Urinary dopamine and sodium excretion in spontaneously hypertensive rats

We measured urinary dopamine in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) before (days 0-6) and during high-salt diet, in the absence (days 6-10) and presence (days 10-14) of added L-dopa (2 mg/kg/day by gavage). Urinary excretion of sodium (UNaV) increased 20-fold during intake of chow containing 8% NaCl in both strains. Systolic blood pressure (SBP) of SHR increased slightly (9 +/- 4 mmHg; p < 0.05) on the high-salt diet, whereas SBP did not change in WKY. Urinary dopamine excretion was not different between strains in the basal state, and was as great or greater in SHR than WKY during high-salt intake with and without added L-dopa. SBP was unaffected by L-dopa administration and UNaV did not increase or differ between strains despite higher urinary dopamine excretion in SHR. We conclude that renal dopamine formation in vivo is not diminished in SHR, compared with WKY, on normal or high-salt diets, and that elevation of renal dopamine formation secondary to L-dopa administration is not associated with reductions in SBP or altered UNaV in these rats.     

Influence of the renal sympathetic nerves on renal renin and angiotensinogen gene expression in spontaneously hypertensive rats during development

OBJECTIVE: To investigate the influence of renal sympathetic denervation on renin and angiotensinogen gene expression in the kidney during growth and the development of hypertension in spontaneously hypertensive rats (SHR). Comparative studies were undertaken in age-matched normotensive Wistar rats. DESIGN: Four-week-old SHR and Wistar rats were subjected to either denervation of the left kidney or sham operation. At age 5, 7 or 9 weeks the rats were lightly anaesthetized, carotid blood pressure was measured, a blood sample was taken and both kidneys were removed. METHOD: Plasma renin activity was measured by radioimmunoassay, and renal renin and angiotensinogen messenger RNA (mRNA) levels were measured by Northern blot hybridization followed by densitometric analysis. RESULTS: In 5- and 7-week-old SHR the renin mRNA level in the left kidney was significantly suppressed compared with that in the sham-operated right kidney and with the level in 9-week-old SHR. The renal renin mRNA level in sham-operated SHR decreased significantly with increasing age, whereas in the Wistar rats the renal renin mRNA level did not change at any age and was not affected by renal denervation. The renal angiotensinogen mRNA level gradually increased with age in both rat strains and was not affected by denervation, but much higher levels were attained in the Wistar rats than in the SHR. CONCLUSION: Renal angiotensinogen gene expression was depressed in the SHR, with little evidence of neural regulation at any age in the SHR or the Wistar rats. However, in the SHR the renal sympathetic nerves elevated renal renin gene expression in the prehypertensive stage, but their influence decreased as hypertension developed.     

Diversity in the renal hemodynamic effects of dihydropyridine calcium blockers in spontaneously hypertensive rats

BACKGROUND: Death rates from coronary hearts disease have exhibited remarkable declines in most industrialised countries. Cardiovascular mortality has been the subject of extensive research and we considered it important to analyse recent local population based data on hospital outcomes of acute myocardial infarction (AMI). AIM: To document the trends in in-hospital mortality from AMI in Victoria from 1987-1994. METHODS: This was a retrospective analysis of data from the Victorian Inpatient Minimum Database relating to all public acute care hospitals. All separations recording a principal diagnosis 410 (AMI) were selected. Changes in distribution of AMI separations, in-hospital mortality, and changes in length of stay were examined. RESULTS: The mean age of women admitted was 72 years compared with 64 years for men. Women comprised around a third of the overall sample but the proportion varied from 13% in those under 50 years to 57% among those aged 80 years and over. A striking decline in mortality was observed throughout the eight year period. The relative age adjusted decline was 33.5% (40% in males and 26% in females) with rates remaining higher in women. This decline occurred despite the increasing representation of those aged over 80 years. There was a significant decline in the mean length of stay (1.8 days) over the eight year period but this is likely to have had only minimal impact on mortality rates. CONCLUSION: We have documented welcome declines in in-hospital mortality from AMI that are not an artefact of declining lengths of stay. Our observations parallel those in similar overseas studies. Large changes in medical management have taken place from the mid 1980s and may be partly responsible, but a change in disease process cannot be ruled out.     

Nephroprotection by long-term ACE inhibition with ramipril in spontaneously hypertensive stroke prone rats

BACKGROUND: The effect of life-long treatment with the ACE inhibitor ramipril on hypertension-induced histological changes in the kidney was tested in stroke-prone spontaneously hypertensive rats (SHR-SP). METHODS: One-month-old pre-hypertensive SHR-SP were randomized into three groups of 45 animals each, and exposed via drinking water for their lifetime to a dose of: 1 mg.kg-1.d-1 ramipril (antihypertensive dose, HRA); 10 micrograms.kg-1.d-1 slight dose of ramipril (non-antihypertensive dose, LRA); or placebo. Histological and biochemical assessments were conducted after 15 months in ten rats each, when about 80% of the placebo group had died. RESULTS: Kidneys from placebo treated SHR-SP showed pronounced arterial wall hypertrophy and sclerosis, arterial fibrinoid necrosis, glomerulopathy and tubular interstitial injury that were, in concert with normalized blood pressure, completely prevented by HRA treatment. LRA treatment did not affect any blood pressure increase, and also attenuated the development of arterial wall hypertrophy, sclerosis and arterial fibrinoid necrosis, though to a minor extent only, but did not change glomerular and tubulointerstitial degeneration. These effects of ramipril were associated with a dose-dependent inhibition of plasma and renal tissue ACE activities as well as lower serum concentrations of creatinine, but there were no changes in serum potassium. CONCLUSIONS: Life-long HRA-induced ACE inhibition protects against hypertension-induced renal damages in SHR-SP. This is associated with a doubling of the lifespan in these animals.     

Cardiovascular effects of chronic inhibition of nitric oxide synthesis and dietary salt in spontaneously hypertensive rats

This report presents a study of the effects of the membrane fluidizer, benzyl alcohol, on NHE isoforms 1 and 3. Using transfectants of an NHE-deficient fibroblast, we analyzed each isoform separately. An increase in membrane fluidity resulted in a decrease of approximately 50% in the specific activities of both NHE1 and NHE3. Only Vmax was affected; KNa was unchanged. This effect was specific, as Na+, K+, ATPase activity was slightly stimulated. Inhibition of NHE1 and NHE3 was reversible and de novo protein synthesis was not required to restore NHE activity after washout of fluidizer. Inhibition kinetics of NHE1 by amiloride, 5-(N,N-dimethyl)amiloride (DMA), 5-(N-hexamethyl)amiloride (HMA) and 5-(N-ethyl-N-isopropyl)amiloride (EIPA) were largely unchanged. Half-maximal inhibition of NHE3 was also reached at approximately the same concentrations of amiloride and analogues in control and benzyl alcohol treated, suggesting that the amiloride binding site was unaffected. Inhibition of vesicular transport by incubation at 4 degrees C augmented the benzyl alcohol inhibition of NHE activity, suggesting that the fluidizer effect does not solely involve vesicle trafficking. In summary, our data demonstrate that the physical state of membrane lipids (fluidity) influences Na+/H+ exchange and may represent a physiological regulatory mechanism of NHE1 and NHE3 activity.     

Hemodynamic effects of amlodipine and benazeprilat in spontaneously hypertensive rats

We wished to assess the hemodynamic effects of administration of the combination of the calcium channel blocking agent amlodipine and the angiotensin-converting enzyme (ACE) inhibitor benazeprilat in conscious spontaneously hypertensive rats (SHR). In SHR previously instrumented for measurement of mean arterial blood pressure (MAP) and heart rate (HR), intravenous (i.v.) injection of amlodipine (0.25-4 mg/kg) produced dose-dependent decreases in blood pressure (BP). Administration of benazeprilat (0.1-10 mg/kg i.v.) decreased arterial MAP, and benazeprilat (10 mg/kg) effectively blocked the effects of exogenously administered angiotensin I (AI). In animals surgically prepared for measurement of BP, HR, and hindquarter, renal, and mesenteric blood flows, administration (i.v.) of the combination of amlodipine (0.5 mg/kg) with benazeprilat (10 mg/kg) evoked a decrease in BP that was greater than that elicited by monotherapy. The tachycardic response observed after administration of the combination was no different from that observed after monotherapy with amlodipine. Simultaneous administration of amlodipine and benazeprilat produced reductions in vascular resistance in the hindquarter, renal and mesenteric beds that were greater than the responses evoked by injection of either agent. The major finding of these studies was that dual therapy with amlodipine and benazeprilat produced an additive hypotensive effect in conscious SHR. Regional vasodilation accompanied the large degree of hypotension evoked by the combination.     

The effects of intrathecal clonidine in spontaneously hypertensive rats

The relationship between intrathecal clonidine and hypertension was investigated in SHR rat and WKY rat. After the animals were given clonidine 15 micrograms into the lumbar intrathecal space, blood pressure, heart rate and respiratory rate were recorded for 60 minutes under nembutal anesthesia. Percent change of mean blood pressure was significantly larger in SHR rat than in WKY rat at 50 and 60 minutes after clonidine injection. No difference was observed in percent change of heart rate and respiratory rate. The results suggest the possibility that lumbar intrathecal clonidine injection produces greater hypotension in hypertensive subjects than in normotensive subjects.     

Protective effect of nicardipine treatment on renal microanatomical changes in spontaneously hypertensive rats

The effects of nicardipine administration on kidney morphology were studied in spontaneously hypertensive rats (SHR). Male 12-week-old SHR received an oral dose of 1 mg/Kg/day of nicardipine or vehicle for 8 weeks Age-matched Wistar-Kyoto rats were used as normotensive reference animals. At 20 weeks, the non treated SHR exhibited hypertension, albuminuria, decreased urinary sodium excretion and renal microanatomical changes. These changes were characterized by vascular alterations consisting in hypertrophy of the tunica media accompanied by a decrease of luminal surface. Glomerular changes consisting primarily in signs of glomerulosclerosis of varying degrees were noticeable in the kidneys of SHR. Treatment with nicardipine significantly reduced blood pressure and albuminuria and increased urinary sodium excretion. Moreover, hypertrophy of the tunica media and the luminal surface were decreased and increased respectively in nicardipine-treated SHR. The above results suggest that treatment with nicardipine reduces blood pressure in SHR and counteracts hypertension-dependent changes in the morphology of the kidney. The protective effect of the drug on hypertensive changes of renal microanatomy probably have functional relevance given of the influence of nicardipine treatment on albuminuria and urinary sodium excretion in SHR.     

Effect of rapeseed and dietary oils on the mean survival time of stroke-prone spontaneously hypertensive rats

Low-fat conventional diets supplemented with 5 or 10% vegetable oils were fed to stroke-prone spontaneously hypertensive rats (SHR-SP) from weaning and the mean survival times were determined. A 1% aqueous sodium chloride solution was used as drinking water throughout the experiments. In four separate experiments, the rapeseed oil group showed a significantly shorter mean survival time. The relative mean survival times were 50-59% (rapeseed oil group), 78-100% (soybean oil group) and 86% (microbial oil group) as compared with the group fed perilla oil (100%). The group which received 4-fold diluted rapeseed oil exhibited a significantly shorter survival time as compared with the group receiving soybean oil. Although the feeding experiments were performed under very simple and restricted conditions, these results suggest that the rapeseed oil prepared for human use contains a factor (s) which is toxic to SHR-SP rats.     

Do kinins mediate cardioprotective and renoprotective effects of cilazapril in spontaneously hypertensive rats with renal ablation?

1. We assessed the potential of the kallikrein-kinin system in mediating the cardioprotective and renoprotective effects of an angiotensin-converting enzyme inhibitor (ACEI), cilazapril (CIL) in rats with renal ablation. 2. Eight week old spontaneously hypertensive rats (SHR) were subjected to 5/6 nephrectomy. One week after the operation, the rats were divided into 5 groups: (i) vehicle; (ii) CIL 1 mg/kg per day per os (p.o.); (iii) Hoe140 (HOE) 70 mu g/kg per day given intraperitoneally (i.p.); (iv) CIL 1 mg/kg per day p.o. plus HOE 7 mu g/kg per day i.p.; (v) CIL 1 mg/kg per day p.o. plus HOE 70 mu g/kg per day i.p. The treatment lasted for 4 weeks. 3. CIL alone significantly reduced systolic blood pressure, urinary protein excretion, heart weight and serum creatinine level. HOE alone did not induce any significant changes in these parameters. CIL in combination with HOE (7 or 70 mu g/kg per day) did not induce any changes in these parameters, in addition to those associated with the effects of CIL alone. 4. These results indicate that the kallikrein-kinin system might not play a major role in the cardioprotective and renoprotective effects of ACE inhibitors in the rat remnant kidney model of chronic renal failure.     

An electrogenic sodium pump and baroreceptor function in normotensive and spontaneously hypertensive rats

Postexcitatory depression (PED) and adaptation were examined in slowly adapting aortic baroreceptors of normotensive rats (NTR) and spontaneously hypertensive rats (SHR); an aortic arch-aortic nerve preparation in vitro was used. PED was elicited either mechanically by employing single or double pressure steps, or electrically by antidromic stimulation of the aortic nerve. During PED the axon of the receptor was capable of conducting action potentials and the receptor itself could respond to increased pressures. The relationship between duration of PED and number of impulses preceding it was hyperbolic. In NTR's and SHR's PED was abolished by ouabain or solutions containing no potassium, neither of which affected the steady state pressure-volume relationship of the aorta. These interventions, which are known to block electrogenic pumps, also lowered the pressure threshold and increased the curvature of the steady state pressure-frequency curve. Furthermore, lithium, another agent that blocks electrogenic pumps, also abolished PED. Thus, PED is attributed mainly to an electrogenic sodium pump which operates normally in baroreceptors. We found that adaptation from peak transient to steady state frequency did not appear to be altered significantly when the pump was blocked. Blockage of the pump by ouabain is responsible for the baroreceptor reflex effects elicited by this drug. We conclude that resetting and reduced sensitivity in SHR baroreceptors are not attributed to significant differences in electrogenic pump activity.     

Renal sodium excretion after oral or intravenous sodium loading in sodium-deprived normotensive and spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats that had been on a low sodium diet for 3 days were given 1.5 mmol sodium chloride kg-1 body weight either orally or intravenously. The rats receiving an oral sodium load showed a greater natriuresis than those receiving the same saline load intravenously. No increase of renal sodium excretion was observed when the rats received a hypertonic mannitol solution orally. The cumulative sodium excretion during the 8 h following oral loading was two to three times larger in SHR than in WKY, whereas no difference between strains could be demonstrated after giving saline intravenously. Furthermore, after switching from normal to low sodium diet the rate of decrease of renal sodium excretion was greater in SHR than in WKY rats. It is proposed that there exists a gastrointestinal sensory mechanism for sodium controlling the renal sodium excretion. Furthermore, it is suggested that the function of this mechanism differs between SHR and WKY.     

Altered permeability of the erythrocyte membrane for sodium and potassium ions in spontaneously hypertensive rats

Permeability of the erythrocyte membrane for sodium and potassium ions was studied in 8-10-week old spontaneously hypertensive rats (SHR, Kyoto Wistar strain), normotensive Wistar and Sprague-Dawley rats. The rate constnat of Na/Na exchange was considerably greater in the SHR than in the normotensive Wistar and Sprague-Dawley rats. This difference remained the same in the rats adrenalectomized 7 days prior to the experiment. The maximum difference in the constants was found when the sodium pump was blocked by ouabain. The accumulation of 42K in the erythrocytes of the SHR (the sodium pump being blocked) took place at a considerably slower rate, and the K+ washout into a potassium-free medium was faster than in the normotensive Wistar and Sprague-Dawley rats. These results seem to indicate a higher permeability of the SHR's erythrocyte membrane for Na+ and K+ ions, as compared to normotensive Wistar and Sprague-Dawley strains. It is suggested that the increased permeability of the erythrocyte membrane for Na+ and K+ in the SHR may reflect a more widespread cell membrane defect, which could serve as a general cause for activating the mechanisms maintaing high blood pressure.     

Upregulation of renal and vascular nitric oxide synthase in young spontaneously hypertensive rats

The available data on the role of the L-arginine/nitric oxide (NO) pathway in the genesis of hypertension in spontaneously hypertensive rats (SHR) are limited and contradictory. In an attempt to address this issue, male SHR were studied during the early phase of evolution of hypertension (age 8 to 12 weeks) to distinguish the primary changes of NO metabolism from those caused by advanced hypertension, vasculopathy, and aging late in the course of the disease. A group of age-matched male Wistar-Kyoto rats (WKY) served as controls. The SHR exhibited a marked rise in arterial blood pressure and a significant increase in urinary excretion and plasma concentration of NO metabolites (nitrite/nitrate [NOx]). Likewise, the SHR showed a significant elevation of thoracic aorta NO synthase (NOS) activity coupled with significant increases of kidney, aorta, inducible NOS (iNOS), and endothelial NOS (eNOS) proteins. In an attempt to determine whether the enhanced L-arginine/NO pathway is a consequence of hypertension, studies were repeated using 3-week-old animals before the onset of hypertension. The study revealed significant increases in urinary NOx excretion as well as vascular eNOS and renal iNOS proteins. In conclusion, the L-arginine/NO pathway is upregulated in young SHR both before and after the onset of hypertension. Thus, development of hypertension is not due to a primary impairment of NO production in SHR. On the contrary, NO production is increased in young SHR both before and after the onset of hypertension.     

Role of beta-adrenoceptor on renal interleukin-6 and tumor necrosis factor in spontaneously hypertensive rats

We have shown previously in the spontaneously hypertensive rat (SHR) kidney that interleukin-6 (IL-6) and tumor necrosis factor (TNF) mRNA levels were low under conditions of acute anaesthesia and surgical stress. The reasons for the suppression of IL-6 and TNF gene expression in the SHR were investigated by examining the influence of enhanced beta-adrenergic stimulation, high blood pressure, and renal function (renal blood flow, glomerular filtration rate, plasma creatinine levels) on renal IL-6 and TNF mRNAs. The experiments were performed by means of the following three studies; (1) SHR and Wistar rats at 4, 7, 9 week old were injected with lipopolysaccaride (LPS), and then a relationship between blood pressure levels and IL-6 and TNF mRNA levels were estimated, (2) isoproterenol and propranolol were administered into SHR and WKY rats, and the levels of IL-6 and TNF mRNA were compared, (3) under condition of anaesthesia and surgical stress, blood pressure and renal functions in SHR were measured, and then the relationships between these factors and IL-6 or TNF mRNA levels were analyzed. Renal IL-6 and TNF mRNAs in SHR remained low even though blood pressure increased with age and there was no significant correlation between IL-6 or TNF mRNA levels and values of blood pressure or renal function under anaesthesia and surgical stress. However, the inhibition of the IL-6 and TNF mRNAs in SHR was prevented by propranolol treatment. These results suggested that suppression of IL-6 and TNF mRNAs in the SHR kidney could be due to overactivity of beta-adrenergic influences which may importantly contribute to the development of hypertension.     

Protective effects of valsartan and benazeprilat in salt-loaded stroke-prone spontaneously hypertensive rats

These experiments examined the effectiveness of chronic blockade of the renin angiotensin system with either valsartan or benazeprilat on survival, blood pressure and end-organ damage in salt-loaded stroke-prone SHR. Valsartan or benazeprilat given continuously by subcutaneous osmotic minipump beginning at 10.5 weeks of age lowered blood pressure, as determined by radiotelemetry, prevented proteinuria, prolonged survival and decreased the severity of histopathological changes in the heart and kidney. These results indicate that angiotensin receptor blockade affords a similar degree of protection as inhibition of angiotensin converting enzyme in salt-loaded stroke-prone SHR. Furthermore, our results are consistent with a primary contribution of angiotensin II to the maintenance of blood pressure and support a principal role for angiotensin II-dependent mechanisms in the development of end-organ damage in the salt-loaded stroke-prone SHR.     

Renal protective effects of efonidipine in partially nephrectomized spontaneously hypertensive rats

The influence of the internal features (eyes, nose, and mouth) in the age processing of unfamiliar faces was examined. Younger and older versions of the faces of six individuals (covering three different age ranges, from infancy to maturity) were used as donor stimuli. For each individual in turn, the effects on age estimates of placing older features in the younger face version (or vice versa) were investigated. Age estimates were heavily influenced by the age of the internal facial features. Experiment 2 replicated these effects with a larger number of faces within a narrower age range (after growth is complete and before major skin changes have occurred). Taken together, these two experiments show that the internal facial features may be influential in conveying age information to the perceiver. However, the mechanisms by which features exert their influence remain difficult to determine: although age estimates might be based on local information from the features themselves, an alternative possibility is that featural changes indirectly influence age estimates by altering the global three-dimensional shape of the head.     

Protective effects of CD-832 on organ damage in stroke-prone spontaneously hypertensive rats

Effects of a newly developed Ca2+ channel antagonist, (4R)-(-)-2-(nicotinoylamino)ethyl 3 nitrooxypropyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) 3,5-pyridine-dicarboxylate (CD-832), on hypertensive complications in stroke-prone spontaneously hypertensive rats (SHRSPs) were compared with effects of diltiazem. We examined changes in histological and hematological parameters in SHRSPs given the following treatments at 8 to 20 weeks of age: (a) CD-832; (b) diltiazem; (c) no treatment. CD-832 and diltiazem were added to the diet, in doses of 0.05 and 0.15% (approximately 30 and 100 mg/kg per day), respectively, throughout the experimental period. In untreated control SHRSPs, systolic blood pressure increased and severe renal lesions such as fibrinoid necrosis, smooth muscle proliferation, glomerular and tubular lesions and some cardiac fibrosis were observed at age 20 weeks. 12-week repeated-administration of CD-832 and diltiazem led to a comparable hypotension and decreased heart rate. CD-832 and diltiazem decreased the ratios of weights of kidney and heart to body weight and the concentration of blood urea nitrogen and creatinine in serum, compared to values in controls. In SHRSPs treated with CD-832 and diltiazem, the incidence of renal lesions and myocardial fibrosis was significantly reduced when compared with control SHRSPs. These results suggest that 12-week repeated-administration of CD-832 prevents the development of hypertension and the incidence of organ damage in SHRSPs. CD-832 and diltiazem were equally efficacious in preventing organ damage but this organ-protective effect was obtained at a lower dose for CD-832 (30 mg/kg per day) than that of diltiazem (100 mg/kg per day).