has been formed 100 μl/min, column temperature – 37 - 40 °С; pump pressure – 2,8 – 3,2 MPa; injection volume – 4 μl. Multi-channel detection of a substance was performed by a UV detector in 8 wavelengths: 210, 220, 230, 240, 250, 260, 280 and 300 nm. Results and their discussion. In carrying out identification of propranolol were established absolute parameters of retention time (19,40-19,54 min) and retention volume (1940,8-1955,2 μl), spectral relationships, detection limit of the substance in the sample (4,0 μg / ml or 16,0 ng in the sample), the values of the coefficients of the symmetry of the peaks of the substance (0,94-1,10) and the coefficients of capacity ratio (11,94-12,04).The regression coefficients of the calibration graph, which corresponds to the equation of the straight line S = 0,00565 С were calculated by the least squares method. The correlation coefficient was equal to 0,9987. Validation characteristics of HPLC-method for determination of propranolol: linearity range (5,0-100,0 μg / ml), limit of quantitative determination (5,0 μg / ml or 20 ng in the sample), correctness and accuracy on the basis of the results of the quantitative determination of the preparation by the HPLC method in model solutions were calculated. It was established that the relative uncertainty of the average result did not exceed ± 2,11% when using the proposed method of HPLC analysis of propranolol hydrochloride in model solutions.Conclusions. Identification and quantitative determination of propranolol hydrochloride with the use of a unified HPLC method suitable for a chemical toxicological study was carried out.

Occurrence, bioaccumulation, and trophic magnification of pharmaceutically active compounds in Taihu Lake, China

The occurrence, bioaccumulation, and trophic magnification of pharmaceutically active compounds, (PhACs) including antibiotics (roxithromycin and erythromycin), non-steroidal anti-inflammatory drugs (ibuprofen and diclofenac), a non-selective β-adrenoceptor blocker (propranolol), an antiepileptic drug (carbamazepine), and steroid estrogens (17β-estradiol and 17α-ethynylestradiol), were investigated in Taihu Lake, China. All eight PhACs were widely detected in surface water and sediment samples with maximal concentrations in the range of 8.74–118ngL−1 and 0.78–42.5ngg−1 dry weight (dw), respectively. The investigated organisms in the natural freshwater food web in Taihu Lake included phytoplankton, zooplankton, zoobenthos, and fish, and the maximal concentrations of target compounds in these biota samples ranged from 0.65 to 132ngg−1dw. Bioaccumulation factors (BAFs) for all target PhACs were lower than 1000Lkg−1, suggesting their low bioaccumulation potential in aquatic organisms from Taihu Lake. Trophic magnification factors (TMFs) were estimated at 1.11 for roxithromycin, 0.31 for propranolol, and 1.06 for diclofenac, indicating none of these PhACs underwent trophic magnification in this freshwater food web.

Pharmacokinetic and Pharmacodynamic Interaction of Nadolol With Itraconazole, Rifampicin and Grapefruit Juice in Healthy Volunteers

To evaluate effects of itraconazole, rifampicin and grapefruit juice on pharmacokinetics and pharmacodynamics of a hydrophilic non-selective β-adrenoceptor blocker nadolol, we conducted an open-label, four-way crossover study in 10 healthy male volunteers. A single oral dose of 30 mg nadolol was administered with water (control), itraconazole (100 mg), or grapefruit juice (300 mL), or after a 6-day pretreatment with rifampicin (450 mg/day). Plasma concentrations and urinary excretions of nadolol were measured over 48 hours after its dosing. Systolic and diastolic blood pressures and pulse rate were periodically recorded after nadolol administration as pharmacodynamic parameters. Itraconazole increased the peak plasma concentration and the area under the plasma concentration-time curve (AUC0-∞ ) of nadolol by 468% and 224% of control, respectively (P < .001). A slight, but not statistically significant, decrease in AUC0-∞ of nadolol was observed in rifampicin and grapefruit juice phases as compared to control. Elimination half-life for nadolol did not differ among the four phases. During itraconazole phase, nadolol reduced pharmacodynamic parameters to a greater extent than the other phases. These results suggest that itraconazole substantially increases the oral availability of nadolol possibly by the inhibition of intestinal P-glycoprotein, whereas grapefruit juice has little effect on nadolol pharmacokinetics.

Synthesis of (R)-Bufuralol

Bufuralol is a non-selective β-adrenoceptor blocker comparable to propanol-ol in potency. It is also a β-adrenergic receptor antagonist and an inhibitor of testosterone 6β-hydroxylase. The key step in the synthesis depicted is the dynamic kinetic resolution of racemic chlorohydrin F using racemization catalyst G together with selective esterification of the (R)-chlorohydrin F by lipase PS-C Amano II and isopropenyl acetate.

Synthesis of (S) and (R)-tilisolol hydrochloride

Tilisolol hydrochloride 1, a non-selective β-adrenoceptor blocker, was developed as a drug for the treatment of hypertension and angina pectoris. The optical active forms of 1, 1a and 1b were synthesized from inexpensive phthalic anhydride 2 in eight steps with 13% (S) and 15% (R) overall yield.

Pharmacological characterization of isoproterenol-treated medaka fish

The transparent bodies of see-through medaka fish has led to their use as models for in vivo cell and tissue imaging. However, these fish may also prove useful as models for pathological processes. Accumulating reports show that pathology in fish is similar to that in mammals, including humans. In this study, pathological characterization, comparison of data from rodents and in vivo pharmacological analyses of isoproterenol (Iso)-treated fish were performed. Larval fish showed cardiac hypertrophy-like changes after exposure to >10 μg/ml Iso for more than one day. Hearts of Iso-treated fish had a larger size and a thicker wall, especially in the ventricle, compared with normal hearts. Several messenger RNA levels dose-dependently increased in Iso-treated fish in a manner similar to that in rodents. Symptoms that accompany mammalian cardiac hypertrophy, such as congestion, were also observed. Propranolol (Pro), a non-selective β-adrenoceptor blocker (AR), significantly protected the increase in heart rate and volume and other simultaneous symptoms induced by Iso exposure. Athletic capability, measured by optomotor response, showed a dose-dependent decrease after Iso treatment, but was protected by Pro. In contrast, metoprolol (Met) and butoxamine (Btx), selective β1- and β2-AR blockers, had little effect in this analysis. These results show that Iso-treated fish develop pathologies analogous to those found in mammalian systems, suggesting that medaka fish can be used for investigation of cardiac hypertrophy; however, drug affinity differences should be considered between species.

Contribution of glibenclamide-sensitive, ATP-dependent K + channel activation to acetophenone analogues-mediated in vitro pulmonary artery relaxation of rat

Compared to the currently available therapeutic drugs for peripheral vascular diseases, agents that are selective for relaxing pulmonary circulation are scarce. The present study was undertaken, using isometric tension change measurement and whole-cell patch-clamp electrophysiology methods, to evaluate the vascular relaxation effect and the underlying mechanisms involved of two naturally found alkaloids: paeonol (2-hydroxy-4-methoxy-acetophenone), acetovanillone (4-hydroxy-3-methoxy-acetophenone) and the non-substituted analogue acetophenone on pulmonary artery of Sprague-Dawley rats. Cumulative administration (3 μM–1 mM) of acetophenone analogues resulted in a concentration-dependent relaxation of phenylephrine (1 μM) pre-contracted pulmonary artery. A relative order of inhibitory potency, estimated by comparing the concentration at which a 50% relaxation of phenylephrine-induced contraction observed was: acetovanillone > paeonol > acetophenone. Endothelial denudation and inhibition of nitric oxide synthase (with 20 μM N G-nitro- l-arginine methyl-ester) only moderately suppressed (17.6 ± 4.2%) acetovanillone- but not paeonol- or acetophenone-mediated maximum relaxation. Glibenclamide (3 μM, an ATP-sensitive K + (IK ATP) channel blocker) markedly attenuated all acetophenone analogues-mediated endothelium-independent relaxation. Neither cis- N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL 12330A, 10 μM), iberiotoxin (300 nM), 4-aminopyridine (3 mM), (±)-propranolol (1 μM, a non-selective β-adrenoceptor blocker) nor 1 H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ) (3 μM, a guanylate cyclase inhibitor) altered endothelium-independent relaxation. In electrophysiological experiments using single pulmonary artery smooth muscle cells, acetovanillone, paeonol, acetophenone and cromakalim activated glibenclamide-sensitive, IK ATP channels. In conclusion, our results demonstrate that acetophenone analogues caused pulmonary artery relaxation through opening of IK ATP channels. In addition, acetovanillone-mediated pulmonary artery relaxation is partly depended on nitric oxide released from endothelium.

Pharmacological effects of an aldehyde type α/β-adrenoceptor blocking agent with vasodilating properties

KMUP 880723 (0.5, 1.0, and 3.0 mg/kg, iv) produced dose-dependent hypotensive and bradycardia responses in pentobarbital-anesthetized Wistar rats. KMUP 880723 (1.0 mg/kg, iv) also markedly inhibited both the tachycardia effects induced by (−)isoproterenol and arterial pressor responses induced by phenylephrine. In the isolated Wistar rat right atria, left atria, and guinea pig tracheal strips, KMUP 880723 competitively antagonized the (−)isoproterenol-induced positive chronotropic effects, inotropic effects, and tracheal relaxation effects in a concentration-dependent manner. The parallel shift to the right of the concentration–response curve of (−)isoproterenol suggested that KMUP 880723 was a β 1/β 2-adrenoceptor competitive antagonist. The apparent p A 2 values were 6.89±0.10 in the right atria, 7.02±0.09 in the left atria, and 6.59±0.11 in the trachea, indicating that KMUP 880723 was a nonselective β-adrenoceptor blocker. In thoracic aorta experiments, KMUP 880723 also produced a competitive antagonism of norepinephrine-induced contraction with a p A 2 value of 7.14±0.06. In isolated rat thoracic aorta, KMUP 880723 more potently relaxed the contractions induced by norepinephrine (3×10 −6 M) than those by high K + (75 mM). In the radioligand-binding assay, the p K i values of [ 3H]CGP-12177 binding to rat ventricle and lung membranes were 6.56 and 6.40, respectively, and the value of [ 3H]prazosin binding to rat brain membranes was 6.66. These results further confirmed the α/β-adrenoceptor blocking activities of KMUP 880723 reported in the functional studies. We conclude that KMUP 880723 is a nonselective β-adrenoceptor antagonist with α-adrenoceptor blocking-associated vasorelaxant activity.

Isoeugenodilol: A vasorelaxant ?/?-adrenoceptor blocker with antioxidant activity

Isoeugenodilol, derived from isoeugenol, was investigated under in vivo and in vitro conditions. Isoeugenodilol (0.1, 0.5, 1.0, and 3.0 mg kg–1, i.v.) produced dose-dependent hypotensive and bradycardia responses in pentobarbital-anesthetized Wistar rats. Isoeugenodilol (0.5 mg kg–1, i.v.) also markedly inhibited both the tachycardia effects induced by (-) isoproterenol and arterial pressor responses induced by phenylephrine. A single oral administration of isoeugenodilol at doses of 10, 30, and 100 mg kg–1 dose-dependently reduced blood pressure, with a decrease in heart rate in conscious spontaneously hypertensive rats (SHRs). In the isolated Wistar rat right atria, left atria, and guinea pig tracheal strips, isoeugenodilol competitively antagonized the (-) isoproterenol-induced positive chronotropic effects, inotropic effects, and tracheal relaxation effects in a concentration-dependent manner. The parallel shift to the right of the concentration–response curve of (-) isoproterenol suggested that isoeugenodilol was a β1/β2-adrenoceptor competitive antagonist. The apparent pA2 values were 7.33 ± 0.12 in the right atria, 7.80 ± 0.09 in the left atria, and 7.26 ± 0.11 in the trachea, indicating that isoeugenodilol was a nonselective β-adrenoceptor blocker. In thoracic aorta experiments, isoeugenodilol also produced a competitive antagonism of norepinephrine-induced contraction with a pA2 value of 7.47 ± 0.45. In isolated atria of reserpinized rats, cumulative additions of isoeugenodilol and propranolol produced significantly cardiodepressant responses at high concentrations (10–5 M) and were without intrinsic sympathomimetic activity (ISA). In isolated rat thoracic aorta, isoeugenodilol more potently relaxed the contractions induced by norepinephrine (3 × 10–6 M) than those by high K+ (75 mM). The vasorelaxant effects of isoeugenodilol on norepinephrine-induced contractions were attenuated by pretreatment with tetraethylammonium (TEA) and glibenclamide, implying the involvement of K+ channel opening. In addition, isoeugenodilol inhibited norepinephrine-induced biphasic contraction; it affected the fast phase significantly more than the slow phase. Furthermore, the binding characteristics of isoeugenodilol and various β-adrenoceptor antagonists were evaluated in [3H]CGP-12177 binding to rat ventricle and lung tissues and [3H]prazosin binding to brain membranes. The ranking order of inhibition for [3H]CGP-12177 binding on β-adrenoceptor was propranolol > labetalol > isoeugenodilol, and that for [3H]prazosin binding to α-adrenoceptors was isoeugenodilol > labetalol. Furthermore, isoeugenodilol inhibited lipid peroxidation induced by Fe2+ and ascorbic acid with IC50 of 0.74 ± 0.03 mM, indicating that it possesses the antioxidant activity inherent in isoeugenol. In conclusion, isoeugenodilol was found to be a new generation α/β-adrenoceptor antagonist with vasorelaxant activity by inhibiting Ca2+ channel, receptor-mediated Ca2+ mobilization and by K+ channel opening, and to have additional potentially antioxidant effects. Drug Dev. Res. 51:29–42, 2000. © 2000 Wiley-Liss, Inc.

Study of Propranolol and Its Related Adrenoceptor Antagonists on Changes of Gastric Electrical Parameters Induced by Ethanol in Rats

The actions of different adrenoceptor antagonists on gastric potential difference (PD), electrical current (I) and resistance (R) were studied, using the voltage clamp technique. In an isolated gastric mucosal tissue, 5% ethanol was able to reduce the PD and I across the gastric mucosa. Direct incubation with propranolol 10^–4 mol/l either from the mucosal or submucosal sides attenuated such effects. Intraperitoneal administration of propranolol (2.5–10 mg/kg), a nonselective β-adrenoceptor blocker with significant membrane-stabilizing activity, given 30 min before the preparation of the gastric tissue, not only alleviated the fall in PD and I across the gastric mucosa, but also increased the R of the stomach tissue. Butoxamine, a selective β₂-antagonist, produced the similar but less significant effects in the same experimental setting. Metroprolol, a β₁-adrenoceptor blocker, given by the similar doses did not produce significant effects. Nonselective β-adrenoceptor blocker, nadolol but not the β- and α-adrenoceptor blocker, labetalol, also significantly preserved the decrease of PD induced by ethanol, but to a lesser extent. These findings suggest that blockade of the β₂-receptors in the gastric mucosa together with membrane-stabilizing activity could improve the integrity of the gastric mucosa, and these effects are probably acting through its direct action on the tissue.

Role of adrenergic pathways of the medial preoptic area in ANGII-induced water intake and renal excretion in rats

In this study, we investigated the participation of adrenergic neurotransmission in angiotensin II- (ANGII)-induced water intake and urinary electrolyte excretion by means of injection of the α 1-, α 2-, and β-adrenoceptor antagonists and ANGII into the medial preoptic area (MPOA) in rats. Prazosin (an α 1-adrenergic antagonist) entagonized the water ingestion, Na +, K + and urine excretion induced by ANGII, whereas yohimbine (an α 2-adrenergic antagonist) enhanced the Na +, K + and urine excretion induced by ANGII. Propranolol (a nonselective β-adrenoceptor blocker) antagonized the water ingestion and enhanced the Na +, and urine excretion induced by ANGII. Previous treatment with prazosin reduced the pressor responses to ANGII, whereas yohimbine had opposite effects. Previous injection of propranolol produced no effects in the pressor responses to ANGII. These results suggest that the adrenergic neurotransmission in the MPOA may actively participate in ANGII-induced dipsogenesis, natriuresis, kaliuresis and diuresis in a process that involves α 1-, α 2-,andβ-adrenoceptors.

Differences in the Haemodynamic Effects of Acebutolol and Propranolol during Long Term Treatment of Patients with Hypertension

The aim of this study was to compare the haemodynamic effects of acebutolol, a β1-selective adrenoceptor blocker with intrinsic sympathomimetic activity, and propranolol, a nonselective β-adrenoceptor blocker without intrinsic sympathomimetic activity. 44 males aged 35 to 59 (mean 49.7 ± 1.0) years with mild to moderate arterial hypertension (diastolic blood pressure 95 to 114mm Hg) without severe concomitant diseases requiring medication, and without contraindications to β-adrenoceptor blockade, were included in this double-blind randomised parallel group study. It was shown that during 12 weeks’ treatment the magnitude and duration of the antihypertensive effect of acebutolol 400 or 800mg daily did not differ from that of propranolol 80 or 160mg daily. However, there was a trend towards more patients achieving a full or partial antihypertensive effect with acebutolol than propranolol. Moreover, bradycardia was more pronounced with propranolol. The antihypertensive effect of acebutolol was observed after 2 weeks and maintained throughout all 12 weeks of treatment. Unlike propranolol, acebutolol did not cause such unwanted haemodynamic effects as decreased cardiac output and increased total peripheral resistance. Acebutolol was well tolerated.

Cantharidin poisoning associated with specific binding site in liver

Compared to the currently available therapeutic drugs for peripheral vascular diseases, agents that are selective for relaxing pulmonary circulation are scarce. The present study was undertaken, using isometric tension change measurement and whole-cell patch-clamp electrophysiology methods, to evaluate the vascular relaxation effect and the underlying mechanisms involved of two naturally found alkaloids: paeonol (2-hydroxy-4-methoxy-acetophenone), acetovanillone (4-hydroxy-3-methoxy-acetophenone) and the non-substituted analogue acetophenone on pulmonary artery of Sprague-Dawley rats. Cumulative administration (3 μM–1 mM) of acetophenone analogues resulted in a concentration-dependent relaxation of phenylephrine (1 μM) pre-contracted pulmonary artery. A relative order of inhibitory potency, estimated by comparing the concentration at which a 50% relaxation of phenylephrine-induced contraction observed was: acetovanillone > paeonol > acetophenone. Endothelial denudation and inhibition of nitric oxide synthase (with 20 μM NG-nitro-l-arginine methyl-ester) only moderately suppressed (17.6 ± 4.2%) acetovanillone- but not paeonol- or acetophenone-mediated maximum relaxation. Glibenclamide (3 μM, an ATP-sensitive K+ (IKATP) channel blocker) markedly attenuated all acetophenone analogues-mediated endothelium-independent relaxation. Neither cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL 12330A, 10 μM), iberiotoxin (300 nM), 4-aminopyridine (3 mM), (±)-propranolol (1 μM, a non-selective β-adrenoceptor blocker) nor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (3 μM, a guanylate cyclase inhibitor) altered endothelium-independent relaxation. In electrophysiological experiments using single pulmonary artery smooth muscle cells, acetovanillone, paeonol, acetophenone and cromakalim activated glibenclamide-sensitive, IKATP channels. In conclusion, our results demonstrate that acetophenone analogues caused pulmonary artery relaxation through opening of IKATP channels. In addition, acetovanillone-mediated pulmonary artery relaxation is partly depended on nitric oxide released from endothelium.

Antihypertensive and renal effects of tertatolol, a new beta-blocking agent, in hypertensive patients.

Tertatolol, a new nonselective beta-adrenoceptor blocker, was administered to 11 hypertensive patients in a short-term study. Systolic and diastolic blood pressure and heart rate were significantly decreased when compared to the placebo period: in spite of that glomerular filtration rate and renal plasma flow were unchanged. The administration of metoclopramide (a dopaminergic receptor antagonist) caused a significant reduction of renal plasma flow and a significant rise of renal vascular resistances during placebo, but no change during tertatolol therapy. A possible interference of tertatolol on dopaminergic receptors is discussed as the mechanism responsible for the unmodified renal plasma flow despite the significant blood pressure lowering with tertatolol.

A marked H 1-receptor-mediated vasodilator effect of histamine in the isolated perfused rat heart

Infusion of histamine into the coronary circulation of the isolated perfused rat heart produced a marked and concentration-dependent fall in perfusion pressure. A similar effect was obtained with 2-pyridylethylamine, a histamine H 1-receptor agonist. Impromidine, a potent H 2-receptor agonist, however, was found to be ineffective. Mepyramine but not cimetidine competitively inhibited the fall in perfusion pressure induced by histamine and 2-pyridylethylamine. Propranolol, a non-selective β-adrenoceptor blocker, failed to abolish the coronary vasodilator effect of both histamine and 2-pyridylethylamine. From these results it was concluded that although the rat is known to be insensitive to histamine, this amine has a marked H 1-mediated vasodilator effect in the isolated perfused coronary vasculature of this species.