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Biomedical subjects

A Monopoli

Publications and source records attributed to A Monopoli.

At least 55 records · Page 3Linked to original sources
PubMed1993

Spirapril prevents left ventricular hypertrophy, decreases myocardial damage and promotes angiogenesis in spontaneously hypertensive rats.

To test whether angiotensin-converting enzyme (ACE) inhibition may prevent myocardial damage and may affect coronary microvasculature in spontaneously hypertensive rats (SHR), young 5-week-old SHR were treated for 3 months with spirapril and changes in blood pressure (BP) were monitored. Untreated SHR were used as controls. The rats were killed; left ventricular (LV) shape, weight, and wall thickness were examined and the ventricular myocardium was analyzed morphometrically to determine the effect of the drug on the relative amount, number per unit area of myocardium, and average dimension of foci of myocardial scarring. Moreover, volume fraction, surface, numerical density, and diffusion distance for oxygen of the coronary capillaries were analyzed. BP remained 20-30% lower in treated SHR with respect to controls, and LV weight and thickness decreased 20 and 21%, respectively. The number and dimension of the foci of fibrosis were reduced, resulting in an overall 68% decrement in the amount of myocardial damage. Finally, a 28% increment in numerical density of capillary profiles associated with a 13% reduction in their cross-sectional area decreased the diffusion distance for oxygen from the capillary wall to the myocytes by 14% in treated SHR. Spirapril decreases BP and LV weight and thickness in the SHR model of hypertension and substantially improves coronary capillary microvasculature, decreasing hypertensive myocardial damage. These results may be attributed to inhibition of the systemic effects of angiotensin II (AII) as well as to a local protective action of the drug against possible intramyocardial AII production.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Effect of SCH 37224 on anti-IgE-induced formation of sulfidopeptide leukotrienes in human lung parenchyma.

SCH 37224, 1-(1,2-dihydro-4-hydroxy-2-oxo-1-phenyl-1,8-naphthyridin-3-yl) pyrrolidinium, is a structurally novel compound that had been shown to inhibit leukotriene D4 formation in guinea pig lung in vitro. We tested whether SCH 37224 is able to inhibit both the formation of eicosanoids from human lung parenchyma in vitro and the binding of sulfidopeptide leukotrienes to membranes of lung parenchyma and bronchi. SCH 37224, at a concentration of 30 and 100 microM, was able to inhibit antigen-induced formation of sulfidopeptide leukotrienes, measured as leukotriene E4, while it did not significantly affect the formation of prostaglandin D2. At concentrations up to 100 microM, it did not affect either the binding of [3H]leukotriene C4 to membranes of human lung parenchyma or human bronchi, or the binding of [3H]leukotriene D4 to the parenchyma. In conclusion, SCH 37224 is a selective inhibitor of leukotriene formation in human lung in vitro, which might be of potential therapeutic interest in the treatment of asthma.

Eicosanoids↗
PubMed1992

The neutral endopeptidase inhibitor, SCH 34826, reduces left ventricular hypertrophy in spontaneously hypertensive rats.

SCH 34826, i.e., (S)-N-(N-(2,2[(2,2-dimethyl-1,3-dioxolan-4- yl)methoxy]-2-oxo-1-(phenyl-methyl)ethyl)-phenylalanyl)-beta-alanine, is a potent and selective inhibitor of neutral endopeptidase 24.11 (NEP), an enzyme that degrades the atrial natriuretic peptide (ANP). The effects of SCH 34826 on hypertension and left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHRs) were evaluated following 1 month of treatment by measuring the blood pressure, cardiac weight, and left ventricular fibrosis. Adult SHRs were treated with SCH 34826 at 10, 30, or 100 mg/kg given orally twice daily or with vehicle. The systolic blood pressure (SBP) and heart rate (HR) were recorded weekly by the tail-cuff method. Cardiac structural damage was determined by morphometric analysis. Over the dose range examined, the drug produced no significant changes in either blood pressure or heart rate. Despite the lack of antihypertensive activity, SCH 34826 at 100 mg/kg reduced both the cardiac mass (-10%) and the amount of fibrotic tissue present in the left ventricle (-42%). These data indicate that chronic inhibition of NEP by SCH 34826 interacts with mechanisms underlying myocardial hypertrophy and cardiac remodeling.

Animals↗
PubMed1992

Angiotensin converting enzyme binding sites in human heart and lung: comparison with rat tissues.

1. Angiotensin converting enzyme (ACE), a dipeptidyl carboxypeptidase which catalyzes the final activation step in the formation of angiotensin II, was identified by radioligand studies in rat heart and lung. In this work we identified ACE binding sites in human left ventricle and lung by radioligand binding using the ACE inhibitor [3H]-ramiprilat in all tissues tested was saturable, temperature and zinc-dependent, and inhibited by EDTA. In human left ventricle homogenate we found a density of binding sites of 121 +/- 15 fmol mg-1 protein (n = 4) with an affinity (Kd) of 850 +/- 55 pM, whereas in rat left ventricle the same values were 23 +/- 4 fmol mg-1 protein and 315 +/- 30 pM, (n = 4), respectively. 3. [3H]-ramiprilat binding to rat (n = 4) and human lung (n = 4) showed a binding site density of 2132 +/- 155 and 1085 +/- 51 fmol mg-1 protein respectively with an affinity of 639 +/- 54 and 325 +/- 22 pM. The lung:heart ratio of ACE binding site density was about 9:1 in man and 100:1 in rat. 4. The binding affinities of 13 ACE inhibitors were evaluated on human heart and lung: the drugs tested showed a wide range of affinities for the ACE binding sites in both tissues, and the affinity for lung was significantly greater than for heart for most of the drugs. 5. The greater potency of some ACE inhibitors in displacing [3H]-ramiprilat in human lung compared with the heart indicates differences between ACE binding sites in these tissues and suggests the possibility of a selective organ-targeted therapeutic approach.

Adult↗
PubMed1992

[Arrhythmogenicity in left ventricular hypertrophy in mild to moderate arterial hypertension].

BACKGROUND: Several studies have evidenced that hypertensive patients (pts) with left ventricular hypertrophy (LVH) have an increased incidence of malignant ventricular arrhythmias and sudden death. The purpose of our study was to investigate the prevalence of risky ventricular arrhythmias in uncomplicated hypertensive pts (untreated during last 10 days) in comparison with normotensive ones. In this context, not only the value of left ventricular mass index (LVMI) was taken into account, but also the type of LVH and the related functional behaviour. PATIENTS AND METHODS: 59 untreated mild to moderate essential hypertensives (EH), without symptoms or signs of coronary artery disease, were classified in 3 groups: normal (i.e. without hypertrophy) EH (NEH: 12 pts, 6 M and 6 F, mean age +/- SD 52 +/- 10 yrs), concentric hypertrophic EH (CEH: 30 pts, 15 M and 15 F, mean age +/- SD 59 +/- 10 yrs), and eccentric hypertrophic EH (EEH: 17 pts, 7 M and 10F, mean age +/- SD 60 +/- 10 yrs), according to echocardiographic measurements. Values and duration of arterial hypertension were comparable among the groups. A normotensive, age-matched group was studied as control (C: 21 pts, 11 M and 10 F, mean age +/- SD, 57 +/- 10 yrs). 24-hour Holter electrocardiographic monitoring (ECG-H) and Signal-Averaged electrocardiography (SAECG) were performed seeking to identify the arrhythmogenic risk. Echocardiographic analysis was accomplished by means of a computerized system: LVMI, ratio of LV wall thickness to LV internal radius (relative wall thickness = RWTh), systolic velocity of circumferential fractioning (VCFs), peak of LV relaxation rate (pLVRr) and peak-systolic stress (pSS) were evaluated. RESULTS: Normal LV systolic function was generally found, but both NEH and EEH groups showed a significant reduction in pLVRr in comparison with C and CEH groups (mean values +/- SD: 3.52 +/- 1,3 and 3.40 +/- 0.9 vs 4.92 +/- 0.4 and 4.27 +/- 1.4 sec-1, respectively, p < .05 for both). pSS was significantly higher in EEH and NEH than in CEH and C (mean values +/- SD: 149 +/- 42 and 157 +/- 66 vs 116 +/- 28 and 122 +/- 15 10(3) dynes/cm2, respectively; p < .05 for both). At ECG-H, EEH had a prevalence of potentially malignant ventricular arrhythmias (PMVA: ventricular extrasystoles > or = 30/h; ventricular couplets, > or = 2 episodes/24h, or triplets, > or = 1 episode/24h; R on T), significantly larger than in C (35.3% vs 4.8%, p < .05) and almost significantly larger than in NEH and CEH (8.3% and 10%, respectively). No differences in LVMI were found between EEH with or without PMVA. In respect of functional LV behaviour, the former group showed lower values of VCFs (2.33 +/- 0.6 vs 3.71 +/- 1.32 sec-1, (p < .005) than the latter group. At SAECG, the EEH exhibited again a greater prevalence of abnormal findings than C (35.3% vs 0%, p < 0.5). No correlations were found between ECG-H and SAECG abnormalities, nor between the latter group and LVMI or LV functional indexes. Among pts showing a more pronounced impairment of diastolic function (pLVRr < 4 sec-1), EEH exhibited the highest prevalence of both PMVA (50%) and late potentials (41%). CONCLUSIONS: Our data suggest that uncomplicated mild to moderate essential hypertension may be associated with higher risk of ventricular arrhythmias, particularly when cardiac involvement is characterized by eccentric LVH. On the contrary, in this stage of hypertensive disease, LVMI as well as LV function do not seem to influence the ventricular arrhythmogenesis. The clinical importance of these findings is uncertain, and further studies are needed.

Adult↗
PubMed1991

The dopamine D1 receptor is involved in the regulation of REM sleep in the rat.

The dopamine D1 receptor agonist, SKF 38393, and the D1 antagonist, SCH 23390, were studied for their effects on sleep in the rat. Over 6 h, SKF 38393 (0.1-10 mg/kg s.c.) dose dependently reduced the amount of rapid eye movement (REM) sleep and enhanced the duration of wakefulness. The drug affected REM at low doses (ED50 = 0.4 mg/kg) at which wakefulness was unchanged and the characteristic grooming behavior was not apparent. REM changes were characterized by a decrease in the number of episodes with no alteration of latency to the first episode. Over a very low dose range (0.003-0.3 mg/kg s.c.), SCH 23390 enhanced the amount of REM by increasing both number and average duration of episodes. There was also a moderate increase of non-REM sleep but the percent change was less marked than that occurring for REM. Given at 0.003 mg/kg, SCH 23390 prevented the REM changes induced by SKF 38393 (0.3-3 mg/kg). It is suggested that D1 receptors are involved in the regulation of the REM sleep process.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Alpha 1 adrenoceptor subtype mediates noradrenaline induced contraction of the human internal mammary artery: radioligand and functional studies.

STUDY OBJECTIVE: The aim was to evaluate the characteristics of alpha adrenergic binding sites on human internal mammary arteries and the alpha adrenoceptor mediated vasoconstrictor response to catecholamines. DESIGN: Human internal mammary arteries were cut longitudinally, the intimal layer was scraped, and the arteries homogenised and centrifuged at 50,000 g to obtain a membrane pellet. Saturation isotherms with [3H]-prazosin were done with 50-100 micrograms plasma membranes per tube and increasing concentrations of [3H]-prazosin (non-specific binding: 2.5 mM noradrenaline plus superoxide dismutase and catalase). Kinetic isotherms were done with 100 micrograms plasma membranes and 1-5 nM [3H]-prazosin for time periods ranging from 1 to 90 min; at the equilibrium, dissociation of [3H]-prazosin was achieved by 10 microM prazosin. alpha 2 Adrenoceptor density on internal mammary artery membranes was assessed with [3H]-rauwolscine (non-specific binding: 1 microM yohimbine). Separation of membrane bound radioactivity was achieved by rapid vacuum filtration through Whatman GF/C fibre filters. Saturation isotherms were evaluated by Scatchard plots and kinetic data, and competition isotherms by Enzfitter analysis. Contractility studies were done with helical strips of artery (without adventitial layer) placed in a thermostated perfusion bath. Data were obtained in the presence of different concentrations of agonists and antagonist to obtain Schild plots. Antagonist drugs were employed at only one concentration for each preparation. SUBJECTS: Mammary arteries were collected from 51 patients (age range 42-65 years) undergoing surgery for coronary grafting. MEASUREMENTS AND MAIN RESULTS: The binding of [3H]-prazosin to arterial plasma membrane was rapid and reversible. The K + 1 was 0.13 (SD 0.03) X 10(9) M.min-1 (n = 5) and the Kd, determined as a ratio between k-1/K + 1, was 0.34(0.01) nM (n = 5). [3H]-Prazosin binding, displaceable by 2.5 mM (-)-noradrenaline, was saturable and disclosed an alpha 1 adrenoceptor density of 30(3) fmol.mg-1 protein with a dissociation constant (Kd) of 215(50) pM (n = 18). The adrenergic agonists competed with [3H]-prazosin in the following order of potency: (-)-adrenaline [Ki = 0.6(0.1) microM; n = 5] greater than (-)-noradrenaline [Ki = 1.05(0.015) microM; n = 12] much greater than (-)-isoprenaline [Ki = 150(10) microM; n = 4]. Specific binding of [3H]-rauwolscine to IMA plasma membranes was negligible (about 2 fmol.mg-1 protein) (n = 15) with an unfavourable ratio of non-specific v specific binding. Catecholamines induced a dose dependent contractile response in arterial strips; (-)-noradrenaline: EC50 = 0.48(0.12) microM, n = 20; (-)-adrenaline: EC50 = 0.15(0.16) microM, n = 10; and methoxamine, a selective alpha 1 adrenergic agonist: EC50 0.67(0.15) microM, n = 10. The alpha 2 adrenoceptor agonists BHT-933, BHT-920, and guanabenz did not contract the arterial strips (up to 10 mM). Prazosin (0.03-0.1 microM) produced concentration dependent right shifts of the (-)-noradrenaline [pA2 = 9.83(0.11), n = 19], (-)-adrenaline [pA2 = 9.50(0.31), n = 10], and methoxamine [pA2 = 8.96(0.18), n = 10] concentration-response curve. CONCLUSIONS - Internal mammary artery plasma membranes possess alpha 1 adrenoceptors which are involved in the vasoconstrictor response to catecholamines. alpha 2 Adrenoceptors seem not to be involved.

Adult↗
PubMed1991

Effect of right atrial stimulation on both atrial pressure and atrial natriuretic peptide release in essential hypertension.

UNLABELLED: Several reports indicated a direct relationship between atrial pacing and atrial natriuretic peptide (ANP) blood levels, but few controlled hemodynamic studies have been reported. In particular, the relationship between increase in heart rate, release of ANP and increase in right atrial pressure (RAP) are still uncertain. Moreover, the effect of accelerated heart rate on ANP secretion in patients with essential hypertension has not yet been fully elucidated. For this, we studied 12 untreated essential hypertensive (EH; WHO stage I-II) and 10 age-matched normotensive subjects (NO) as control by right atrial stimulation (parasinusal site) in consecutive steps of 110, 130 and 150 b.p.m., each step lasting for 5 min. Both before and during stimulation at each pacing rate (after 5 min) RAP and systolic blood pressure (SBP) were measured and blood was drawn from the right atrium for ANP measurements (radioimmunoassay method). During stimulation we observed significant differences in the ANP release in comparison to the initial values: at 130 (p less than 0.05) and at 150 b.p.m. (p less than 0.01) in EH; at 150 b.p.m. (p less than 0.005) in NO. RAP and SBP did not differ significantly at each pacing rate from initial values both in EH and NO. No significant differences in ANP and RAP were found between EH and NO. IN CONCLUSION: (a) ANP release increases in both EH and NO, even if beginning at 130 in EH and at 150 b.p.m. in NO; (b) in both EH and NO, there is no relationship between RAP or SBP values and ANP secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Natriuretic Factor↗
PubMed1991

Autoradiographic localization of beta-adrenergic receptors in human large coronary arteries.

The distribution of beta-adrenergic receptors in sections of the human right and left coronary arteries and of the anterior intraventricular branch was studied by the use of combined in vitro radioreceptor binding and autoradiographic techniques. [125I]Cyanopindolol was used as a ligand for beta-adrenergic receptors. Binding of the radioligand to sections of the three coronary arteries under study was saturable, stereoselective, reversible, and displaceable by antagonists and agonists with the rank order of potency expected for beta-adrenergic receptors. Analysis of binding isotherms indicated maximum binding capacities of 41.5 fmol/mg protein for the right coronary artery, 35.4 fmol/mg protein for the left coronary artery, and 25.7 fmol/mg protein for the anterior interventricular branch. Dissociation constants were approximately 35 pM in the arteries examined. The relative amounts of beta 1- and beta 2-receptor subtypes were as follows: 72% beta 1-receptors and 28% beta 2-receptors in the right coronary artery; 65% beta 1-receptors and 35% beta 2-receptors in the left coronary artery; 40% beta 1-receptors and 60% beta 2-receptors in the anterior interventricular branch. The results of autoradiographic analysis revealed a predominance of beta 1-receptors in the medial layer. beta 2-Receptors were localized primarily in the adventitia, in the adventitia-media border, and in the intimal layer. These results should lead to a better understanding of the mechanisms involved in the control of coronary circulation in humans.

Adolescent↗
PubMed1991

Effects of selected beta-adrenergic blocking agents on sleep stages in spontaneously hypertensive rats.

The effects on sleep of six beta-adrenergic blockers (propranolol, dilevalol, pindolol, metoprolol, celiprolol and atenolol) which differ in their pharmacological characteristics were studied in spontaneously hypertensive rats. Electroencephalographic activity was recorded for 6 hr after p.o. administration of drugs or vehicle, and the stages of wakefulness, rapid eye movements (REM) sleep and non-REM sleep (non-REM) were classified thereafter. In separate experiments antihypertensive activity of each drug was assessed by the tail-cuff technique. The most common effect of the beta-blockers examined was a decrease of the duration of REM. The effect was marked for propranolol (10-100 mg/kg), celiprolol (10-100 mg/kg) and pindolol (1-10 mg/kg), whereas it occurred at low doses, but not at high doses for metoprolol (10 mg/kg) and atenolol (3 and 10 mg/kg). Dilevalol induced a moderate REM decrease at 30 mg/kg only. For the beta-1 antagonists, the dose reducing REM substantially (ED30) was slightly above (1.4- to 3.7-fold) that effective on blood pressure (ED10), whereas the separation was high for pindolol (17.4-fold) and dilevalol (22.4-fold). Conversely, propranolol displayed a weak antihypertensive activity in this model and was more potent on REM than in reducing blood pressure. Propranolol, celiprolol and atenolol also increased duration of wakefulness. Considering the pharmacological characteristics of the beta-blockers examined, it is suggested that selective beta-1 antagonism and interaction with other neurotransmitters, such as serotonin, are relevant to the potential effects of this class of antihypertensive drugs on sleep function.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1990

Role of 5-HT2 receptors in serotonin-induced contraction in the human mammary artery.

We studied the effects of serotonin (5-HT) on isolated human mammary arteries obtained from patients undergoing coronary by-pass grafting. 5-HT induced a concentration-dependent contractile response in the mammary artery, with an EC50 value of 0.34 microM. The 5-HT2 antagonist, ketanserin, reversed the contractions evoked by 5-HT in a competitive manner at a low concentration (10(-8) M), whereas non-competitive antagonism was apparent at higher concentrations (5 X 10(-8)-5 X 10(-7) M). To investigate whether the alpha 1-blocking component of ketanserin plays a role in the response observed in this vessel, we evaluated the effect of ketanserin on contractions induced by (-)-norepinephrine. Ketanserin, in concentrations up to 10(-7) M, did not influence the norepinephrine-induced contractions. Moreover, a threshold concentration of 5-HT (10(-7) M) amplified the contractile effect induced by norepinephrine (5 X 10(-8) M), and this response was inhibited by ketanserin (10(-7) M). The selective 5-HT3 antagonist, GR 38032F, did not affect the 5-HT-induced contractions. These findings indicate that the human mammary artery is a vascular tissue sensitive to 5-HT. The 5-HT2 receptor subtype appears to mediate the response.

Female↗
PubMed1990

5-Hydroxytryptamine induces contraction in isolated human mammary artery: effect of ketanserin.

5-hydroxytryptamine (5HT) treatment produced dose-related contractions in the human internal mammary artery with an EC50 value of 3.4 X 10(-7) M. The 5HT2 receptor antagonist ketanserin reversed the contractions evoked by 5HT in a competitive manner at a low concentration (10(-8) M), whereas a noncompetitive antagonism was apparent at higher concentrations (5 X 10(-8) M to 5 X 10(-7) M). The alpha 1-blocking component of ketanserin was evaluated by studying the effect of ketanserin upon the contractile response evoked by norepinephrine. Up to 10(-7) M, ketanserin did not influence norepinephrine-induced contractions. These findings indicate that the mammary artery is a vascular tissue sensitive to contractions induced by 5HT and that the drug ketanserin antagonizes this contractile response through the 5HT2 receptor subtype.

Female↗
PubMed1990

Effects of the enkephalinase inhibitor SCH 34826 on the sleep-waking cycle and EEG activity in the rat.

The sedative effect of SCH 34826, an enkephalinase inhibitor, was evaluated by studying electroencephalographic (EEG) activity, behaviour and the sleep-waking cycle in the rat. The reference opioid, morphine, was used for comparison. After administration of morphine (10 mg/kg s.c.) the rats were motionless and stuporous at first and then hyperactive. An increase of slow wave sleep, at the expense of both wakefulness and REM sleep was recorded, with high-amplitude slow wave bursts appearing in the EEG tracings during the waking, albeit stuporous, phase. Relative spectral power in the 1-4 and 12-16 Hz bands was increased and there was a shift of the dominant frequency to a lower frequency. The specific opioid antagonist, naltrexone, readily reversed most of these effects. The drug SCH 34826 (10-100 mg/kg p.o.) had no effect on the parameters examined; large doses (300 and 1000 mg/kg p.o.) induced restlessness in some animals, resulting in increased waking. This effect was antagonized by naltrexone. The data indicate that SCH 34826, at doses far greater than those proposed for clinical use, is devoid of sedative liability and does not induce any of the behavioural or EEG effects typical of morphine.

Animals↗
PubMed1990

Gastroepiploic artery free graft for coronary bypass.

The internal mammary artery (IMA) is the graft of choice for CABG but has a limited number and length. For multivessel coronary disease, saphenous vein grafts have to be added but they show poorer long-term patency. Investigation to provide adjunctive reliable grafts has recently focussed on the right gastroepiploic artery (GEA) and encouraging results have been reported employing this vessel as a pedicled graft to bypass distal coronary vessels. From December 1988 to February 1989, to achieve complete myocardial revascularization with only arterial grafts we used a GEA free graft in combination with the two IMAs in 20 consecutive patients under 70 years of age undergoing elective surgery. Before starting, histological studies were carried out and a significant similarity between IMA and GEA was found. In the 20 patients, 76 coronary anastomoses were performed (3.8 bypasses/patient), the GEA graft revascularized the right coronary artery in 9 patients, the circumflex in 8 patients and the anterior descending and/or diagonal in 3 patients; in 7 patients the GEA graft was used for sequential anastomoses. No perioperative deaths, no myocardial infarctions and no gastroenterological complications occurred. Coronary angiographic postoperative control showed 20/20 patent GEA grafts. After follow-up ranging from 7 to 9 months, all patients are free from angina. The GEA free graft is not difficult to harvest, is easier than the pedicled GEA graft to handle in the pericardium and is suitable for sequential anastomoses. The use of GEA graft however increases the complexity of bypass operations.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Artery Bypass↗
PubMed1989

Effects of nonsedating histamine H1-antagonists on EEG activity and behavior in the cat.

The central effects of the newly-developed antihistamines (H1-receptor antagonists) loratadine, astemizole, mequitazine and terfenadine were evaluated by studying brain electrical activity (EEG), sleep-waking patterns and behavior in the cat. The different stages of the sleep-waking cycle, i.e., wakefulness (W), spindle sleep (SS), slow wave sleep (SWS) and REM sleep (REM) were evaluated. The power spectrum analysis of the EEG was obtained by a computerized technique. For comparison, the sedating agent diphenhydramine was examined. Given at 3 mg/kg orally, a dose slightly above that effective therapeutically, diphenhydramine markedly affected behavior and all sleep stages. In particular, it depressed REM and increased SS (drowsiness). The EEG showed occasional spikes typical of subconvulsive states. Loratadine did not modify either sleep patterns or behavior over the 3-30 mg/kg dose range orally, which is far above that used clinically. The EEG, evaluated either visually or by spectral power analysis, was unaffected. Astemizole at 10 and 30 mg/kg PO reduced REM, markedly altered behavior at 30 mg/kg, but did not modify EEG activity. Mequitazine, at low doses (1-10 mg/kg PO), enhanced SS and decreased SWS and REM. Like diphenhydramine, mequitazine induced EEG changes typical of subconvulsive states and affected EEG power over the frequency range of 0.1-15.0 Hz. Terfenadine did not change sleep patterns and slightly affected behavior only at the high dose of 30 mg/kg orally; EEG activity was not influenced. These data show that: a) diphenhydramine and mequitazine appear to produce CNS effects by altering basic processes within the brain; b) astemizole and terfenadine seem to cross the blood-brain barrier at high doses only; c) loratadine has the lowest liability to produce central side effects. Of the sleep features examined, REM appeared to be the most sensitive stage to blockade of central H1-receptor pathways.

Animals↗
PubMed1989

Interaction of selected vasodilating beta-blockers with adrenergic receptors in human cardiovascular tissues.

beta- And alpha 1-adrenoceptor antagonist properties of bufuralol, carvedilol, celiprolol, dilevalol, labetalol, and pindolol were investigated in human myocardium and mammary artery using binding techniques and functional studies. In myocardial membranes, beta-adrenoceptor antagonists showed monophasic competition isotherms for [125I]pindolol binding with high affinity (Ki from 1-100 nM), except for celiprolol which displayed a biphasic competition isotherm (pKi = 6.4 +/- 0.06 for beta 1- and 4.8 +/- 0.07 for beta 2-adrenoceptors). Drug interactions with alpha 1-adrenoceptors were evaluated in human mammary artery by [3H]prazosin binding and by measuring contractile responses to norepinephrine (NE). Labetalol and carvedilol showed a moderate affinity for alpha 1-adrenoceptors (pKi = 6.2 +/- 0.01 and 6.1 +/- 0.06, respectively), and inhibited NE-induced contractions (pA2 = 6.93 +/- 0.23 and 8.64 +/- 0.24, respectively). Dilevalol, bufuralol, and pindolol displayed weak effect both in binding (Ki in micromolar range) and functional experiments (pA2 = 5.98, 5.54, and 6.23, respectively). Celiprolol did not show antagonist properties up to 100 microM in functional studies, but displayed a slight affinity for alpha 1-adrenoceptors in binding studies. The data indicate that the vasodilating activity of these beta-adrenoceptor antagonists is caused in some instances by an alpha 1-adrenoceptor antagonism (labetalol, carvedilol), whereas for the others alternative mechanisms should be considered.

Adrenergic beta-Antagonists↗