Alpha-blocking Properties Research Articles

Curcumin and α/β-Adrenergic Antagonists Cotreatment Reverse Liver Cirrhosis in Hamsters: Participation of Nrf-2 and NF-κB

Liver cirrhosis is the result of an uncontrolled fibrogenetic process, due to the activation and subsequent differentiation into myofibroblasts of the hepatic stellate cells (HSC). It is known that HSC express adrenoreceptors (AR), and the use of AR antagonists protects experimental animals from cirrhosis. However, several studies suggest that the toxicity generated by metabolism of these antagonists would hinder its use in cirrhotic patients. In addition, liver fibrosis may be associated with a decrease of the antioxidant response of the nuclear factor erythroid 2-related factor 2 (Nrf-2) and the overregulation of the proinflammatory pathway of nuclear factor kappa B (NF-κB). Therefore, in the present work, the capacity of doxazosin (α1 antagonist), carvedilol (nonselective beta-adrenoceptor blocker with alpha 1-blocking properties), and curcumin (antioxidant and anti-inflammatory compound) to reverse liver cirrhosis and studying the possible modulation of Nrf-2 and NF-κB were evaluated. Hamsters received CCl4 for 20 weeks, and then treatments were immediately administered for 4 weeks more. The individual administration of doxazosin or carvedilol showed less ability to reverse cirrhosis in relation to concomitantly curcumin administration. However, the best effect was the combined effect of doxazosin, carvedilol, and curcumin, reversing liver fibrosis and decreasing the amount of collagen I (Sirius red stain) without affecting the morphology of hepatocytes (hematoxylin and eosin stain), showing normal hepatic function (glucose, albumin, AST, ALT, total bilirubin, and total proteins). In addition, carvedilol treatment and the combination of doxazosin with curcumin increased Nrf-2/NF-κB mRNA ratio and its protein expression in the inflammatory cells in the livers, possibly as another mechanism of hepatoprotection. Therefore, these results suggest for the first time that α/β adrenergic blockers with curcumin completely reverse hepatic damage, possibly as a result of adrenergic antagonism on HSC and conceivably by the increase of Nrf-2/NF-κB mRNA ratio.

BETA-BLOCKERS AND RENOPROTECTION: THE POTENTIAL OF CARVEDILOL

The review presented the importance of carvedilol using in terms of renoprotection in renal dysfunction at the pre-dialysis stage of the disease in order to reduce the risk of progression of chronic kidney diseases (CKD) and the development of cardiovascular complications. Immune and non-immune mechanisms (proteinuria, dyslipidemia, anemia, arterial hypertension) of renal dysfunction progression in patients with CKD of inflammatory and non-inflammatory origin are described. Moreover, with the slowing down of the glomerular filtration rate in CKD, the role of non-immune factors in the development of cardiovascular complications becomes very important. In contrast to non-selective and some β 1-selective beta-blockers, the use of beta-adenoblocker with vasodilating activity, in particular carvedilol, makes it possible to prevent the onset of the terminal stage of CKD. Carvedilol, being a lipophilic beta-adrenoblocker of the third generation with alpha-blocking properties, influences the possible mechanisms of renoprotection: antihypertensive (including in combined antihypertensive therapy), anti-inflammatory, antiproliferative, anti-apoptotic, antioxidant, antiplatelet and others. Carvedilol due to the vasodilating effect softens the stress of the parietal shear, exerting a retarding action on the progression of CKD. Carvedilol with a pronounced vasodilating effect and a long half-life significantly reduces central arterial pressure that is also an important renoprotective mechanism in the treatment of patients with renal dysfunction. Carvedilol has an important renoprotective mechanism in CKD – inhibition of the secretion of the potent vasoconstrictor endothelin. In the metabolic syndrome, in which there is a significant risk of developing renal dysfunction, carvedilol levels the imbalance of adipokine secretion, insulin resistance, sodium and water retention, and the activation of renin-angiotensin-aldosterone and sympathoadrenal systems. Carvedilol at the early stages of CKD development shows predominantly antihypertensive action due to inhibition of the renin-angiotensin-aldosterone system activity directly in the kidneys. At the late stage of the disease, the drug is able to retain residual kidney function. That is, carvedilol can be used at all stages of CKD development, regardless of the etiology of kidney damage.

English

INTRODUCTION: Normal pregnancy is characterized by unique physiological changes. It is mandatory for an anesthesiologist to understand these changes and their anesthetic implications. Pregnancy induced hypertension (PIH) is a disorder of unknown etiology affecting 5-10% of all pregnancies characterized by the development of hypertension with proteinuria after 20 weeks of gestation. Hypertension-Sustained systolic pressure of at least 140mmHg or a sustained diastolic pressure of at least 90 mmHg that occurs after 20 weeks of gestation in a woman with previously normal blood pressure. Maternal complications of severe pregnancy induced hypertension include pulmonary edema, intracerebral hemorrhage and renal failure. Fetal complications include intra uterine growth retardation (IUGR), perinatal mortality. Management of severe pregnancy induced hypertension requires multidisciplinary approach. Definitive treatment consists of termination of pregnancy along with prevention of seizures and control of blood pressure. The drugs used in the control of blood pressure are oral antihypertensives like Alphamethyldopa and intravenous agents like Hydralazine, Labetalol, Nitroglycerin etc. Intravenous Labetalol injection is a unique drug with both alpha and beta adrenergic receptor blocking properties. It has both blood pressure and heart rate reducing properties. This makes it a good choice in treating high blood pressure in severe pregnancy induced hypertension patients. Our study is to find out the efficacy of intravenous Labetalol injection in the acute preoperative control of high blood pressure in severe pregnancy induced hypertension (PIH) patients. AIM OF STUDY: The aim of this study is to find out and compare the efficacy of intravenous Labetalol injection with the routinely used regimen of oral antihypertensives tablet Alphamethyldopa and tablet Nifedipine in the acute preoperative control of high blood pressure in severe pregnancy induced hypertension patients. MATERIALS AND METHODS: After obtaining the necessary institutional and ethical committee clearance following study was conducted in the Institute of obstetrics and gynecology, (IOG), Madras Medical College & Research Institute, Chennai . All antenatal mothers were screened for severe pregnancy induced hypertension (PIH) in the casualty department and 40 patients with severe PIH were selected. Informed consent was obtained from them and randomly divided into 2 groups namely group A and group L of 20 each. Inclusion criteria: (any one of the following): 1. Systolic blood pressure> 160mmHg, 2. Diastolic blood pressure>110mmHg, 3. Proteinuria (dipsticks)>+3or+4, 4. History of oliguria or urine output < 500ml in 24 hours, 5. Presenting with imminent features– blurring of vision, epigastric pain, hyperreflexia, HELLP. Exclusion criteria: 1. Secondary hypertension, 2. Cardiac arrhythmia, 3. Bronchial asthma, 4. Diabetes mellitus, 5. Complications due to severe Pregnancy induced hypertension like intracerebral hemorrhage, acute left ventricular failure, coagulopathy, bleeding disorders, 6. Patients already on oral antihypertensives are not included in-group L. SUMMARY: Comparative clinical study of acute preoperative management of high blood pressure in severe pregnancy induced hypertension patients using two methods: one by (Group A) an oral combination of tablets Alphamethyldopa and Nifedepine and other by (Group L) intravenous Labetalol was undertaken at the Institute of Obstetrics and Gynaecology, Madras medical college & research institute, Chennai during the year 2006-2008. Summarizing the findings in the study: 1. Oral antihypertensive combination of tablets Alphamethyldopa and Nifedepine achieved blood pressure control that often necessitated intravenous Nitroglycerin as rescue drug. 2. Intravenous Labetalol achieves adequate and faster blood pressure control with better heart rate maintenance than the routinely used oral antihypertensive combination. CONCLUSION: In conclusion, intravenous Labetalol achieves adequete and faster blood pressure control with better heart rate maintenance than the routinely used oral antihypertensive combination of tablets Alphamethyldopa and Nifedipine in the control of blood pressure in preoperative severe pregnancy induced hypertension patients.

Doctor I have painful erections

IntroductionIschemic (veno-occlusive, low flow) priapism is a painful and persistent penile erection unrelated to sexual desire or stimulation. In some cases, it is an adverse event of antipsychotic medications.Materials and methodsAn Internet search was initiated using the search engines: Direct Sciences; Medline and keywords “Penile erection; priapism; Antipsychotic agents; Side effects” and we illustrated our literature review by a clinical vignette of a man aged 38 years followed for schizophrenia placed under Fluphenazine 125 mg/month from 5 years who consulted us in may 2015 because of priapism and he described painful and prolonged erection episodes evolving for approximately 5 days.DiscussionMedical literature mentions many cases of venous priapism in patients treated by conventional or atypical neuroleptics. About 30% of venous priapisms could be related to drugs of which approximately 50% to neuroleptics. This side effect is related to alpha1-adrenergic blocking properties of these treatments, more or less important depending on the drugs in this class. After emergency treatment, the priapism is the problem of the continued neuroleptic treatment. The substitution of one molecule by another alpha-1 blocking properties to the less marked is recommended.ConclusionThe venous priapism is a uro-andrological emergency requiring prompt treatment to prevent erectile sequelae.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Priapisme sous antipsychotiques et défis de prise en charge : à propos d’un cas

Priapism is a persistent, and often painful, penile erection, lasting more than 3 hours, not usually associated with sexual stimuli. It is a urological emergency that can cause serious complications. Drugs are responsible of the onset of 25 to 40% of cases of priapism. Several classes of medication are involved: antidepressants, antihypertensives, anticoagulants, alpha-blockers and some psychoactive substances (alcohol, cocaine, cannabis...). However, about 50% of drug related priapism is due to antipsychotics (AP). Clinicians should be aware of this rare side effect because of the severity of its complications and the difficulty of its management, especially in non-stabilized psychotic patients. We report a case of a 22-year-old male Moroccan patient, diagnosed with schizophrenia, who had been admitted for the first time to a psychiatric hospital for management of a psychotic episode. First, he received 15 mg per day of haloperidol, and seven days later he developed priapism. The patient was immediately referred for urological care. Aspiration and irrigation of the corpora cavernosa was proposed, but could not be performed because of patient refusal, and the erection resolved spontaneously after 10 hours. Haloperidol was stopped, and four days later the patient was switched to 10mg per day of olanzapine. After 10 days of treatment, he developed a second episode of priapism, and olanzapine was also stopped. A cavernosal aspiration-irrigation was performed in emergency; which resulted in the partial detumescence of the penis. Two days later, and despite therapeutic abstention, the patient presented another episode of priapism. The indication of a revascularization of the corpora cavernosa was proposed, but again the patient refused the surgery. Finally, the patient was administered 400mg/day of amisulpride, with a favorable outcome. Priapism disappeared after a month with the installation of fibrosis and partial loss of erectile function. The precise mechanisms of the role of AP in the occurrence of priapism are not all known and a multifactor etiology seems the most likely. Neuromuscular hypothesis is the most mentioned, involving the blocking action of alpha1-adrenergic receptors of the corpora cavernosa for which most of AP have an affinity. The occurrence of priapism in a psychotic patient, especially during periods of decompensation, raises a number of challenges for the medical staff. First, the non-recognition by the patient of this side effect, and its potentially severe consequences. Second, the absence of link between dose and duration of AP treatment on one side, and the onset of priapism on the other, which makes it hard to predict. The third challenge is the choice and initiation of another AP. The literature reveals many cases of priapism in both conventional and atypical AP, the presence of a predisposition to this type of incident has been reported. However, few authors have focused on alternatives to provide for these patients. Amisulpride is currently the only molecule that does not have alpha-adrenergic affinity and is therefore preferred in these cases. Priapism is a rare but serious adverse event of AP medication. Informing patient about the risk of priapism would help to report it early and prevent erectile dysfunction. Switching to another AP with less alpha1-blocking properties is generally recommended.

The Effect of Body Mass Index on Patients Admitted with Acute Decompensated Heart Failure

Introduction: Elevated body mass index (BMI) is associated with ventricular remodeling by augmenting hemodynamic load and increasing neurohumoral activation in patients with heart failure. Carvedilol is unique among beta blockers because of its alpha blocking properties giving it increased non-nitric oxide dependent vasodilatory properties. We sought to evaluate the effect of BMI on changes in systemic vascular resistance (ΔSVR) in patients with acute decompensated heart failure treated with B1 selective beta-blockers compared with carvedilol.

Effects of carvedilol on heart rate dynamics in patients with congestive heart failure.

Patients with congestive heart failure (CHF) have alterations in the traditional and nonlinear indices of heart rate (HR) dynamics, which have been associated with an increased risk of mortality. This study was designed to test the effects of carvedilol, a nonselective beta-blocker with alpha-1 blocking properties, on HR dynamics in patients with CHF. We studied 15 patients with CHF secondary to ischemic or idiopathic cardiomyopathy who met the following inclusion criteria: NYHA functional class II-III, optimal conventional medical therapy, normal sinus rhythm, left ventricular ejection fraction (LVEF) of < 40%, and resting systolic blood pressure greater than 100 mmHg. The 6-minute corridor walk test, estimation of LVEF, and 24-hour Holter recording were performed at baseline and after 12 weeks of therapy with carvedilol. Traditional time and frequency domain measures and short-term fractal scaling exponent of HR dynamics were analyzed. After 12 weeks of therapy with carvedilol, the mean LVEF improved significantly (from 0.27 +/- 0.08 to 0.38 +/- 0.08, P < 0.001). The average HR decreased significantly (from 86 +/- 11 to 70 +/- 8 beats/min, P < 0.001). The mean distance traveled in the 6-minute walk test increased significantly (from 177 +/- 44 to 273 +/- 55 m, P < 0.01). The frequency-domain indices (HF and LF), the time domain indices (rMSSD and PNN5 ), and the short-term fractal scaling exponent increased significantly. The scaling exponent increased particularly among the patients with the lowest initial values (< 1.0), and the change in the fractal scaling exponent correlated with the change in ejection fraction (r = 0.63, P < 0.01). Carvedilol improves time and frequency domain indices of HR variability and corrects the altered scaling properties of HR dynamics in patients with CHF. It also improves LVEF and functional capacity. These specific changes in HR behavior caused by carvedilol treatment may reflect the normalization of impaired cardiovascular neural regulation of patients with CHF.

Carvedilol inhibits platelet-derived growth factor-induced signal transduction in human cardiac fibroblasts.

In the current study, first the platelet-derived growth factor (PDGF)-induced stimulation of the PDGF-beta receptor kinase in human cardiac fibroblasts was examined, and then the possibility of counterbalancing this signal transduction by carvedilol, a beta-blocker with alpha1-blocking properties, was investigated. Human cardiac fibroblasts were cultured from myocardial biopsy samples taken from patients with idiopathic dilated cardiomyopathy. The stimulation of the PDGF-beta receptor kinase by recombinant human PDGF (BB) in the cells and the inhibitory effect of carvedilol (1, 5, 10, and 20 microM) were investigated by analyzing PDGF-induced PDGF receptor tyrosine phosphorylation using Western blotting and by measuring DNA synthesis with a colorimetric assay. In human cardiac fibroblasts, the PDGF receptor kinase could be stimulated with PDGF (100 ng/ml) and inhibited with carvedilol (5 microM). In addition, carvedilol at a concentration of 5 microM significantly decreased DNA synthesis by approximately 50%. The inhibition of PDGF-stimulated mitogenesis by carvedilol at concentrations of 10 and 20 microM was 64 or 75%, respectively. Other beta-adrenoceptor antagonists such as propranolol (10 microM) and metoprolol (10 microM) did not significantly affect the PDGF-induced beta-receptor autophosphorylation. These findings provide novel experimental support for the known beneficial clinical effects of carvedilol in the treatment of chronic heart failure associated with myocardial fibrosis.

Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity

Hypertensive patients frequently show resistance to insulin-stimulated glucose uptake and hyperinsulinemia. Diuretics and beta-adrenoceptor blocking agents have been found to decrease insulin sensitivity, whereas alpha 1-blockers and angiotensin converting enzyme inhibitors seem to improve it. To compare the effects of a 3 months' antihypertensive treatment with carvedilol, a non-selective beta-adrenoceptor blocker with alpha 1-blocking properties, with the beta 1-selective receptor blocker metoprolol on insulin sensitivity in non-diabetic hypertensive patients. A multicenter double-blind randomized study. Seventy-two non-diabetic hypertensive patients were randomly assigned to treatment with either carvedilol or metoprolol. An isoglycemic, hyperinsulinemic glucose clamp was conducted before and after 12 weeks of treatment; the metabolic clearance rate for glucose was taken as an indicator of insulin sensitivity. The two groups did not differ in age, sex, body mass index, blood pressure or lipids, and treatment effectively lowered blood pressure. In both groups, insulin sensitivity was impaired at baseline. After metoprolol treatment, insulin sensitivity further decreased significantly by about 14%, whereas it increased after carvedilol. There was also a decrease in high-density lipoprotein and an increase in triglycerides levels in patients in the metoprolol-treated group, whereas these parameters remained unchanged in patients in the carvedilol-treated group. This study confirms previous findings of a reduction in insulin sensitivity after chronic metoprolol treatment. Carvedilol treatment, however, resulted in a small amelioration of insulin resistance and a better lipid profile [corrected]. We thus demonstrate that a beta-blocker with alpha 1-blocking properties has favorable effects on glucose metabolism, suggesting a potentially important role of peripheral blood flow in regulating glucose uptake. These findings imply that beta-blocker treatment, when combined with alpha 1-blocking activity has advantageous effects on insulin sensitivity and lipids and could therefore be suitable for patients with the metabolic syndrome.

A Risk-Benefit Assessment of Carvedilol in the Treatment of Cardiovascular Disorders

Carvedilol is a nonselective beta-adrenoceptor blocking vasodilator drug that may be a promising new agent in the management of cardiovascular disease. The rationale for the development of agents of this type is that the alpha-blocking component may overcome the direct vasoconstrictor consequence of beta 2-blockade, whilst the beta-blocker component may inhibit the reflex tachycardia that occurs following alpha-blockade. In clinical trials published to date, carvedilol has been demonstrated to be effective as an antihypertensive agent as monotherapy and also as additional therapy in those patients whose blood pressure cannot be controlled on other standard agents. It is also effective in the management of angina. Carvedilol has beneficial haemodynamic effects in patients with congestive heart failure. beta-Blocker vasodilator drugs of this type may be particularly useful in this condition as the vasodilator component of the drug may overcome the initial negative inotropy of the beta-blocker. In addition, carvedilol possess potentially useful pharmacological actions. In particular, the drug has antimitogenic and free radical scavenging effects that may make it a useful therapy in the long term management of atherosclerotic vascular disease. Its metabolic profile is also favourable, presumably on the basis of its alpha-blocking properties. Thus, beta 2-mediated adverse effects on peripheral vascular tone, glycaemic control and lipid status appear to be offset by the alpha-blocking property of the drug. Carvedilol thus far appears to be well tolerated, with postural dizziness the major adverse effect, especially in the elderly. As with nonselective beta-blockers, carvedilol is contraindicated in patients with asthma.

Dose-effect and pharmacokinetic-pharmacodynamic relationships of the β1adrenergic receptor blocking properties of various doses of carvedilol in healthy humans

To evaluate the pharmacodynamic properties of carvedilol across a broad range of doses in relation to its enantiospecific kinetics and adrenergic receptor occupancies, relative to placebo and propranolol. Twelve healthy male subjects were investigated on six separate occasions at least 1 week apart when they received either a single peroral dose of 40 mg propranolol, 12.5, 25, 50, or 100 mg carvedilol, or placebo. The subjects were extensively profiled at supine rest, and they underwent supine bicycle ergometry before and at 2, 4, 6, 9, 12, and 22 hours after dosing. At these time points blood was drawn for the high performance liquid chromatographic determination of the enantiomers of carvedilol and for the radioreceptor assay determination of alpha 1- and beta 1-adrenergic receptor binding and related concentrations. Carvedilol was confirmed to bind to beta 1-adrenergic receptors and (albeit to a lesser extent) to alpha 1-adrenergic receptors. Carvedilol furthermore attenuated the ergometric increase in heart rate in a closely dose-related fashion, which exemplified its beta 1-adrenergic receptor blocking effects. However, the basal efferent adrenergic drive might have been too low to show consistent alpha 1-blocking properties. The radioreceptor and enantiomer kinetics were proportional with dose. There was no indication that the overall kinetic behavior of contributing active metabolites would differ from that of the S(-)-enantiomer. On average, there was a smooth linear relationship between the ergometric treatment responses and log-transformed dose, log-transformed concentrations of the S(-)-enantiomer, and the radioreceptor assay derived beta 1-adrenergic receptor occupancies. The relative complexity of the kinetics of carvedilol (enantiospecific kinetics and dynamics, protein binding, and involvement of active metabolites) does not preclude relatively simple and straight-forward dose-effect and kinetic-dynamic relationships.

Antihypertensive treatment with a dual-acting beta-blocker in the elderly

Risk factors in elderly hypertensives: Recent large-scale clinical trials have shown that antihypertensive treatment in the elderly produces meaningful reductions in strokes and other cardiovascular events. However, the treatment of hypertension in older patients is often complicated by the presence of concomitant disorders. Clinical and silent myocardial ischemia, as well as left ventricular hypertrophy and both systolic and diastolic left ventricular dysfunction, frequently coexist with hypertension. Additional clinical considerations in elderly hypertensives include a high prevalence of abnormal lipid and glucose metabolism and a tendency toward decreased renal function. Effects of different antihypertensive drugs: Although diuretics and conventional beta-blockers have been used as first-line drugs in the major clinical trials, some of their effects on metabolic parameters and on the myocardium can make them inappropriate in some patients. Newer drug classes, including angiotensin converting enzyme (ACE) inhibitors, calcium-channel blockers and, more recently, alpha 1-adrenergic blockers are effective alternatives. Dual-acting beta-blockers offer an important new approach for treating hypertension in elderly patients. Effects of carvedilol: Carvedilol possesses both beta- and alpha 1-blocking activity and appears to exhibit calcium channel blocking activity in animals. The alpha 1-blocking properties of this drug help to produce a desirable hemodynamic profile and facilitate appropriate blood pressure and heart rate responses to exercise. Carvedilol does not appear to adversely affect left ventricular systolic function and, in selected patients with heart failure, has been shown to increase the ejection fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Can Intravenous β-Blockade Predict Long-Term Hemodynamic Benefit in Chronic Congestive Heart Failure Secondary to Ischemic Heart Disease?

Several studies have demonstrated the long-term beneficial effects of beta-blockers in the treatment of congestive heart failure. Despite interest in this mode of therapy, clinical application of beta-blockers has been limited due to their negative inotropic effect. A subset of the heart failure patients do not show improvements with standard beta-blocker therapy. Carvedilol, a new nonselective beta-blocking agent with concurrent alpha-blocking properties, was evaluated in 17 patients with chronic heart failure secondary to ischemic heart disease. All had resting left ventricular ejection fraction less than or equal to 45% and were maintained on diuretic therapy. Acute hemodynamic measurements were made after administration of intravenous carvedilol (2.5-7.5 mg) and after chronic therapy for 8 weeks (12.5 to 50 mg b.i.d.). Radionuclide ventriculography, ambulatory intra-arterial blood pressure monitoring, and right heart catheterization were performed before and after 8 weeks of chronic therapy. Twelve patients completed the study (five were withdrawn). Symptomatic and hemodynamic improvements were demonstrated in 11 of the 12 patients after 8 weeks of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

The reversal of the ischemic effects of epinephrine on a finger with local injections of phentolamine

The use of phentolamine (Regitine®) as a specific competitive antagonist of epinephrine by virtue of its alpha-blocking properties is well known. Its use via digital nerve block infiltration has been described in cases of IV infiltration of sympathomimetics. We discuss a recent case of local and direct infiltration of phentolamine along the course of the digital arteries and directly into the thumb tuft to reverse the local ischemic effects of epinephrine.

Clinical Use of ??-Andrenoceptor Blockade in Systemic Hypertension

beta-Blockers are effective in reducing the blood pressure of many patients with systemic hypertension. They differ in terms of the presence or absence of intrinsic sympathomimetic activity, membrane-stabilising activity, beta 1-selectivity, alpha-blocking properties, and relative potency and duration of action. All beta-blockers appear to have blood pressure lowering effects. The choice of which beta-blocker to use in an individual patient is determined by the pharmacodynamic and pharmacokinetic differences between the drugs in conjunction with the patient's other medical condition(s). This review discusses the practical use of beta-blockers and provides rational suggestions for which drug(s) to use in selected patient groups (Black, elderly, postinfarction, diabetes, renal disease, obstructive lung disease, elevated lipid levels, coexisting angina, and left ventricular hypertrophy).

Effects of ketanserin on intraocular pressure

There is evidence that some antihypertensive drugs, such as beta blockers, are effective in reducing intraocular pressure (IOP) and are commonly used in the medical treatment of glaucoma. The aim of this study was to evaluate the effects of the anti-serotonergic agent ketanserin, which has associated alpha 1-blocking properties, on IOP in normotensive and hypertensive eyes. The first part of the study was performed in six arterial hypertensive patients (mean +/- SD blood pressure 156/102 +/- 10/6 mmHg) with a pretreatment IOP in the normal range (15.7 +/- 1 mmHg). Both blood pressure and IOP were measured at baseline and at 1 hour intervals up to 3 hours following the oral administration of ketanserin 20 mg or placebo, given in a randomized manner. Three hours after ketanserin treatment, mean systolic and diastolic blood pressures dropped by 10/5 mmHg and mean IOP was reduced by 2.7 mmHg; after placebo, no change was observed in these variables. Thereafter, four normotensive patients with chronic open-angle glaucoma (IOP = 22.8 mmHg) were given 20 mg ketanserin orally. Three hours after administration, a 22% reduction in mean IOP occurred (-5.8 mmHg), with a concomitant reduction in mean systolic blood pressure of 13.0 mmHg. These results indicate that ketanserin treatment reduces IOP and systemic blood pressure. Further, long-term studies are needed in order to confirm the efficacy of ketanserin in the medical treatment of ocular hypertension.

Failure of enhancement by labetalol of bronchopulmonary effects of histamine in guinea-pigs: independence of alpha-adrenoceptor antagonism.

The effect of labetalol on histamine-induced bronchoconstriction was studied in anaesthetized guinea-pigs. Unlike propranolol (1 mg kg-1), the same dose of labetalol did not enhance histamine-induced bronchoconstriction. To determine whether the absence of enhancement of the respiratory effects of histamine by labetalol was due to its alpha 1-blocking properties or to its partial agonist activity at beta 2-adrenoceptors, the effects of propranolol plus prazosin and of propranolol plus labetalol on histamine-induced bronchoconstriction were examined. In both cases, the bronchoconstrictor effects of histamine were enhanced to the same extent as with propranolol alone. These data support the hypothesis that the non impairment of respiratory mechanics by labetalol is not due to antagonism at alpha-adrenoceptors and may be mediated by its partial agonist activity at beta 2-adrenoceptors.

Studies on the Mode of Vasodilating Action of Carvedilol

Investigations were performed on isolated rat aortic strips and in pithed rats in order to elucidate the mechanism of vasorelaxation or the acute blood pressure lowering effect induced by carvedilol. In particular, the possible role of the beta-receptor-stimulating activities or alpha-blocking properties has been investigated. beta 2-stimulation can be ruled out, since preincubation of isolated vessels with the beta 2-receptor blocker ICI 118.551 does not influence the vasorelaxing activity of carvedilol. Additionally, its optical enantiomers also induce the same vasorelaxing effect in vitro. In contrast to the standard alpha-blocking agents phentolamine or prazosin, carvedilol does not inhibit effects of alpha-receptor agonists at hypotensive doses, but inhibition of the effects of alpha-receptor agonists has been found in vitro and in vivo at high concentrations or doses and indicates a potential alpha-blocking activity of carvedilol. For example, the dose required for a specific inhibitory effect on norepinephrine responses observed in pithed rats is at least 20 times higher than that required for a decrease in blood pressure in spontaneously hypertensive rats. Furthermore, the alpha-blocking activity is at least 20 times lower than the beta-blocking activity, whereas hypotension and beta-blockade can be observed in intact animals after acute administration in the same dose range of carvedilol. It can therefore be assumed that the alpha-blocking activity does not contribute substantially to the decrease in blood pressure at doses normally used. It is suggested that a not yet defined postreceptor mechanism is involved in the vasorelaxing and acute blood pressure lowering activity of carvedilol.

Pharmacology of terazosin

Terazosin is a quinazoline antihypertensive agent that is chemically similar to prazosin. The saturated furan ring of terazosin distinguishes these two compounds. Terazosin (0.1 to 3.0 mg/kg) lowered blood pressure without increasing heart rate when given orally to spontaneously hypertensive rats. No tolerance was observed during five days of repeated oral administration. Although equally efficacious in spontaneously hypertensive rats as its congener prazosin, terazosin exhibited a more gradual onset of action than prazosin, a more uniform and linear dose-response curve, and a less variable duration of action. When administered intravenously to dogs, terazosin lowered blood pressure primarily by decreasing peripheral vascular resistance. Pretreatment with phenoxybenzamine but not with atropine or propranolol resulted in a greatly reduced hypotensive response to terazosin, demonstrating that this effect of terazosin is mediated by a sympatholytic mechanism of the alpha type. The nature of the alpha-blocking properties of terazosin was evaluated in vitro using both radioligand binding studies and functional tests in rabbit aorta and pulmonary artery. These studies demonstrated that terazosin is highly selective for alpha 1 receptors. The affinity for alpha 1 receptors was approximately one-third that of prazosin. Like prazosin, terazosin displayed minimal interaction with alpha 2 receptors. Median lethal dose values in rats ranged from 0.255 to 0.270 g/kg for intravenous administration and from 5.5 to 6.0 g/kg, for oral administration. Oral administration of high doses of the compound to rats did not produce any gastrointestinal irritation and/or apparent abnormal behavioral effects. Comparison of the oral activity of terazosin in spontaneously hypertensive rats with the oral toxicity values in normal rats revealed a high efficacy/ safety ratio. Terazosin given intravenously to rats and mice was 2.6 to 5.0 times less toxic than prazosin. The absorption of terazosin appeared to be slower than that of prazosin in rats. However, from eight to 16 hours after dosing, terazosin concentrations in plasma exceeded those of prazosin, suggesting the possibility of once-daily dosing with terazosin. In addition, terazosin exhibited statistically significant cholesterol lowering effects in gerbils.

The Additional Properties of Beta Adrenoceptor Blocking Drugs

Beta adrenoceptor blocking drugs are all competitive inhibitors of the beta receptor although they may or may not possess, beta 1-(cardio)selectivity, intrinsic sympathomimetic activity (ISA) or partial agonist activity, alpha-blocking properties, while membrane stabilizing activity is now thought not to be important. Drugs with ISA give less of a reduction in resting and maximal exercising heart rate and consequently in cardiac output, than those without ISA. The possession of alpha-blocking activity also leads to less fall in cardiac output. Overall evidence suggests that peripheral resistance and peripheral blood flow is less reduced by ISA drugs. Post-beta blockade hypersensitivity which may be important in patients with ischemic heart disease if beta blocking drugs are suddenly stopped, is absent after beta-blocking drugs with ISA as they result in down regulation of beta receptors. Beta 1-selective drugs may result in less of a rise in blood pressure in response to isometric exercise, insulin hypoglycemia or smoking. There do not appear to be important differences in the effect on coronary flow. While presently available drugs can produce asthma in susceptible subjects there seems little doubt that beta 1 selective agents have less effect than other beta-blocking drugs, and give less inhibition of sympathomimetic bronchodilators. Nonselective, non ISA, beta-blocking drugs elevate triglycerides, cardioselective drugs possibly less so. Those with ISA may elevate HDL unlike those beta-blocking agents without this property. Beta adrenergic blocking drugs without ISA do not lower resting plasma noradrenaline, evidence suggests an increase; whereas those agents with marked ISA, suggests an increase; whereas those agents with marked ISA, e.g., pindolol, reduce it. Renin levels are lowered, but less so with ISA possessing agents. Some agents, e.g. atenolol, nadolol, sotalol, are hydrophilic, show poor brain penetration, are long-acting, are not liver metabolized, but are excreted by the kidneys unchanged. Others are lipophilic, e.g., metoprolol, propranolol, penetrate the brain, and are liver metabolized. Pindolol is metabolized about 50% by each route. Similarities between beta blocking drugs are dominant but differences are often clinically relevant.