Contribution of pre- and post-synaptic components to heightened central cholinergic activity in spontaneously hypertensive rats.

In several models of essential hypertension in the rat, the pressor response to central cholinergic stimulation is enhanced with respect to age-matched normotensive controls. Neurochemical evidence is available from previous studies to suggest that both pre- (transmitter synthesis and release) and post-synaptic (muscarinic receptors) components of cholinergic transmission may be enhanced in hypertensive rats and that such alterations might be responsible for the exaggerated pressor response to centrally-acting cholinergic agonists. The present study, employing pharmacological approaches, was designed to determine whether pre- or post-synaptic components of central cholinergic transmission were more important in this regard. The pressor response to intravenous injection of the indirect-acting agonist, physostigmine, but not to that of the direct-acting agonist, arecoline, was significantly reduced by pretreatment with hemicholinium-3 (to deplete acetylcholine in brain). The pressor response to physostigmine, but not to arecoline, was enhanced in adult, spontaneously-hypertensive rats, with respect to their normotensive controls. The pressor response to oxotremorine was partially inhibited by pretreatment with hemicholinium-3, but was only partially effective at inducing an exaggerated pressor response in spontaneously hypertensive rats. These results are consistent with the hypothesis that heightened cholinergic activity in spontaneously hypertensive rats is derived primarily through altered pre-synaptic mechanisms, and that the actions of oxotremorine may involve a multi-synaptic cholinergic pathway.

Synthesis and anticonvulsant properties of 2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzimidazol-1-ones.

A series of 2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzimidazol-1-ones were synthesized and evaluated for anticonvulsant activity in DBA/2 mice against sound-induced seizures and in rats against maximal electroshock-induced seizures. Most of the derivatives showed an anticonvulsant effect better than that of valproate, a commonly used anticonvulsant drug. Compound 3 possessed an anticonvulsant activity comparable to that of diphenylhydantoin in both tests and was selected for further studies. Structure-activity relationships are discussed.

Effects of captopril on the development of rat doxorubicin nephropathy.

The effects of a daily administration of an anti-converting enzyme inhibitor. Captopril (CPT) (100 mg/kg/orally), on the development of functional and morphological alterations induced in rats by a single injection (7.5 mg/kg/iv) of Doxorubicin (DXR) (Adriamycin*), were investigated. Twenty-four-hour protein excretion, urine output, food intake, water intake, and body weight gain were measured weekly for 30 days. Transmission and scanning electron microscopy observations were performed on kidney samples after 30 days. Four groups were studied. Group 1 were control rats. Group 2 were rats injected with DXR. Group 3 were rats injected with DXR and treated with CPT for 30 days. Group 4 were rats injected with DXR and treated with CPT for 15 days (CPT treatment started 15 days after DXR injection). Group 1 did not show significant functional or morphological changes. Group 2 showed severe proteinuria, significant increase in urinary volume within 2 weeks, significant body weight reduction and diffuse morphological changes. These changes mainly consisted of podocyte swelling, severe foot process fusion, and presence of casts within tubular lumen. Group 3, with respect to group 2, showed a significant reduction of the 24 h protein excretion and urine output. This group displayed morphological changes similar to those observed in group 2, but with a focal distribution. Group 4 showed functional and morphological changes comparable with those of group 2. It is concluded that CPT partially inhibits the development of the functional and morphological damage induced by DXR in the rat kidney. However, CPT did not influence the natural development of nephropathy when treatment started 15 days after DXR injection.

Cholinergic neurons and the cardiovascular response produced by central injection of substance P in the normotensive rat.

The role of cholinergic neurons in central cardiovascular regulation is not well understood, however, activation of brain cholinergic neurons in several species evokes a hypertensive response. As with central cholinergic stimulation, intracerebroventricular (i.c.v.) injection of substance P (sP) elicits a pressor response in unanesthetized rats. The purpose of this study was to determine whether the cardiovascular effects following i.c.v. injection of this neuropeptide are mediated by central cholinergic neurons. Therefore, the cardiovascular response to sP was examined in control rats, and in animals pretreated centrally with classical pre- and post-synaptic cholinergic antagonists. Drugs were administered directly into the lateral ventricle while rats were freely-moving in their home cages. I.c.v. injection of sP produced a dose - dependent increase in arterial pressure and heart rate. The hypertensive response was significantly reduced by pretreatment with hemicholinium-3. This dose (20 ug) of hemicholinium-3 is capable of producing a maximal depletion of brain acetylcholine levels. The increase in heart rate to substance P was not as sensitive to hemicholinium-3 pretreatment as was blood pressure. Central pretreatment with the nicotinic receptor antagonist, hexamethonium was more effective than the muscarinic antagonist, atropine in blocking the pressor response to sP. Hexamethonium did not significantly alter the tachycardic response to the peptide, but atropine produced a small, but significant reduction in the response. Therefore, the pressor response to central injection of sP may be mediated to a large extent through cholinergic pathways involving nicotinic receptors.

Effects of fructose-1,6-bisphosphate on brain polyamine biosynthesis in a model of transient cerebral ischemia.

We evaluated the effects on cerebral ischemia of a treatment with fructose-1,6-bisphosphate, a compound known to possess protective effects on acute ischemic injury in a variety of different tissues. We investigated the ability of the compound, administered either 15 minutes before or 15 minutes after the ischemic insult, in reducing the ischemia-induced changes in polyamine brain levels. The experiments were performed in adult, chloral hydrate-anesthetized Mongolian gerbils that underwent a 15 minutes ligation of the common carotid arteries followed by recirculation. Animals were sacrificed 1, 8 and 24 hours and immediately after the release of the occlusion. Polyamine brain levels were not modified during ischemia. Putrescine began to increase after eight hours from the release of the occlusion and we found it significantly increased after 24 hours in the hippocampus and striatum. We did not detect any significant changes in spermidine brain levels either during ischemia or during recirculation. Conversely, spermine appeared to decrease in the hippocampus while it did not show changes in striatum and medulla-pons. The activity of ornithine decarboxylase, a key enzyme in the biosynthesis of polyamines, resulted enhanced at the end of the ischemic period in all the brain regions tested and showed a peak at eight hours of recirculation in striatum and hippocampus whereas returned to control values in the medulla-pons. Fructose-1,6-bisphosphate significantly reduced the ischemia induced changes in polyamine brain content when administered before the ischemic insult while did not show protective properties when administered post-ischemically.

Changes in urine volume and urinary electrolyte excretion after intracerebroventricular injection of arecoline and hemicholinium-3.

Activation of cholinergic neurons in specific brain regions evokes a hypernatriuretic response, which appears to be atropine-sensitive and, perhaps, independent from the renal innervation. However the role of cholinergic neurons in central control of renal function is not well understood. The purpose of this study was to further investigate whether brain acetylcholine stores are able to influence kaliuresis and natriuresis in conscious rats. Therefore, the renal response to cholinergic drugs was examined in Wistar rats which underwent to a 0.15 M NaCl solution (saline) load administered by gavage. Central injection of arecoline, a muscarinic agonist, produced a dose-dependent reduction in water diuresis and a highly significant increase in sodium excretion within two hours from the oral saline load. An intracerebroventricular (ICV) injection of methylatropine completely blocked both the antidiuretic and the natriuretic response induced by arecoline. Hemicholinium-3 (HC), centrally administered at a dose (34.8 nmol) known to be capable of inducing a maximal depletion of brain acetylcholine, elicited a time-dependent antidiuretic effect accompanied by a highly significant reduction in potassium and sodium urinary excretion. Therefore, we suggest that brain cholinergic neurons are involved in the regulation of the electrolyte balance.

Effects of fructose-1,6-biphosphate on microsphere-induced cerebral ischemia in the rat.

Fructose-1,6-bisphosphate has been shown to exert beneficial effects in different experimental models of cerebral ischemia. In view of this evidence, we have determined whether the compound protects the brain during microsphere-induced ischemia. One thousand two hundred microspheres were injected into female rats through a catheter inserted into the right common carotid artery and, 15 minutes and again 24 hours later, we intravenously treated the animals with 333 mg Kg(-1) of fructose-1,6-bisphosphate. The injection of microspheres produced significant changes in the rats' gross behavior, in their performance in the beam walking test, and in their brain lactate concentrations. The treatment with fructose-1,6-bisphosphate significantly attenuated the behavioral alterations induced by microsphere ischemia, but not in reducing brain accumulation of lactate. Moreover, the compound was shown to ameliorate the blood-brain barrier dysfunction, produced 2 and 4 hours after microsphere injection, evaluated by the Evans blue method. These results suggest that fructose-1,6-bisphosphate possesses salutary properties against the damages induced by microsphere ischemia.

Effect of 2,6-diisopropylphenol on the delayed hippocampal cell loss following transient forebrain ischemia in the gerbil.

We examined the protective activity of 2,6-diisopropylphenol on mortality and delayed hippocampal cell death induced by transient cerebral ischemia in the gerbil. Forebrain ischemia was produced by bilaterally occluding the common carotid arteries for 10 minutes; then the blood supply to the brain was restored. The number of survivors was counted for 8 days, and the histopathological damage in the CA1 region of the hippocampus was scored according to the semiquantitative scale of Rudolphi and Colleagues. When intraperitoneally injected immediately after the ischemic attack, 2,6-diisopropylphenol (25, 50, 100 mg kg-1) produced no significant reduction in the rate of mortality in comparison with its vehicle. However, the survivors that had received the compound at the dose of 50 and 100 mg kg-1 elicited a significant increase in the number of viable pyramidal cells in the CA1 hippocampal region. Moreover, we obtained similar results by injecting the compound 30 minutes after the release of the carotid artery occlusion. These results suggest that 2,6-diisopropylphenol, although it does not show any capability of improving the rate of survival, it elicits protective properties against the transient forebrain ischemia-induced delayed hippocampal neuronal death.

Effects of fructose 1,6-diphosphate on splanchnic artery occlusion shock in the rat.

Splanchnic artery occlusion (SAO) shock, produced by clamping splanchnic arteries for 45 min followed by the release of occlusion, was induced in male rats, treated 15 min before surgery, with fructose 1,6-diphosphate (FDP) or with equivalent doses of fructose or inorganic phosphate. Survival rate, peritoneal macrophage phagocytosis and plasma levels of myocardial depressant factor (MDF) were measured. Shocked animals pretreated with vehicle exhibited 24.6 +/- 0.9% phagocytic activity, 110 +/- 3.9 units/ml MDF plasma levels and 0% survival. Sham animals showed the following values: survival 100%; phagocytosis, 49.5 +/- 1.3%; MDF, 22 +/- 2.9 units/ml. Pretreatment with FDP (25 mg/kg/i.v.) significantly improved survival rate (50%) and macrophage phagocytosis (37.9 +/- 0.4%) and reduced plasma MDF levels (77 +/- 3 units/ml). Equivalent doses of fructose and inorganic phosphate did not improve survival, as well as lower doses of FDP. These results suggest a beneficial effect of FDP in SAO shock.

Oral toxicity of bis(2-ethylhexyl) phthalate during pregnancy and suckling in the Long-Evans rat.

Bis(2-ethylhexyl) phthalate (DEHP) is a compound widely used in plastics technology to impart flexibility to rigid polymers. We sought to determine whether the oral exposure of female rats to DEHP during gestation and suckling produces alterations in the litter. Female rats were exposed to different concentrations of DEHP suspended in drinking water (32.5 and 325 microl/litre) from day 1 of pregnancy to day 21 after delivery. Pup body weight gain and kidney, liver and testes weight was measured at different times (21, 28, 35, 42 and 56 days) after birth. Plasma concentrations of DEHP and histopathological alterations in kidneys, liver and testes were also studied. In addition, the ability of female pups (1 month of age) to perform a learned avoidance test, the 'beam walking' test, was evaluated. Perinatal exposure to DEHP produced no statistically significant changes in the body weight gain of offspring. Conversely, it produced a significant decrease in kidney and testes relative weight (organ/body weight) with a significant increase in relative liver weight. Signs of histological damage in kidneys, liver, and particularly testes, were observed. Pups exposed perinatally to the highest concentration of DEHP elicited a significant increase in the time necessary to perform the beam walking test.

Interaction between pefloxacin and aminophylline in genetically epilepsy-prone rats.

The effects of a chronic treatment with pefloxacin on aminophylline-induced seizures in genetically epilepsy-prone rat have been investigated. Two series of experiments were performed. In the first, animals received pefloxacin orally twice a day for five days, then were administered aminophylline intraperitoneally and the occurrence of seizures was evaluated. In the second series of experiments, theophylline serum concentration was evaluated in rats subject to the same experimental protocol. Pefloxacin significantly, and in a dose-dependent manner, increased the occurrence of seizure phases induced by aminophylline, but did not influence theophylline serum levels measured at different times after the injection of aminophylline. We suggest that additive neurotoxic effects of both pefloxacin and aminophylline might contribute to the increased severity of seizure score. The possible role of GABA-benzodiazepine, excitatory amino acid and purinergic mechanism, and the role of pharmacokinetic factors are discussed.

Increased cardiovascular responsiveness to central cholinergic stimulation in the genetically epilepsy-prone rat.

We sought to determine whether differences in cardiovascular responsiveness to central stimulation of the cholinergic system existed between the genetically epilepsy-prone and outbred Sprague-Dawley rats. We treated the unanaesthetized, restrained rats with the indirect cholinergic agonist physostigmine (25, 50, 100 and 200 micrograms kg-1, i.v.) and the direct muscarine agonist arecoline (50, 100 and 200 micrograms kg-1, i.v.). Blood pressure and heart rate were evaluated. Genetically epilepsy-prone rats demonstrated to be more susceptible to the action of physostigmine than the outbred Sprague-Dawley rats. Conversely, we did not note any difference between the two strains in the extent of the pressor response induced by arecoline. Moreover, we treated both strains with hemicholinium-3 (34.8 nmol, i.c.v.) to deplete endogenous stores of acetylcholine. This treatment did not affect the pressor response to arecoline, whereas it greatly reduced the response to physostigmine. The present results support an increased cardiovascular responsiveness to central cholinergic stimulation in the genetically epilepsy-prone rat which appears to be related to a pre-synaptic rather than a post-synaptic component.

Direct viable count as test for toxicity assessment: the effects of four metals on a Salmonella enteritidis strain.

The toxicity of synthetic sewage containing increasing concentrations of arsenic (.125, .25, .5, 1.0 mg L-1), cadmium (.02, .05, .1, .2 mg L-1), lead (.2, .5, 1.0, 2.0 mg L-1) and nickel (.5, 1.0, 2.0, 4.0 mg L-1) has been investigated by determining the total direct count (TDC) and the direct viable count (DVC) of Salmonella enteritidis by means of an immunofluorescence technique (IFA). This has been done in order to evaluate the possibility of using the IFA technique to estimate the toxicity of complex effluents. Arsenic, cadmium and nickel produced a concentration-dependent reduction in the number of viable bacterial cells. This was more clear when the viable bacterial cells were considered than when only the culturable part was used. Lead did not show a concentration-dependent and reproducible effect. At the highest concentrations allowed by the Italian wastewater regulations, lead, cadmium, arsenic and nickel reduced the viable/total bacterial cells ratio to 74.5%, 68.5%, 28.4% and 6.9%, respectively. The toxic effects of the metals were also tested using the standard Microtox assay.

Changes in regional brain synaptosomal high affinity choline uptake during the development of hypertension in spontaneously hypertensive rats.

The high-affinity uptake of choline (HAChU) by freshly prepared crude synaptosomal fractions was employed as relative measure of regional brain cholinergic activity. The Vmax for uptake as determined by the accumulation of a tracer amount of 3H-choline in the presence of unlabeled choline (0.2-2 microM) varied 6 fold depending upon the region examined (stratum greater than hypothalamus greater than medulla-pons). HAChU was hemicholinium-3-sensitive and linear at 37 degrees C from 1 to 8 min in all brain regions. Respective brain synaptosomal fractions derived from adult (12 week old) spontaneously hypertensive (SH) rats and normotensive Wistar Kyoto (WK) rats revealed no difference in the Vmax for HAChU from synaptosomes derived from the striatum of either strain. However, there was a significant increase in the Vmax for HAChU measured from the medulla-pons of SH rats compared with WK rats. In older (22 weeks) rats, the Vmax for HAChU was 78% greater than age-matched WK control rats. In addition, a highly significant correlation was found between resting systolic blood pressure and the Vmax for HAChU both in the medulla-pons (r = 0.76) and hypothalamus (r = 0.48). That the increase in HAChU in SH rats was not a consequence of elevated pressure, was indicated by the lack of effect of prolonged i.v. infusion of pressor agents in normotensive rats on HAChU. These findings are consistent with a role for brain cholinergic neurons in the maintenance of hypertension in SH rats.

Effects of some calcium antagonists upon the activity of common antiepileptic compounds on sound-induced seizures in DBA/2 mice.

1. Flunarizine (2.65 mumol/kg, i.p.) and nimodipine (5.25 mumol/kg, i.p.) potentiated the anticonvulsant properties of phenytoin, phenobarbital and valproate against audiogenic seizures in DBA/2 mice. 2. Diltiazem (5.25 mumol/kg, i.p.) was able to potentiate the antiseizure activity of phenytoin but was not effective against the anticonvulsant action of phenobarbital and valproate. 3. Verapamil (5.25 mumol/kg, i.p.) was unable to potentiate the anticonvulsant properties of all antiepileptic drugs studied. 4. Bay K 8644 (1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluorophenyl)-pyridine- 5-carboxylic acid), a calcium agonist at a dose of 2.65 mumol/kg, i.p., induced a reduction of anticonvulsant potency of phenytoin, phenobarbital and valproate. 5. None of the calcium antagonists used significantly increased the plasma levels of antiepileptic compounds or significantly affected the body temperature changes induced by anticonvulsant drugs. 6. It may be concluded that some calcium antagonists enhance the anticonvulsant properties of some antiepileptic drugs against audiogenic seizures. A pharmacokinetic interaction does not seem responsible for these effects.

Repeated treatment with quinolones potentiates the seizures induced by aminophylline in genetically epilepsy-prone rats.

1. The effects of a chronic treatment with several quinolone derivatives on on the aminophylline-induced convulsions in the genetically epilepsy-prone rat have been investigated. 2. Two series of experiments have been performed: in the first one animals received the quinolone twice a day for 5 days, then were given aminophylline (80-140 mg.kg-1, i.p.); in the second series of experiments the rats were treated once a day with the quinolone plus 120 mg.kg-1 of aminophylline for 5 days. The changes induced by both treatment protocols on electrocortical activity and on the occurrance of seizures have been evaluated. 3. Enoxacin reduced the dose of aminophylline necessary for the induction of seizures in a higher degree with respect to the other quinolone derivatives. The derivatives which showed minor proconvulsant properties were ofloxacin, ciprofloxacin and cinoxacin. The potentiation of seizures induced by quinolones appeared a dose-dependent phenomenon which was more evident when high doses of quinolones were used. 4. The chronic treatment carried out daily with quinolones and aminophylline suggests that additive neurotoxic effects of both classes of drugs may contribute to the increase of severity of seizure scores. 5. The possible role of GABA-benzodiazepine, excitatory amino acid, purinergic mechanisms as well as the role of pharmacokynetic factors are discussed.

Cloricromene improves survival rate and peritoneal macrophage function in splanchnic artery occlusion shock in rats.

Splanchnic artery occlusion (SAO) shock, induced by a transient occlusion of splanchnic arteries for 45 min, was performed in male rats, treated with vehicle or cloricromene, a coumarin derivative, 15 min before surgery. Survival rate, plasma levels of myocardial depressant factor (MDF), macrophage phagocytosis and killing of Candida albicans, and thromboxane B2 (TxB2) synthesis by peritoneal macrophages were evaluated. Of the SAO-shocked animals, 10% survived for 6 hr after the release of the occlusion of the splanchnic arteries, whereas none of the sham-shocked rats died. Peritoneal macrophages of shocked animals exhibited decreased phagocytosis (24.7 +/- 2.7%) and killing (8.0 +/- 2.1%) and increased TxB2 levels (3.23 +/- 0.27 ng/ml) with respect to those collected from sham-shocked animals (phagocytosis 48.8 +/- 3.0%; killing 16.5 +/- 2.4%; TxB2 0.30 +/- 0.18 ng/ml). MDF was also increased (114.3 +/- 21.5 U/ml) compared with sham-shocked animals (31.5 +/- 3.7 U/ml). Cloricromene, given intravenously (i.v.) at doses of 1, 2, and 4 mg/kg, significantly increased survival rate and lowered MDF in shocked rats. Lower doses (0.25 and 0.5 mg/kg/i.v.) were without effect. Doses that were able to reduce mortality partially reverted shock-induced macrophage impairment of phagocytosis, killing of C. albicans, and TxB2 synthesis. In addition, cloricromene (5, 10, and 25 microM) added in vitro to peritoneal macrophages, collected from shocked rats, significantly enhanced their phagocytic activity depressed by shock.

Anticonvulsant effects of U-54494A and U-50488H in genetically epilepsy-prone rats and DBA/2 mice: a possible involvement of glycine/NMDA receptor complex.

1. The effects of U-54494A and U-50488H on convulsions produced by sound have been studied in genetically epilepsy-prone DBA/2 mice and genetically epilepsy-prone rats. 2. Both compounds showed a dose-dependent anticonvulsant activity. U-54494A was less potent as an anticonvulsant than U-50488H in genetically epilepsy-prone rats and elicited a similar potency to that of U-50488H in DBA/2 mice when administered intracerebroventricularly or intraperitoneally. 3. Similar sedative and hypothermic effects were observed after the highest dose of U-54494A and U-50488H in DBA/2 mice. U-50488H seems to exhibit a greater sedative effect and to affect the rotarod test in rats much more than U-54494A. U-54494A elicited a better therapeutic index than U-50488H. 4. The anticonvulsant properties of both compounds are antagonized by high doses of naloxone and nor-binaltorphimine, a selective kappa-opioid antagonist. 5. The effects of U-50488H and U-54494A in DBA/2 mice were also antagonized by the glycine/NMDA receptor antagonist D-serine. 6. The present results suggest a possible interaction between kappa-opioid and the glycine/NMDA receptors during epileptic phenomena.

Cerebral GABAergic control of arterial blood pressure and heart rate in diabetic rats.

Cardiovascular responsiveness to intracerebroventricular (icv) administration of dopamine (50, 100 and 200 micrograms/kg), muscimol (1 and 2 micrograms), and ethanolamine-O-sulphate (EOS; 5, 10, 20 and 40 mumol) as well as GABA content in several brain areas were examined in rats, made diabetic by an intravenous (iv) injection of streptozotocin (STZ; 40 mg/Kg). Citrate buffer (pH 4.5) treated animals were used as controls. Experiments were carried out in conscious rats with chronically implanted icv cannulae and iv and intraarterial catheters, 1 and 3 weeks after STZ injection. Diabetic rats exhibited: 1) higher hyperglicaemia after 1 week than after 3 weeks; 2) normal mean arterial pressure (MAP) both after 1 and 3 weeks, and 3) bradycardia only after 3 weeks. Icv injections of muscimol, a GABA receptor agonist, and EOS, an inhibitor of GABA breakdown, caused a dose-dependent decrease in MAP and heart rate (HR), which was significantly higher than that elicited in control animals. GABA content was reduced in the hypothalamus (already after 1 week), and in the brainstem (but only after 3 weeks). No changes in GABA content were detected in other brain areas. Icv injection of dopamine elicited a dose dependent decrease in MAP and HR either in diabetic or in control rats, with no difference between groups. The results suggest that diabetes alters cerebral GABAergic control of arterial blood pressure and heart rate in the rat.

Antihypertensive activity of indolepyruvic acid: a keto analogue of tryptophan.

We studied the effect of indole-3-pyruvic acid (IPA) on systolic blood pressure of normotensive, spontaneously hypertensive, DOCA + salt hypertensive, and Grollman hypertensive rats. Experiments were also carried out in order to investigate whether IPA may influence the development of hypertension in spontaneously hypertensive rats. Age-matched normotensive, spontaneously hypertensive, DOCA + salt hypertensive, and Grollman hypertensive rats treated with N-methylglucamine, were used as controls. Acute oral (up to 50 mg/kg) and intravenous (5 mg/kg) administration of IPA did not change systolic blood pressure in any models of hypertension. By contrast, a repeated administration of IPA (100 mg/kg/day, by oral gavage for 10 days) significantly decreased systolic blood pressure in all models of hypertension, while it elicited no significant effect in normotensive rats. Moreover, when IPA was given daily to 5-week-old spontaneously hypertensive rats for 7 weeks, it partially inhibited the development of hypertension. In addition, chronic administration of IPA caused enhanced levels of tryptophan and 5-hydroxyindoleacetic acid in the cortex and diencephalon. Brainstem serotonin content in both normotensive and spontaneously hypertensive rats was also enhanced by IPA treatment. Our results suggest that IPA lowers blood pressure in different rat models of hypertension and this effect seems to be correlated with an increase in cerebral serotonin metabolism.