Inhibitory effect of idebenone (CV-2619), a novel compound, on vascular lesions in hypertensive rats

The effects of a novel compound, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone, CV-2619), on cerebral and renal vascular changes were examined in stroke-prone spontaneously hypertensive rats (SHRSP) and in rats with experimentally induced hypertension. CV-2619 (35 mg/kg/day, p.o.) significantly inhibited the onset of cerebrovascular lesions (stroke) and the elevation of blood pressure in SHRSP with mild hypertension. A higher dose (2 X 50 mg/kg/day, p.o.) clearly delayed the onset of both stroke and proteinuria without any effect on the blood pressure in SHRSP with severe hypertension. In DOCA-salt hypertensive rats, CV-2619 (2 X 5 or 2 X 25 mg/kg/day, p.o.) dose-dependently inhibited decreases in body weight and water balance and the development of cerebral and renal vascular changes. These results suggest that CV-2619 inhibits the development of stroke and renal vascular lesions in hypertensive rats.     

The role of the sympathetic nervous system in oestrogen-induced hypertension in rats.

Albino rats of either sex received chronic ethinyl oestradiol (EO) treatment (1.5 mg kg-1 daily, i.m.) for 3 weeks. Untreated control rats received arachis oil vehicle alone. Chronic EO treatment resulted in elevation of blood pressure in both sexes. Female rats exhibited significantly greater elevation in blood pressure than males. In chronic EO-treated rats pressor responses to low doses (0.5 micrograms kg-1) of noradrenaline were significantly increased, while those to angiotensin II, acetylcholine and isoprenaline were unaltered. Chronic EO treatment also sensitized the vascular bed of the rats' hindquarters to noradrenaline. EO-induced hypertension was associated with significant increase in dopamine-beta-hydroxylase activity of adrenal glands. Complete bilateral adrenalectomy or chemical sympathectomy prevented the development of EO-induced hypertension. It is suggested that chronic treatment of rats with EO induces and maintains hypertension. The peripheral sympathetic system plays an important role in this phenomenon.     

Enalapril and valsartan improve cyclosporine A-induced vascular dysfunction in spontaneously hypertensive rats

Cyclosporine A causes hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR). In the present study, arterial function was investigated using in vitro vascular preparations after long-term treatment with cyclosporine A. SHR received cyclosporine A (5 mg kg(-1) day(-1) s.c.) and high-Na(+) diet for 6 weeks during the developmental phase of hypertension. Part of the rats were treated concomitantly either with the angiotensin converting enzyme inhibitor enalapril (30 mg kg(-1) day(-1) p.o.) or with an angiotensin AT(1) receptor antagonist valsartan (3 or 30 mg kg(-1) day(-1) p.o.). In renal arteries, contractile responses to noradrenaline and angiotensin II, as well as relaxation responses to acetylcholine (endothelium-dependent) and to sodium nitroprusside (endothelium-independent), were severely impaired by cyclosporine A-treatment. There was also a trend for the dysfunction of the mesenteric arteries, but the impairment did not reach statistical difference. Enalapril and valsartan improved the impaired renal arterial functions. Cyclosporine A-induced hypertension and nephrotoxicity seem to be associated with renal arterial dysfunction in SHR on high-Na(+) diet. Antagonism of the renin-angiotensin system protects from vascular toxicity of cyclosporine A.     

Reduction in blood pressure and vascular reactivities to pressor substances by chronic treatment with piretanide in spontaneously hypertensive rats

1. Effects of treatment with piretanide (10 and 30 mg/kg per day p.o.) for 9 weeks on blood pressure, urinary excretion of electrolytes, and vascular reactivities to pressor substances were investigated in 10-week-old spontaneously hypertensive (SHR) rats. 2. Piretanide (30 mg/kg) prevented development of hypertension and produced a significant reduction in blood pressure from the 2nd week of the treatment. A slight decrease in blood pressure was observed in rats treated with the lower dose of piretanide. 3. Piretanide produced significant and dose-dependent diuresis throughout the experiment. Although significant natriuresis was observed in the 1st and 4th week of the treatment, natriuresis disappeared in the 8th week. Urinary excretion of potassium was decreased significantly by piretanide throughout the experiment. 4. Attenuation of pressor responses to phenylephrine and angiotensin II was observed after chronic administration of piretanide (30 mg/kg). 5. These data demonstrate the contribution of attenuated vascular reactivities to pressor substances as well as a diuretic action to the antihypertensive effect of piretanide during its long-term administration in SHR rats.     

Effects of ponalrestat on depressor responses to arachidonic acid in streptozotocin-diabetic rats

1. This study measured reductions in diastolic blood pressure to arachidonic acid (AA, 0.125-2.0 mg/kg i.v.) in 14-day streptozotocin-diabetic (60 mg/kg i.v.) and control rats anaesthetized with pentobarbitone (50-70 mg/kg i.p.) having been treated acutely or chronically with saline or ponalrestat (25 mg/kg p.o. 1 hr prior to anaesthesia, or 25 mg/kg p.o. daily for 14 days). 2. Streptozotocin-treated diabetic rats displayed reduced sensitivity to depressor effects of AA (0.125-2.0 mg/kg) when compared with controls. 3. Acute treatment with ponalrestat did not change responses to AA in controls or diabetics, whereas chronic treatment resulted in a small increase in depressor responses to AA (0.125, 0.25 and 2.0 mg/kg) in diabetics but not controls. 4. The mechanism of this action of ponalrestat remains to be elucidated, although the results are compatible with the hypothesis that increased polyol pathway activity may affect responses to, or metabolism of eicosanoids.     

Reactivity of resistance blood vessels ex vivo after administration of toxic chemicals to laboratory animals: arteriolotoxicity

Three vasotoxic metals (arsenic, lead, cadmium) were investigated for their arteriolotoxicity in rats. A perfused hindleg preparation from control and treated animals was used to determine the vasoreactivity to norepinephrine. After 2 and 4 weeks of treatment with arsenic trioxide (15 mg/kg p.o.) and after 4 weeks of treatment with lead acetate (100 mg/kg p.o.), there was a significant reduction in vasoreactivity (10 20%) expressed as the maximum increase in perfusion pressure (EAmax). A single dose of cadmium chloride (1 mg/kg i.p.) caused a non-significant reduction of 12% in EAmax. We conclude that this method is suitable for detecting arteriolotoxic effects of chemicals in small laboratory animals.     

Effects of 2,3-dimethoxy-5-methyl-6-(10'-hydroxydecyl)-1,4-benzoquinone (CV-2619) on myocardial energy metabolism in the hypertrophied heart of spontaneously hypertensive rats

Effects of CV-2619 (10 and 30 mg/kg/day, p.o.) or ubiquinone-10 (Q-10, 10 mg/kg/day, p.o.) treatment for 5 weeks on systolic blood pressure (SBP) and myocardial energy metabolism were studied in spontaneously hypertensive rats of 20 weeks of age. The systolic blood pressure was about 205 mmHg at the start of the experiment, and a slight increase was noted thereafter in the control (vehicle) group. CV-2619, but not Q-10, inhibited the increase in the blood pressure. At 25 weeks of age, cardiac hypertrophy was noted to the same extent in either treated group. Myocardial contents of glycolytic intermediates (glycogen, glucose, pyruvate and lactate) and creatine phosphate (Cr-P), ATP, ADP, and AMP were not significantly influenced by CV-2619 or Q-10 treatment. CV-2619, however, significantly increased the energy charge, an index of myocardial energy state, with higher dose and lowered the lactate/pyruvate ratio with either dose. These results suggest that CV-2619 has a mild antihypertensive effect and improves the myocardial energy state in the hypertrophied heart during the sustained phase of hypertension in SHR rats.     

Increased vasoconstriction to noradrenaline by 1400W, inhibitor of iNOS, in rats with streptozotocin-induced diabetes

There is evidence that inducible nitric oxide synthase (iNOS) is activated at the acute phase of diabetes. We examined if selective inhibition of iNOS by 1400W (N-3-aminomethyl-benzyl-acetamidine) increases vascular response to noradrenaline in rats with streptozotocin (60 mg/kg i.v.)-induced diabetes for a duration of 3 weeks. The effects of noradrenaline on mean arterial pressure (MAP; 6, 16, 45 and 122x10(-9) mol/kg/min) and mean circulatory filling pressure (MCFP; 16 and 45x10(-9) mol/kg/min) were obtained in conscious and unrestrained diabetic rats and control rats before as well as after treatment with 1400W (3 mg/kg followed by 3 mg/kg/h, i.v.). Rats with early streptozotocin-induced diabetes had decreased mean arterial pressure and mean circulatory filling pressure responses to noradrenaline. Treatment with 1400W did not affect responses in the control rats but increased maximum pressor response to noradrenaline (from 46+/-3 to 63+/-5) and mean circulatory filling pressure response to the high dose (45 nmol/kg/min) of noradrenaline (from 1.0+/-0.2 to 3.8+/-0.3 mmHg) in the diabetic rats. Thus, selective inhibition of iNOS by 1400W increases arterial and venous constriction to noradrenaline in conscious rats with streptozotocin-induced diabetes.     

Interpretation of changes in apomorphine-induced stereotyped behaviour in rats receiving continuous administration of trifluoperazine for 15 months

Rats treated continuously with trifluoperazine dihydrochloride (4.4–4.9 mg/kg per day) for 15 months showed an exaggerated stereotyped response to large doses of apomorphine (1.0 mg/kg, s.c.), but inhibition of stereotyped behaviour by a small dose of apomorphine (0.125 mg/kg, s.c.) as compared to responses obtained in age-matched control animals. Apomorphine (0.03–1.0 mg/kg, s.c.) produced more hyperactivity in trifluoperazine-treated rats than in control animals. After withdrawal of the drug for a period of 2 weeks or more. the stereotyped responses to all doses of apomorphine (0.0625–0.5 mg/kg, s.c.) were exaggerated in animals treated with trifluoperazine compared with age-matched control rats. Acute administration of trifluoperazine (4.5 mg/kg. p.o., 3 hr previously) to animals withdrawn from trifluoperazine abolished the stereotyped behaviour induced by a small dose of apomorphine (0.125 mg/kg) but a maximal response still was obtained with large doses (1.0 mg/kg). In contrast, acute challenge with trifluoperazine (4.5 mg/kg, p.o.) in control animals inhibited the stereotyped behaviour at virtually all doses of apomorphine, as compared with the responses to apomorphine in both animals withdrawn from trifluoperazine, given the same treatment, and naive control rats.Administration of trifluoperazine (0.28 and 0.56 mg/kg, p.o.) inhibited stereotypy induced by small doses of apomorphine (0.125 mg/kg, s.c.) in control animals but the response in animals withdrawn from trifluoperazine was exaggerated. Larger doses of trifluoperazine (1.125–4.5 mg/kg) totally inhibited apomorphine-induced (0.125 mg/kg, s.c.) stereotypy in both groups.These findings do not support the concept of separate mechanisms controlling low grade and high grade stereotyped behaviour during chronic treatment with neuroleptics.     

Effects of 6-hydroxydopamine on spontaneously hypertensive rats

Summary In order to evaluate the role of the sympathetic nervous system in the development and maintenance of spontaneous hypertension, spontaneously hypertensive and normotensive rats were give 6-hydroxydopamine (6-OH-dopamine).A single i.v. dose of 6-OH-dopamine (100 mg/kg) caused a biphasic rise in blood pressure in both hypertensive and normotensive rats.During long-term treatment the first dose of 6-OH-dopamine (25 or 50 mg/kg i.v.) lowered the blood pressure, measured 24 h after injection, two or three times more in hypertensive than in normotensive rats. As a result, the blood pressure reached the same level in both groups, i.e. 90–100 mm Hg. Within three days this hypotension subsided. After repeated weekly administration of 6-OH-dopamine the depressor effect declined gradually and after 4 weeks it was no longer significant. When this stage was reached, adrenal demedullation as such neither lowered the basal blood pressure, nor prevented the development of tolerance to 6-OH-dopamine. Accordingly, the adrenal medulla is not decisive in maintaining the blood pressure and in the development of tolerance to the depressor effect of 6-OH-dopamine in spontaneously hypertensive and normotensive animals.After treatment with 8 weekly doses of 6-OH-dopamine, the pressor response to noradrenaline increased in both hypertensive and normotensive rats, while the response to tyramine decreased.When, on the second day after birth, new-born rats of the hypertensive strain were given a single dose of 6-OH-dopamine (50 mg/kg i.p.) the development of hypertension was inhibited to some degree. This inhibition was more marked when the animals were given weekly doses of 6-OH-dopamine (50 mg/kg i.p.) during 5 weeks. On the other hand, when pregnant rats of the same strain received 6-OH-dopamine (50 mg/kg i.v.) twice during the last week before delivery, the offsprings did develop hypertension.It is evident that the adrenergic nervous system plays an important part in the development of hypertension in rats of a spontaneously hypertensive strain, but it is no longer of essential importance once the hypertension is established.Partly presented at the Fifth International Congress on Pharmacology, San Francisco, July 23–28, 1972 (Neuvonen et al., 1972).     

Effects of detergent formula chelating agents on the metabolism and toxicity of cadmium in mice.

Chelating agents like NTA (nitrilotriacetic acid) STPP (sodiumtripolyphosphate, Na5P3O10) and EDTA (ethylenediaminetetraacetic acid) are used as components of detergents. An increased toxicity of some metal compounds when combined with NTA has led to decreased use of this chelating agent in relation to STPP. In the present studies short-term and long-term effects of these chelating agents on cadmium toxicity in mice were investigated. I: In the short-term study, mice subcutaneously exposed to CdCl2 (3.2 mg Cd/kg b. wt.) in combination with STPP (32 mg/kg b. wt.) demonstrated a markedly higher mortality compared to animals given CdCl2 alone. This increase in mortality was similar to the one encountered when CdCl2 (3.2 mg Cd/kg b. wt.) and NTA (32 mg/kg b. wt.) were combined. Animals exposed subcutaneously to CdCl2 + STPP or CdCl2 + NTA showed histological evidence of liver necrosis 24 hrs after exposure not seen in animals given the same dose of CdCl2 alone and also had markedly lower cadmium concentrations in the livers compared to only Cd-exposed animals. II: In the long-term study, mice were exposed orally to CdSO4 (50p.p.m Cd) alone or in combination with STPP (500 p.p.m.), NTA (500 p.p.m.) or EDTA (50 p.p.m.) by continuous administration via the drinking water for 18 months. A decreased total excretion of urine proteins was seen in all Cd-treated animals irrespectively of the combination with various chelating agents. The conclusion of the present work was the NTA and STPP given by subcutaneous injection to mice markedly increased the toxicity of cadmium but that neither NTA, STPP nor EDTA given orally altered the toxicity of cadmium during a period of long-term exposure of 18 months.     

The ruthenium-based nitric oxide scavenger, AMD6221, augments cardiovascular responsiveness to noradrenaline in rats with streptozotocin-induced diabetes

Excess production of nitric oxide by inducible nitric oxide synthase (iNOS) has been implicated in cardiovascular dysfunction associated with the acute phase of diabetes mellitus. We examined if the selective nitric oxide scavenger, AMD6221 (ruthenium[hydrogen(diethylenetrinitrilo)pentaacetato] chloride) improved cardiovascular function in rats with streptozotocin (60 mg/kg, i.v.)-induced diabetes. The cardiovascular effects of noradrenaline (16.5 nmol/kg/min, i.v.) were measured in thiobutabarbitone-anaesthetised diabetic and control rats before and after acute administration of AMD6221 (80 mg/kg). Rats in the acute phase of diabetes (3 weeks post injection of streptozotocin) had impaired mean arterial pressure, left ventricular systolic pressure and maximum rate of increase (+dP/dt) and decrease (-dP/dt) of left ventricular pressure responses to noradrenaline compared with control rats. AMD6221 significantly augmented noradrenaline-induced increases in left ventricular systolic pressure and +/-dP/dt in the diabetic but not control rats. The results show that selective scavenging of nitric oxide by AMD6221 improved cardiac response to noradrenaline in rats with streptozotocin-induced diabetes.     

Protective effects of acetyl-L-carnitine on neurodegenarative changes in chronic cerebral ischemia models and learning-memory impairment in aged rats

This study investigated the effects of acetyl-L-carnitine (ALC) in secondarily-induced cerebral chronic ischemia models using rats with permanent ligation of bilateral common carotid arteries (BCCL) and spontaneously hypertensive rats (SHR). Additionally, we used normal aged rats as a primary dementia model. Chronic ALC administration at 100 mg/kg (p.o.) for 4 weeks significantly attenuated neurodegenerative changes. In groups receiving 50 mg/kg or 100 mg/kg, ALC inhibited the active astrocyte increase in cerebral tissues of both BCCL and SHR models. In BCCL rats, ALC administration (50 mg/kg or 100 mg/kg, p.o.) resulted in significant promotion of glutathione levels in brain tissues. We also confirmed behavioral improvement after ALC treatment (100 mg/kg for 8 weeks, p.o.) on learning-memory function using aged rats (18 months old) in a passive avoidance task and preservation of CA1 pyramidal neurons was coincided on histopathological observation. In conclusion, chronic ALC administration may ameliorate cerebral ischemia progress after a cerebrovascular disorder as well as spontaneous ageing-related cerebral dysfunction via hippocampal protection.     

Pulmonary vascular remodelling in hypoxic rats: effects of amlodipine, alone and with perindopril

This study investigated whether pulmonary vascular remodelling in hypoxic pulmonary hypertensive rats (10% oxygen; 4 weeks) could be prevented by treatment, during hypoxia, with amlodipine (10 mg/kg/day, p.o.), either alone or in combination with the angiotensin converting enzyme inhibitor, perindopril (30 mg/kg/day, p.o.). Medial thickening of pulmonary arteries (30-500 microm o.d.) was attenuated by amlodipine whereas it was totally prevented by the combination treatment (amlodipine plus perindopril); neomuscularisation of small alveolar arteries (assessed from critical closing pressure in isolated perfused lungs) was not affected. Pulmonary vascular resistance (isolated perfused lungs) was reduced by both treatment regimes but only combination treatment reduced right ventricular hypertrophy. Thus, amlodipine has anti-remodelling properties in pulmonary hypertensive rats. The finding that combining amlodipine with another anti-remodelling drug produced effects on vascular structure that were additive raises the question of whether combination therapy with two different anti-remodelling drugs may be of value in the treatment of patients with hypoxic (and possibly other forms of) pulmonary hypertension.     

Pharmacological efficacy of CPU 86017 on hypoxic pulmonary hypertension in rats: mediated by direct inhibition of calcium channels and antioxidant action, but indirect effects on the ET-1 pathway

Endothelin-1 (ET-1) plays a key role in the pathogenesis of pulmonary hypertension. The present study was conducted to examine the effects of a novel compound p-chlorobenzyltetrahydroberberine (CPU 86017) on endothelin-1 system of hypoxia-induced pulmonary hypertension in rats. SD male rats were divided into control, untreated pulmonary hypertension, nifedipine (10 mg/kg p.o.), and CPU 86017 (80, 40, and 20 mg/kg p.o.) groups. The pulmonary hypertension was established by housing the rats in a hypoxic (10 +/- 0.5% oxygen) chamber 8 hours per day for 4 weeks. Hemodynamic and morphologic assessment exhibited a significant increase in the central vein pressure (CVP), right ventricular systolic pressure (RVSP), and pulmonary arteriole remodeling in the pulmonary hypertensive rats, which were improved by CPU 86017 80 and 40 mg/kg administration (P < 0.01). The elevated pulmonary endothelin-1 level and the over-active preproET-1 and iNOS mRNA expression were also decreased significantly (P < 0.01) in CPU 86017 groups. The maladjustment of redox enzyme system in pulmonary hypertension rats was corrected after treatment. We concluded that CPU 86017 improves pulmonary hypertension mainly to suppress the endothelin-1 pathway at the upstream and downstream via calcium antagonism and antioxidative action, then, resulting in a relief in pathogenesis of the disease.     

Influence of ACTH on the effects of imipramine, desipramine and lithium on duration of immobility of rats in the forced swim test.

We examined the effects of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test with the administration of imipramine, desipramine, or lithium. A single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) significantly decreased the duration of immobility in normal rats in a dose-dependent manner. Lithium (10-100 mg/kg, p.o.), however, had no affect on the performance of rats in the forced swim test. ACTH (100 microg/day), administered subcutaneously to rats for 1, 3, 7, and 14 days, had no apparent effect on the duration of immobility in this test. The immobility-decreasing effect induced by a single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) was blocked by chronic administration of ACTH for 3-14 days. The reduction of immobility, induced by chronic administration of imipramine (10 mg/kg, i.p.) for 15 days, was blocked by treatment with ACTH for 14 days. When lithium (100 mg/kg, p.o.) was administered for 15 days concurrently with imipramine (10 mg/kg, i.p.), we observed a significant decrease in immobility in rats treated with ACTH for 14 days. We suggest that chronic treatment of rats with ACTH may prove to be an effective model of tricyclic antidepressants-treatment-resistant depression.     

Hepatotoxicity of metals in glutathione-depleted mice

Sublethal doses of cadmium chloride (CdCl2; 3 mg/kg i.v.), mercuric chloride (HgCl2; 2 mg/kg i.v.) and sodium vanadate (6 mg/kg i.v.) were administered to normal and glutathione (GSH)-depleted mice (phorone, 250 mg/kg i.p.). In normal mice serum sorbitol dehydrogenase (SDH) activity as a measure of hepatotoxicity was elevated 24 h after treatment with CdCl2 and HgCl2. Following GSH depletion more pronounced increments of SDH activities were observed only after CdCl2 treatment. No difference was seen in the exhalation of ethane by normal and GSH-depleted animals, neither in metal-treated nor in control mice, indicating that lipid peroxidation is not involved in their hepatotoxicity.     

Interaction of some atypical antidepressants and adrenoceptor antagonists with imipramine: a behavioural study with isoprenaline-induced drinking

The systemic administration of isoprenaline to rats produced a dose-dependent increase in drinking which was antagonized by propranolol. While oral administration of the antidepressant, imipramine, alone had no significant effect on this response, the increase was significantly inhibited by administration of imipramine together with each of the following drugs over a period of 4 days: bupropion (21.0 mg/kg/day, p.o.), a selective inhibitor of the uptake of dopamine and nomifensine (10.6 mg/kg/day, p.o.), a relatively selective dopamine and a blocker of the uptake of noradrenaline. Similarly, the combination of the selective alpha 1-adrenoceptor antagonist, prazosin (2.37 mg/kg/day, p.o.); the selective alpha 2-adrenoceptor antagonist, yohimbine (2.38 mg/kg/day, p.o.) or the non-selective alpha-adrenoceptor blocker, phentolamine (4.65 mg/kg/day, p.o.) with imipramine caused a significant inhibition of the isoprenaline-induced drinking. It is concluded that fast desensitization of central beta-adrenoceptors in the rat can be produced after the oral subacute simultaneous administration of imipramine with alpha-adrenoceptor antagonists or atypical antidepressants, such as nomifensine or bupropion.     

Effect of chronic administration of selective 5-hydroxytryptamine and noradrenaline uptake inhibitors on a putative index of 5-HT2C/2B receptor function

Chronic treatment with selective 5-HT reuptake inhibitors (SSRI) are therapeutic in obsessive compulsive disorder, depression, anxiety, bulimia nervosa and migraine. In the present study the possibility that SSRI's act by desensitizing 5-HT_2C/5-HT_2B receptors was assessed using a putative in vivo model of 5-HT_2C/5-HT_2B receptor function, mCPP-induced hypolocomotion. mCPP (2,4 and 6 mg/kg i.p. 20 min pretest) reduced locomotion and rears in rats treated acutely or chronically with saline. Acute oral administration of the SSRI's fluoxetine (10 mg/kg), paroxetine (10 mg/kg), or clomipramine (70 mg/kg) or the noradrenaline reuptake inhibitor, desipramine (10 mg/kg), all 1 hr pretest, did not prevent mCPP-induced hypolocomotion. In contrast, chronic treatment with the SSRI's paroxetine and fluoxetine (both 10 mg/kg p.o. daily × 21 days), significantly attenuated the effect of mCPP (4 and 6 mg/kg i.p.) on locomotion and rears 24 hr after the last pretreatment dose. Chronic clomipramine (70 mg/kg p.o. daily × 21 days) also significantly attenuated the effect of mCPP (4 mg/kg i.p.) on rears and tended to reduce the hypolocomotor response. However, chronic treatment with desipramine, (10 mg/kg p.o.daily × 21) had no effect on any of the parameters measured. As chronic fluoxetine and paroxetine did not reduce brain mCPP levels (determined by HPLC 30 min after 4 mg/kg i.p.) the results suggest that chronic SSRI's, but not desipramine, reduce 5-HT_2C/5-HT/_2B receptor responsivity. If this occurs in man, it may mediate or contribute to their reported therapeutic efficacy in depression, anxiety, bulimia, migraine and alcoholism. It may also be of particular relevance to their unique efficacy in OCD.     

ADRENOCORTICOTROPHIC HORMONE-INDUCED HYPERTENSION IN THE RAT: EFFECTS OF THE ENDOTHELIN ANTAGONIST BOSENTAN

1. The effects of the endothelin antagonist bosentan on adrenocorticotrophic hormone (ACTH)-induced hypertension were examined in the conscious male Sprague-Dawley rat. 2. In order to confirm endothelin antagonism, 18 rats were randomly divided into two groups: receiving either (i) endothelin-1 (0.125, 0.25, 0.5 and 1 nmol/kg, i.v.); or (ii) endothelin-1 at these doses following bosentan (100 mg/kg gavage) and mean arterial pressure recorded (study A). Subsequently, 40 male rats (320 +/- 5 g) were randomly divided into four groups (n = 10): (i) Sham (0.9% saline, s.c.) + 5% acacia gum gavage; (ii) ACTH (500 micrograms/kg per day, s.c.) + 5% acacia gum gavage; (iii) Sham injection + bosentan (100 mg/kg per day) gavage; or (iv) ACTH + bosentan. Six control days (C1-C6) were followed by 11 treatment days (T0-T10). Systolic blood pressure, water intake, urine volume, food intake and bodyweight were measured every second day (study B). 3. Bosentan significantly attenuated the endothelin-1-induced blood pressure rise at 0.125 nmol/kg (P < 0.05), but not at higher doses. 4. Bosentan at a dose which attenuated endothelin-1-induced blood pressure increase had no effect on either blood pressure or metabolic parameters in ACTH-treated rats. 5. These results suggest that endothelin does not play a major role in ACTH-induced hypertension.