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E Ongini

Publications and source records attributed to E Ongini.

At least 73 records · Page 4Linked to original sources
PubMed1994

In vivo and ex vivo effects of adenosine A1 and A2 receptor agonists on platelet aggregation in the rabbit.

We have investigated both in vivo and ex vivo antiaggregatory activity of three adenosine receptor agonists in the anesthetized rabbit: the non-selective, 5'-N-ethyl-carboxamidoadenosine (NECA), the selective adenosine A1 receptor agonist, 2-chloro-N6-cyclopentyladenosine (CCPA) and the new selective A2 receptor agonist, 2-hexynyl-NECA. The drugs were administered by 30-min intravenous infusion at a dose reducing mean blood pressure by 40-50%. NECA and CCPA also markedly decreased heart rate. In ex vivo experiments, NECA (10 micrograms/kg) and 2-hexynyl-NECA (10 micrograms/kg) maximally inhibited adenosine 5'-diphosphate (ADP)-induced platelet aggregation at the end of drug infusion by 26.7 +/- 2.9% and 25.2 +/- 3.5%, respectively. In in vivo studies, the inhibition of platelet aggregation was evaluated using the technique based on selective accumulation of 111In-labeled platelets in pulmonary microcirculation upon challenge with ADP 100 micrograms/kg. NECA (10 micrograms/kg) and 2-hexynyl-NECA (10 micrograms/kg) decreased peak values for platelet accumulation by 35.3 +/- 6.9% and 52.5 +/- 5.9% and the area under curve values by 37.7 +/- 8.7% and 41.2 +/- 12.0%, respectively. In comparison, CCPA (100 micrograms/kg) did not affect platelet responses to ADP in either of the experimental models. Thus, the present study clearly demonstrates for the first time the in vivo antiplatelet activity of adenosine A2 receptor agonists, whereas the adenosine A1 receptor agonist was inactive, in consonance with the in vitro data.

Adenosine↗
PubMed1994

2-Alkynyl derivatives of adenosine-5'-N-ethyluronamide: selective A2 adenosine receptor agonists with potent inhibitory activity on platelet aggregation.

A series of new 2-alkynyl and 2-cycloalkynyl derivatives of adenosine-5'-N-ethyluronamide (NECA) and of N-ethyl-1'-deoxy-1'-(6-amino-2-hexynyl-9H-purin-9-yl)-beta-D- ribofuranuronamide (1, HE-NECA), bearing hydroxy, amino, chloro, and cyano groups in the side chain, were synthesized. The compounds were studied in binding and functional assays to assess their potency for the A2 compared to A1 adenosine receptor. The presence of an alpha-hydroxyl group in the alkynyl chain of NECA derivatives accounts for the A2 agonist potency, leading to compounds endowed with sub-nanomolar affinity in binding studies. However, these analogues also possess good A1 receptor affinity resulting in low A2 selectivity. From functional experiments the 4-hydroxy-1-butynyl (6) and the 4-(2-tetrahydro-2H-pyranyloxy)-1-butynyl (16) derivatives appear to be very potent in inducing vasorelaxation without appreciable effect on heart rate. The new compounds were also tested as inhibitors of platelet aggregation induced by ADP. Introduction of an alpha-hydroxyl group in the alkynyl side chain caused a greater increase in antiaggregatory activity than either NECA or HE-NECA, resulting in the most potent inhibitors of platelet aggregation so far known in the nucleoside series. The presence of an alpha-quaternary carbon such as the 3-hydroxy-3,5-dimethyl-1-hexynyl (12) and the 3-hydroxy-3-phenyl-1-butynyl (15) derivatives markedly reduced the antiaggregatory potency without affecting the A2 affinity. The hydrophobicity index (k') of the new nucleosides barely correlated with the binding data, whereas high k' values were associated with increased A2 vs A1 selectivity but with reduced activity in all functional assays. Some of the compounds synthesized possess interesting pharmacological properties. Compounds having an appropriate balance between vasorelaxation and antiplatelet activity, if confirmed in vivo, deserve further development for the treatments of cardiovascular disorders.

Adenosine↗
PubMed1994

Hemodynamic and humoral effects of chronic treatment with the neutral endopeptidase inhibitor SCH 42495 in spontaneously hypertensive rats.

Blockade of atrial natriuretic factor (ANF) degradation by specific neutral endopeptidase (NEP) inhibitors may be useful in treatment of hypertension because of the potential diuretic, natriuretic, and arterial pressure (AP)-lowering effects. To test this possibility, we examined the effects of chronic oral treatment with the NEP inhibitor SCH 42495 on BP, diuresis, natriuresis, plasma ANF, cyclic GMP, and the renin-angiotensin system (RAS) in conscious unrestrained spontaneously hypertensive rats (SHR) and compared them with the effects induced by the angiotensin-converting enzyme (ACE) inhibitor spirapril (SPIR). Four groups of adult SHR were treated orally for 4 weeks with placebo, SCH 42495 3 mg/kg twice daily (b.i.d.), SCH 42495 30 mg/kg b.i.d., and spirapril 1 mg/kg b.i.d. Systolic BP (SBP) was measured weekly, and 24-h urine was collected every week for measurement of urinary volume, sodium, potassium, and cyclic GMP excretion. Plasma ANF, cyclic GMP, renin activity (PRA), and aldosterone (ALDO) were determined from blood collected when the rats were killed. After 4-week treatment with SCH 42495, circulating levels of ANF were similar in both SCH 42495- and placebo-treated SHR; plasma cyclic GMP was higher, however, in the treated rats than in controls and urinary cyclic GMP increased only with the higher dose of SCH 42495. PRA and plasma ALDO tended to be lower in both SCH 42495-treated groups than in controls, yet BP, diuresis, and natriuresis throughout the study were not different from controls. In contrast, spirapril decreased BP; this effect was associated with significant increments in renin and decrements in ALDO and ANF, without changes in plasma and urinary cyclic GMP.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Effects of the new A2 adenosine receptor antagonist 8FB-PTP, an 8 substituted pyrazolo-triazolo-pyrimidine, on in vitro functional models.

1. We have characterized the in vitro pharmacological profile of putative A2 adenosine antagonists, two non-xanthine compounds, 5-amino-8-(4-fluorobenzyl)-2-(2-furyl)-pyrazolo [4,3-e]-1,2,4-triazolo[1,5-c] pyrimidine (8FB-PTP) and 5-amino-9-chloro-2-(2-furyl 1,2,4-triazolo [1,5-c] quinazoline (CGS 15943), and the xanthine derivative (E)7-methyl-8-(3,4-dimethoxystyryl)-1,3-dipropyl- xanthine (KF 17837). 2. In binding studies on bovine brain, 8FB-PTP was the most potent (Ki = 0.074 nM) and selective (28 fold) drug on A2 receptors, whereas CGS 15943 and KF 17837 exhibited affinity in the low and high nanomolar range, respectively, and showed little selectivity. 3. In functional studies, 8FB-PTP antagonized 5'-N-ethyl-carboxamidoadenosine (NECA)-induced vasorelaxation of bovine coronary artery (pA2 = 7.98) and NECA-induced inhibition of rabbit platelet aggregation (pA2 = 8.20). CGS 15943 showed weak activity in the platelet aggregation model (pA2 = 7.43) and failed to antagonize NECA-induced vasodilatation. KF 17837 was ineffective in both models up to micromolar concentrations. 4. Antagonism of A1-mediated responses was tested versus 2-chloro-N6-cyclopentyladenosine (CCPA) in rat atria. 8FB-PTP and CGS 15943 also antagonized competitively the negative chronotropic response induced by CCPA. Conversely, KF 17837 was unable to reverse A1-mediated responses. 5. 8FB-PTP is a potent and competitive antagonist of responses mediated by A2 adenosine receptors. The data provided a basis to reduce, by further chemical modifications, the affinity at A1 receptor and therefore enhance A2 receptor selectivity.

Adenosine↗
PubMed1994

Pharmacology of the new selective A2a adenosine receptor agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine.

The pharmacological profile of 2-hexynyl-5'-N-ethylcarboxamidoadenosine (2HE-NECA, CAS 141018-30-6), a new selective A2a adenosine receptor agonist, was characterized. In binding studies on both rat and bovine brain, 2HE-NECA was more potent on A2a receptors (Ki = 2.2 and 1.5 nmol/l, respectively) than the reference A2a agonist, 2-[4-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoaden osi ne (CPEC) or the non-selective adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA). The drug displayed a good A2a vs A1 receptor selectivity in brain tissues of both animal species (60- and 160-fold, respectively). In functional studies, 2HE-NECA showed marked vasodilating properties in rat aorta, bovine and porcine coronary arteries. The vasodilatory response in the porcine coronary preparation was greater for 2HE-NECA (EC50 = 23.3 nmol/l) than for CPEC (EC50 = 58.7 nmol/l) or NECA (EC50 = 76.6 nmol/l). In the rat Langendorff model, in which global ischemia was induced, 2HE-NECA (100 nmol/l) significantly prevented the risk of diastolic pressure and coronary perfusion pressure occurring during postischemic reperfusion. The in vitro antiaggregatory activity of 2HE-NECA (IC50 = 0.07 mumol/l), as tested in rabbit platelets, was higher than that found with NECA (IC50 = 0.2 mumol/l) or CPEC (IC50 = 2.16 mumol/l). In spontaneously beating rat atria, which are responsive to A1-receptor stimulation, 2HE-NECA did not show any negative chronotropic activity up to micromolar concentrations. In conscious spontaneously hypertensive rats, 2HE-NECA administered intraperitoneally caused a dose-dependent reduction in systolic blood pressure (ED30 = 0.005 mg/kg) with minimal reflex tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1994

Pharmacology of the highly selective A1 adenosine receptor agonist 2-chloro-N6-cyclopentyladenosine.

The pharmacological profile of 2-chloro-N6-cyclopentyladenosine (CCPA, CAS 37739-05-2), a highly selective A1 adenosine receptor agonist, was characterized. Its effects were compared with those of the non-selective adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA). In binding studies on both rat and bovine brain, CCPA was highly potent on A1 receptors (Ki = 1.3 and 0.5 nmol/l, respectively) and displayed good A1 vs A2a receptor selectivity (500- and 920-fold, respectively). In functional studies, CCPA showed marked negative chronotropic activity in spontaneously beating rat atria (EC50 = 8.2 nmol/l). This effect was antagonized dose-dependently by the A1 selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). In the rat Langendorff model, in which global ischemia was induced, CCPA (3 nmol/l) prevented significantly the rise of diastolic pressure and coronary perfusion pressure during postischemic reperfusion. In vascular preparations, a functional activity responsive to A2a adenosine receptor stimulation, CCPA did not show any vasodilating properties up to micromolar concentrations, whereas NECA had a good relaxing activity in bovine coronary arteries (EC50 = 167 nmol/l). In rabbit platelets, a model sensitive only to A2a-receptor stimulation, CCPA did not elicit any relevant antiaggregatory properties, whereas NECA was found to be effective (IC50 = 200 nmol/l). Likewise, in an in vivo model of platelet aggregation in the rabbit using a non-invasive radioisotopic technique, CCPA (100 micrograms/kg, 30 min i.v. infusion) did not influence platelet function, whereas NECA (10 micrograms/kg, 30 min i.v. infusion) decreased peak value for platelet accumulation by 35%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1994

Repeated administration of selective adenosine A1 and A2 receptor agonists in the spontaneously hypertensive rat: tolerance develops to A1-mediated hemodynamic effects.

We investigated the effects of the selective A1 adenosine receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA), the selective A2 adenosine agonists 2-hexynyl-5'-N-ethyl-carboxamidoadenosine(2-hexynyl-NECA) and 2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosi ne (CGS 21680), and the nonselective adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA) on systolic blood pressure (SBP), heart rate (HR) and receptor binding characteristics. The drugs were studied after acute and repeated i.p. administration in conscious, spontaneously hypertensive rats (SHRs). SBP and HR were recorded by the tail-cuff method. In acute studies the drugs induced a dose-dependent antihypertensive effect with the following order of potency: 2-hexynyl-NECA > NECA > CCPA = CGS 21680. As expected, the A1 agonist CCPA induced a dose-dependent bradycardia, whereas the A2 agonists had minimal influence on HR, and the nonselective agonist NECA induced bradycardia only at the two highest doses. In chronic experiments, the compounds were administered twice daily at equihypotensive doses. 2-Hexynyl-NECA, CGS 21680 and NECA maintained their antihypertensive effects throughout the experimental period. After 21 days, SBP levels were -32, -38 and -28% vs. baseline, respectively. HR was slightly affected. Conversely, tolerance developed to both hypotensive and bradycardic effects of CCPA: at day 21 SBP regained the pretreatment value (+2% vs. baseline), and HR also recovered (-14% vs. baseline). Binding studies were performed on cerebral tissues: no differences were observed between treated and control rats in number and affinity of either A1 and A2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1993

The dopamine D1 receptor agonists, A68930 and SKF 38393, induce arousal and suppress REM sleep in the rat.

The effects of the dopamine D1 receptor full agonist, A68930, on sleep-wake patterns and grooming behaviour were studied in the rat. The partial dopamine D1 receptor agonist, SKF 38393, was used for comparison. A68930 (0.003-0.3 mg/kg s.c.) increased waking time, reduced the amount of rapid eye movement (REM) sleep and enhanced spontaneous grooming dose dependently. The ED50 were 0.06, 0.02 and 0.05 mg/kg, respectively. The D1 antagonist, SCH 23390 (0.003 mg/kg s.c.), blocked the effects of A68930 on wakefulness and grooming but not those on REM sleep. SKF 38393 (0.1-10 mg/kg s.c.) increased grooming with an ED50 of 1.4 mg/kg and a dose-response relationship similar to that of A68930 (potency ratio 28). Conversely, the increase of wakefulness and reduction of REM sleep caused by SKF 38393 had dose-response curves different from those of A68930. The results support the view that D1 receptors may have a physiological function in producing arousal.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Beta 1 and beta 2 adrenoceptors are involved in mediating vasodilation in the human coronary artery.

We have characterized beta-adrenoceptors in the human coronary artery and investigated the mechanism underlying vasodilating activity of dilevalol, a non-selective beta-blocking agent with beta 2 agonist properties. Specific [125I]-pindolol binding was saturable, reversible and of high affinity (Kd = 91 +/- 7 pM; Bmax = 10 +/- 3 fmol/mg protein). Competition curves of [125I]-pindolol in the presence of ICI 118,551, a selective beta 2 antagonist, or CGP 20712A, a selective beta 1 antagonist, were best explained by a two-site binding model (48 +/- 5% beta 1 and 52 +/- 4% beta 2 receptors). In isolated coronary strips, isoproterenol induced a dose-dependent vasorelaxant effect which was blocked by either ICI 118,551 (100 nM) or CGP 20712A (100 nM). Dilevalol produced about 30-40% of vasodilating activity starting at a concentration of 100 nM. The response was antagonized selectively by ICI 118,551 suggesting that dilevalol produces vasodilation through the stimulation of beta 2 receptors. These findings show that in the human coronary artery both beta 1 and beta 2 receptor subtypes are present and mediate vasodilation. This suggests that the human coronary artery could be used for the evaluation of the vasodilating component of new beta-adrenoceptor blocking agents.

Adult↗
PubMed1993

Effects of selective A1 and A2 adenosine receptor agonists on cardiovascular tissues.

We investigated the negative chronotropic and vasodilating properties of new selective A1 and A2 adenosine agonists such as 2-chloro-N6-cyclopentyladenosine (CCPA) and 2-hexynyl-5'-N-ethyl-carboxamidoadenosine (2-hexynyl-NECA) as compared with reference adenosine analogues. The potency of these compounds on heart rate was assessed in the rat atrial preparation and their activity on the vascular tone was determined in both rat aorta and bovine coronary artery. CCPA was found to be the most potent A1 agonist of those currently available in producing negative chronotropic effects (EC50 = 8.2 nM). The A1 antagonist 8-cyclopentyl-1,3-dipropyl-xanthine (DPCPX) blocked CCPA activity in a dose-dependent manner. There was also a significant correlation between its biological effect and the affinity for A1 receptors as measured in the rat brain by [3H]-N6-cyclohexyladenosine (3[H]-CHA) binding. The A2 selective agonist 2-hexynyl-NECA showed vasodilating properties comparable with those observed with the reference compounds, CGS 21680 and NECA. EC50 values were 596 and 569 nM in rat aorta and bovine coronary artery, respectively. Moreover, the rank order of potency was similar in the two vascular districts examined, suggesting that the rat aorta is a useful model for studying the effects of adenosine derivatives on vascular tone. In addition, the potency of the compounds in inducing vasodilation was found to be correlated with their affinity for A2 receptors as measured in the rat striatum by 3[H]-CGS 21680 binding. These data further support that A1 receptors are involved in depressing cardiac activity and A2 receptors in inducing vasorelaxation.

Adenosine↗
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↗
PubMed1993

Differential effects of dopamine D-1 and D-2 receptor antagonist antipsychotics on sleep-wake patterns in the rat.

A series of antipsychotics having different selectivity for dopamine (DA) D-1 and D-2 receptors were studied for their effects on sleep stages in the rat. Electroencephalographic activity was recorded and classified according to the stages of wakefulness, rapid eye movement (REM) sleep and non-REM sleep. Total sleep duration, non-REM and REM latencies, number and duration of REM episodes were calculated. The DA D-1 antagonists, SCH 23390 (0.001-0.1 mg/kg s.c.), SCH 39166 (0.01-0.3 mg/kg s.c.) and NNC-756 (0.003-0.1 mg/kg s.c.), enhanced markedly the time spent in sleep through a significant increase of both non-REM and REM. Enhancement of REM was due to an increase in the number of episodes. The selective DA D-2 antagonists, raclopride (0.03-1 mg/kg s.c.) and remoxipride (1-10 mg/kg s.c.), did not affect sleep stages. Haloperidol (0.1-3 mg/kg p.o.) increased the duration of total sleep through an increase of non-REM, leaving REM unmodified. The nonselective DA antagonists, chlorpromazine (0.3-3 mg/kg s.c.) and clozapine (0.3-3 mg/kg s.c.) produced either no effect or slightly increased non-REM, respectively. Both drugs reduced REM duration by lowering the number and duration of episodes. The data show that there are differences between DA D-1 and D-2 antagonists with regard to their effects on sleep and wakefulness. Concomitant enhancement of both total sleep and REM appears to be a peculiar feature which clearly distinguishes DA D-1 antagonists from the other DA receptor blockers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Anticonvulsant doses of 2-chloro-N6-cyclopentyladenosine, an adenosine A1 receptor agonist, reduce GABAergic transmission in different areas of the mouse brain.

The possible relationship between A1 adenosine receptors and the gamma-aminobutyric acid (GABAA) receptor complex was evaluated in the mouse brain. We studied the effect of in vitro addition and in vivo administration of 2-chloro-N6-cyclopentyladenosine (CCPA), the most selective ligand for A1 receptors, on the biochemical parameters used currently to evaluate GABAergic function. In vitro, CCPA (0.01-100 microM) failed to modify [3H] GABA binding, [3H]flunitrazepam binding, t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding and muscimol-stimulated 36Cl- uptake. On the contrary, in vivo, CCPA (1.4-27.6 mumol/kg i.p.) increased [35S]TBPS binding in membranes from the cerebral cortex, hippocampus, striatum and substantia nigra, but not from the cerebellum, thalamus, hypothalamus and olfactory tubercle. The specific A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxantine (9.8 mumol/kg i.p.) abolished the effect of CCPA on [35S]TBPS binding, indicating that the action of this compound is mediated by its interaction with A1 receptors. Diazepam (1.7 mumol/kg i.p.), a positive modulator of GABAergic transmission, antagonized the increase of [35S]TBPS binding induced by CCPA. CCPA (2.8-8.3 mumol/kg i.p.) antagonized convulsions induced by isoniazid, an inhibitor of GABA synthesis, but neither antagonized nor potentiated isoniazid-induced increase of [35S]TBPS binding. CCPA (2.8-8.3 mumol/kg i.p.) antagonized the convulsions induced by pentylenetetrazol (398 mumol/kg i.p.), methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (50 mumol/kg i.p.) and bicuculline methiodide (9.8 mumol/kg i.p.). The results show that, in spite of its anticonvulsant activity, CCPA reduces the function of the GABA-coupled chloride channel function. This finding suggests that the anticonvulsant target sites are different from those involved in the action of CCPA on GABAA receptors.

Adenosine↗
PubMed1992

Effects of adenosine derivatives on human and rabbit platelet aggregation. Correlation of adenosine receptor affinities and antiaggregatory activity.

The inhibitory effects of several adenosine analogues, including the new A2-selective agonists 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido-adenosi ne (CGS 21680) and 2-hexynyl-5'-N-ethylcarbox-amidoadenosine (2-hexynyl-NECA), were investigated in vitro on human and rabbit platelet aggregation. The compounds examined inhibited ADP-induced platelet aggregation over a wide range of potency. The rank order of activity was similar between the two species thus showing that the rabbit is a useful animal model for studying the effects of adenosine derivatives on platelet aggregation. 2-Hexynyl-NECA was found to be the most potent adenosine compound of those currently available, having IC50 values of 0.10 and 0.07 microM in human and rabbit platelets, respectively. Conversely, the A1 agonists R(-)-N6-(2-phenylisopropyl) adenosine (R-PIA), S(+)-N6-(2-phenylisopropyl) adenosine (S-PIA) and 2-chloro-N6-cyclopentyladenosine (CCPA) were the least potent compounds with IC50 values in the micromolar range. The potency of the compounds in inhibiting platelet aggregation was found to be highly correlated with their affinity for A2 receptors as measured using 3H-CGS 21680 binding in rat brain striatum.

Adenosine↗
PubMed1992

Effects of remoxipride, a dopamine D-2 antagonist antipsychotic, on sleep-waking patterns and EEG activity in rats and rabbits.

The antipsychotic remoxipride, a selective dopamine D-2 receptor antagonist, was studied for its effects on sleep-waking patterns in the rat and electroencephalographic (EEG) activity in the rabbit. Haloperidol, which has lesser selectivity for D-2 receptors, was used for comparison. In the rat, remoxipride (1-10 mg/kg SC) did not affect either total sleep or non-rapid eye movement (non-REM) sleep. Only REM was slightly reduced by the high dose of 10 mg/kg. Haloperidol (0.1-1 mg/kg PO) enhanced duration of both total sleep and non-REM sleep. In the rabbit, remoxipride (3 and 10 mg/kg IV) induced no significant changes of the EEG power spectrum over 0.1-38.5 Hz or individual frequency bands. In both cortex and hippocampus the drug did not alter the arousal response to acoustic sensory stimuli. Plasma concentration of remoxipride 10 mg/kg IV in rabbits declined biexponentially and was 4 and 2 mumol/l at 30 min and 1 h, respectively. Haloperidol (0.3 and 1 mg/kg) slowed down the EEG activity, enhanced the power spectrum of the cortical and hippocampal activity, and significantly reduced the duration of arousal induced by sensory stimuli. The results indicate that, unlike haloperidol, remoxipride has weak or no sedative effects. The data also provide support to the notion that D-2 receptors are not involved in the regulation of states of sleep and sedation.

Animals↗
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↗