RELATIONSHIP BETWEEN NIFEDIPINE SENSITIVITY OF AORTAE AND BLOOD PRESSURE OF STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1. We have previously described an increased sensitivity to inhibition by nifedipine of noradrenaline-induced contractures of blood vessels in hypertension. In this study we have investigated whether changes in blood pressure (BP) change the sensitivity to nifedipine and K⁺ of aortic rings from normotensive (Wistar-Kyoto rats, WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP were treated with: hydralazine plus hydrochloro-thiazide; captopril plus hydrochlorothiazide; hydralazine plus guanethidine; or captopril alone. WKY rats were treated with deoxycorticosterone acetate (DOCA) and NaCl. Treatment commenced from 5 weeks of age and continued until 13–15 weeks. 3. The SHRSP treatments produced similar reductions in BP, and the BP of all the treated groups were significantly lower than the mean BP of untreated SHRSP (201.0 ± 7.7 mmHg). The mean BP of the treated WKY rats (134.2 ± 7.6 mmHg) was significantly higher than the mean BP of the untreated WKY rats (86.8 ± 7.4 mmHg). 4. An area-under-curve (AUC) analysis of the inhibitory effects of nifedipine on responses of aortae to noradrenaline showed no differences between treated and untreated SHRSP groups (overall mean 40.6 ± 1.9% and 43.4 ± 3.4% inhibition of control AUC, respectively), or between DOCA-salt treated WKY and untreated WKY groups (58.8 ± 5.9 and 64.8 ± 2.3, respectively). Noradrenaline-induced contractures of aortae from all SHRSP groups were significantly more sensitive to inhibition by nifedipine than aortae from both WKY groups. 5. The molar concentration of agonist required to evoke 50% of the maximum response (EC₅₀) values for potassium chloride (KCI) were significantly increased in the aortae of all treated SHRSP groups in comparison to those from untreated SHRSP (treated SHRSP groups, 15.53 ± 0.68 mmol/L vs untreated SHRSP group, 11.36 ± 1.10 mmol/L). The EC₅₀ values for KC1 for the aortae from the DOCA-treated WKY rats were significantly less than those from aortae of the untreated WKY (11.80 ± 0.80 and 17.08 ± 1.50 mmol/L, respectively). 6. We conclude that reduction (in SHRSP) or increase (in WKY) of the BP has no effect on the sensitivity of aortic smooth muscle to the inhibitory effects of nifedipine on responses to noradrenaline, suggesting that alterations in voltage-dependent Ca²⁺ mechanisms may be a primary phenomenon in the SHRSP. In contrast, the fact that sensitivity to KC1 changes in the treated SHRSP and WKY aortae suggests such sensitivity is secondary to the BP and thus a separate phenomenon from voltage-dependent Ca²⁺ mechanisms.     

GENE RELATED TO STROKE IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1. In order to study genes related to stroke in stroke-prone spontaneously hypertensive rats (SHRSP), linkage analysis was performed using F2 rats (SHRSP/Izm x WKY/Izm). The brainweight that reflected cerebral stroke in F2 rats showed cosegregation with three genetic markers, D4Mit19 (P < 0.0015), D4Mgh7 (P < 0.0014) and D4Mgh8 (P < 0.004) on chromosome 4, but not blood pressure. 2. These results suggest that a chromosomal region other than the region responsible for hypertension contributes to the development of stroke in SHRSP.     

PROTECTIVE EFFECTS OF ME3221 ON HYPERTENSIVE COMPLICATIONS AND LIFESPAN IN SALT-LOADED STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1. A comparison was made on the protective effects of the following: ME3221, a competitive angiotensin AT₁ receptor antagonist; losartan, in which a major active metabolite is a non-competitive angiotensin AT₁ receptor antagonist; and enalapril, an angiotensin-converting enzyme inhibitor, using the salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP received orally ME3221 (3 and 10mg/kg per day), losartan (10mg/kg per day) and enalapril (10mg/kg per day) from the 6th to the 20th week of age. All the control rats showed rapid elevation of systolic blood pressure (SBP), accompanied by hypertensive complications, and died by 15 weeks of age. 3. ME3221, losartan and enalapril suppressed the elevation of SBP in the salt-loaded SHRSP to a comparable degree. ME3221 and losartan increased the survival rate to >90%, and diminished hypertensive complications such as cerebral apoplexy (stroke), renal injury (increased proteinuria, and total N-acetyl-β-D-glucosaminidase activity) and heart failure (cardiac hypertrophy and pleural effusion). 4. Competitive (ME3221) and non-competitive (losartan) angiotensin AT₁ receptor antagonists showed comparable efficacy against the complications and mortality of the salt-loaded SHRSP; both were more potent than enalapril in the protective effect.     

PLASMA AND PITUITARY PROLACTIN AND BLOOD PRESSURE IN BROMOCRIPTINE-TREATED SPONTANEOUSLY HYPERTENSIVE AND WISTAR-KYOTO RATS

1. The effects on blood pressure (BP) and plasma and pituitary prolactin (PRL) of a 13 day intraperitoneal infusion of bromocriptine delivered by osmotic minipump were investigated in spontaneously hypertensive rats (SHR) and their normotensive controls, the Wistar-Kyoto rats (WKY). 2. In the SHR, a fall in BP which was steepest over the initial few days and sustained up to day 12 was observed in the bromocriptine-treated group compared with the lack of a change in BP observed in the vehicle-treated group. The plasma PRL level taken on day 13 was found to be significantly lower in the bromocriptine-treated group than in the vehicle-treated group. 3. In the WKY, bromocriptine had no significant effect on either BP or plasma PRL. 4. Pituitary PRL content was significantly lower in the SHR than in the WKY. The suppression by bromocriptine treatment was greater in the SHR than in the WKY. 5. These results provide further evidence for a central dopaminergic insufficiency in the SHR and raise the possibility that PRL may, either directly or indirectly by interacting with other factors in the SHR, influence BP.     

PREVENTATIVE AND THERAPEUTIC EFFECTS OF AE0047 ON RENAL INJURY IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1. The present study was designed to investigate the preventative and therapeutic effects of AE0047 on renal injury compared with those of nitrendipine in stroke-prone spontaneously hypertensive rats (SHRSP). 2. In the preventative study, drug administration was started before the appearance of renal injury, such as proteinuria. Treatment for 6 weeks with AE0047 (1 and 3 mg/kg, p.o.) led to a dose-related reduction in systolic blood pressure (SBP). Nitrendipine, at doses of 10 and 30 mg/kg, also lowered SBP to a similar degree to that seen with AE0047 at 1 and 3 mg/kg, respectively. 3. In the vehicle-administered SHRSP group, urinary excretion of protei. (U_proteinV) increased progressively from 14 weeks of age for another 6 weeks. AE0047 at both doses maintained U_proteinV within normal levels throughout the experimental period. However, the elevation of U_proteinV was only inhibited in the 30 mg/kg nitrendipine-treated group. Urinary N-acetyl-β-D-glucosaminide (NAG) activity in the vehicle-treated SHRSP group was elevated. Urinary NAG activity remained at a low level only in AE0047-treated groups. 4. Histopathological examination revealed severe lesion. (i.e. fibrinoid necrosis, proliferative vasculitis and glomerular lesions) of the kidney in SHRSP. AE0047 treatment at each dose attenuated the development of renal lesions in SHRSP. In contrast, nitrendipine, at 10 mg/kg, was ineffective against the development of renal lesions. Although nitrendipine at 30 mg/kg suppressed the development of renal lesions, this effect was still weaker than that seen with AE0047 at 1 mg/kg. 5. In the therapeutic study, drugs were administered to 17-week-old SHRSP with moderate renal damage for 10 days. Treatment with AE0047 (1 and 3 mg/kg) produced dose-dependent decreases in U_proteinV. In the nitrendipine-treated group, U_proteinV tended to decrease but the changes were not significant. 6. Histopathological studies revealed that 3 mg/kg AE0047 improved renal lesions, such as fibrinoid necrosis, proliferative vasculitis and glomerular lesions, whereas 30 mg/kg nitrendipine di. not. 7. Taken together, the results indicate that AE0047 is capable of preventing proteinuria as well as renal lesions, in part via a mechanism independent of its depressor action on SBP. Furthermore, AE0047 improves proteinuria and renal lesions in proteinuria-established SHRSP. Thus, AE0047 may have therapeutic potential in suppressing either the development or the progression of renal disease in hypertensive patients.     

EFFECTS OF NEONATAL SYMPATHECTOMY BY 6-HYDROXYDOPAMINE ON BLOOD PRESSURE AND INTRAVASCULAR VOLUME IN YOUNG STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1. Stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar Kyoto rats (WKY) were 'chemically sympathectomized' immediately after birth with 6-hydroxydopamine (6-OHDA, 100 mg/kg s.c. daily) for the first 10 days of life. 2. Body weight gain was diminished in both groups as compared with sham-treated controls. Blood pressure was reduced in 'sympathectomized' SHRSP, and also WKY rats had a slightly lower blood pressure than control rats. 3. Plasma concentration of angiotensin II and renin content of the kidney were not influenced by 6-OHDA. 4. 'Sympathectomized' SHRSP retained similar amounts of sodium than sham-treated SHRSP when sodium retention is expressed per body weight gained. Plasma and blood volumes were increased in both SHRSP and WKY rats, whereas packed cell volume was significantly decreased. 5. These results demonstrate the significance of an intact sympathetic nervous system for the development of hypertension in SHRSP. The expanded plasma and blood volume in 'sympathectomized' rats indicate an important role of the sympathetic nervous system and/or the arterial blood pressure for the regulation of intravascular volume.     

INCREASED OXIDATIVE DNA DAMAGE IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1. The amount of urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of the total systemic oxidative stress in vivo, in stroke-prone spontaneously hypertensive rats (SHRSP) was not different from that in control normotensive Wistar-Kyoto (WKY) rats at 6 weeks of age, but became higher than control values after the development of severe hypertension at 14-17 weeks of age. 2. The amount of urinary 8-OHdG was not significantly different between SHRSP treated with anti-hypertensive agents and those not treated at 14 weeks of age. 3. Stroke-prone spontaneously hypertensive rats were exposed to DNA damage by oxidative stress at the early stage when they developed severe hypertension, but this increase in DNA damage was not the secondary effect of hypertension.     

RELAXANT EFFECTS OF VASODILATOR PEPTIDES ON ISOLATED BASILAR ARTERIES FROM STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1. The relaxant effects of vasodilator peptides were examined in ring preparations of basilar arteries from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats. 2. Vasoactive intestinal peptide and peptide histidine iso-leucine produced similar endothelium-independent relaxations in basilar arteries from WKY rats and SHRSP. Calcitonin gene-related peptide (CGRP) elicited endothelium-independent relaxations in both groups and the CGRP-induced relaxation was greater in SHRSP than in WKY rats. Substance P and neurokinin A did not relax basilar arteries from either group. 3. Both WKY rat and SHRSP basilar arteries were relatively insensitive to atrial natriuretic peptide, brain natriuretic peptide and C-type natriuretic peptide. 4. Bradykinin (BK) potently relaxed basilar arteries with endothelium, but BK produced contractions in endotheliumrubbed arteries in both WKY rats and in SHRSP. There was no significant difference in the relaxant response to BK between WKY rat and SHRSP arteries. 5. Adrenomedullin (AM) produced endothelium-independent relaxations in both groups and the relaxant response to AM was significantly greater in SHRSP than in WKY rats. 6. Human CGRP(8–37; 1 μmol/L), a CGRP receptor antagonist, significantly inhibited both relaxant responses induced by CGRP and AM in WKY rats and in SHRSP arteries. 7. Among various peptides tested, the responses to CGRP and AM were higher in basilar arteries from SHRSP than in those from WKY rats. The relaxation produced by AM may be via CGRP receptors in WKY rat and SHRSP basilar arteries.