Topical treatment with CYP26 inhibitor talarozole (R115866) dose dependently alters the expression of retinoid-regulated genes in normal human epidermis.

BACKGROUND: An alternative approach to retinoid therapy is to inhibit the cytochrome P450 (CYP)-mediated catabolism of endogenous all-trans retinoic acid in the skin by applying retinoic acid metabolism blocking agents such as talarozole (R115866). OBJECTIVES: To study the effects of topical talarozole on retinoid biomarkers in normal skin in a randomized phase I trial. METHODS: Gels containing talarozole (0.35% or 0.07%) and vehicle were applied once daily for 9 days on either buttock of 16 healthy volunteers. Epidermal shave biopsies (for mRNA analysis) and punch biopsies (for histology and immunofluorescence analysis) were collected from the treatment areas. Genes encoding the following were studied by quantitative real-time polymerase chain reaction: cellular retinoic acid binding protein 2 (CRABP2), cytokeratins (KRT2 and KRT4), CYP26A1, CYP26B1, CYP26C1 and CYP2S1, two enzymes in the retinol metabolism (retinal dehydrogenase-2 and retinol acyltransferase) and two proinflammatory cytokines [interleukin (IL)-1alpha and tumour necrosis factor-alpha]. RESULTS: Talarozole treatment increased the mRNA expression of CRABP2, KRT4, CYP26A1 and CYP26B1 dose dependently, and decreased the expression of KRT2 and IL-1alpha compared with vehicle-treated skin. No mRNA change in retinol-metabolizing enzymes was obtained. There was no induction of epidermal thickness or overt skin inflammation in talarozole-treated skin. Immunofluorescence analysis confirmed an upregulation of KRT4 protein, but no upregulation of CYP26A1 and CYP26B1 expression was detected. CONCLUSIONS: Talarozole influences the biomarker pattern consistently with increased retinoic acid stimulation. The low irritancy of talarozole at the two examined dosages is a possible advantage over topical retinoids.

Evaluation of factors influencing myocardial infarct size in unconscious dogs.

STUDY OBJECTIVE: The aim was to evaluate the factors determining myocardial infarct size in unconscious dogs. DESIGN: In anaesthetised open chest dogs, the left anterior descending coronary artery was occluded either by ligation or by thrombosis for different time periods (1.5 h, 4 h, 24 h), with or without reperfusion. Haemodynamic variables were recorded throughout the experiment. Radioactive microspheres (15 microns) were injected at the end of the ischaemic period to measure regional myocardial blood flow. Infarct size and area at risk were determined by the Evans blue triphenyltetrazolium staining technique followed by planimetry. SUBJECTS: Mongrel dogs of either sex (n = 16-42 per experiment), weight 18-25 kg, were used. MEASUREMENTS AND MAIN RESULTS: A large interindividual variability in infarct size was observed after occlusion of the left anterior descending coronary artery at a standardised location for a well defined period. An examination of the factors responsible for this variability was carried out in order to develop a statistical model which would make it possible to predict infarct size. Using multiple regression analysis, it was found that in most protocols (except 90 min thrombosis) more than 85% of the variability in infarct size could be explained by the size of the area at risk and the amount of collateral flow. Thus, knowing the area at risk and the collateral flow, a fairly accurate prediction can be made of the size of the infarct that the dog will develop after a defined occlusion period. Furthermore, it was found that the infarct size increased with duration of occlusion, while duration of reperfusion had no effect. In the 90 min occlusion group thrombosis induced a larger final infarct than ligature. CONCLUSIONS: A correction for baseline variables is necessary in order to compare infarct size between experimental groups. The usefulness of this procedure is shown by an example of an experimental intervention, i.e., R 56,865, a drug with known cardioprotective effects.

Cardioprotective effects of mioflazine during 1 h normothermic global ischaemia in the canine heart.

The cardioprotective effects of mioflazine, a recently developed cardiovascular drug, were investigated in 41 anaesthetised open chest Beagle dogs subjected to 1 h normothermic global myocardial ischaemia. The severity of the model is evidenced by the finding that only one out of 20 control dogs could be weaned from extracorporeal bypass. Oral pretreatment with mioflazine (2.5 mg X kg-1) resulted in complete functional recovery in 17 out of 20 animals. Biochemical analysis of left ventricular biopsies taken before, during and after aortic cross clamping showed a preservation of purines and a better recovery of ATP, ATP/ADP X Pi ratio and energy charge (p less than 0.05) in the pretreated animals. Morphological and cytochemical assessment of the myocardium demonstrated that the ultrastructure of the sarcolemma and its calcium binding capacity is remarkably well preserved in the drug treated animals. These results indicate a strong cardioprotective effect of mioflazine. The biochemical, cytochemical and ultrastructural findings suggest an interaction of the drug with the sarcolemma.

Sabeluzole stabilizes the neuronal cytoskeleton.

There is growing evidence that cytoskeletal instability of neuronal cells is an important step towards tangle formation and subsequent functional disconnection in the AD brain. Sabeluzole, a new drug in clinical trials for Alzheimer's disease (AD), has been shown to slow down the clinical progression of the disease. In a search for the mechanism of action of this compound, the effect of sabeluzole on the neuronal cytoskeleton was investigated. Previous studies have shown that in human TR14 neuroblastoma cells and in rat hippocampal neurons a hyperstimulating medium of kinase activators leads to induction of aberrant tau phosphorylation followed by neurotoxicity. This report documents the attenuation of this neurotoxicity by sabeluzole. By selective permeabilization procedures and quantitative immunocytochemistry we show that the compound is found to preferentially increase the fraction of polymerized tubulin. Evidence is presented that the compound differentially modulates a nocodazole-induced depolymerization in contrast to a cold-induced depolymerization. In the mouse, N4 neuroblastoma cells sabeluzole decreases the spontaneous retraction frequency of neurites and lowers the lateral mobility of the cells. We, therefore, propose that sabeluzole exerts its neuroprotective effect by a stabilization of the neuronal cytoskeleton and that this mechanism provides a completely new approach for treatment in Alzheimer's disease.

Validation of bioelectrical-impedance measurements as a method to estimate body-water compartments.

Single-frequency bioelectrical-impedance analyses (BIA) and bioelectrical spectroscopy (modeling multifrequency measurements; BIS) were validated as methods to predict body water (BW) compartments in 29 healthy adults. Total body water (TBW) and extracellular water (ECW) were determined by deuterium- and bromide-dilution techniques. Contribution of BIA to anthropometry and influence of the position of electrodes were examined. Stepwise-regression analysis revealed that inclusion of BIA to anthropometric data greatly improved the fit with BW compartments. Highly significant correlations were observed between BIS and BW compartments (TBW: r2 = 0.98, SEE = 1.2; ECW: r2 = 0.95, SEE = 0.6). Cross-correlation (14 males, and 15 females) indicated predictive potential of the method. Results from BIS and BIA were comparable, but it is argued that BIS has the potential of improved standardization of the method.

Total energy expenditure and spontaneous activity in relation to training in obese boys.

Obese boys [n = 10, aged 10-11 y, average percent body fat (%BF) 32.4] were given a regimented training program (4 wk, 5 1-h sessions, 45 min cycling/wk at 50-60% of predetermined VO2max) to investigate whether they modify their energy expenditure by reducing or augmenting their spontaneous physical activities. No change was observed in mean weight (52.7 vs 52.9 kg), %BF based on 2H- and 18O-dilution and densitometry (32.4 vs 31.7), sleeping metabolic rate (5.83 vs 5.68 MJ/24 h), and spontaneous activity by heart rate recording (percent time of light intensity: 85.3 vs 83.6; medium: 11.2 vs 12.4; and heavy: 3.5 vs 3.9) and activity questionnaires (861 vs 821 min physical activity/wk). There was a 12% increase in average daily metabolic rate by doubly labeled water, half of which can be explained by the energy cost of training and the rest by an increase in energy expenditure outside the training hour. In conclusion, training leads to an appreciable augmentation in the overall energy expenditure of obese children, even with a lack of change in spontaneous physical activity.

Levamisole plus 5-fluorouracil inhibits the growth of human colorectal xenografts in nude mice.

Fragments of human colorectal adenocarcinomas were inserted under the renal capsule of nude mice. The growth of these tumour grafts was significantly inhibited by the combination of 5-fluorouracil (5-FU) and levamisole. An alternating regimen of levamisole 2.5 mg/kg and 5-FU 20 mg/kg decreased the size of tumour implants by 33-59% and/or increased the number of macroscopically disappeared fragments in the combined group compared with ineffective monotherapy with saline, levamisole or 5-FU. This model could be valuable for investigating the mechanism of action of levamisole and to evaluate the effects of this adjuvant therapy in other oncological settings.

Interaction between the microtubule inhibitor tubulozole and gamma-irradiation in murine tumors in vivo.

The combined effect of the microtubule inhibitor tubulozole and gamma-irradiation has been investigated in vivo in subcutaneous MO4 fibrosarcomas and Lewis Lung carcinomas. A marked interactive effect on tumor growth was observed when 160 mg/kg tubulozole was orally administered before the tumors were treated with 10 Gy radiation. Dose dependency and optimal effect were obtained on tumor growth of MO4 tumor bearing animals when the drug treatment was given 6 hr prior to the irradiation. The optimal pretreatment time coincided with the time at which a peak mitotic index in the tumor tissue was observed. An enhancing effect is also noticed at other doses of radiation in MO4 tumors pretreated 6 hr before with 160 mg/kg tubulozole. The interactive effect is maintained in a clinically relevant dose fractionation schedule whereby 8 fractions of 2 Gy each were pretreated 6 hr before with 80 mg/kg tubulozole. Tubulozole-T, the stereo-isomer of tubulozole, neither exhibits any antimicrotubular action nor exerts an antitumoral effect on its own or in combination with gamma-irradiation. The possible mechanisms of interaction between tubulozole and gamma-irradiation in tumor tissue are discussed.

Ridogrel inhibits systemic and renal formation of thromboxane A2 and antagonizes platelet thromboxane A2/prostaglandin endoperoxide receptors upon chronic administration to man.

The effects of ridogrel, a dual thromboxane A2 (TXA2) synthase inhibitor and TXA2/prostaglandin (PG) endoperoxide receptor antagonist, on systemic and renal production of prostaglandins and on platelet TXA2/PG endoperoxide receptors was evaluated upon chronic administration (300 mg b.i.d. orally, for 8 and 29 days) to man. Such a medication with ridogrel inhibits the systemic as well as the renal production of TXA2 as measured by the urinary excretion of 2,3-dinor-TXB2 and TXB2 respectively without inducing significant changes in systemic or renal PGI2 production. Simultaneously with the latter effects, the production of TXB2 by spontaneously coagulated whole blood ex vivo is inhibited (greater than 99%) while that of PGE2 and PGF2 alpha is largely increased. Administration of ridogrel causes a three- to five-fold shift to the right of concentration-response curves for U46619 in eliciting platelet aggregation; no tachyphylaxis is observed after 29 days of treatment in this respect. Apart from a reduction of serum uric acid levels with a concomitant increase in urinary uric acid excretion during the first days of treatment, no clinically significant changes in hematological, biochemical, hemodynamic and coagulation parameters occur during the 8 days or 29 days study. The study demonstrates that ridogrel is a potent inhibitor of the systemic as well as renal TXA2 synthase and an antagonist of platelet TXA2/PG endoperoxide receptor in man, covering full activity during 24 h at steady-state plasma level conditions without tachyphylaxis during 29 days of medication. The compound is well tolerated, at least during 1 month of administration.

5-Hydroxytryptamine and arachidonic acid metabolites modulate extensive platelet activation induced by collagen in cats in vivo.

1. The pathways contributing to the platelet adhesion/aggregation reaction elicited by collagen microfibrils, administered to cats in vivo, were analysed. 2. The intra-aortic infusion of collagen (100 micrograms kg-1 in 1 min) caused an extensive activation of platelets, as evidenced by the time-dependent drop of free platelet numbers in whole blood, and the increases of 5-hydroxyindoles (5-HI), 5-hydroxytryptamine (5-HT) and thromboxane B2 (TXB2) levels in plasma, prepared from effluent venous blood sampled from the inferior caval vein. 3. 5-HT2 receptor blockade with ketanserin (0.63 mg kg-1 i.v., 10 min) and cyclo-oxygenase inhibition with aspirin (10 mg kg-1 i.v., 10 min) slightly attenuated the peak reduction of free platelets in whole blood in response to collagen without affecting changes in plasma 5-HI. Aspirin, but not ketanserin, reduced the collagen-induced changes in plasma TXB2, prostaglandin E2 (PGE2) and 6K-PGF1 alpha. 4. Dual TXA2 synthetase inhibition/TXA2-prostaglandin endoperoxide receptor antagonism with ridogrel (5 mg kg-1 i.v., 10 min) halved the drop in free platelets, reduced the release of platelet 5-HI, inhibited the increase in plasma TXB2 and elevated that of 6K-PGF1 alpha and PGE2 in response to collagen. 5. Combined treatment with ketanserin and aspirin reduced the collagen-induced drop of free platelets and the release of platelet 5-HI to a similar extent as ridogrel alone; plasma prostanoids were affected as with aspirin alone. 6. Combined administration of ketanserin and ridogrel virtually eliminated the collagen-induced platelet adhesion/aggregation response and release of 5-HI; prostanoids were affected as with ridogrel alone. 6. Combined administration of ketanserin and ridogrel virtually eliminated the collagen-induced platelet adhesion/aggregation response and release of 5-HI; prostanoids were affected as with ridogrel alone. 7. The results indicate that the interplay between 5-HT and arachidonic acid metabolites is causally involved in the platelet reaction to activation induced by collagen in cats in vivo.

Impaired autoregulation of cerebral blood flow in an experimental model of traumatic brain injury.

In order to study the pathophysiology and the intracranial hemodynamics of traumatic brain injury, we have developed a modified closed-head injury model of impact-acceleration that expresses several features of severe head injury in humans, including acute and long-lasting intracranial hypertension, diffuse axonal injury, neuronal necrosis, bleeding, and edema. In view of the clinical relevance of impaired autoregulation of cerebral blood flow after traumatic brain injury, and aiming at further characterization of the model, we investigated the autoregulation efficiency 24 h after experimental closed-head injury. Cortical blood flow was continuously monitored with a laser-Doppler flowmeter, and the mean arterial blood pressure was progressively decreased by controlled hemorrhage. Relative laser-Doppler flow was plotted against the corresponding mean arterial blood pressure, and a two-line segmented model was applied to determine the break point and slopes of the autoregulation curves. The slope of the curve at the right hand of the break point was significantly increased in the closed head injury group (0.751 +/- 0.966%/mm Hg versus -0.104 +/- 0.425%/mm Hg,p = 0.028). The break point tended towards higher values in the closed head injury group (62.2 +/- 20.8 mm Hg versus 46.9 +/- 12.7 mm Hg; mean +/- SD, p = 0.198). It is concluded that cerebral autoregulation in this modified closed head injury model is impaired 24 h after traumatic brain injury. This finding, in addition to other characteristic features of severe head injury established earlier in this model, significantly contributes to its clinical relevance.

Psychometric properties of the Subjective Well-Being Under Neuroleptics scale and the Subjective Deficit Syndrome Scale.

RATIONALE: Subjective experience of antipsychotic drugs is relevant for medication compliance and quality of life. There is, however, sparse knowledge about the assessment of subjective experience. OBJECTIVES: To examine the internal consistency, test-retest reliability, sensitivity to medication change and concurrent validity of two test instruments: the Subjective Well-Being Under Neuroleptics (SWN) and the Subjective Deficit Syndrome Scale (SDSS). METHODS: Both instruments were used at admission and after 6 weeks of medication stabilization in 105 consecutively admitted patients diagnosed with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edn) diagnoses of recent-onset schizophrenia, schizophreniform disorder or schizoaffective disorder. RESULTS: Almost all patients were capable of reproducing their subjective experience in a consistent way both before and after medication stabilization. The internal consistency of both instruments was high. The test-retest reliability was high if medication was not changed, especially for the SWN. The SWN was sensitive for changes in medication and dosage. The short form of the SWN (SWN-20 items) had comparable psychometric qualities to the original instrument (SWN-38 items). The concurrent validity of the SWN and the SDSS was good, indicating that both tests measure the same concept. CONCLUSIONS: The assessment of subjective experience with the SWN (both versions) may be used in evaluating differential effects of anti-psychotics and dose on subjective well-being.

125I-Tyr0-hCRH labelling characteristics of corticotropin-releasing hormone receptors: differences between normal and adenomatous corticotrophs.

The presence of corticotropin-releasing hormone (CRH) receptors has been previously demonstrated in corticotrophs from normal pituitaries using a method combining immunocytochemistry and liquid emulsion autoradiography. The aim of this study was to compare the characteristics of the 125I-Tyr0-hCRH binding in corticotrophs from normal pituitaries (three obtained at autopsy and one obtained at surgery) with corticotrophs from pituitary adenomas (six corticotroph adenomas responsible for Cushing's disease and two silent corticotroph adenomas secreting a biologically inactive ACTH molecule). In normal corticotrophs, the larger part of the 125I-Tyr0-hCRH binding was localised in patchy conglomerates at the centre of the cell and, to a much lesser degree, in a diffuse pattern at the cell periphery. In adenomatous corticotrophs, CRH receptor expression is disturbed both quantitatively and qualitatively. Except for a minority of cells in one adenoma, all adenomatous corticotrophs showed only peripherally bound 125I-Tyr0-hCRH and no centrally localised binding. Furthermore, adenomatous corticotrophs revealed a statistically significant lower signal intensity when compared to normal corticotrophs and a strongly negative correlation was found between the labelling area in adenomatous corticotrophs and both the basal and CRH-stimulated plasma ACTH levels. These findings suggest defective processing of CRH receptors and could be relevant to the sustained ACTH secretion by adenomatous corticotrophs in Cushing's disease and, more generally, provide an explanation to its pathology. The silent corticotrophs secreting a biologically inactive ACTH molecule were characterised by a very faint signal intensity, although present on almost every cell.

Water balance and acute mountain sickness before and after arrival at high altitude of 4,350 m.

The present study is a first attempt to measure water balance and its components at altitude by using labeled water and bromide dilution and relating the results with acute mountain sickness (AMS). Water intake, total water output, and water output in urine and feces were measured over a 4-day interval before and a subsequent 4-day interval after transport to 4,350 m. Total body water and extracellular water were measured at the start and at the end of the two intervals. There was a close relationship between energy intake and water intake, and the relationship was unchanged by the altitude intervention. Subjects developing AMS reduced energy intake and water intake cor respondingly. The increase in total body water (TBW) in subjects developing AMS was accompanied by a reduction in total water loss. They did not show the increased urine output, compensating for the reduced evaporative water loss at altitude. Subjects showed a significant increase in TBW after 4 days at altitude. Subjects with AMS showed the biggest shifts in extracellular water relative to TBW. In conclusion, fluid retention in relation to AMS is independent of a change in water requirements due to altitude exposure. Subjects developing AMS were those showing a fluid shift of at least 1 liter from the intracellular to the extracellular compartment or from the extracellular to the intracellular compartment.

Energy balance at high altitude of 6,542 m.

Weight loss due to malnutrition and possibly intestinal malabsorption is a well-known phenomenon in high-altitude climbers. Up to approximately 5,000 m, energy balance may be attained and intestinal energy digestibility remains normal. To see whether 1) energy balance may also be attained at 6,542 m and, if not, 2) whether decreased energy digestibility would play a significant role in the energy deficit, energy intake (EI), energy expenditure, body composition, and energy digestibility of 10 subjects (4 women, 6 men; 27-44 yr) were assessed during a 21-day sojourn on the summit of Mt. Sajama, Bolivia (6,542 m). EI was measured during two 3-day intervals: EI1 (days 7-9) and EI2 (days 17-19). Total fecal energy loss during EI1 was calculated from fecal energy measured by bomb calorimetry. Average daily metabolic rate (ADMR) at altitude was measured in six subjects (2 women, 4 men) using doubly labeled water over a 10-day interval (days 9-19). Basal metabolic rate was measured before and after the expedition by respiratory gas analysis. Body composition was estimated from skinfolds and body mass before and during the altitude sojourn. Subjects were in negative energy balance throughout the observation period (EI1-ADMR = -2.9 +/- 1.8 MJ/day and EI2-ADMR = -2.3 +/- 1.8 MJ/day based on a gross energy digestibility of 95%). The activity level, expressed as ADMR to basal metabolic rate, was 1.56-2.39. The loss of fat mass (3.7 +/- 1.5 kg) represented 74 +/- 15% of the loss of body mass.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of combined and sequential treatment with tamoxifen and the aromatase inhibitor vorozole on 7,12-dimethylbenz(a) anthracene-induced mammary carcinoma in the rat.

The aromatase inhibitor vorozole dose-dependently inhibited the growth of dimethylbenz(a) anthracene (DMBA)-induced mammary carcinoma in the rat. An oral dose of 5 mg/kg per day brought about growth inhibition and reduction of tumor multiplicity similar to that produced by ovariectomy. Tamoxifen (8 mg/kg per day) also reduced tumor growth, albeit to a lesser extent than did ovariectomy. Concomitant administration of varying doses of tamoxifen with the fully effective dose of vorozole (5 mg/kg per day) tended to be less effective than ovariectomy of vorozole alone. This is likely to be due to the estrogen-agonistic effects of tamoxifen. Combination of tamoxifen with the partially effective dose of vorozole (1 mg/kg per day) gave results comparable with those obtained for either of the compounds used in monotherapy. Combining tamoxifen with a marginally active low dose of vorozole (0.2 mg/kg per day) resulted in a minor additional growth inhibition as compared with that obtained with this dose of vorozole alone. Sequential treatment with tamoxifen (8 mg/kg per day) for 42 days and vorozole (5 mg/kg per day) for 42 days, and vice-versa, was performed with a drug-free interval of 14 days between treatments. Tumors regressing under vorozole therapy relapsed when subsequently treated with tamoxifen. In contrast, vorozole further reduced tumor volumes in rats previously treated with tamoxifen. Furthermore, monotherapy with tamoxifen as well as the two sequential tamoxifen-vorozole treatment schedules were in most cases less effective than vorozole monotherapy in inhibiting both tumor growth and tumor multiplicity. Although extrapolation of these findings in cycling animals to the clinical situation, involving postmenopausal women, is not straightforward, these results warrant further studies in preclinical models. Moreover, clinical trials comparing the most effective aromatase inhibitors with tamoxifen in previously untreated postmenopausal patients with breast cancer may also be warranted.

The cerebral blood distribution in dogs and cats. An anatomical and functional study.

On the basis of corrosion preparations and of microsphere studies, the following characteristics of the canine and feline cerebral circulation were observed. (1) In cats, a greater part of the vertebral arterial blood goes to the brain and it is more specifically restricted to the ponto-medullary and cerebellar structures. These structures received approximately 3 times more microspheres in cats than in dogs. (2) In dogs, an important amount of vertebral blood goes to the neck muscles, and the intracranial vertebral blood supply is spread over a greater area of the brain, including the thalamo-hypothalamic and posterior cortical zone. (3) In cats the thalamo-hypothalamic area receives a greater amount of blood via the common carotid artery than in dogs. (4) In both animal species, the vascular connections between the left and right side of the brain are more extensive in the vertebral than in the carotid bed. However, for either vascular bed, a more important left to right transmission was found in the dog.

Oversensitivity to serotonin of the collateralized vascular bed in rat hindquarters: mechanisms of increased vasoconstriction.

A buffered solution was perfused at a constant flow rate (2 ml/min) through both iliac arteries in rat hindquarters. Perfusion pressures were measured in normal and collateralized vascular beds of the left and right hind-leg, respectively. Bolus injections of various agonists produced concentration-dependent increases in perfusion pressure in both collateralized and normal circulatory beds. Serotonin, in particular, and noradrenaline, to a lesser extent, produced more pronounced vasoconstriction on the collateral side than on the normal side. The difference in vasoreactivity to serotonin was related to a difference in both vascular structure and sensitivity of both types of vascular bed. Vasoconstriction induced by serotonin was inhibited by 5-HT2 antagonists. Selective blockade of alpha 1,alpha 2,beta 1-beta 2 adrenoceptors and amine uptake blockade were ineffective. This study indicates that, in rat hind-legs, the collateralized vascular bed is superreactive to serotonin in comparison with the normal bed. This resetting of reactivity to serotonin is due to the specific vascular structure as well as to an increased 5-HT2 receptor-mediated sensitivity.

Effects of beta-adrenoceptor antagonists on cardiac function in ischemic-reperfused myocardium of the isolated working rabbit heart.

The effects of beta-adrenoceptor antagonists (dl-nebivolol, atenolol and propranolol) and of 1-nebivolol on cardiodynamics and mitochondrial oxidative phosphorylation were studied in the isolated working rabbit heart subjected to normothermic global ischemia, followed, in some cases, by reperfusion. The hearts were pretreated with the different drugs (0.32 mg/l) 30 min before the start of ischemia, dl-Nebivolol and propranolol provided protection for both cardiodynamic and mitochondrial functions, as did l-nebivolol, which lacks beta-adrenoceptor blocking properties, while atenolol failed to protect mechanical activity and cardiac mitochondria against the effects of ischemia and post-ischemic reperfusion. Catecholamine depletion with reserpine did not have a beneficial effect on the recovery of cardiodynamic and mitochondrial function during post-ischemic reperfusion. It is concluded that the beneficial effects of beta-blockers on the ischemic and reperfused myocardium can not be explained by a specific beta-blocking action alone.

The l-enantiomer of nebivolol potentiates the blood pressure lowering effect of the d-enantiomer.

In this study the effect of l-nebivolol on the blood pressure lowering action of d-nebivolol was investigated after intraperitoneal administration of the drugs to spontaneously hypertensive rats. Doses of l-nebivolol which did not affect blood pressure when given alone potentiated the decrease in systolic and diastolic blood pressure induced by 1.25 mg.kg-1 d-nebivolol. The potentiating effect of l-nebivolol was seen at doses higher than 0.16 mg.kg-1. At 1.25 mg.kg-1 d-nebivolol significantly reduced the heart rate, an effect which was not potentiated by l-nebivolol in doses up to 1.25 mg.kg-1. Higher doses of l-nebivolol (2.5 and 5.0 mg.kg-1) in combination with 1.25 mg.kg-1 d-nebivolol not only lowered the blood pressure further, but also significantly reduced the heart rate; thus at these doses the enantiomers together exerted more pronounced beta 1-adrenoceptor blocking properties. This is probably disadvantageous, because d,l-nebivolol has been shown to decrease arterial blood pressure in hypertensive patients and animals before it reaches its maximal beta 1-adrenoceptor blocking effect. Therefore, the racemic mixture of 50% d-nebivolol and 50% l-nebivolol seems to contain the two compounds in near optimal proportions for an antihypertensive effect.