Effects of nitric oxide synthase inhibition and low-salt diet on blood pressure and mesenteric resistance artery remodelling in genetically hypertensive rats.

1. Nitric oxide synthase (NOS)-inhibited genetically hypertensive (GH) rats on normal and low-sodium diets were additionally given valsartan or felodipine to establish whether low-Na intake would have extra beneficial effects on blood pressure and cardiovascular structure. 2. Male GH rats on normal or low-Na diets were treated with the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) from the age of 7 to 12 weeks and were given either valsartan (10 mg/kg per day) or felodipine (30 mg/kg per day). 3. Systolic blood pressure (SBP; tail-cuff) was measured weekly. At 12 weeks of age, mesenteric resistance arteries (MRA) were fixed by perfusion and embedded in Technovit (Heraeus Kulzer GmbH, Werheim, Germany). Serial sections were cut and stained. Stereological analysis was used to obtain MRA media width, lumen diameter, ratio of media width/lumen diameter (M/L) and medial cross-sectional area (CSA). Left ventricular (LV) mass was determined. 4. In GH L-NAME-treated rats on a normal diet, SBP was significantly reduced (P < 0.001) by valsartan and felodipine, as was LV mass (valsartan P < 0.001; felodipine P < 0.05). A low-Na diet with valsartan caused a further fall in SBP (P < 0.01) but, with felodipine, SBP increased in rats on a low-Na diet (P < 0.05). 5. Valsartan with the low-Na diet had no further effect on LV mass, but the felodipine-treated group on a low-Na diet had a lower LV mass (P < 0.05) than rats on a normal diet. 6. In MRA from the GH L-NAME + valsartan-treated group, there was hypotrophic inward remodelling; the M/L ratio was reduced (P < 0.001) compared with GH L-NAME-treated rats. The lumen was outwardly remodelled in the group on the low-Na diet. 7. The GH L-NAME + felodipine-treated group showed hypotrophic outward remodelling and a reduction in M/L ratio compared with the GH L-NAME-treated group (P < 0.001). A low-Na diet had no further effect on MRA. 8. A low-Na diet + valsartan had beneficial effects on SBP and MRA, where outward remodelling of the lumen occurred and, thus, resistance was reduced. In contrast, felodipine with a low-Na diet increased SBP, reduced LV mass and had no effect on MRA structure. Valsartan treatment with a low-Na diet confers extra benefits on blood pressure and MRA structure.

The effect of (R)-HA966 or ACEA 1021 on dexfenfluramine or (S)-MDMA-induced changes in temperature, activity, and neurotoxicity.

The glycine site-specific N-methyl-D-aspartate (NMDA) antagonist 5-nitro-6,7-dichloro-2,3-quinoxalinedione (ACEA 1021, 4x30 mg/kg, i.p.) given 30 min before dexfenfluramine (4x15 mg/kg, i.p., every 2 h) was unable to prevent dexfenfluramine-induced depletion of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) content, and 5-HT transporter (5-HTT) density. Another glycine site-specific NMDA antagonist, R(+)-3-aminohydroxypyrrolidin-2-one [(R)-HA 966] (2x30 mg/kg, ip), given 30 min before dexfenfluramine (2x10 mg/kg, ip, 2 hourly) was also unable to prevent regional depletion of 5-HT, 5-HIAA, and 5-HTT density. However, ACEA 1021 (4x30 mg/kg, i.p.) given 30 min before (S)-3,4-methylenedioxymethamphetamine (MDMA, 4x10 mg/kg, 2 hourly, ip) attenuated the regional depletion of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), 5-HT, 5-HIAA content, and 5-HTT density. ACEA 1021 combined with (S)-MDMA also prevented (S)-MDMA-induced hyperthermia without causing hypothermia or preventing an (S)-MDMA-induced increase in locomotor activity.

The effects of protein kinase C and calmodulin kinase II inhibitors on vestibular compensation in the guinea pig.

Previous studies have demonstrated that vestibular compensation, the process of behavioural recovery which occurs following unilateral deafferentation of the vestibular labyrinth (UVD), is correlated with changes in in vitro phosphorylation of various protein substrates in the brainstem vestibular nucleus complex (VNC). The aim of the present study was to investigate the possible causal relationship between protein kinase activity and the induction of the vestibular compensation process, by delivering inhibitors of protein kinase C (PKC) or Ca(2+)/calmodulin-dependent kinase II (CaMKII) into the ipsilateral VNC at the time of the UVD and determining their effects on three static symptoms of UVD, spontaneous nystagmus (SN), yaw head tilt (YHT) and roll head tilt (RHT) in guinea pigs. Infusion of the PKC inhibitor, 3-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrr ole-2,5-dione, HCl (bisindolylmaleimide I, HCl/GF 109203X, HCl) ('Bis I'), at a concentration of 5 or 50 microM, significantly increased SN frequency at the earliest time points (6 and 8 h post-UVD) compared to vehicle controls and the less selective analogue, 2,3-bis(1H-indol-3-yl)-N-methylmaleimide (bisindolylmaleimide V) ('Bis V'). However, the compensation of YHT and RHT was unaffected by the PKC inhibitor. By contrast, the cell-permeable CaMKII inhibitor, myristoylated autocamtide-2 related inhibitory peptide (N-Myr-Lys-Lys-Ala-Leu-Arg-Arg-Gln-Glu-Ala-Val-Asp-Ala-Leu-OH) ('myr-AIP') or the cell-impermeable analogue, autocamtide-2 related inhibitory peptide (N-Lys-Lys-Ala-Leu-Arg-Arg-Cln-Glu-Ala-Val-Asp-Ala-Leu-OH) ('AIP'), failed to alter the compensation of SN, YHT or RHT at any dose compared to vehicle controls. These results implicate PKC-, but not CaMKII-, signal transduction pathways in the initiation of SN compensation in guinea pig.

Correlation between 5-HT content and uptake site density following (S)-MDMA and dexfenfluramine-induced depletion, and with neuroprotection by the glycine site-specific NMDA antagonist ACEA 1021.

3,4-Methylenedioxymethamphetamine (MDMA) and fenfluramine are amphetamine analogues that both cause long-term depletion of serotonin (5-HT) and 5-HT uptake sites in brain tissue. Depletion caused by these amphetamines is commonly measured by labeling 5-HT uptake sites using 3H-paroxetine combined with autoradiography or, alternatively measuring the concentration of 5-HT in tissue using high-performance liquid chromatography (HPLC). A close correlation between the 5-HT concentration measured in micropunch samples and the density of 3H-paroxetine-labeled 5-HT uptake sites measured in corresponding 20 micron coronal slices was determined (R2 = 0.92). These methods combined demonstrated that the glycine-site specific NMDA antagonist ACEA 1021 (4 x 30 mg/kg, i.p., 2 hourly) given 30 minutes before (S)-MDMA (4 x 10 mg/kg, i.p., 2 hourly) was able to prevent the depletion of both 5-HT content and uptake site density but unable to prevent the depletion of 5-HT content and uptake site density caused dexfenfluramine (4 x 15 mg/kg, i.p., 2 hourly).

Basilar artery remodelling in the genetically hypertensive rat: effects of nitric oxide synthase inhibition and treatment with valsartan and enalapril.

1. The structure of the basilar artery and the relationship of structure to blood pressure and ventricular hypertrophy was examined in genetically hypertensive (GH) rats, their control normotensive (N) Wistar strain, GH given the nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) and GH given L-NAME and either valsartan or enalapril. 2. Systolic blood pressure (SBP; tail-cuff) was measured weekly from age 7-12 weeks. At the end of the experiment at 12 weeks, the basilar artery was fixed by perfusion and embedded in Technovit (Heraeus Kulzer GmbH, Werheim, Germany). Serial sections were cut and stained and stereological analysis applied to quantify the morphology of the vessels. Left ventricular (LV) mass was determined. 3. Both SBP and LV mass were significantly increased in GH compared with N (P < 0.001) and increased further in GH given L-NAME (P < 0.05). The GH L-NAME + valsartan and GH L-NAME + enalapril groups had significantly lower (P < 0.001) SBP and LV mass than the GH L-NAME group. 4. Basilar arteries in GH (which are frankly hypertensive, but have no apparent endothelial defect) showed hypotrophic inward remodelling compared with the N control group with no change in media to lumen ratio. 5. In the GH L-NAME group, further inward remodelling occurred and the media to lumen ratio was increased compared with N (P < 0.01) and GH (P < 0.05). Valsartan treatment in GH L-NAME rats caused eutrophic outward remodelling. Enalapril caused hypertrophic outward remodelling, suggesting that the angiotensin II-stimulated growth was not entirely suppressed with an angiotensin-converting enzyme inhibitor or that there was a bradykinin effect with enalapril. 6. In GH with an endothelial defect induced by treatment with L-NAME, the further remodelling, together with an increased media to lumen ratio and the development of a stroke-like syndrome, indicates the NOS-inhibited GH rat may be a useful model for essential hypertension (where it is known that endothelial abnormalities exist) and where stroke can develop as a consequence of the hypertension.

Effects of chronic inhibition of nitric oxide synthase in the genetically hypertensive rat.

1. The effects of graded inhibition of nitric oxide synthase (NOS) on blood pressure in the genetically hypertensive (GH) rat strain and NOS activity in regions of the brain (cerebellum, striatum, hippocampus, frontal cortex and medulla oblongata) as a measure of body NOS inhibition were studied. 2. Male GH and normotensive (N) rats (n = 7-10 per group) were given N(G)-nitro-L-arginine methyl ester (L-NAME; 2, 5, 10 or 20 mg/kg per day in drinking water) from age 7 weeks. Age- and weight-matched controls received water only. Systolic blood pressure (SBP) was measured weekly by the tail-cuff method from age 6 weeks. By age 10 weeks, rats were killed and NOS activity was measured. 3. Some GH rats that received over 5 mg/kg per day L-NAME developed stroke-like symptoms and were killed before the end of the treatment period. 4. No difference in NOS activity was found between untreated N and GH strains but, in those that received treatment, a graded inhibition was observed with increasing L-NAME dose levels. The frontal cortex in the GH strain given 20 mg/kg per day L-NAME had NOS inhibition of 90% where the N strain had 73% inhibition. Similar results were seen in the other areas of the brain. 5. Left ventricular mass, weight related, was significantly greater in the GH compared with N and was further elevated by treatment with L-NAME. 6. The SBP at 10 weeks was significantly elevated in GH rats by NOS inhibition with L-NAME in a dose-dependent manner; 25% for 2 mg/kg per day, 31% for 20 mg/kg per day (P < 0.001). There was a non-significant increase in BP in the N-treated groups (average change of 7.5%). 7. Nitric oxide synthase inhibition causing increased SBP in GH rats suggests an abnormality in the nitric oxide-L-arginine pathway in this strain.

Cardiovascular effects of chronic nitric oxide synthase inhibition in genetically hypertensive rats.

1. The possible role of an endothelial defect in the hypertension of the New Zealand genetically hypertensive (GH) rat strain was assessed by examining cardiovascular responses to the nitric oxide synthase (NOS) inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) and the endothelium-dependent depressor agent acetylcholine (ACh). The vascular sensitivity of the hindquarter to nitric oxide (NO) was examined using the NO donor sodium nitroprusside (SNP). 2. NG-Nitro-L-arginine methyl ester (10 mg/kg per day in drinking water) was given to GH and normotensive (N) rats from age 7-9 weeks, with GH and N untreated control groups. Systolic blood pressure (tail-cuff) was monitored weekly from age 5-9 weeks. At age 9 weeks, pressure responses to various vasoactive agents were measured in vivo and in the rat isolated hindquarter. Left ventricular (LV) mass was measured at the time of death. 3. NG-Nitro-L-arginine methyl ester induced a greater hypertensive effect in GH (P < 0.001) compared with N (P < 0.05) rats and caused a significant increase in hindquarter perfusion pressure in GH rats only (P < 0.01). 4. Genetically hypertensive rats had LV hypertrophy that was exacerbated by L-NAME (P < 0.01). Left ventricular hypertrophy was not induced by L-NAME in N rats. 5. The normalized response to ACh did not differ between GH and N control rats and was unaffected by L-NAME treatment in vivo and in vitro except at the highest ACh dose (3 micrograms/kg) in GH hindquarters (P < 0.01). The response to SNP was similar in GH and N hindquarters and enhanced by L-NAME in GH (0.1 microgram; P < 0.05) and N rats (0.01 microgram, P < 0.01; 0.01 microgram, P < 0.001). 6. These results suggest that the L-arginine/NO system is not deficient in GH rats and that endothelial function in the GH hindquarter is preserved. They confirm that NO is involved in mediating blood pressure in GH and N rats and raise the possibility that a non-NO-mediated mechanism may underlie ACh-induced vasodilation in GH and N.

Prevention of increases in blood pressure and left ventricular mass and remodeling of resistance arteries in young New Zealand genetically hypertensive rats: the effects of chronic treatment with valsartan, enalapril and felodipine.

The relative efficacy of three antihypertensive drugs in the prevention of further elevation of blood pressure (BP) and cardiovascular structural remodeling in 4-week-old genetically hypertensive (GH) rats was studied by means of two complementary methods, stereology and myography. Four to 10-week-old GH rats were treated with valsartan (10 mg/kg/day), enalapril (10 mg/kg/day) or felodipine (30 mg/kg/day). Untreated GH and normotensive control rats of Wistar origin served as controls. Tail-cuff systolic SBP was measured weekly and left ventricular (LV) mass determined at the end of the experiment. Mesenteric resistance arteries (MRA) were either fixed by perfusion, embedded in Technovit and sections stained for stereological analysis, or mounted on a wire myograph for structural and functional measurements. BP and LV mass were significantly reduced by all drugs; decreases in BP and LV mass were smaller after felodipine treatment. Valsartan and enalapril caused a decrease in BP to normotensive control values. Felodipine kept BP at the 4-week level and prevented further rise with age. Valsartan caused hypotrophic outward remodeling of MRA, enalapril eutrophic outward remodeling and felodipine hypotrophic remodeling. Myograph measurements showed remodeling of the same order. While all drugs lowered the media/lumen ratio in GH to normal, the outward remodeling after valsartan and enalapril indicates that valsartan and enalapril might be more effective in reversing the inward remodeling of resistance arteries found in essential hypertension.

Vestibular nucleus N-methyl-D-aspartate receptors contribute to spontaneous nystagmus generation following unilateral labyrinthectomy in guinea pigs.

We investigated the effects of a non-competitive N-methyl-D-aspartate (NMDA) receptor/channel antagonist ((+)MK-801)) or an L-type Ca(2+) channel antagonist (nifedipine), delivered into the ipsilateral vestibular nucleus complex (VNC) before a unilateral labyrinthectomy (UL), on spontaneous nystagmus (SN) generation. Guinea pigs received either (+)MK-801 (5 or 12.5 microg); the less active enantiomer, (-)MK-801 (5 or 12.5 microg); nifedipine (5 or 10 microg); or vehicle, via cannula in the ipsilateral VNC. (+)MK-801, but not nifedipine, significantly decreased mean SN frequencies at 6 h post-UL, compared to controls (P<0.02) and reduced the rate of SN compensation (P<0.05). These results suggest that the SN expression is partly induced by NMDA receptor activation in the ipsilateral VNC at the time of the UL.

Role of brain nitric oxide in (+/-)3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity in rats.

The role of nitric oxide (NO) in the long-term serotoninergic neurotoxicity induced by (+/-)3,4-methylenedioxymethamphetamine (MDMA) in rats was investigiated. Pretreatment with Nomega-nitro-L-arginine (L-NOARG) (10 mg kg-1), a nitric oxide synthase (NOS) inhibitor, partially protected against long-term serotonin (5-HT) depletion induced by MDMA (40 mg kg-1) in frontal cortex and parietal cortex, but not in other brain regions examined. Brain NOS activities in these two regions were significantly elevated at 6 h after MDMA administration. Moreover, L-NOARG pretreatment caused significant inhibition of brain NOS activity but did not affect the acute 5-HT and dopamine (DA) changes or the hyperthermia induced by MDMA. These results suggest that it is the NOS inhibitory properties of L-NOARG, rather than its effects on the acute monoamine changes or the hyperthermia induced by MDMA, that are responsible for the prevention of neurotoxicity. The regional differences on the protection of L-NOARG and on the activation of NOS by MDMA indicate the unequal role that NO may play in MDMA-induced neurotoxicity in different brain regions.

Evidence for reduced nitric oxide synthase (NOS) activity in the ipsilateral medial vestibular nucleus and bilateral prepositus hypoglossi following unilateral vestibular deafferentation in the guinea pig.

The aim of the present study was to examine, using a radioenzymatic assay technique, nitric oxide synthase (NOS) activity in the bilateral medial vestibular nuclei (MVN) and prepositus hypoglossi (PH), during the development of vestibular compensation for unilateral vestibular deafferentation (UVD) in the guinea pig. In the MVN ipsilateral to the UVD, and bilaterally in PH, NOS activity decreased following UVD compared to sham controls and did not recover significantly up to 50 h later, when a substantial degree of behavioural vestibular compensation had occurred. These results suggest that UVD causes a decrease in NOS activity in the ipsilateral MVN and the bilateral PH, and that a consequent decrease in NO may be responsible for some of the ocular motor and postural symptoms of UVD.

Renal afferent arteriolar structure in the genetically hypertensive (GH) rat and the ability of losartan and enalapril to cause structural remodelling.

OBJECTIVE: This study aimed to compare the structure of renal afferent arterioles in the genetically hypertensive (GH) rat strain with the normotensive (N) control strain in relation to pathogenesis, and to quantify structural remodelling in GH rats after treatment with losartan and enalapril and to relate this to blood pressure (BP) and left ventricular (LV) mass. METHODS: GH rats were given losartan 15 mg/kg/day, enalapril 10 mg/kg/day (enalapril 10) or 3 mg/kg/day (enalapril 3) from the age of 4 to 10 weeks. Untreated GH and N groups served as controls. Tail-cuff systolic BP was measured weekly from 4 weeks. At the age of 10 weeks, kidneys were perfused with microspheres to identify afferent arterioles, kidney pieces were fixed, embedded in Technovit and stained sections analysed. Lumen and media plus lumen diameters were measured; media width, media cross-sectional area (CSA) and media/lumen (M/L) ratio were derived. RESULTS: BP and LV mass were elevated in GH compared with N rats, and reduced by losartan and enalapril 10 and to a lesser degree by enalapril 3. In afferent arterioles, lumen diameter, media width and CSA were smaller in GH than N and M/L ratio was larger. Losartan and enalapril 10 reduced media width and increased lumen diameter, while enalapril 3 increased CSA (in distal arterioles) and lumen diameter. M/L ratio was reduced by losartan and enalapril. CONCLUSION: Abnormal structure of the afferent arteriole, resulting in an increased M/L ratio, could explain abnormalities of renal blood flow and vascular resistance in GH and contribute to the hypertension. In GH, losartan and enalapril reduce BP and LV mass, cause remodelling of afferent arterioles, and lower the M/L ratio to below N levels.

Nitric oxide synthase inhibition with N omega-nitro-L-arginine methyl ester affects blood pressure and cardiovascular structure in the genetically hypertensive rat strain.

1. Inhibition of nitric oxide (NO) synthesis with the nitric oxide synthase (NOS) inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) was used as a tool to investigate further a possible endothelial defect in the New Zealand genetically hypertensive (GH) rat strain compared with its normotensive (N) control strain. 2. N omega-nitro-L-arginine methyl ester was given to GH and N groups in their drinking water from age 7-10 weeks (10 mg/kg per day for week 1 and 2 and then 5 mg/kg per day for week 3). Tailcuff blood pressure (BP) was measured weekly and at the end of the experiment the mesentery was fixed by perfusion, second order branches of the mesenteric artery were embedded in Technovit and stained sections were used to quantify the structure of the mesenteric resistance arteries (MRA). The heart was removed and weighed for determination of left ventricular (LV) mass. 3. In GH rats, BP and LV mass were significantly raised by L-NAME, while in N rats L-NAME treatment significantly elevated BP, but had no effect on LV mass. 4. In GH rats, the media width was significantly increased by L-NAME treatment (P < 0.01); lumen diameter remained unchanged. Thus, the ratio of media width/lumen diameter (M/L) was significantly increased by exacerbation of the hypertrophic outward remodelling characteristic of the GH strain. There were no significant changes in the M/L ratio in L-NAME-treated N rats. 5. Thus, in the GH strain, cardiovascular structure is more sensitive to NOS inhibition than either its N control strain or (on evidence from the literature) the spontaneously hypertensive rat strain.

The effects of aminorex and related compounds on brain monoamines and metabolites in CBA mice.

Acute and long-term neurochemical effects of aminorex, an appetite-suppressing drug related to amphetamine in chemical structure, and stereoisomers of its analogues were examined and compared with those of 3.4-methylenedioxymethylamphetamine (MDMA) and fenfluramine. Aminorex and its analogues, with exception of 4S, 5S-dimethylaminorex, did not cause the long-term neurotransmitter depletion in either the dopaminergic or 5-HT-ergic systems that was observed after MDMA or fenfluramine in CBA mice. These results are discussed in terms of possible structurally related mechanisms of neurotoxicity. The acute neurochemical effects showed that aminorex and analogues all produced increases in 5-hydroxytryptamine (5-HT) levels, unlike fenfluramine and MDMA in the present study or in published data. This suggests that inhibition of 5-HT metabolism, rather than direct 5-HT release, may be involved in their anorectic effect. The parallel study of acute dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) changes suggest that in CBA mice MDMA may be a better dopamine releaser and this may contribute to its dopaminergic neurotoxicity. However the ability to release dopamine or 5-HT, or both, may be important, but not the only factor involved in causing the long-term neurotoxicity observed with amphetamine derivatives.

In vitro phosphorylation of medial vestibular nucleus and prepositus hypoglossi proteins during behavioural recovery from unilateral vestibular deafferentation in the guinea pig.

Unilateral removal of vestibular nerve input to the vestibular nuclei (e.g. by unilateral labyrinthectomy, UL) results in severe ocular motor and postural disorders which disappear over time (vestibular compensation). We investigated whether recovery of ocular motor function is temporally correlated with changes in protein phosphorylation in the medial vestibular nucleus (MVN) and prepositus hypoglossi (PH; MVN/PH) in vitro. Bilateral MVN/PH were dissected from 48 guinea pigs following decapitation at 10 h, 53 h or 2 weeks post-UL, or -sham operation and frozen. Tissue extracts were incubated with [gamma-32P]ATP +/- Ca2+ plus phorbol 12,13-dibutyrate and phosphatidylserine. UL resulted in a significant bilateral increase in the 32P-incorporation into a 65-85 kDa band (probably the myristoylated alanine-rich C kinase substrate, MARCKS) in compensated animals (53 h post-UL) under conditions which favoured the activation of protein kinase C. Under identical conditions, the labelling of a 42-49 kDa protein (P46) was increased significantly in the bilateral MVN/PH between either 10 h or 53 h and 2 weeks post-UL; there were no significant changes over time in sham controls. These results show that later stages of vestibular compensation are accompanied by changes in the phosphorylation of several likely protein kinase C substrates in the MVN/PH in vitro.

Remodelling of resistance arteries in genetically hypertensive rats by treatment with valsartan, an angiotensin II receptor antagonist.

1. In the present study, New Zealand genetically hypertensive (GH) rats were treated with valsartan, a specific angiotensin II (AT1) receptor antagonist, to measure the effects on blood pressure (BP), cardiac hypertrophy and the structure of resistance arteries. Normotensive (N) rats were used as controls. 2. Valsartan (val) was given to GH rats at three different doses (10, 3 or 0.3 mg/kg per day, via osmotic mini-pumps implanted i.p.) from age 4-10 weeks. Untreated GH (mini-pump + vehicle) and N rats (mini-pump + vehicle) were used as controls. BP was measured weekly and at the end of the experiment, left ventricular (LV) mass was recorded and the structure of mesenteric resistance arteries (MRA) was determined using stereological methods. 3. BP fell in a dose-dependent fashion, being reduced to normotensive levels by 10 mg/kg; LV mass was significantly reduced (P < 0.0001) to below normotensive values in the GH group given 10 mg/kg val and significantly reduced (P < 0.001), although not normalized, in the other two treatment groups. 4. In MRA, the media/lumen (M/L) ratio was reduced by val according to dose level, to below normotensive values in GHval10, and to levels not different from normotensive values in the GHval3 and GHval0.3 groups. 5. The hypertrophy of smooth muscle cells in GH rats was reduced with val treatment at all doses. 6. Reversal of cardiac and vascular hypertrophy occurred even when BP was not reduced to normotensive levels, indicating an effect on vessel growth but without any retardation of body growth. 7. These results suggest that the vascular structural changes seen after val and angiotensin converting enzyme inhibitor treatment are probably due to the blocking of angiotensin rather than any bradykinin effect.

Effect of felodipine treatment and withdrawal on blood pressure and cardiovascular structure in New Zealand genetically hypertensive rats.

1. Four groups of New Zealand genetically hypertensive (GH) rats were treated with felodipine as follows: (A) from ages 4-12 weeks; (B) 4-20 weeks; (C) 4-12 weeks then withdrawn from felodipine till age 20 weeks; and (D) 12-20 weeks. 2. Effects on blood pressure (BP), left ventricular (LV) weight and the structure of myograph-mounted mesenteric resistance arteries (MRA) were measured. 3. BP was about 170 mmHg in 4 week old GH rats and did not change substantially from this value in groups A and B but rose to over 230 mmHg in untreated controls. In rats of group D, started on felodipine at 12 weeks, BP fell rapidly and was 173 mmHg at 20 weeks. On withdrawal of felodipine at 12 weeks (group C) BP rose rapidly and exceeded control levels at 20 weeks. 4. LV mass was significantly lower (P < 0.001) in all groups (A, B and D) killed while on felodipine but rose to control levels in the rats taken off felodipine. 5. In the four treated groups there were no significant changes in MRA structure (lumen diameter, medial thickness, media/lumen ratio and volume of medial tissue) as measured on the myograph. 6. Felodipine induces substantial falls in BP in GH rats which are sufficient to prevent cardiac hypertrophy but do not alter MRA structure. Resistance artery structure in GH rats does not seem to relate to the level of hypertension, and may therefore not have a necessary role in the pathogenesis of this hypertensive strain.

Long-term effects of treatment with enalapril on the structure of mesenteric resistance arteries in New Zealand genetically hypertensive rats.

1. New Zealand genetically hypertensive (GH) rats were treated with enalapril (20 mg/kg per day in drinking fluids) from age 4-10 weeks; one group (GHex-enal) was then taken off enalapril and followed for 6 more weeks to see if the drug-induced changes in blood pressure (BP) and structure of mesenteric resistance arteries (MRA) were long lasting once the enalapril was withdrawn. Control groups consisted of untreated GH and their normotensive (N) control strain. 2. Tail-cuff BP in GH treated rats fell significantly to N BP levels during treatment. On cessation of treatment BP rose rapidly. At age 16 weeks BP, although at a hypertensive level (mean +/- s.e.m., GHex-enal, 210.8 +/- 4.7 mmHg), was still significantly below the GH controls (230 +/- 6.9, P < 0.05), but above the N control group (137 +/- 3, P < 0.001). 3. Left ventricular (LV) mass in GH rats was reduced by enalapril to that in N rats; at the end of the subsequent period without treatment it was still significantly lower than the GH control group, but also significantly above the N group (GHex-enal, 255 +/- 6; GH 306 +/- 11; N 179 +/- 3, mg/100 g bodyweight). 4. The large changes in media, lumen and media/lumen ratio seen after 6 weeks of treatment were not sustained over the subsequent non-treatment period. However, values in the GHex-enal group at 16 weeks were closer to those in the N16 control group. 5. The persisting effects on smooth muscle (SM) cell density and SM fraction of the media contributed to an increase in SM cell volume which was significantly greater than the N16 group (P < 0.01). The number of layers of SM in the media was less than in the GH16 control group and not different from the N16 controls. 6. In GH rats the effect of ACEI on PB, LV mass and MRA structure is relatively longlasting once treatment is withdrawn.

Remodelling of resistance arteries by treatment with enalapril in the New Zealand genetically hypertensive rat.

1. New Zealand genetically hypertensive (GH) rats were treated with enalapril from the age of 4 to 10 weeks and the effects of treatment on the structure of mesenteric resistance arteries (MRA) was measured by use of stereological analysis of stained sections and by myograph techniques. 2. Tail-cuff blood pressure (BP) was measured weekly and intra-arterial BP recorded just before MRA were either fixed by perfusion or mounted on a myograph. 3. Stereological techniques (Cavalieri and optical dissector) were used to determine media and lumen volume, fraction of smooth muscle (SM) within the media and SM cell density. For MRA mounted on the myograph, lumen diameter, media thickness, active tension and active pressure were recorded. 4. BP was significantly (P < 0.0001) lowered by enalapril throughout the experiment. Intraarterial BP and left ventricular (LV) mass were also significantly lower in the enalapril treated GH rats (P < 0.0001). 5. Stereological measurements showed that enalapril treatment significantly (P < 0.0001) reduced media volume by 50%, doubled lumen volume (P < 0.0001), reduced the fraction of SM in the media (P < 0.04), and had no effect on the number of SM cell layers or on SM cell density. 6. Myograph measurements showed a decrease in the ratio media thickness/lumen diameter which was accompanied by a decrease in maximum active tension and pressure development. 7. In the GH rat early treatment with enalapril causes a true loss of medial tissue that is not simply due to rearrangement of existing media around an enlarged lumen.(ABSTRACT TRUNCATED AT 250 WORDS)

The infusion of an NMDA antagonist into perirhinal cortex suppresses amygdala-kindled seizures.

The seizure-modulating role of N-methyl-D-aspartate (NMDA) receptors located in several limbic areas was investigated. Amygdala-kindled rats were microinfused with the selective NMDA-receptor antagonist 2-amino-5-phosphonovalerate (APV, 1 microliter, 70 nmol) or artificial cerebrospinal fluid (ACSF) applied through a cannula located in either the amygdala or perirhinal, pyriform or deep prepyriform cortices. APV infused into the stimulation site raised the threshold for seizure generation. Surprisingly, APV infused into perirhinal cortex, but not into other regions, also dramatically suppressed behavioural seizures and afterdischarges (AD) elicited 5 min after the infusion. If stimulus intensities were markedly elevated however, the seizure suppression was overcome. This latter effect was reversible and repeatable, as seizures and AD were reliably reinstated when these animals were stimulated after infusion with ACSF. A similar effect, whereby perirhinal infusions blocked seizure activity, was also demonstrated in an animal kindled from the olfactory bulb and in one kindled from the perforant path. These results suggest that NMDA receptors located in the perirhinal cortex may play a major role in the modulation of AD activity elicited from more distal brain regions. Furthermore, activation of perirhinal cortex may be a critical requirement for the generation of amygdala-stimulated AD in the kindled animal.