Remodelling of mesenteric arteries in genetically hypertensive rats cross-fostered from birth to normotensive Wistar rats

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.     

Relative contribution of the prenatal versus postnatal period on development of hypertension and growth rate of the spontaneously hypertensive rat

1. To determine the relative roles of the prenatal and postnatal (preweaning) environment on the development of blood pressure and growth rate in the spontaneously hypertensive rat (SHR) of the Okamoto strain, we used combined embryo transfer and cross-fostering techniques between SHR and normotensive Wistar-Kyoto (WKY) rats to produce offspring whose development was examined during the first 20 weeks of life. 2. We measured litter sizes, bodyweights and tail-cuff blood pressures in offspring at 4, 8, 12 and 20 weeks of age. We also recorded heart, kidney and adrenal weights at 20 weeks of age, when the study concluded. 3. We found that both the in utero and postnatal environments provided by the SHR mother could significantly affect WKY rat offspring growth rates, but blood pressure was unaffected in this strain. In SHR offspring, the SHR maternal in utero and suckling period both contributed to the rate of blood pressure development in the SHR, but not the final blood pressure of offspring at 20 weeks of age. This effect was greater for male than female offspring. Organ weights were largely unaffected by the perinatal environment in either strain. 4. We conclude that although the SHR maternal in utero and immediate postnatal environment both contribute to the rate of blood pressure development in the SHR, they do not appear to contribute to the final blood pressure of offspring at maturity. The SHR maternal environment also alters growth rate that may, in turn, underlie these effects on SHR blood pressure development, particularly in males.     

Maternal Environment Alters Renal Response To Angiotensin II In The Spontaneously Hypertensive Rat

1. The level of hypertension displayed by the adult spontaneously hypertensive rat (SHR) may be reduced by 20-30 mmHg if SHR pups are cross-fostered to a normotensive dam at birth (SHRX). The mechanisms involved are largely unknown, but may involve the kidney and the renin-angiotensin system (RAS) because renal responses to angiotensin (Ang) II are enhanced in the SHR and brief blockade of the RAS in the young rat permanently lowers blood pressure in the SHR. Accordingly, the aim of the present study was to investigate the effect of cross-fostering on the renal response to AngII in the SHR. 2. Renal function was studied in anaesthetized 4-week-old SHR, cross-fostered SHRX and control Wistar-Kyoto (WKY) rats. Standard clearance methods were used to investigate the renal haemodynamic and tubular effects of AngII. The nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) was coinfused in some experiments to abolish the counterbalancing effect of nitric oxide. 3. Angiotensin II induced a fall in glomerular filtration rate (GFR) in both SHR and SHRX, but not in WKY rats. This was accompanied by a significant reduction in sodium excretion by SHR but not SHRX pups. This effect appeared to be tubular in origin, because sodium clearance was comparable between the two strains after AngII, but fractional sodium excretion was significantly higher in the SHRX. Coinfusion of the NOS inhibitor L-NAME had little further effect on sodium excretion in SHR and SHRX, but restored GFR in SHRX to levels comparable with those in WKY rats. 4. These data suggest that renal tubular sensitivity to AngII in the SHR can be altered during the early stages of postnatal development, which may contribute to the blood pressure- lowering effect of cross-fostering in the SHR.     

Effect of cross-fostering on renal anti-oxidant/oxidant status and development of hypertension in spontaneously hypertensive rats

1. The hypotensive effect of cross-fostering in spontaneously hypertensive rats (SHR) is thought to involve adjustments in renal function. However, its association with renal anti-oxidant/oxidant balance during cross-fostering is not known. 2. The present study examined the effect of cross-fostering and in-fostering of 1-day-old offspring between SHR and Wistar-Kyoto (WKY) dams on renal anti-oxidant/oxidant status and systolic blood pressure (SBP). Renal anti-oxidant/oxidant status and SBP were determined in the offspring from 4-16 weeks of age. 3. Cross-fostered SHR had significantly lower SBP than in-fostered SHR at 6, 8 and 12 weeks, but not at 16 weeks (127 ± 1 vs 144 ± 2, 138 ± 1 vs 160 ± 1, 174 ± 2 vs 184 ± 2 and 199 ± 2 vs 194 ± 3 mmHg at 6, 8, 12 and 16 weeks, respectively). No differences in SBP were evident between cross-fostered and in-fostered WKY rats. There were no significant differences in levels of thiobarbituric acid-reactive substances (TBARS), protein carbonyl and total anti-oxidant status (TAS) or superoxide dismutase, catalase, glutathione peroxidase (GPx), glutathione S-transferase and glutathione reductase activity between cross-fostered and in-fostered SHR or WKY offspring. However, compared with WKY rats, catalase activity was higher at 6 and 16 weeks, TAS was higher at 16 weeks and GPx activity and TBARS were lower at 16 weeks in SHR. 4. It appears that cross-fostering of SHR offspring to WKY dams during the early postnatal period causes a transient delay in the rise in blood pressure in SHR and that this does not involve the renal anti-oxidant/oxidant system.     

Regional changes in the activities of aminergic biosynthetic enzymes in the brains of hypertensive rats.

The activities of monoamine biosynthetic enzymes were measured in brain regions of several hypertensive rat models at various ages. The types of hypertensive rats were the spontaneously hypertensive rat (SHR) and a stroke-prone substrain of the SHR as well as DOCA-salt and renal hypertensive rats. The genetically hypertensive rats had significantly elevated blood pressures as compared to the Wistar-Kyoto control rat after 5 weeks of age. During the early development of hypertension in the SHR, the activities of tyrosine hydroxylase in the hypothalamus and corpus striatum and of dopamine-beta-hydroxylase in the hypothalamus and pons-medulla were significantly higher than in the control rats. Tryptophan-hydroxylase was also elevated in the hypothalamus in SHR. From 3 to 8 weeks of age there appeared to be a significant correlation between hypothalamic dopamine-beta-hydroxylase activity and blood pressure in the hypertensive rats. In contrast, the activities of tyrosine hydroxylase and dopamine-beta-hydroxylase were slightly decreased in the DOCA-salt and renal hypertensive rats. It is suggested that noradrenergic or adrenergic neurons in the hypothalamus may participate in the initiation of elevated blood pressure in the genetic, but not in the DOCA-salt or renal hypertensive rats.     

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.     

EFFECT OF CROSS-FOSTERING ON NEONATAL SODIUM BALANCE AND ADULT BLOOD PRESSURE IN THE SPONTANEOUSLY HYPERTENSIVE RAT

1. The aim of the present study was to compare electrolyte handling in naturally reared neonatal spontaneously hypertensive rats (SHR) with those reared by a Wistar-Kyoto (WKY) rat foster mother (denoted SHRX), as cross-fostering SHR pups to a WKY rat dam lowers adult blood pressure in the SHR. 2. The electrolyte content of WKY rat and SHR dams’ milk was determined and electrolyte intake and urinary excretion rates were calculated in both naturally reared and cross-fostered WKY rat and SHR pups. 3. The milk sodium concentration fell in both strains (WKY rat: 31.8 ± 2.0 to 15.2 ± 1.2 mmol/L; SHR 31.9 ± 2.5 to 18.2 ± 1.6 mmol/L; P < 0.001), as did potassium (P < 0.001), over lactation, but there were no differences between strains. Calcium and magnesium concentrations increased (P< 0.001), although SHR dam's milk contained less calcium (P < 0.001) than that of WKY rat dams during the third week of lactation. 4. Spontaneously hypertensive rat pups ingested less milk (P<0.05) than WKY rat pups; therefore, their cumulative sodium intake over postnatal days 4–15 was significantly lower than that of WKY rat pups (WKY rat vs SHR: 84.4 ± 3.6 vs 59.7 ± 2.6 μmol/g bodyweight, respectively; P < 0.05) and fostered SHRX pups (77.7 ± 7.0 μmol/g bodyweight; P < 0.05). Potassium and magnesium intakes were comparable between SHR, WKY rat and SHRX pups, but SHR pups ingested significantly less calcium than either WKY rat pups (136.1 ± 6.4 vs 200.1 ± 9.5p, mol/g bodyweight, respectively; P<0.05) or SHRX pups (200.0 ± 18.0 μmol/g bodyweight; P<0.05). 5. These data show that the neonatal SHR experiences a period of sodium deficiency during the developmental stage when cross-fostering is effective in lowering blood pressure. This is consistent with the reported up-regulation of the renin-angiotensin system observed in SHR at this time and may have a long-term influence on blood pressure.     

Salt and water intake and sodium and potassium excretion in spontaneously hypertensive rats

1. Total fluid and saline intakes were greater in spontaneously hypertensive rats (SHR) than in normotensive rats (NTR). 2. Total fluid and saline intake were significantly elevated in prehypertensive SHR, 5 weeks old, compared with age-matched NTR, and the intakes fell with age in both strains but remained considerably greater in SHR. 3. In SHR, in which the blood pressure was maintained at normotensive levels by treatment with hydralazine, the saline and fluid intakes remained elevated above those of NTR. 4. SHR and NTR fed low sodium diet with water alone to drink have similar excretion rates of sodium, suggesting that their ability to conserve sodium was normal. 5. Measurement of sodium excretion after three different levels of sodium loading, on normal or low sodium diets, also failed to demonstrate an abnormality of renal function in SHR. 6. These results demonstrate that the fluid and saline intakes of SHR are elevated compared with NTR and this difference is independent of the hypertension in SHR and is not secondary to enhanced renal sodium loss.     

罗沙坦对自发性高血压肾小动脉重建的逆转作用

目的　研究血管紧张素Ⅱ受体拮抗剂罗沙坦对高血压肾小动脉重建的逆转作用。方法　 16wk龄 大鼠分为 :正常血压大鼠 (WKY)组、自发性高血压大鼠 (SHR)对照组、罗沙坦治疗高剂量组 (15mg·kg-1·d-1)和罗沙坦治疗低剂量组 (0 75mg·kg-1·d-1)。每组 6只大鼠 ,饲养 10wk。在肾组织切片上用光镜结合计算机图像分析法观测肾内小动脉的几何形态学指标 ,离体肾脏灌流法测定最小肾血管阻力。结果　罗沙坦高剂量组的尾动脉收缩压、肾内小动脉壁厚、壁面积、壁厚内径比和最小肾血管阻力 ,均较高血压对照组显著下降或减小 ;罗沙坦低剂量组的肾内小动脉壁厚和壁厚内径比较高血压对照组显著下降或减小。结论　AngⅡ受体拮抗剂能逆转SHR肾小动脉的重建 ,而且是非血压依赖性的     

Effects of single and repeated oral administration of MK-421 and captopril on blood pressures in normotensive and experimental hypertensive rats

In the single dose study, the aortic blood pressure in conscious normotensive rats, 2-kidney, 1-clip renal hypertensive rats (2K-RHR), 1-kidney, 1-clip renal hypertensive rats (1K-RHR) or DOCA hypertensive rats was measured for 24 hr after the oral administration of angiotensin converting enzyme (ACE) inhibitors such as MK-421 or captopril. MK-421 at 3 mg/kg and captopril at 10 mg/kg markedly lowered the blood pressure of 2K-RHR. MK-421 at 10 mg/kg and captopril at 30 mg/kg only modestly lowered the blood pressure of 1K-RHR. In contrast, both ACE inhibitors failed to reduce blood pressure in DOCA and normotensive rats. In the repeated dose study, the systolic blood pressures in normotensive rats, 2K-RHR or spontaneously hypertensive rats (SHR) were measured twice a week for 3 weeks treatment of either MK-421 at 3 mg/kg or captopril at 10 mg/kg. Both ACE inhibitors produced significant antihypertensive effects in these model rats, and the effects were sustained throughout the treatment period. The antihypertensive effects in 2K-RHR were greater than those in SHR and normotensive rats. These results indicate that MK-421 and captopril cause the most significant antihypertensive effect in 2K-RHR in which the renin-angiotensin system played a dominant role in blood pressure regulation. The antihypertensive effect of MK-421 was approximately 3 times as potent as that of captopril in these hypertensive models.     

Pubertal administration of antiserum against nerve growth factor regresses renal vascular remodeling in spontaneously hypertensive rats

To investigate the role of nerve growth factor (NGF) in the development of hypertensive renal vascular remodeling, antiserum against NGF (anti‐NGF) or vehicle was injected at 3 weeks of age in spontaneously hypertensive rats (SHR) and Wistar–Kyoto (WKY) rats (n = 9 for each treatment in each strain). Flow‐pressure (F‐P) and pressure‐glomerular filtration rate (P‐GFR) relationships at vasodilated perfused kidneys were determined at 10 weeks of age. In the vehicle rats, blood pressure, renal noradrenaline content, the gradient of F‐P (minimal vascular resistance at pre‐ and post‐glomerular vasculature) and the X‐intercept of P‐GFR (preglomerular : postglomerular vascular resistance ratio) were greater in SHR than in WKY rats, although the gradient of P‐GFR (glomerular filtration capacity) did not differ significantly between the strains. Blood pressure and renal noradrenaline content were lower in SHR receiving anti‐NGF than in SHR receiving vehicle, although such difference was not observed in WKY rats. The gradient of F‐P was less but the gradient of P‐GFR was greater in SHR receiving anti‐NGF compared with SHR receiving vehicle, although the similar differences did not occur in WKY rats. Blood pressure and renal noradrenaline content remained greater in SHR treated with anti‐NGF compared with WKY rats treated with vehicle; however, the gradient of F‐P did not differ significantly between them. Contrary, anti‐NGF did not affect the X‐intercept of P‐GFR in either strain. In conclusion, NGF could contribute to the genesis of renal vascular remodeling, at least in part, through modification of renal sympathetic activity and blood pressure in SHR.     

PERTUSSIS TOXIN-SENSITIVE G-PROTEINS AND REGULATION OF BLOOD PRESSURE IN THE SPONTANEOUSLY HYPERTENSIVE RAT

1. Increased Gi-protein-mediated receptor-effector coupling in the vasculature of the spontaneously hypertensive rat (SHR) has been proposed as a contributing factor in the maintenance of elevated blood pressure. If increased Gi-protein-mediated activity plays an important role in hypertension in SHR, then inhibition of Gi-proteins by pertussis toxin would be expected to decrease blood pressure in this genetic hypertensive model. To address this hypothesis, studies were undertaken comparing the cardiovascular effects of pertussis toxin in SHR and normotensive Wistar-Kyoto (WKY) rats. 2. Spontaneously hypertensive and WKY rats were instrumented with radiotelemetry devices and blood pressure measurements were recorded in conscious rats. Following a single injection of pertussis toxin (10 micrograms/kg, i.v.), mean arterial blood pressure fell from 161 +/- 3 to 146 +/- 1 mmHg in the SHR and the effect was sustained for more than 2 weeks. In contrast, 10 micrograms/kg, i.v., pertussis toxin produced no significant effect on blood pressure in WKY rats (103 +/- 4 vs 101 +/- 5 mmHg). 3. In a separate study, SHR and WKY rats were administered 30 micrograms/kg, i.v., pertussis toxin or 150 microL/kg, i.v., saline and, 3-5 days later, rats were anaesthetized and instrumented to permit measurement of blood pressure and renal function. At this higher dose, pertussis toxin reduced blood pressure in both strains of rat, although the effect was markedly greater in SHR (approximately 40 mmHg decrease) compared with WKY rats (approximately 15 mmHg decrease). In SHR, pertussis toxin increased renal blood flow (from 5.7 +/- 0.3 to 7.5 +/- 0.8 mL/min per g kidney) and decreased renal vascular resistance (from 31 +/- 2 to 19 +/- 2 mmHg/mL per min per g kidney). In WKY rats, pertussis toxin had no significant effect on renal parameters. 4. Results from these studies indicate that a pertussis toxin-sensitive Gi-protein-mediated pathway contributes to the maintenance of hypertension and elevated renal vascular tone in the SHR.     

Hypotensive effects of dihydropyridine derivatives

Effects of six dihydropyridine derivatives (nifedipine, nisoldipine, nitrendipine, nicardipine, nimodipine and niludipine) and hydralazine on blood pressure and heart rate in spontaneously hypertensive rats (SHR) were studied in comparison with those in normotensive rats (NR). Nisoldipine, nitrendipine and nicardipine showed stronger hypotensive effect in SHR than in NR. All the dihydropyridine derivatives--especially nifedipine, nitrendipine and niludipine--lowered blood pressure of SHR at doses smaller than those producing positive chronotropic effect. Hydralazine caused hypotensive effect in the same extent both in SHR and in NR and, moreover, it brought about tachycardia at doses smaller than those lowering blood pressure.     

NITRIC OXIDE SYNTHASE INHIBITION WITH Nω-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^ω-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^ω-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 weeks 1 and 2 and then 5 mg/kg per day for week 3). Tail-cuff 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.     

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.     

TOTAL BODY SODIUM IN IMMATURE SPONTANEOUSLY HYPERTENSIVE AND WISTAR KYOTO RATS

Total body sodium of male and female spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats was estimated weekly during the first 8 weeks of life by measuring exchangeable sodium (ENa). Blood pressure and sodium intake was measured from weeks 4 to 8. SHR had significantly higher blood pressure and sodium intake than WKY from 4 to 8 weeks of age. ENa was higher in SHR than WKY throughout the first 8 weeks of life. Relative sodium retention was observed in SHR during weeks 5 to 8 despite a significant rise in SHR blood pressure and fall in sodium intake. These findings suggest a change in the renal pressure/natriuresis relationship at this age in the SHR.     

Antihypertensive and haemodynamic properties of the potassium channel activating (-) enantiomer of cromakalim in animal models

The present studies describe the blood pressure lowering, and some other haemodynamic effects, of the potassium channel activator, BRL 38227 ((-) enantiomer of cromakalim, CAS 94470-67-4) in various animal models. BRL 38227 was a potent antihypertensive agent following oral administration to conscious spontaneously hypertensive rats, SHR, (0.038, 0.075 and 0.15 mg/kg), renal hypertensive cats (0.035 and 0.05 mg/kg) and renal hypertensive dogs (0.05 and 0.1 mg/kg). The (+) enantiomer of cromakalim (BRL 38226) was without effect on blood pressure in the conscious rat and cat confirming the stereospecific mode of action of this potassium channel activator. Tachycardia accompanied the antihypertensive effect of BRL 38227 in these models and in the rat this effect could be abolished by pretreatment with atenolol (conscious SHR), diltiazem, verapamil, propranolol and alinidine (anaesthetised rats). In addition to reflex tachycardia, BRL 38227 also increased plasma renin activity and aldosterone levels in the conscious renal hypertensive cat. In both the anaesthetised normotensive cat (0.001 mg/kg/min i.v.) and dog (0.0025 to 0.02 mg/kg i.v.) BRL 38227 lowered blood pressure and total peripheral resistance while increasing cardiac output via increased heart rate and stroke volume in the cat and via increased heart rate alone in the dog. BRL 38227 reduced renal vascular resistance in both conscious (0.01, 0.015 and 0.02 mg/kg p.o.) and anaesthetised (0.001 mg/kg/min i.v.) cats and the effect was maintained despite marked reductions in blood pressure. In the anaesthetised dog, BRL 38227 was a potent coronary arterial dilator and this effect was also maintained in the face of marked blood pressure lowering activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Hypotensive and hemodynamic effects of the new non-sulfhydryl angiotensin converting enzyme inhibitor N-[8-amino-1(S)-carboxyoctyl]-L-alanyl-L-proline

The hypotensive effects of N-[8-amino-1(S)-carboxyoctyl] -L-alanyl-L-proline (AB-47, CAS 120008-53-9) were examined in normotensive rats and various hypertensive rat models. The hemodynamic effect of AB-47 was also examined in anesthetized spontaneously hypertensive rats (SHR). In 2-kidney, 1-clip renal hypertensive rats (2K, 1C-RHR) and SHR, the single administration of AB-47 (10 mg/kg, p.o.) induced potent and long-lasting hypotensive effects. The repeated administration of AB-47 (1 to 10 mg/kg, p.o.) to SHR for 29 days produced a dose-dependently and sustained hypotensive effect of 20 to 70 mmHg. AB-47 (10 mg/kg, p.o.) had a weak hypotensive effect in DOCA-salt hypertensive rats but no effects in normotensive and 1-kidney, 1-clip renal hypertensive rats (1K, 1C-RHR). AB-47 (3 mg/kg, p.o.) reduced blood pressure in intact SHR but not in bilateral nephrectomized SHR. The single intravenous injection of AB-47 (10 to 100 micrograms/kg) dose-dependently lowered systemic blood pressure, left ventricular systolic pressure (LVSP) and dp/dtmax without affecting heart rate (HR) and these effects of AB-47 were more potent than those of captopril and enalaprilat. These results suggest that AB-47 is a potent and long-lasting hypotensive agent and may be useful for the therapy of both hypertension and congestive heart failure.     

Cardiovascular activities of the new potent and long-lasting antihypertensive calcium entry blocker (+-)-3-ethyl,5-methyl,2- ([2-(formylamino)-ethyl]- thiomethyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicar box ylate.

BBR 2160 ((+-)3-ethyl,5-methyl,2-([2-(formylamino)-ethyl]- thiomethyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarb oxy late, CAS 118587-22-7) is a new calcium entry blocker (CEB) which completely displaces 3H-nitrendipine from binding sites, is 10 times more potent than amlodipine (A) and equiactive with nifedipine (N). On the rat aorta contracted by 10 mmol/l Ca++, or 45 mmol/l K+, BBR 2160 shows higher CEB activity than N and A, achieving the maximum effect on voltage operated channels-induced contractions in 6 h, while N takes about 2 h. BBR 2160, N and A negatively affect the chronotropism on spontaneously beating, and inotropism on electrically driven guinea pig atria, respectively. In vitro BBR 2160 has marked vasoselectivity. Administered orally to conscious hypertensive rats (SHR) and renal hypertensive dogs (RHD), it caused a dose-dependent reduction in systolic blood pressure with a relatively slow onset, peak effect at 3-6 h and duration over 6 h. BBR 2160 and A have more pronounced activity on SHR than on normotensive rats (NR) (ED20 NR/SHR 3.3 for both compounds), while the antihypertensive and hypotensive activities of N are in the same dose-range (ED20 NR/SHR 1.3). No tolerance develops to the antihypertensive effects of BBR 2160 after five days' dosing up to 3.2 mg/kg in SHR and 1 mg/kg in RHD. In instrumented conscious normotensive dogs BBR 2160, N and A mostly lower diastolic blood pressure and total peripheral resistance, and do not increase total oxygen consumption.(ABSTRACT TRUNCATED AT 250 WORDS)