Beta-blocker Propranolol Research Articles

Nonsurgical treatment of variceal bleeding

Patients with cirrhosis, especially those who have a platelet count of less than 100,000, who are considered compliant, and have no contraindications to beta-blocker therapy, should have a screening endoscopy to ascertain the presence of esophageal varices. Patients with medium to large esophageal varices who are appropriate candidates should be placed on a nonselective beta-blocker (propranolol hyrdochloride, nadolol, timolol maleate) for the prevention of initial variceal hemorrhage. Patients presenting with acute variceal hemorrhage, as determined endoscopically, should be treated with a combination of vasoactive drugs and endoscopic therapy (sclerotherapy or variceal ligation) for the control of acute variceal bleeding and the prevention of early rebleeding. Transjugular intrahepatic portosystemic shunt (TIPS) should be reserved for failures of initial medical therapy. After successful control of initial variceal bleeding is reached, the rebleeding rate approaches 70% in most studies, with the highest risk period being in the first 6 months after control of the index bleed is obtained. Therefore, all patients should be placed on therapy to prevent recurrent variceal bleeding. Options include pharmacologic therapy, endoscopic therapy, and combinations of endoscopic and pharmacologic therapy. TIPS, surgical shunts, and liver transplantation should be reserved for special circumstances and in general, should only be considered for failures of initial medical therapy.

Beta-blockers reduce the release and synthesis of endothelin-1 in human endothelial cells.

Endothelins play an important role in cardiovascular diseases, and clinical trials have shown a reduction in endothelin levels after long-term treatment of chronic heart failure with beta-adrenergic antagonists. It is not known, however, whether this effect is caused by haemodynamic changes associated with the use of beta-adrenergic antagonists or by direct interaction of beta-blockers with human endothelial cells. The aim of this study was to determine whether beta-adrenergic antagonists have an influence on endothelin-1 (ET-1) synthesis and release in human endothelial cells. Pretreatment of cultured endothelial cells from human umbilical veins (HUVECs) with different concentrations of the non-selective beta-blocker propranolol, the beta 1-blocker metoprolol and the beta 1-blocker and beta 2-agonist celiprolol (all 10(-7)-10(-4) mol L-1) was found to reduce ET-1 production. This ET-1-reducing effect was even more pronounced in thrombin-stimulated cells (10(-5) mol L-1 of propranolol, metoprolol and celiprolol: 19% +/- 5.8%, 25% +/- 4% and 37% +/- 5.2% respectively). Quantitative reverse transcriptase polymerase chain reaction and Northern blotting confirmed an inhibitory effect of the beta-blocker on biosynthesis. Furthermore, the ET-1-reducing effect of propranolol, metoprolol and celiprolol was not due to a compensatory increase in prostacyclin and was not reversible by N-nitro-L-arginine. The effect of beta-adrenergic antagonists on ET-1 production of the endothelium may at least partially explain the efficacy of beta-blockers in the treatment of diseases such as advanced heart failure, essential hypertension as well as acute coronary syndromes.

Effects of antihypertensive drugs on cholesterol metabolism of human mononuclear leukocytes and hepatoma cells.

Primary prevention trials of antihypertensive therapy have shown conflicting results on coronary events. Potential interference of antihypertensive agents with cellular lipid metabolism may alter the atherosclerotic risk of individuals. The effects of the calcium antagonist's verapamil, diltiazem, and nifedipine and of the beta-blockers propranolol and metoprolol on low density lipoprotein (LDL) receptor activity, cholesterol esterification rate, oleate incorporation in triglycerides and sterol synthesis were studied in freshly isolated human leukocytes and HEP G2 cells. Up to a concentration of 3-10 mumol/L, verapamil, propranolol, and metoprolol led to an increased cellular content of 125I-LDL by an inhibition of degradation. In mononuclear cells verapamil stimulated accumulation and degradation. No effect on binding was observed. Diltiazem was only stimulatory on 125I-LDL processing in leukocytes. Beta blockers and verapamil significantly reduced the LDL mediated 14C-oleate incorporation in cholesterol esters. In the presence of 25-hydroxycholesterol the esterification was not diminished, which suggests that cholesterolacyltransferase (ACAT) was not affected per se. Whereas all the agents induced the synthesis of lanosterol, metoprolol inhibited cholesterol synthesis. None of the agents had a significant influence on 14C-oleate incorporation in triglycerides, suggesting a specific influence on cholesterol metabolism. Antihypertensive drugs affect the cholesterol metabolism on a cellular level. Mechanisms are an interference with degradation of LDL and consequent alterations of cholesterol esterification. Using leukocytes as peripheral cells and HEP G2 as a model of human liver, these results may have importance when antihypertensive long-term therapy is conducted for primary or secondary prevention of atherosclerotic complications.

Relationship between the skin permeation movement of propranolol and skin inflammatory reactions.

We studied inflammatory reactions induced by dermal application of the beta-blocker propranolol (PRL) in ethanol to guinea pigs in order to elucidate the relation of the reactions with the cumulative PRL permeating amount through the stratum corneum or the PRL content in the stripped skin, and to investigate the chemical mediators responsible for the reactions. The cumulative PRL permeating amount through the stratum corneum increased rapidly up to 2 h after dermal application, then increased linearly with time up to 24 h after application. Visual observation revealed formation of erythema and edema at the applied site of PRL, and histopathological examination revealed infiltration of pseudoeosinophiles of dermis and epidermis and degeneration/necrosis of epidermis. In general, it was considered that the duration and the extent of these reactions were dependent on the PRL dosage and application time. It was expected that the cumulative PRL permeating amount through the stratum corneum could be used to predict possible inflammatory reactions during development of transdermal drug delivery systems. On the other hand, contact of PRL with guinea pig skin tissues released histamine, and intradermal injection of PRL caused an increase of capillary permeability at the site of application. Also, the inhibitory effects of anti-inflammatory agents (diphenhydramine, dexamethasone, indomethacin, cyproheptadine hydrochloride, CV3988 and AA-861) to PRL-induced erythema formation demonstrated that histamine and prostaglandins were responsible for the inflammatory reactions induced by PRL.

Differences in refractory-period response of canine subendocardium and subepicardium to bunazosin, an alpha1-adrenoceptor antagonist, and propranolol during myocardial ischemia.

Our objective was to investigate the effects of alpha1- or beta-adrenoceptor blockers on endocardial and epicardial refractory-period changes during myocardial ischemia in alpha-chloralose-anesthetized dogs. The first and second diagonal branches of the left anterior descending coronary artery were ligated. The refractory period was determined by an S1-S2 extrastimulus method. Dogs were treated with the alpha1-blocker bunazosin (0.1-0.2 mg/kg, i.v.; n = 16), the beta-blocker propranolol (0.2 mg/kg, i.v.; n = 15), or saline (n = 11). Dogs that developed ventricular tachycardia/fibrillation (VT/VF) during the experiment were excluded from the statistical assessment in refractory periods. In all groups, coronary ligation produced a significant shortening of the refractory period of ischemic epicardial tissue (p < 0.05) but only minimal shortening of ischemic endocardial refractory periods, resulting in an increased difference in repolarization time between the endo- and epicardial sites. Treatment with bunazosin ameliorated this ischemia-related shortening of refractory periods at both the endo- and epicardial sites, with a greater effect seen epicardially (p < 0.05), resulting in values similar to those in the nonischemic tissue. Treatment with propranolol prolonged refractory periods more in the epicardial (p < 0.01) than in endocardial sites, exacerbating the disparity in the refractory period between the endo- and epicardial sites (p < 0.05). Propranolol also prolonged the refractory period of nonischemic tissue (p < 0.05 and p < 0.01 in endo- and epicardial sites, respectively), resulting in a significant difference between the ischemic and normal myocardium at the endocardial site (p < 0.05). Results suggest that the alpha1-blocker bunazosin reduces the refractory-period disparity between the ischemic and normal myocardium without increasing the disparity between the endo- and epicardial surfaces, whereas propranolol produces a greater disparity.

Failure of the nonselective beta-blocker propranolol to affect lipoprotein lipase gene expression in the rat.

Treatment with beta-blockers has been reported to be associated with the development of hypertriglyceridemia. The etiology, even the existence, of this phenomenon is controversial. The purpose of our study was to examine whether the nonselective beta-blocker propranolol causes hypertriglyceridemia in the rat and whether its action is mediated by the modulation of lipoprotein lipase (LPL) messenger RNA (mRNA) accumulation or activity. LPL activity was assayed in fresh tissue by incubation with tritiated triglycerides. LPL mRNA was quantified in total RNA by slot-blot analysis using a mouse LPL complementary DNA probe. We have conducted three series of experiments in unanaesthetized rats in order to study the effects of different single doses of propranolol (1.5 to 6 mg i.p.) and different durations of treatment (15 min to 4 wk). We measured triglyceride and cholesterol levels in plasma as well as the LPL activity and mRNA levels in the heart and adipose tissue before and after propranolol administration. In these experiments we did not find any significant decrease in either the activity or the amount of mRNA of lipoprotein lipase nor was there any change in plasma lipids following treatment. Our results lead us to the conclusion that the nonselective beta-blocker propranolol affects neither the activity nor the mRNA level of LPL in the rat.

Effect of adrenaline and alpha-agonists on net rate of liquid absorption from the pleural space of rabbits.

Indirect evidence supporting a solute-coupled liquid absorption from the pleural space of rabbits has recently been provided; moreover, the beta 2-adrenoceptor agonist terbutaline has been found to increase this absorption. In this study the effect of adrenaline and alpha-adrenoceptor agonists on net rate of liquid absorption (Jnet) from albumin Ringer hydrothoraces of various sizes has been determined in anaesthetized rabbits. In hydrothoraces with adrenaline (5 x 10(-6) M) the relationship between Jnet and volume of liquid injected was displaced upwards by 0.09 ml h-1 relative to that in control hydrothoraces (P < 0.01). This displacement did not occur with lower adrenaline concentrations or after pretreatment with the beta-blocker propranolol. Hence, this increase in Jnet is mediated by stimulation of beta-receptors. It seems to be caused by an increase in solute-coupled liquid absorption, since beta-agonists inhibit lymphatic activity while, at relatively high concentrations, they may increase active transport. Conversely, the strong stimulation of lymphatic alpha-receptors that should occur with adrenaline after beta-blockade may fail to increase lymphatic drainage, because it has been shown that the increase in contraction frequency of lymphatics may be balanced by the decrease in their stroke volume. Arterial blood pressure during the hydrothoraces with adrenaline was unchanged. In hydrothoraces with the alpha 2-agonist clonidine (5 x 10(-6) M; a less potent agent than adrenaline) the slope of the relationship between Jnet and volume injected increased by 26% (P < 0.01), while its origin did not change. This increase in slope did not occur with a lower clonidine concentration or after pretreatment with the alpha-blocker phentolamine. Hence, it is caused by stimulation of alpha 2-receptors, which probably lead to an increase in lymphatic drainage related to liquid load. In hydrothoraces with the alpha 1-agonist phenylephrine (5 x 10(-6) or 10(-7) M) Jnet was simlar to control values.

Daily changes in sympathetic activity. The thermoregulatory effects of the beta blocker propranolol.

Daily changes in sympathetic activity. The thermoregulatory effects of the beta blocker propranolol.

Regulation of cardiac sodium-calcium exchanger by beta-adrenergic agonists.

Na+-Ca2+ exchanger and Ca2+ channel are two major sarcolemmal Ca2+-transporting proteins of cardiac myocytes. Although the Ca2+ channel is effectively regulated by protein kinase A-dependent phosphorylation, no enzymatic regulation of the exchanger protein has been identified as yet. Here we report that in frog ventricular myocytes, isoproterenol down-regulates the Na+-Ca2+ exchanger, independent of intracellular Ca2+ and membrane potential, by activation of the beta-receptor/adenylate-cyclase/cAMP-dependent cascade, resulting in suppression of transmembrane Ca2+ transport via the exchanger and providing for the well-documented contracture-suppressant effect of the hormone on frog heart. The beta-blocker propranolol blocks the isoproterenol effect, whereas forskolin, cAMP, and theophylline mimic it. In the frog heart where contractile Ca2+ is transported primarily by the Na+-Ca2+ exchanger, the beta-agonists' simultaneous enhancement of Ca2+ current, ICa, and suppression of Na+-Ca2+ exchanger current, INa-Ca would enable the myocyte to develop force rapidly at the onset of depolarization (enhancement of ICa) and to decrease Ca2+ influx (suppression of INa-Ca) later in the action potential. This unique adrenergically induced shift in the Ca2+ influx pathways may have evolved in response to paucity of the sarcoplasmic reticulum Ca2+-ATPase/phospholamban complex and absence of significant intracellular Ca2+ release pools in the frog heart.

Cardiovascular responses to ß-blockade and 5&lt;sup&gt;0&lt;/sup&gt;C cold air stress

To determine the cardiovascular responses to beta-blockade and cold air stress, six males were randomly exposed at rest to three drug conditions (placebo, nonselective beta-blockade (propranolol), and selective beta-blockade (atenolol)) in each of two environments (5 and 25 degrees C) for 1 h. Cardiac output was lower on beta-blockade than on the placebo in both the 25 and 5 degrees C environments. Cardiac output on propranolol (4.2 +/- 0.3 L.min-1) at 5 degrees C was lower than on atenolol (4.7 +/- 0.4 L.min-1, p < 0.05). Mean arterial pressure was greater (p < 0.05) at 5 than 25 degrees C for each drug condition. There was no drug effect on total peripheral resistance at 25 degrees C. At 5 degrees C, total peripheral resistance on both beta-blockers (propranolol 1942.7 +/- 169.9 dyn.s.cm-5 (1 dyn = 10 microN); atenolol 1706.7 +/- 160.0 dyn.s.cm-5) was higher (p < 0.05) than on the placebo (1485.3 +/- 111.8 dyn.s.cm-5). Total peripheral resistance was also higher on propranolol than atenolol (p < 0.05). In conclusion, cold air stress interacts with beta-blockade to elevate total peripheral resistance by decreasing cardiac output while having little effect on mean arterial pressure. These effects are greater on nonselective than on selective blockade.

Risk assessment of adverse pulmonary effects induced by adrenaline β-receptor antagonists and rational drug dosage regimen based on receptor occupancy

To clarify the beta-1 selectivity of beta-adrenergic receptor blocking agents (beta-blocking agents) after typical oral doses, the relationships between the effects on exercise heart rate or FEV1 and beta-1 or beta-2 receptor occupancies (phi 1, phi 2) of seven beta-blocking agents, acebutolol, atenolol, metoprolol, oxprenolol, timolol, propranolol, and pindolol were analyzed retrospectively. Nonlinear relationships between the pharmacologic effect and phi 1 and between the pulmonary adverse effect and phi 2 were obtained. Based on these findings, a new index of cardiovascular selectivity is proposed, given by the ratio of beta-1 receptor occupancy to beta-2 receptor occupancy (phi 1/phi 2). Using this new index, there was a little difference in beta-1 selectivity between acebutolol and pindolol (3.1:1.0), in contrast to a marked difference in beta-1 selectivity (320:1) as a conventional index between these two drugs. This finding indicates that even beta-1 selective drugs must be administered carefully to patients with pulmonary disease. Furthermore, the relationship between the pharmacologic or pulmonary effects and phi 1 or phi 2 has been analyzed quantitatively with a ternary complex model and used to develop rational dosage regimens for beta-1 selective beta-blocking agents, such as atenolol, to obtain the desired pharmacologic effects with minimum adverse pulmonary effects.

Role of epinephrine in TNF and IL-6 production from isolated perfused rat liver.

A bidirectional communication exists between the nervous system and the immune system. Evidence has accumulated suggesting that cytokines-immune peptides influence sympathetic neuronal survival and that cytokines can promote the secretion of catecholamines. Using an isolated perfused rat liver (IPRL) preparation, we have shown that the liver is an important source of circulating cytokines in response to lipopolysaccharide (LPS) and that corticosterone dose dependently influenced LPS-induced production of tumor necrosis factor (TNF) and interleukin-6 (IL-6). In this study, we investigated the direct effect of epinephrine (another stress hormone) on the production of TNF and IL-6 in liver. We demonstrated that epinephrine (1 microM/ml) alone did not induce TNF bioactivity but significantly increased IL-6 bioactivity from IPRL effluent. When the IPRL was infused with LPS, epinephrine significantly decreased TNF bioactivity. Epinephrine in LPS-treated livers also significantly increased IL-6 bioactivity. Both responses were totally inhibited by the beta-blocker propranolol (10 microM/ml). Anisomycin, a protein synthesis inhibitor, infused into the IPRL completely blocked the rise in TNF and IL-6 concentrations in the effluent leaving the IPRL, supporting the hypothesis that the synthesis (or release) of these cytokines was dependent on protein synthesis. We then attempted to determine whether epinephrine exerts similar effects in vitro. Using isolated Kupffer cells and hepatocytes, we found that epinephrine alone had no effect on TNF and IL-6 production in Kupffer cells and hepatocytes but significantly decreased LPS-induced TNF bioactivity and increased LPS-induced IL-6 bioactivity in Kupffer cells. Our data support the hypothesis that epinephrine can promote IL-6 secretion from IPRL.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of centrally administered prolactin upon mammary contractility in anesthetized lactating rats.

The possibility was investigated that centrally administered rat prolactin (PRL), i.e., intracerebroventricularly (ICV) or intrathecally (IT), may influence mammary contractility in urethane-anesthetized lactating rats. In addition to the monomer (23 kD PRL), the 16- and 7-kD PRL fragments were also tested and their effects were determined on isometrically recorded intramammary pressure (IMP) responses to exogenous oxytocin (OXY). ICV injection of 23 kD PRL provoked increased IMP responses; similar, but inconsistent effects were obtained after 16 kD PRL, and no effect occurred after either saline or the 7 kD PRL fragment. The 23 kD PRL effect had a latency of about 5 min, reached plateau at 10-15 min and its magnitude was dose-dependent. Also, a stronger dose-related effect was shown by 23 kD PRL after IT than after ICV administration, which suggests that lower threshold for the PRL actions exist at the spinal level. On the other hand, ICV or IT injections of antiserum to PRL, but not of normal rabbit serum, fully prevented the respective facilitatory effects of 23 kD PRL on mammary contractility. Further experiments into the mechanisms involved showed that neither adrenalectomy nor hypophysectomy prevented the PRL effect whereas complete blockage occurred after either spinal cord transection, ventral root section (T8-T10 level), or i.v. or ICV administration of the adrenergic beta-blocker propranolol. These results indicate that central effects of PRL upon mammary contractility were neurally mediated and may have resulted from depressed beta-adrenergic control of ductal tone.

Effects of sympathetic stimulation, with and without previous 1 and adrenoceptor blockade, on refractoriness dispersion in canine heart

The aim was to determine the electrophysiological effects of cardiac sympathetic stimulation, with and without prior alpha 1 and beta adrenoceptor blockade during myocardial ischaemia in dogs. Chloralose anaesthetised dogs were studied 2 h after ligation of the obtuse marginal branches of the circumflex artery (OMB). The refractory period was measured at eight sites in the ischaemic zone, two sites in the border zone, and two sites in the normal zone with S1-S2 extrastimulus methods. In group 1 (n = 13), before OMB ligation, stimulation of the ventrolateral cardiac nerve shortened the refractory period only in the ischaemic zone (p < 0.01). OMB ligation resulted in a significant shortening of the refractory period in the ischaemic zone (p < 0.01). In group 2 (n = 12), the alpha 1 blocker bunazosin (0.2 mg.kg-1, intravenously) blunted the shortening of the refractory period in the ischaemic zone induced by OMB ligation (p < 0.01), resulting in a reduction in refractory period dispersion between the ischaemic and non-ischaemic (border and normal) zones. Subsequent administration of the beta blocker propranolol (0.2 mg.kg-1, intravenously) prolonged refractory periods both in the ischaemic and in the non-ischaemic zones (p < 0.05 v p < 0.001). Ventrolateral cardiac nerve stimulation reversed the effects of bunazosin on the refractory period in the ischaemic zone; however, after the addition of propranolol, neural stimulation no longer influenced the refractory period. In group 3 (n = 13), propranolol (0.2 mg.kg-1, intravenously) reversed the shortening of the refractory period in the ischaemic zone (p < 0.01) induced by OMB ligation but also prolonged the refractory period in the non-ischaemic zone (p < 0.001); refractory period dispersion between the ischaemic and non-ischaemic zones was thus not reduced. Ventrolateral cardiac nerve stimulation had no effect on refractory period after administration of propranolol alone or propranolol followed by bunazosin. Although an alpha 1 blocker may be better than a beta blocker in reducing refractory period dispersion between the ischaemic and non-ischaemic myocardium, a beta blocker may protect more effectively than an alpha 1 blocker against the detrimental effects of cardiac nerve activity on electrical instability in the ischaemic myocardium.

Adrenergic control of swimbladder perfusion in the European eel Anguilla anguilla.

Adrenergic control of swimbladder blood flow was analysed in blood-perfused preparations of the European eel as well as in situ by recording the changes in swimbladder blood flow and blood pressure following an injection of catecholamine into the dorsal artery. In blood-perfused swimbladder preparations, injection of the alpha-adrenergic agonist phenylephrine into the perfusion loop caused a marked dose-dependent increase in perfusion pressure at constant flow, while injection of the beta-agonist isoproterenol slightly decreased perfusion pressure. The beta-effect was not as pronounced as the alpha-adrenergic vasoconstriction and was observed only during the first application of catecholamine in each preparation. In situ injection of adrenaline (final concentration 10(-8)-10(-9) mol kg-1 body mass) into the dorsal aorta caused a dose-dependent transient increase in dorsal aortic blood pressure and in cardiac output which, after 5-10 min, returned to resting levels. Swimbladder perfusion also increased initially after an injection of adrenaline, but after about 1-2 min suddenly decreased and then slowly recovered to preinjection levels. Following the injection of adrenaline into the dorsal aorta, blood pressure changes in vessels at the swimbladder pole of the rete mirabile revealed a similar biphasic pattern with an initial increase, a subsequent decrease and a slow return to preinjection levels, while pressure in the arterial influx vessel of the rete resembled dorsal aortic pressure. After injection of the beta-blocker propranolol, adrenaline evoked a smaller initial increase in blood flow, but the subsequent reduction in flow was even more pronounced. Injection, in addition, of the alpha-adrenergic blocker phentolamine abolished the sharp adrenaline-induced decrease in swimbladder perfusion. It is concluded that alpha- and beta-adrenergically controlled resistance vessels are located close to the rete mirabile, probably at the arterial entrance into the rete. These vessels control perfusion of the rete mirabile and of the swimbladder and are thus involved in the control of gas deposition into the swimbladder.

Inhibition of Fatty Acid Synthesis by Stimulation of α- and β-Adrenergic Receptors in Human Mononuclear Leukocytes

Selective alpha- and beta-adrenergic agonists and antagonists were used to determine the action of catecholamines on fatty acid biosynthesis in freshly isolated human mononuclear leukocytes. Incubation of cells for 22 h in a lipid-free medium resulted in a 4-fold increase in the incorporation of [14C]acetate into fatty acids. Addition of (-)-epinephrine in increasing concentrations to the incubation medium inhibited the rate of fatty acid synthesis by 42% at a concentration of 0.1 M. Similar effects were observed using (-)-norepinephrine and the beta-agonist isoproterenol. The catecholamine action was diminished by the unselective beta-blocker propranolol and mimicked by dibutyryl cyclic AMP. Since human mononuclear leukocytes possess beta 2-, but not beta 1-adrenoceptors (Brodde, Engel and Hoyer 1981), catecholamines may act via beta-adrenergic receptors of the beta 2-subtype. In addition, it appears that stimulation of alpha-adrenergic receptors inhibits fatty acid synthesis, too. In the presence of a beta-blockade by 1 microM propranolol, the alpha 2-agonist alpha-methylnorepinephrine, but not the alpha 1-agonist phenylephrine inhibited fatty acid synthesis rate. Accordingly, the epinephrine effect was attenuated by the alpha 2-antagonist yohimbine, but not by the alpha 1-antagonist prazosin. The results provide evidence that catecholamines may inhibit the synthesis rate of fatty acids by stimulation of both, beta 2- and alpha 2-adrenergic receptors.

Quality of life and cost-effectiveness in the treatment of hypertension.

By and large, the results of the different studies on quality of life in hypertension suggest that among beta-blockers only the nonselective beta-blocker propranolol has a negative effect on well-being, being associated with depression and side-effects. The findings on diuretics are comparatively few, and mainly observed as an adverse impact on sexual function. If one broadens the treatment scenario to include mortality and morbidity, evidence of a beneficial impact has only been proven for beta-blockers and diuretics. With the primary aim of antihypertensive drug therapy given as a reduction in cardiovascular risk factors, the aim with regard to quality of life is that quality of life be maintained. The new guidelines on the management of mild hypertension issued in the United States highlight the danger of relaxing the concern for risk reduction and costs in favour of surrogate end-points, even though these may carry great significance in the individual patient.

In vitro and in vivo studies of drug residue accumulation in pigmented tissues.

A procedure was developed to enable ready isolation of melanin granules from pigmented tissues of the bovine eye. The granules were used in a simple in vitro test to model the potential for a range of veterinary drugs to accumulate in melanin-containing tissues such as hair and the choroid/pigmented retinal epithelium (choroid/PRE) of the eye. The beta-agonists clenbuterol and salmeterol, but not salbutamol, showed appreciable binding, as did the beta-blockers propranolol and carazolol and the tranquillizers azaperone and xylazine. All of the natural and synthetic growth promoters tested gave rise to significant binding (17 beta-estradiol, testosterone, alpha-zeranol, diethylstilbestrol and 19-nortestosterone) but progesterone and 17 alpha-trenbolone bound to a lesser extent. To provide a preliminary indication of the validity of the model, animals were treated with clenbuterol for 21 d, to enable the assessment of accumulation in vivo. Clenbuterol was detected in choroid/PRE and hair at high concentrations from the last day of treatment (1779 ng g-1 and 424 ng g-1, respectively) until the end of the study period, 63 d later (512 ng g-1 and 483 ng g-1, respectively). These studies clearly indicate the wider potential for pigmented tissue analysis in monitoring for the use of veterinary drugs (particularly unlicensed substances) in food producing animals. Hair analysis may offer particular advantages for on-farm monitoring and in providing historic information.

Review of Studies on the Clinical Pharmacodynamics of Cilazapril

Several studies were performed to evaluate the degree of inhibition of angiotensin-converting enzyme (ACE) by an ACE inhibitor by assessing the blood pressure response to a continuous i.v. infusion of increasing doses of angiotensin I in healthy volunteers. We assessed pharmacokinetic and pharmacodynamic interactions of the ACE inhibitor cilazapril and the beta-blocker propranolol in healthy volunteers and patients with essential hypertension. We also evaluated the effect of cilazapril on aortic compliance in hypertension by pulse-wave velocity along the aorta. We showed that single oral doses of cilazapril 4 mg, captopril 25 mg, or enalapril 10 mg shifted the angiotensin I dose-effect curve to the right and determined a pharmacologic half-life of about 4 h for cilazapril. Increasing single oral doses (1.25, 3.75, 10, and 30 mg) of cilazapril reduced diastolic blood pressure dose-dependently and shifted the angiotensin I dose-response curves to the right. The dose representing 50% inhibition of ACE activity (apparent Ki dose) was about 0.6 mg 3 h after cilazapril administration. Cilazapril and propranolol did not exhibit significant pharmacokinetic interaction in healthy volunteers; each drug reduced diastolic and systolic blood pressure by about 7 mm Hg, and this was doubled by the combination. Monotherapy with each drug reduced blood pressure, and combined administration enhanced the antihypertensive effect. The reduction in cardiac output and the increase in total peripheral resistance induced by propranolol were attenuated by the cilazapril-propranolol combination.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of Lens β-Adrenergic Receptors by Receptor Occupancy and Dexamethasone

Beta-adrenergic binding sites in primary cultures of chick lens annular pad (CLAP) cells were characterized with dihydroalprenolol (DHAP). Binding site affinities and densities were similar to beta-adrenergic receptors (BARs) previously characterized on crude membranes from freshly isolated cells. In competitive displacement studies, the beta-blocker propranolol was shown to increase the number of available binding sites in a concentration dependent manner. Acute exposure of CLAP cells to propranolol prior to DHAP binding also resulted in an increase in the number of available binding sites. Finally, lens beta-adrenergic binding site levels could be modulated by dexamethasone treatment. These results indicate that lens BARs are subject to common regulatory mechanisms and further implicate ophthalmic pharmaceuticals as possible cataractogenic agents.