Stroke-prone Spontaneously Hypertensive Rats Research Articles

Vascular endothelin-1 expression and effect of an endothelin ETA antagonist on structure and function of small arteries from stroke-prone spontaneously hypertensive rats.

There is some evidence that the endothelin (ET) system may participate in blood pressure elevation and in vascular hypertrophy in stroke-prone spontaneously hypertensive rats (SHR-SP). To further understand the involvement of the ET system in this hypertensive model, we examined preproendothelin-1 (preproET-1) mRNA abundance in blood vessels of 5-week and 18-week SHR-SP in comparison to SHR, and treated 12-week old SHR-SP with the ETA-selective receptor antagonist A-127722.5 (30 mg/kg/day in the drinking water) for 10 weeks. Abundance of preproET-1 mRNA by Northern blot analysis was increased more than twofold in aorta and mesenteric arteries of SHR-SP relative to SHR at 18 weeks but not at 5 weeks of age. SHR-SP treated with A-127722.5 had a tail-cuff systolic blood pressure at 22 weeks of age of 241 +/- 2 mm Hg vs. 251 +/- 3 mm Hg in untreated SHR-SP (p < 0.05). Heart:body weight ratio was no different in both groups, but aortic segment:body weight ratio was slightly but significantly smaller in treated SHR-SP (p < 0.05). Pressurized mesenteric small arteries from treated SHR-SP had a smaller media width (12.6 +/- 0.6 microns vs. 14.9 +/- 0.5 microns; p < 0.05) and media:lumen ratio (5.8 +/- 0.2% vs. 7.3 +/- 0.3%; p < 0.01), whereas media cross-sectional area and lumen diameter tended to decrease and increase, respectively, without achieving statistical significance. Acetylcholine-induced relaxation was improved in treated SHR-SP (99.6 +/- 0.6% vs. 90.0 +/- 3.6%; p < 0.05), whereas relaxation responses to sodium nitroprusside were similar in both groups. These results show increases of preproET-1 expression in blood vessels that appear to be secondary to blood pressure elevation. There is a small ET-dependent component in blood pressure elevation and in conduit and resistance artery changes in adult stroke-prone SHR.

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 I1 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 strokeprone SHR.

Age-related changes of the mechanical properties of the carotid artery in spontaneously hypertensive rats.

We had previously demonstrated that the distensibility of the carotid artery in spontaneously hypertensive rats (SHR) aged 18 weeks does not differ from that of the carotid artery in normotensive animals for common pressure levels, despite vascular hypertrophy in SHR. To examine the time-course effects of hypertension on the geometry and the mechanical properties of the carotid artery in SHR. The mechanical behavior of the carotid arteries of anesthetized SHR, stroke-prone SHR (SHRSP), and Wistar-Kyoto (WKY) rats aged 4, 8, 12, 16, and 32 weeks was examined by simultaneously measuring the internal diameter with an A-mode ultrasonic echo-tracking device and the intra-arterial pressure with a computerized data-acquisition system. Histometric measurements of the carotid artery were performed after death of rats. Blood pressure increased with time in rats of the two genetic hypertensive models. However, it rose earlier and to higher levels in the SHRSP. Cardiac hypertrophy was comparable in the two hypertensive groups whereas vascular hypertrophy was less pronounced in the SHRSP than it was in the SHR. There was an age-related decrease in arterial distensibility in rats of all groups that was more pronounced in the SHRSP than it was in the SHR compared with that in WKY rats (decreases of 57 and 36%, respectively, versus WKY rats aged 32 weeks; P < 0.05). For rats of all ages studied, although aging affected differently the vascular properties of the distinct animal strains, arterial distensibility was increased in the SHR and SHRSP compared with that in control animals for similar blood pressure levels, implying a rightward shift of the distensibility-pressure curves in the two hypertensive models. However, there was a significant reduction in arterial distensibility in rats of the two hypertensive strains at their respective mean blood pressures, compared with that in control animals.

Positive inotropic effect of exogenous and endogenous NO in hypertrophic rat hearts.

1. Recent evidence suggests that nitric oxide (NO) modulates the contractile force of isolated cardiomyocytes in a biphasic manner. We sought to examine whether myocardial hypertrophy induced by long-term hypertension changes the effects of NO on myocardial contractility. 2. We used constant flow perfused non-paced Langendorff preparations of hearts of 3 months old Wistar rats (WIS, n = 23) and of stroke-prone spontaneously hypertensive rats (SHR) at the age of 10 months (SHR10, n = 16) and 15 months (SHR15, n = 8). Changes of left ventricular peak pressure (LVP), +dP/dt(max), -dP/dt(max), coronary perfusion pressure (CPP) and heart rate (HR) were recorded after infusion of noradrenaline (NA, 0.1 micromol l(-1)), glyceryl trinitrate (GTN, 1-100 micromol l(-1)), S-nitroso-N-acetyl-D,L-penicillamine (SNAP, 1-10 micromol l(-1)) and N(omega)-nitro-L-arginine (L-NOARG, 0.1-1 mmol l(-1)). 3. Long-term hypertension induced myocardial hypertrophy and an abnormal response to NA. The relative heart weight (in mg kg(-1)) increased from 2.95 +/- 0.04 (WIS) to 6.67 +/- 0.34 (SHR15), while the increase in +dP/dt(max) induced by NA was absent in SHR15. Hearts of SHR10 showed an intermediate response. 4. Both SNAP and GTN significantly increased LVP, +dP/dt(max) and -dP/dt(max) in hearts of WIS and of SHR. In WIS but not in SHR10, SNAP also increased HR. In SHR10 the lowest concentration of SNAP (1 micromol l(-1)) showed no effect on contractility but a significantly diminished reduction of CPP suggesting inactivation of extracellularly released NO in the coronary circulation of SHR. 5. L-NOARG significantly reduced contractility in hearts of WIS and of SHR to a similar extent. At a concentration of 1 mmol l(-1) L-NOARG also reduced HR. 6. These results suggests that positive inotropic effects of exogenous and endogenous NO are not changed in hypertension induced myocardial hypertrophy.

Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin II AT1 Receptor Antagonism on Cardiac Parameters in Left Ventricular Hypertrophy

Left ventricular hypertrophy (LVH) is considered to be an independent risk factor giving rise to ischemia, arrhythmia, and left ventricular dysfunction. In this article, we summarize recent studies performed in our laboratory to investigate (1) the contribution of the renin-angiotensin system to the cardiac remodeling process, which is triggered by myocardial infarction (MI) or hypertension-induced cardiac hypertrophy; (2) the effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin AT1 receptor antagonism on cardiac parameters, such as myocardial infarct size, cardiac hypertrophy, heart function, and myocardial metabolism; (3) the mechanism of an ACE inhibitor-induced increase in cardiac capillary density in spontaneously hypertensive rats (SHR) and stroke prone SHR (SHR-SP). We observed that AT1 receptor gene expression in rat vascular smooth muscle cells (but not in rat coronary endothelial cells) was markedly enhanced after an ischemic insult in vitro. In a rat model in which MI was induced by coronary artery ligation, the AT1 receptor mRNA levels were transiently increased after MI and reached a peak level 24 hours post-MI. The AT2 receptor gene expression increased in a pattern similar to that of the AT1 receptor. ACE expression at the protein level in the repairing scar, which was demonstrated by monoclonal antibody staining, started to increase 2 weeks after MI and reached a peak level 3 weeks post-MI. Furthermore, long-term treatment with an ACE inhibitor limited infarct size, prevented cardiac hypertrophy, and improved heart function in the rat MI model. In SHR-SP, long-term treatment with either an ACE inhibitor or an AT1 receptor antagonist improved cardiac function and metabolism. Cardiac metabolism was even improved after low-dose ACE inhibitor treatment, which did not prevent hypertension and cardiac hypertrophy. In both SHR and SHR-SP, we found that the ACE inhibitor ramipril significantly increased capillary length density independently of its antihypertensive and antihypertrophic actions. Most of the cardiac effects of the ACE inhibitor could be abolished by a bradykinin B2 receptor antagonist. Thus, these cardiac effects of ACE inhibitors can be ascribed, at least under our experimental conditions, to ACE inhibitor-induced bradykinin potentiation.

Effects of benidipine hydrochloride on antioxidant enzyme activity in stroke-prone spontaneous hypertensive rats (SHR-SP).

Effects of benidipine hydrochloride or triple therapy (hydralazine, reserpine, and hydrochlorothiazide) on renal cortical and medullary intrinsic antioxidant enzyme (AOE) activity were evaluated in stroke-prone spontaneously hypertensive rats (SHR-SP) as an animal model for human essential hypertension with cerebral stroke. This study showed a significant decrease of renal intrinsic glutathione peroxidase (GSH-Px) activity in untreated SHR-SP. Renal GSH-Px activity in untreated SHR-SP was significantly lower than that in Wister Kyoto rats (WKY) as a normotensive reference strain. GSH-Px activity in SHR-SP was significantly improved after benidipine hydrochloride therapy. Levels of urinary albumin excretion or creatinine clearance (Ccr) in SHR-SP were also improved after the therapy. Glomerular sclerosis index was slightly improved in SHR-SP treated with benidipine hydrochloride according to light microscopic analysis. It appears that hypertension may influence the renal intrinsic GSH-Px activity, albuminuria, and Ccr in SHR-SP. Thus it is indicated that control of blood pressure may improve the GSH-Px activity in SHR-SP.

Reduced Expression of Antihypertensive Angiotensin II Type 2 (AT&lt;sub&gt;2&lt;/sub&gt;) Receptor in the kidney and cultured mesangial cells from Stroke-Prone SHR

Reduced Expression of Antihypertensive Angiotensin II Type 2 (AT&lt;sub&gt;2&lt;/sub&gt;) Receptor in the kidney and cultured mesangial cells from Stroke-Prone SHR

Effect of Buckwheat Protein Extract on Lipid Metabolism in Diet-Induced Hypercholesterolemic Stroke-Prone SHR (SHRSP)

Effect of Buckwheat Protein Extract on Lipid Metabolism in Diet-Induced Hypercholesterolemic Stroke-Prone SHR (SHRSP)

Role of adventitia in vascular remodeling in hypertension: a trophobiological view

The vascular wall has the capacity to undergo remodeling in response to long-term changes or injuries. This is a process of structural rearrangement that involves cell growth, cell death, cell migration, cell modulation and secretion/degradation of extracellular matrix molecules. Vascular remodeling is an adaptive phenomenon, e.g. Glagov's compensatory enlargement in atherosclerosis, but it may grow into vascular diseases, such as hypertension, atherosclerosis, and coronary restenosis after angioplasty. Nowadays paradigms defining the cell biology of vascular diseases are the following: (i) the hypertensive vessel is characterized by hyperinnervation-associated medial thickening due to smooth muscle cell (SMC) hypertrophy/hyperplasia and increased extracellular matrix content, (ii) the atherosclerotic plaque is characterized by SMC/immune cells/increased extracellular matrix-containing intimal thickening, and (iii) the restenotic coronary artery is characterized by SMC/immune cells-containing neointimal thickening. The spontaneously hypertensive rats (SHR), the stroke-prone SHR (SHRSP), the genetically hypertensive (GH) rats, and other genetically hypertensive strains are widely used as a model of human essential hypertension. In this volume of Biomedical Reviews, Bell updates the knowledge about vascular wall neurotrophobiology in relation to the pathogenesis of hypertension in SHR and GH rats. Also, Kondo et al systematize the perivascular nerve-related SMC structural changes in the development of hypertension in SHR and SHRSP. The data presented in these reviews are evaluated mainly in terms of Levi-Montalcini's neurotrophic theory. Biomedical Reviews 1996; 6: 5-10.

Perindopril treatment in the prevention of stroke in experimental animals

To determine the effect of perindopril treatment and treatment withdrawal in the prevention of stroke in male stroke-prone spontaneously hypertensive rats (SPSHR). After weaning at 4 weeks of age, male SPSHR were given a Japanese-style rat diet which induces stroke in these animals. Beginning at 6 weeks of age, SPSHR were treated with either distilled water (control) or different daily dosages of perindopril (1 or 4 mg/kg) by gavage for 24 weeks followed by treatment withdrawal. Additional subgroups were treated with the 4 mg/kg dose for different durations (B, 12 or 24 weeks) before treatment withdrawal. Treatment effects on blood pressure, heart rate and body weight were studied during the treatment period and after the withdrawal of the treatment. Myogenic and mechanical properties of the middle cerebral arteries were studied in control SPSHR that had developed stroke, in treated SPSHR at the end of the treatment period, and at certain intervals after the withdrawal of the treatment. Systolic blood pressure, heart rate and body weight of control and treated SPSHR were determined at regular intervals before, during and after the treatment withdrawal periods until they died from stroke, or until 42 or 43 weeks of age when the study was terminated. Functional studies of the cerebral arteries were carried out using a pressurized artery system. At necropsy, macroscopic and microscopic examinations were made of the kidneys and brain. Untreated SPSHR usually died of stroke-related complications by 14 weeks of age. The middle cerebral arteries from these animals had lost their ability to contract in response to pressure increase. Chronic treatment of SPSHR with perindopril when initiated at 6 weeks of age attenuated the sharp blood pressure rise, and prevented the development of stroke during the treatment period. This was associated with the preservation of the myogenic response of the middle cerebral arteries to pressure increase, and the prevention of tissue damage in the kidneys and brain. After withdrawal of the treatment, SPSHR treated for a longer period (12 or 24 weeks) also survived longer than those treated for a shorter period (8 weeks). The subsequent loss of myogenic response in the middle cerebral arteries was associated with the development of stroke and death in these treatment withdrawal groups. Chronic treatment with perindopril is beneficial for the prevention of stroke in SPSHR, through the preservation of the myogenic response properties of the cerebral arteries, and the attenuation of tissue damage in the brain and kidneys.

Platelet Ca 2+ Is Not Increased in Stroke-Prone Spontaneously Hypertensive Rats

We have reported that cytosolic Ca2+ concentration ([Ca2+]i) is increased in platelets from spontaneously hypertensive rats (SHR) in both basal and thrombin-stimulated conditions. To determine whether the correlation between blood pressure and cellular Ca2+ metabolism exists in stroke-prone SHR (SHRSP), we investigated Ca2+ handling using fura 2 and aggregation response in platelets of 12- to 13-week-old male SHRSP, SHR, and Wistar-Kyoto rats (WKY). Systolic pressure was highest in SHRSP and lowest in WKY (213 +/- 8, 172 +/- 7, and 135 +/- 5 mm Hg, respectively). Basal [Ca2+]i was significantly higher in SHR than WKY (45.9 +/- 4.5 versus 41.2 +/- 4.8 nmol/L, P<.05), and that in SHRSP (40.2 +/- 2.8 nmol/L) was similar to that in WKY. Thrombin (0.1 IU/mL)-stimulated [Ca2+]i rise was greater in SHR and smaller in SHRSP than in WKY in the presence of extracellular Ca2+ (530 +/- 50 and 408 +/- 52 versus 475 +/- 50 nmol/L, respectively; P<.05). The recovery rate from the peak [Ca2+]i response to thrombin was greatest in SHRSP and least in WKY. Ionomycin (5 micromol/L)-stimulated [Ca2+]i rise was similar in WKY, SHR, and SHRSP (731 +/- 97, 743 +/- 88, and 683 +/- 70 nmol/L, respectively). Thrombin-induced maximum platelet aggregation response was higher in SHR and lower in SHRSP than WKY (82 +/- 4 percent and 61 +/- 15 percent versus 73 +/- 6 percent, respectively; P<.05). In contrast to SHR, basal [Ca2+]i in SHRSP was similar to that in WKY, and thrombin-stimulated [Ca2+]i was attenuated. These result suggest that platelet Ca2+ handling differs between SHR substrains and that an increased [Ca2+]i is not obligatory in genetically hypertensive rats.

Evidence for activation of endothelium and monocytes in hypertensive rats.

We have proposed that an interaction between perivascular macrophages and endothelium via cytokines could underlie the increased risk of stroke in hypertension. Therefore, the activation of monocytes, the endothelial expression of intercellular adhesion molecule-1 (ICAM-1), and the numbers of monocytes/macrophages in carotid arteries, as well as the cytokine production in carotid tissue, of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto and Sprague-Dawley rats were studied. The total number of blood monocytes (890 +/- 153 cells/mm3, n = 10) and the number of activated (nitro blue tetrazolium-positive) monocytes (220 +/- 51 cells/mm3, n = 10) were significantly greater (P < 0.05) in SHR than in WKY rats (440 +/- 81 and 40 +/- 16 cells/mm3, respectively, n = 10). Patchy endothelial expression of ICAM-1 was found in 77 +/- 9% of carotid sections from stroke-prone SHR (SHR-SP, n = 5) and in 75 +/- 7% of the sections from SHR (n = 7) but in none of the sections from the two normotensive rat strains (n = 7). The number of endothelium-attached monocytes/macrophages per millimeter of internal elastic lamina was significantly greater in SHR-SP than in SHR [5.1 +/- 0.7 (n = 4) and 3.3 +/- 0.3 (n = 6), P < 0.05], whereas no monocytes were found around the endothelium in either of the normotensive rat strains (n = 7 in each group). Incubation of the carotid arteries with lipopolysaccharide (30-300 ng/ml) induced a concentration-dependent expression of mRNAs for interleukin-1 beta and release of tumor necrosis factor-alpha to a significantly greater degree in the SHR than in the Wistar-Kyoto rats. The results demonstrate that hypertension is associated with activation of monocytes and endothelium and an increased endothelial adhesion and subendothelial accumulation of monocytes/macrophages and with an increased vascular capacity to produce cytokines.

The cardiovascular protective role of docosahexaenoic acid

Dietary fish oils rich in n-3 polyunsaturated fatty acids can modulate a diverse range of factors contributing to cardiovascular disease. This study examined the relative roles of eicosapentaenoic acid (20:5 n-3; EPA) and docosahexaenoic acid (22:6 n-3; DHA) which are the principal n-3 polyunsaturated fatty acids regarded as candidates for cardioprotective actions. At low dietary intakes (0.4–1.1% of energy (%en)), docosahexaenoic acid but not eicosapentaenoic acid inhibited ischaemia-induced cardiac arrhythmias. At intakes of 3.9–10.0%en, docosahexaenoic acid was more effective than eicosapentaenoic acid at retarding hypertension development in spontaneously hypertensive rats (SHR) and inhibiting thromboxane-like vasoconstrictor responses in aortas from SHR. In stroke-prone SHR with established hypertension, docosahexaenoic acid (3.9–10.0%en) retarded the development of salt-loading induced proteinuria but eicosapentaenoic acid alone was ineffective. The results demonstrate that purified n-3 polyunsaturated fatty acids mimic the cardiovascular actions of fish oils and imply that docosahexaenoic acid may be the principal active component conferring cardiovascular protection.

Nitric oxide release from kidneys of hypertensive rats treated with imidapril.

To examine whether endothelial dysfunction in hypertension is reversible or not, we studied the effects of imidapril, an angiotensin-converting enzyme inhibitor, on nitric oxide release in stroke-prone spontaneously hypertensive rats (SHR) and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. After a 4-week treatment with imidapril (1 or 10 mg/d SC) or vehicle, acetylcholine-induced vasodilation and nitric oxide release in the isolated kidneys were determined. Nitric oxide release was measured by a chemiluminescense assay. Imidapril lowered blood pressure in stroke-prone SHR in a dose-dependent manner. Untreated stroke-prone SHR exhibited significantly attenuated responses to acetylcholine (10(-8) mol/L) of both renal perfusion pressure (stroke-prone SHE 42 +/- 4% versus Wistar-Kyoto rats [WKY] 58 +/- 4% [mean +/- SE], P < .01) and nitric oxide release (stroke-prone SHR +7.6 +/- 2.1 versus WKY +29.7 +/- 9.7 fmol/min per gram of kidney wt, P < .01). Imidapril at 10 mg/d significantly increased acetylcholine-induced renal vasodilation and nitric oxide release in stroke-prone SHR (renal perfusion pressure, 56 +/- 3%; nitric oxide release, +27.1 +/- 6.4 fmol/min per gram of kidney wt; both P < .01 versus stroke-prone SHR treated with vehicle). On the other hand, imidapril neither decreased blood pressure nor changed nitric oxide release induced by acetylcholine in DOCA-salt hypertensive rats. Staining for endothelial nitric oxide synthase and brain nitric oxide synthase was clearly detected in the kidneys of both stroke-prone SHR and WKY, whereas staining intensity was weaker in DOCA-salt hypertensive rats. Inducible nitric oxide synthase immunoreactivity was barely noticeable in any type of rat. Thus, imidapril restored endothelial damage by pressure-dependent mechanisms. Most of the nitric oxide detected in the perfusate seemed to be derived from constitutive nitric oxide synthase.

Ciliary neurotrophic factor attenuates spatial cognition impairment, cortical infarction and thalamic degeneration in spontaneously hypertensive rats with focal cerebral ischemia

Ciliary neurotrophic factor (CNTF) has been shown to exhibit potent neurotrophic activity on peripheral and central neurons in vitro and in vivo. However, it remains to be determined whether or not CNTF rescues neuronal loss due to focal cerebral ischemia and prevents ischemia-induced disability of space navigation in rats. In the present in vivo study, we infused CNTF continuously for 4 weeks into the lateral ventricle, starting just after permanent occlusion of the left middle cerebral artery (MCA) of stroke-prone spontaneous hypertensive rats. CNTF infusion prevented the occurrence of ischemia-induced learning disability in a dose-dependent manner in rats subjected to the Morris water maze task. Subsequent histological examinations showed that cortical infarction and retrograde degeneration of the ipsilateral thalamic neurons in ischemic rats infused with CNTF were significantly less severe than those in ischemic rats infused with vehicle alone. These findings suggest that postischemic CNTF treatment prevents the occurrence of spatial learning disability in rats with permanent MCA occlusion, possibly by reducing neuronal damage within the cerebral cortex and secondary retrograde degeneration of the thalamus.

Blood pressure and age-dependent changes of endothelium-dependent tension oscillations in different strains of spontaneously hypertensive rats.

The influence of blood pressure and age of spontaneously hypertensive rats on endothelium-dependent tension oscillation of aortic preparation were studied. Rats with different blood pressures, normotensive Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP) and malignant type of SHRSP (M-SHRSP), were used. The effects of antihypertensive treatment of SHRSP on the tension oscillation were also studied. High doses of noradrenaline induced tension oscillations in endothelium-intact preparations of all strains of young rats. The rate of the occurrence of the tension oscillation decreased age-dependently. The decrease was faster when the blood pressure of the rats was higher. Application of acetylcholine in the presence of noradrenaline induced a relaxation and tension oscillations, both of which were negatively dependent on age and blood pressure. Antihypertensive treatment of hypertensive rats with hydralazine or captopril prevented a decrease in incidence of the tension oscillation. These influences of age and blood pressure as well as antihypertensive treatments on the tension oscillation resembled those on the endothelium-dependent relaxation and are thought to be brought about by functional changes of the endothelium.

Effects of Eicosapentaenoic Acid and Docosahexaenoic Acid on Serum Lipid Metabolism in Normocholesterolemic and Hypercholesterolemic Stroke-Prone SHR (SHRSP)

Effects of Eicosapentaenoic Acid and Docosahexaenoic Acid on Serum Lipid Metabolism in Normocholesterolemic and Hypercholesterolemic Stroke-Prone SHR (SHRSP)

Abnormal Platelet Ca2+ Handling in SHR and Stroke-Prone SHR evoked by Thromboxane A2 analog (U46619)-Comparison with Thrombin-Stimulation-

Abnormal Platelet Ca2+ Handling in SHR and Stroke-Prone SHR evoked by Thromboxane A2 analog (U46619)-Comparison with Thrombin-Stimulation-

Urinary excretion of 19-noraldosterone in the spontaneously hypertensive rat and stroke-prone spontaneously hypertensive rat.

1. We measured the urinary excretion of 19-noraldosterone in the spontaneously hypertensive rat (SHR) and stroke-prone SHR (SHRSP) during the development of hypertension and compared these measurements with Wistar-Kyoto (WKY) rats. 2. 19-Noraldosterone in rat urine was confirmed using HPLC-MS. Urine samples were collected from 4 and 9 week old SHR (n = 12), SHRSP (n = 12) and WKY rats (n = 9). 19-Noraldosterone was measured by specific radio immunoassay after purification of the urine extracts with HPLC. 3. There were no significant differences in plasma corticosterone among SHR, SHRSP and WKY rats at 4 and 9 weeks of age. Aldosterone levels were increased in the prehypertensive SHR and SHRSP. Nine week old SHRSP showed high plasma concentration of aldosterone compared with SHR or WKY rats of the same age. 4. Urinary excretion of 19-noraldosterone was increased in 4 week old SHR (15 +/- 4.2 pmol/day) and SHRSP (17 +/- 5.0 pmol/day) compared with WKY rats (9 +/- 3.9 pmol/day) at the same age. Nine week old SHR showed decreased urinary excretion of 19-noraldosterone compared with WKY rats at the same age. Urinary levels of 19-noraldosterone were higher in SHRSP (11 +/- 4.9 pmol/day) than in SHR (7 +/- 4.0 pmol/day) at 9 weeks of age. 5. Adrenal mineralocorticoids are suggested to be responsible for the abnormal vascular reactivity observed in SHRSP. Relatively elevated levels of 19-noraldosterone in SHRSP may contribute to malignant hypertension in this model.

Hypertrophy and hyperplasia of smooth muscle cells of small intramyocardial arteries in spontaneously hypertensive rats.

Hearts of stroke-prone spontaneously hypertensive rats (SHR) were investigated by means of stereology and were compared with those of normotensive. Wistar-Kyoto controls. At the age of 9 months, hypertensive rats showed cardiac hypertrophy, marked myocardial fibrosis, activation of nonvascular interstitium, focal myocytial degeneration, reduction of capillarization, and microarteriopathy of small intramyocardial arteries. Stereologically, a significant increase in the total left ventricular arterial wall volume (+180% versus controls) was found in SHR hearts. By using new stereological techniques, the orientator and the nucleator, we investigated whether this significant increase in total left ventricular arterial wall volume was due to hyperplasia of smooth muscle cells in addition to the process of vascular smooth muscle cell hypertrophy that is common in SHR. Additionally, the nuclear size and ratio of cell volume to nuclear volume were determined using another new stereological technique, the selector. The stereological data indicate a significant increase in mean cell and nuclear volumes as well as in the total number of left ventricular arterial smooth muscle cells of SHR. Additionally, the total length of intramyocardial arteries was also significantly increased in hypertensive rats. The volume and number of arterial smooth muscle cells per arterial length were significantly (P < .001 and P < .05, respectively) higher in SHR than in normotensive controls. Thus, we conclude that hypertrophy and hyperplasia of smooth muscle cells are involved in intramyocardial arterial growth processes in hypertensive heart remodeling.(ABSTRACT TRUNCATED AT 250 WORDS)