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Notes: 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 GHva13 and GHva10.3 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.

Notes: 1. To explore its effect on blood pressure (BP) in relation to body sodium (Na), felodipine was given to New Zealand genetically hypertensive (GH) and normotensive (N) rats and to Japanese SHR and WKY rats, prepared for repeated measurements of body sodium (Na) by a whole body counting technique (22Na) using an Na-free pelleted diet and 22Na-NaCl fluid as the sole source of Na, with water also available. The drug was added to the food before pelleting pellets, 0.5 mg/g food.2. Felodipine reduced BP in each strain; this effect was as great on normal Na intake as when on a zero Na intake. Felodipine caused an increase in plasma renin activity in each strain but the increase reached significant levels only in GH, SHR and WKY. Plasma aldosterone was decreased by treatment in GH and N and increased in SHR and WKY.3. In rats on a zero Na intake (water sole drinking fluid), felodipine caused no fall in body Na (i.e. no natriuretic effect was detectable) except in WKY. When saline was freely available, felodipine tended to stimulate saline intake and was associated with an increase in body Na in all strains except SHR; body Na was high in SHR even in the absence of felodipine and did not increase further with felodipine treatment. Felodipine slightly speeded up the excretion of an Na load in rats on an ample NaCl intake (choice of 0.5%22Na-NaCl and water) but this may have been due, in part, to the treated rats having taken, by choice, a greater intake of saline in the pre-load period.4. In this study, felodipine reduced BP and stimulated PRA and salt appetite. Its effects on Na handling varied to some extent between the strains; there was no consistent natriuretic effect, but rather some evidence of Na retention.

Notes: 1. Groups of rats (n= 9–10 per group) were given a medium sodium (Na) diet or a low Na diet or a low Na diet plus low or high dose frusemide in order to have their body Na in a state of surplus or deficit or neither.2. Body Na was measured by a 22Na whole body counting method involving Na-free chow and the drinking fluid as the only source of Na (22Na-labelled NaCl). Intraperitoneal NaCl (same specific activity) loads were given and their excretion was measured by repeated measurements of body Na over the next 48 h.3. Rats in surplus excreted more than the load; those in neither surplus nor deficit excreted more or less exactly the load (allowing for growth); those with a small deficit retained enough Na to make up most of the deficit; those with a deficit that was larger than the load retained approximately the whole load.4. The results support the Strauss-Hollenberg concept that there is a basal body Na above which Na is excreted and below which any available Na is retained.

Notes: 1. The effects of cross-fostering genetically hypertensive (GH) with normotensive (N) Wistar rats on the structure of mesenteric resistance arteries (MRA) in young (6 week old) and adult (18 week old) rats were investigated to see whether the abnormal remodelling known to exist in GH rats could be prevented by changing the maternal environment.2. Genetically hypertensive and normotensive rat pups were reared either by their natural mothers or a foster mother of the opposite strain (NX and GHX) with fostering done within 24 h of birth.3. Blood pressure (BP) was measured from age 6–18 weeks; at 6 and 18 weeks MRA structure was assessed.4. At the time of death, intra-arterial mean BP was measured (via the femoral artery), after which MRA were fixed by perfusion (at the systolic BP of the rat) via the abdominal aorta, first with 75% Tyrode's solution containing heparin and papaverine, followed by 2% glutaraldehyde in 75% Tyrode's solution. Arteries were dissected out, processed and embedded in Technovit (Heraeus Kulzer, Werheim, Germany) and serial sections were cut and stained with Giemsa.5. Stereological techniques were used to determine media width, lumen diameter and medial cross-sectional area (CSA); in addition, the ratio of media width to lumen diameter was calculated. Smooth muscle cell density was also calculated.6. In MRA from 6-week-old rats, GH rats compared with N rats had increased media width and CSA and an increased ratio of media width to lumen diameter.7. There were no significant changes in structure in the GHX group compared with GH rats. The NX group compared with N rats had increased media width and CSA and lumen diameter, but no change in the ratio of media width to lumen diameter. Smooth muscle cell density, reduced in GH compared with N rats, was increased (P 〈 0.001) in the NX group, but not changed in the GHX group compared with GH rats.8. In 18-week-old GH rats compared with N rats, the MRA had a decreased media width and medial CSA and smaller lumen diameter, but there was no change in the ratio of media width to lumen diameter.9. In the GHX group compared with GH rats, media width and CSA were reduced; in the NX group compared with N rats, media width was increased, lumen decreased and the ratio of media width to lumen diameter increased. Smooth muscle cell density was increased (P 〈 0.001) in the GHX group, but not in the NX group.10. Changing the maternal environment significantly affected BP in GHX and NX groups up to 9–10 weeks of age but, in adult rats, the BP differences were no longer present. Thus, structural changes were seen at 6 weeks of age in MRA from NX rats and also at 18 weeks in GHX and NX rats (even though the BP differences were no longer significant); structural remodelling occurred independently of BP.

Notes: 1. The severity of hypertension displayed by adult spontaneously hypertensive rats (SHR) and Dahl (SS/Jr) rats can be reduced by 20–30 mmHg if the hypertensive pup is cross-fostered to a normotensive mother within the first 2 weeks of birth. In the SHR, at least, this blood pressure-lowering effect arises through programming of the neonatal kidney to excrete sodium more effectively. Thus, cross-fostering may only be effective in lowering pressure in salt-sensitive hypertensive strains. Accordingly, the aim of the present study was to determine whether cross-fostering is effective in lowering adult blood pressure in the salt-resistant New Zealand genetically hypertensive (GH) rat.2. Genetically hypertensive and control normotensive (N) rat pups were reared by either their natural mothers or a foster mother of the opposite strain (NX and GHX). Blood pressure was tracked from the age of 6–18 weeks, at which time renal function was assessed using standard clearance techniques in anaesthetized rats. Renal function was also assessed in a separate group of young rats at 5–6 weeks of age.3. Cross-fostered GHX rats had lower blood pressure than GH rats, but this difference was only apparent until 9 weeks. The NX rats had higher blood pressures than N rats, but again pressure converged at 10 weeks. Basal renal function did not differ between GH and GHX rats or between N and NX rats at either age. However, young GH rats had lower renal blood flow, glomerular filtration rate, urine output and sodium excretion than N rats.4. These data show that cross-fostering is effective in lowering blood pressure in GH rats, albeit transiently. The kidneys do not appear to play a role, because renal function did not differ under the current experimental conditions between GH and GHX rats. However, the kidney may play a greater role in the onset of hypertension in the GH rat than previously thought.

Notes: 1. The aims of the present study were, first, to determine whether, in the genetically hypertensive (GH) rat, fluvastatin would lower blood pressure and remodel mesenteric resistance arteries (MRA) and the basilar artery and, second, to see whether treatment with a combination of fluvastatin and the angiotensin receptor antagonist valsartan would have any extra beneficial effect on blood pressure and vascular remodelling.2. Male GH rats had tail-cuff systolic blood pressure (SBP) monitored weekly from the age of 7 to 12 weeks. Groups (n = 12–14) were treated with fluvastatin (4 mg/kg per day), valsartan (5 mg/kg per day), both mixed in with chow, or a combination of fluvastatin 4 mg/kg per day + valsartan 5 mg/kg per day. Untreated GH and a group of normotensive Wistar (N) rats served as control groups.3. At 12 weeks of age, intra-arterial (i.a.) blood pressure was measured by femoral cannulation and rats were then perfused (at the SBP of the animal) with Tyrode's solution containing heparin and papaverine followed by 2.5% glutaraldehyde in Tyrode's solution; MRA and basilar arteries were embedded in Technovit. Serial sections were cut and Giemsa stained and stereological methods used to obtain media width, lumen diameter, medial cross-sectional area (CSA) and the ratio of media width to lumen diameter. Hearts were weighed to determine left ventricular (LV) mass.4. Fluvastatin had no effect on blood pressure or LV mass, whereas valsartan given alone or with fluvastatin significantly reduced both parameters.5. In MRA, fluvastatin reduced medial CSA, increased lumen size and, therefore, probably decreased vascular resistance. The media/lumen ratio was reduced to a level below that seen with the combination treatment and to below that of the N group.6. In the basilar artery, fluvastatin and valsartan showed similar outward remodelling of the lumen and reduction in the media/lumen ratio. The combination treatment group showed, in addition, a reduction in medial CSA and an even lower ratio than the GH group on fluvastatin or valsartan alone or the N group.7. Although fluvastatin has no effect on blood pressure, it does cause significant remodelling of MRA and the basilar artery. These beneficial structural changes in a peripheral resistance artery bed and in an artery involved in regulating resistance in the brain are worthy of further study.

Notes: 1. New Zealand genetically hypertensive (GH) rats were treated with enalapril (20mg/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 〈 0.0001).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 (GHexenal, 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 BP, LV mass and MRA structure is relatively longlasting once treatment is withdrawn.

Notes: 1. The effects of two of the glitazone (thiazolidinedione) class of drugs, namely rosiglitazone and pioglitazone, on blood pressure and vascular remodelling in the New Zealand genetically hypertensive (GH) rat model were investigated.2. In the first study, a GH group given rosiglitazone (5 mg/kg per day) from the age of 7 to 12 weeks was compared with a GH control group. In the second study, GH rats were given either pioglitazone, simvastatin, valsartan or combinations of pioglitazone with simvastatin or valsartan (all drugs at a dose of 10 mg/kg per day).3. Tail-cuff systolic blood pressure was measured weekly. At the end of the experiment, blood vessels were fixed by perfusion and samples of mesenteric resistance arteries (MRA), second-order branches and basilar artery were embedded in Technovit and serial sections were cut and stained with Giemsa for stereological analysis. Media width, medial cross-sectional area and lumen diameter were determined and the ratio of media width/lumen diameter was calculated.4. Rosiglitazone significantly reduced blood pressure in GH rats.5. In MRA, rosiglitazone had a hypotrophic effect on media, reduced lumen diameter and reduced media/lumen ratio (P 〈 0.001).6. In basilar artery, there was also a hypotrophic effect of rosiglitazone on media and reduced media/lumen ratio (P 〈 0.001).7. Pioglitazone slowed down the rate of blood pressure increase with age in GH rats and had a greater effect on blood pressure when given in combination with simvastatin.8. Pioglitazone had a hypotrophic effect on the media of MRA and basilar artery. The hypotrophic effect was enhanced when pioglitazone was given in combination with simvastatin. The media/lumen ratio was reduced by pioglitazone; in MRA, combination treatment with simvastatin reduced the ratio further to normal and, with valsartan, to below normal. In basilar artery, the media/lumen ratio was reduced further by both combination treatments, but was lowest in the pioglitazone–valsartan combination group.9. The significant effects on MRA and basilar artery structure (and, thus, haemodynamics) seen after rosiglitazone monotherapy and after pioglitazone, given alone and in combination with simvastatin or valsartan, may well indicate a glitazone class effect on vascular structure and, hence, cardiovascular function.

Notes: 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 NG-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.

Notes: 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 NG-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.