Effects of chronic oral treatment with imidapril and TCV-116 on the responsiveness to angiotensin II in ventrolateral medulla of SHR.

OBJECTIVE: To examine whether chronic oral treatment with an angiotensin-converting enzyme inhibitor imidapril and an angiotensin II type 1 receptor antagonist TCV-116 would alter the response to angiotensin II in the rostral ventrolateral medulla. METHODS: Twelve-week-old spontaneously hypertensive rats (SHR) were treated with imidapril (20 mg/kg per day, n = 7), TCV-116 (5 mg/kg per day, n = 8) or vehicle (n = 8) for 4 weeks. Wistar- Kyoto rats (WKY) (n = 8) served as normotensive controls. At 16 weeks of age, angiotensin II (100 pmol) was microinjected into the rostral ventrolateral medulla of anaesthetized rats. RESULTS: Blood pressure decreased significantly in the rats treated with either imidapril or TCV-116. Pressor responses to angiotensin II microinjected into the rostral ventrolateral medulla were comparable in the untreated SHR, the imidapril-treated SHR and WKY (12 +/- 2, 15 +/- 4 and 10 +/- 1 mmHg, respectively), but were abolished in SHR treated with TCV-116 (0 +/- 2 mmHg, P< 0.01). Angiotensin-converting enzyme activity in the brain stem was significantly lower in SHR treated with imidapril (0.70 +/- 0.06 nmol/mg per h), but significantly higher in SHR treated with TCV-116 (1.62 +/- 0.04 nmol/mg per h) than in the untreated SHR (1.37 +/- 0.05 nmol/mg per h). CONCLUSIONS: Chronic oral treatment with imidapril and TCV-116 may have divergent influences on the renin-angiotensin system within the brain stem. TCV-116, but not imidapril, abolishes the pressor effect of angiotensin II in the rostral ventrolateral medulla.     

Comparison of the antihypertensive effects of the new angiotensin II (AT1) receptor antagonist candesartan cilexetil (TCV-116) and the angiotensin converting enzyme inhibitor enalapril in rats.

Antihypertensive effects of an angiotensin (Ang) II receptor antagonist, candesartan cilexetil (TCV-116), were compared with those of an angiotensin converting enzyme (ACE) inhibitor, enalapril, in spontaneously hypertensive rats (SHR), 2-kidney, 1-clip hypertensive rats (2K, 1C-HR) and 1-kidney, 1-clip hypertensive rats (1K, 1C-HR). CV-11974, the active form of TCV-116, had no inhibitory activity for plasma ACE. In rats, TCV-116 inhibited the pressor responses to Ang I, Ang II, and Ang III without an effect on the bradykinin (BK)-induced depressor response. Enalapril inhibited only the Ang I-response and potentiated the BK-response. In SHR, the antihypertensive effect of TCV-116 (10 mg/kg) was larger than the maximum antihypertensive effect of enalapril and was not intensified by combination with enalapril. Administration of CV-11974 potentiated the maximum antihypertensive effect of enalapril. Although both agents reduced blood pressure in 2K, 1C-HR, only TCV-116 had a marked antihypertensive effect in 1K, 1C-HR. These findings indicate that TCV-116 is more effective than enalapril in reducing blood pressure in SHR and 1K, 1C-HR, and that the BK- and/or prostaglandin-potentiating effect of enalapril contributes little to its antihypertensive mechanism in SHR.     

Glomerular dimensions in spontaneously hypertensive rats: effects of AT1 antagonism

OBJECTIVE: A reduction in glomerular number and/or size has been implicated in the development of hypertension. This study investigated whether differences in glomerular number and/or size occur during the development of hypertension in the spontaneously hypertensive rat (SHR) and whether angiotensin II is responsible for any glomerular differences. METHODS: SHR (n=6) and Wistar-Kyoto (WKY) rats (n=6) were administered the angiotensin II type I receptor antagonist TCV-116 from 4 to 10 weeks of age. At 10 weeks of age, the kidneys from these rats and those from untreated SHR (n=6) and WKY rats (n=6) controls were perfusion fixed at physiological pressures and analysed using unbiased stereological techniques. RESULTS: There were no significant differences in glomerular number, glomerular volume or total glomerular volume between SHR and WKY rats. Treatment of SHR with TCV-116 significantly lowered systolic blood pressure but had no significant effect on glomerular number or volume or total glomerular volume. Treatment of WKY rats with TCV-116 reduced systolic blood pressure, body weight, glomerular volume and total glomerular volume; however, total glomerular volume per body weight of treated WKY rats was not significantly different from that of untreated WKY rats. CONCLUSION: There were no differences in glomerular number or volume in SHR compared with WKY rats at 10 weeks of age. We therefore conclude that glomerular changes are not responsible for the development of hypertension in SHR. Angiotensin II, via the type 1 receptor, does not contribute to glomerular growth during the development of hypertension in the SHR.     

Effect of antihypertensive therapy on renal artery structure in type 2 diabetic rats with hypertension

We have previously demonstrated that antihypertensive treatment with doxazosin (DZN), an alpha-adrenergic blocker, and lisinopril (LIS), an ACE inhibitor, reverse glomerular sclerosis in corpulent spontaneously hypertensive rats with type 2 diabetes. In this study, we examined the effects of the above-mentioned antihypertensive drugs alone and in combination on the structure of interlobular and arcuate arteries in these rats. Both male and female rats aged 6 months were treated with antihypertensive drugs for 16 weeks. Various structural parameters were evaluated by light microscopy, with the use of digital image analysis, in kidney sections stained with periodic acid-SCHIFF: Systolic blood pressure was significantly lower in treated than in untreated rats. Untreated diabetic rats had a significantly higher media/lumen ratio (smaller luminal diameter) of both arteries compared with the ratio in treated rats (for interlobular artery, 0.72+/-0.06 [no treatment], 0.49+/-0.03 [DZN treatment], 0.54+/-0.06 [LIS treatment], and 0.52+/-0.04 [combination therapy], P<0.05 to <0.001 for no treatment versus treatment; for arcuate artery, 0.66+/-0.11 [no treatment], 0.40+/-0.02 [DZN treatment], 0.39+/-0.04 [LIS treatment], and 0.40+/-0.03 [combination therapy], P<0.05 for no treatment versus treatment). Antihypertensive treatment caused significant increases in total arterial cross-sectional area, internal and external diameters, luminal and medial cross-sectional area, and medial thickness in both interlobular and arcuate arteries. The improvement in arterial structure after antihypertensive treatment was due to remodeling and growth of the vessels. Both DZN and LIS were equally efficacious, and combination therapy had no additive or synergistic effect.     

Effect of angiotensin II receptor antagonism on vascular hypertrophy and aortic impedance in abdominal aortic-banded rat

Vascular hypertrophy is considered to be an adaptive response to increased arterial wall stress in hypertension. Although there are several reports concerning the effect of angiotensin II inhibition on the development of vascular hypertrophy, little information is available as to its effect on vascular hypertrophy in parallel with the evaluation of arterial wall characteristics. The goal of this study was to evaluate the effect of angiotensin II type 1 receptor antagonist TCV-116 on pressure overload–induced vascular hypertrophy in parallel with the assessment of aortic impedance.Low dose (LD; 0.3 mg/kg/day) or high dose (HD; 3.0 mg/kg/day) of TCV-116 was administered to abdominal aortic-banded rats over 4 weeks; then hemodynamics and morphology were evaluated. In both the LD and HD groups, blood pressures were decreased to a similar extent compared with those of the vehicle-treated group (P < .05). Left ventricular (LV) weight and LV weight/body weight ratio was inhibited in both TCV-116–treated groups (P < .05), whereas the media cross-sectional area of the aorta was inhibited only in the HD group (P < .05). After the treatment of TCV-116 (LD, HD), total systemic resistance was decreased compared with the vehicle-treated group (P < .05), but there was no significant difference between the TCV-116–treated groups. In contrast, the first harmonic of the impedance modulus revealed the decrease only in the HD group (P < .05).TCV-116 attenuated the development of pressure overload LV hypertrophy and vascular hypertrophy as well; however, the dose of TCV-116 required for the inhibition of vascular hypertrophy was significantly higher than that for LV hypertrophy. Vascular hypertrophy may be less pressure dependent than cardiac hypertrophy. On chronic addition of high dose of TCV-116, arterial wave reflection was decreased in association with the attenuation of vascular hypertrophy.     

TCV-116 stimulates eNOS and caveolin-1 expression and improves coronary microvascular remodeling in normotensive and angiotensin II-induced hypertensive rats

Angiotensin II (Ang II) plays an important role as a modulator of vascular structure and function in arterial hypertension. This study investigated the effects of an Ang II type 1 receptor antagonist, TCV-116, on endothelial nitric oxide synthase (eNOS) mRNA and protein expression, and NOS activity and eNOS regulatory protein caveolin-1 protein expression in the left ventricle of Wistar-Kyoto rats treated for 2 weeks with Ang II (200 ng/kg/min) and evaluated these relations to myocardial remodeling. Rats given Ang II alone (ANGII) were compared with rats also receiving TCV-116 (ANGII-TCV). The eNOS mRNA and protein levels, and NOS activity and caveolin-1 protein expression in the left ventricle were significantly decreased in ANGII compared with control rats (CON), and were significantly increased in ANGII-TCV compared with ANGII. Moreover, compared with CON, the eNOS and caveolin-1 expression was significantly greater in CON treated with TCV-116. ANGII showed a significant increase of the wall-to-lumen ratio, perivascular and myocardial fibrosis, and type I collagen mRNA expression, with all these parameters being significantly improved by TCV-116. Thus, coronary microvascular and myocardial remodeling in normotensive and Ang II-induced hypertensive rats was significantly ameliorated by a subdepressor dose of TCV-116, which may be at least in part mediated by an increase in local eNOS mRNA and protein expression, and NOS activity in the left ventricle.     

Role of Angiotensin II in Reflex Tachycardia During Hypotension Caused by a Calcium Channel Blocker

Blood pressure and heart rate were measured by telemetry in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) to investigate the contribution of angiotensin II to the reflex tachycardia resulting from exaggerated hypotension caused by a high dose of a calcium channel blocker. Pre-treatment with TCV-116, an angiotensin II AT1 receptor antagonist, or enalapril partially attenuated the reflex tachycardia induced by manidipine, but TCV-116 had almost no effect on the sinus tachycardia induced by isoproterenol. The suppressive effects of TCV-116 against the reflex tachycardia tended to be more obvious in WKY than in SHR, though the difference was not statistically significant. Concurrent administration of propranolol almost completely inhibited both the reflex tachycardia and the sinus tachycardia in SHR and WKY, indicating that the sympathetic nervous system contributes to both types of tachycardia. We demonstrated that angiotensin II may be involved in the reflex tachycardia induced by calcium channel blockers probably via activation of some component of the sympathetic nervous system other than postsynaptic factors at the sinus node.     

Paradoxical structural effects in the unilaterally denervated spontaneously hypertensive rat kidney

OBJECTIVE: To determine the effects of chronic denervation on renal vascular structure and function in young adult spontaneously hypertensive rats (SHRs). DESIGN: Unilateral renal denervation (SHRUDx) or sham-operation (SHRS) was performed in SHRs at 6 weeks of age. At 10 weeks, rats were allocated to one of three procedures designed to examine renal vascular structure and function. A further group underwent bilateral renal denervation. METHODS: In SHRUDx or SHRS groups, either the kidneys were perfusion-fixed for stereological estimates of artery wall and lumen dimensions or for vascular casting to determine arteriole lumen diameters, or the rats were anaesthetized for estimation of glomerular capillary pressure. RESULTS: Chronic unilateral renal denervation had no significant effect on the development of hypertension between 6 and 10 weeks of age, as previously reported, but resulted in luminal narrowing of the interlobular artery (denervated group 52 +/- 2 mum, sham-operated group 64 +/- 1 mum; P < 0.01 for interaction between strain and treatment), without alterations in interlobular or arcuate artery wall dimensions. There were no significant effects on either afferent or efferent arteriole lumen diameters. Estimated glomerular capillary pressure was significantly lower in the denervated kidneys of SHRUDx (47 +/- 1 mmHg) compared with kidneys of the SHRS (50 +/- 1 mmHg; P < 0.04). Mean arterial pressure was approximately 12 mmHg lower in the bilaterally denervated SHRs than in the sham-operated SHRs. CONCLUSIONS: Although bilateral denervation attenuated the development of hypertension in SHRs, unilateral denervation did not, indicating that one neurally intact kidney was sufficient to drive the normal development of SHR hypertension, but only with apparent prohypertensive compensatory changes in the denervated kidney.     

Renin-angiotensin system blockade improves endothelial dysfunction in hypertension

Angiotensin-converting enzyme (ACE) inhibitor improves the impaired hyperpolarization and relaxation to acetylcholine (ACh) via endothelium-derived hyperpolarizing factor (EDHF) in arteries of spontaneously hypertensive rats (SHR). We tested whether the angiotensin type 1 (AT(1)) receptor antagonist also improves EDHF-mediated responses and whether the combined AT(1) receptor blockade and ACE inhibition exert any additional effects. SHR were treated with either AT(1) receptor antagonist TCV-116 (5 mg. kg(-1). d(-1)) (SHR-T), enalapril (40 mg. kg(-1). d(-1)) (SHR-E), or their combination (SHR-T&E) from 8 to 11 months of age. Age-matched, untreated SHR (SHR-C) and Wistar Kyoto (WKY) rats served as controls (n=8 to 12 in each group). Three treatments lowered blood pressure comparably. EDHF-mediated hyperpolarization to ACh in mesenteric arteries in the absence or presence of norepinephrine was significantly improved in all treated SHR. In addition, the hyperpolarization in the presence of norepinephrine was significantly greater in SHR-T&E than in SHR-E (ACh 10(-5) mol/L with norepinephrine: SHR-C -7; SHR-T -19; SHR-E -15; SHR-T&E -22; WKY -14 mV). EDHF-mediated relaxation, assessed in the presence of indomethacin and N:(G)-nitro-L-arginine, was markedly improved in all treated SHR. Hyperpolarization and relaxation to levcromakalim, a direct opener of ATP-sensitive K(+)-channel, were similar in all groups. These findings suggest that AT(1) receptor antagonists are as effective as ACE inhibitors in improving EDHF-mediated responses in SHR. The beneficial effects of the combined AT(1) receptor blockade and ACE inhibition appears to be for the most part similar to those of each intervention.     

Arterial hypertrophy in the fetal and neonatal spontaneously hypertensive rat

Large artery dimensions in prenatal and postnatal normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were evaluated to determine whether increased medial thickness is evident during early development. Microscopic cross-sections from perfusion-fixed aortas and carotid arteries of fetal (22-day gestation) and neonatal (5-day-old) animals were examined for numbers of laminae, luminal diameter and area, and medial thickness and area. SHR had a smaller mean body weight, and luminal diameters were the same in both strains. However, medial thickness and the numbers of laminae were significantly greater in SHR at both stages. Normalized ratios of medial thickness/luminal diameter and medial area/luminal area were also greater in SHR, indicating a disproportionate size of the arterial wall relative to the luminal space. Medial area/body weight ratios were also larger for SHR, suggesting the presence of greater medial mass per unit of body weight. The data support the view that the increased mass of the hypertensive arterial system is established in SHR as early as the fetal stage.     

Malfunction of arterial sarcoplasmic reticulum leading to faster and greater contraction induced by high-potassium depolarization in young spontaneously hypertensive rats.

The contribution of sarcoplasmic reticulum was studied with regard to the increase in arterial contraction induced by a high-potassium depolarization in spontaneously hypertensive rats (SHR). The 20 mmol/l potassium-induced contraction of femoral arteries was faster and greater in 6-week-old SHR than in age-matched normotensive Wistar-Kyoto (WKY) rats. Relaxation after washing the arteries with a Krebs solution was slower in SHR than in WKY rats. When the sarcoplasmic reticulum of SHR arteries had been depleted of calcium by caffeine in a calcium-free solution, the rate of high-potassium-induced contraction of the calcium-depleted SHR arteries was slowed, the same result as that with non-calcium-depleted WKY arteries. In ryanodine-treated arteries, the rate and magnitude of high-potassium-induced contraction were enhanced slightly in SHR and greatly in WKY rats, resulting in no final difference between SHR and WKY rats. Ryanodine slowed the relaxation rate in WKY rats but not in SHR. These results suggest that the diminution in ability of sarcoplasmic reticulum to sequester calcium may be responsible for the faster rate and greater magnitude of high-potassium-induced contraction with the slower relaxation in SHR arteries. We postulated that genetic malfunction of sarcoplasmic reticulum causes the increased contraction of arterial smooth muscle leading to the enhanced vasoconstriction and elevated blood pressure in SHR.     

Spontaneously occurring hypertrophic cardiomyopathy in the rat. I. Pathologic features

The gross anatomic and microscopic appearance of the hearts of young and adult WKY/NCrj rats was examined in comparison with that of normotensive Wistar and SHR/NCrj rats. In a substantial number of the WKY rats, the heart weight and thickness of ventricular septum were much greater than those of the Wistar and SHR rats. The ventricular septum to left ventricular free wall thickness ratio was greater than 1.3 in about one sixth of the WKY rats. In most of the hypertrophied WKY hearts, the transverse area of the left ventricular cavity was smaller in relation to the wall area than in the Wistar and SHR rat hearts, although in a few it was greater. Abnormal fiber arrangement, myocyte hypertrophy, and myocardial fibrosis were far more prominent in the hypertrophied myocardium of the WKY rats compared with the Wistar or SHR rats. Intramural arteries with marked wall thickening existed frequently in the hypertrophied and dilated hearts. Electron microscopic examination revealed marked disarrangement of bundles of myofilaments and widened Z-bands in the hypertrophied myocardium. Blood pressure was not elevated in the rats with cardiac hypertrophy. These findings show that a disease of the myocardium with the pathologic features similar to those of hypertrophic cardiomyopathy in man occurs spontaneously in rats.     

Effect of hydralazine on the mesenteric vasculature of hypertensive rats

To test whether structural alterations observed in the mesenteric vasculature of Wistar-Kyoto spontaneously hypertensive rats (SHR) were dependent on the presence of hypertension, male SHR and Wistar-Kyoto normotensive (WKY) rats were treated in utero and postnatally with hydralazine up to 28 weeks of age. Treated SHR, WKY, and untreated WKY rats had comparable blood pressures that were less than those of untreated SHR. Treatment altered the dimensions of the superior mesenteric, intermediate-sized, and small arteries of the mesenteric vasculature. In the case of the superior mesenteric artery and intermediate vessels, hydralazine treatment increased the lumen and medial cross-sectional areas of the arteries in WKY rats and slightly decreased both parameters in SHR. Within the small arteries, treatment significantly increased the lumen size in SHR but not WKY rats and had no significant effect on the media of the vessels. Despite the above alterations, the media-to-lumen cross-sectional area ratios remained significantly elevated in SHR over WKY rats in both the treated and control groups of animals within all classes of arteries. The results indicate that there is an inherent increase in the quantity of media surrounding the arteries of SHR when compared with WKY rats that cannot be abolished by normalizing the blood pressure in utero and postnatally with hydralazine treatment. In SHR, such changes persist not only in arteries that exhibit an increase in the media-to-lumen ratio before hypertension but also in the superior mesenteric artery in which an increase in the ratio occurs after hypertension development.     

Characterization of endothelium-dependent vasodilation and vasoconstriction in coronary arteries from spontaneously hypertensive rats

Coronary artery disease often occurs in patients with hypertension. The present study was designed to evaluate coronary vascular function in isolated coronary arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats and to determine the effect of antihypertensive treatment on coronary vascular responsiveness. Male SHR and WKY rats (12 to 14 weeks old) were divided into control and hydralazine-treated (120 mg/L drinking water for 10 days) groups. After 10 days, arterial pressure and heart rate were recorded while rats were conscious and unrestrained. Left ventricular coronary arteries (200 to 300 μm diameter) were isolated and intraluminal diameter was continuously recorded while vessels were maintained at a constant intraluminal pressure of 40 mm Hg. Relaxation of coronary arteries to both acetylcholine and nitroprusside was slightly, but significantly, enhanced in vessels from SHR compared to WKY rats. The enhanced relaxation was a specific effect, since isoproterenol induced similar relaxation in coronary arteries from SHR and WKY rats. Contraction to phenylephrine, but not endothelin-1, was augmented in coronary arteries from SHR compared to WKY rats. Treatment with hydralazine significantly lowered arterial pressure in SHR and WKY rats, but did not alter the enhanced contraction to phenylephrine or the enhanced relaxation to acetylcholine and nitroprusside in coronary arteries from SHR. These results indicate that coronary arteries of 12 to 14 week-old SHR do not have impaired endothelium-dependent relaxation, but do exhibit enhanced α-adrenoreceptor-mediated contraction that is not reduced by lowering arterial pressure.     

The Influence of Antihypertensive Treatment on the Renal Arterial Structure in Spontaneously Hypertensive Rats. A Morphometric Study

Spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHRSP) were treated with a combination of a beta₁-blocker (metoprolol) and a Ca⁺⁺-antagonist (felodipine) from 1 to 4 months or 4 to 6 months of age. The renal arterial trunks as well as more distal parts of the renal arterial bed were fixed by immersion and embedded in plastic. The media cross-sectional area and the length of the internal elastic membrane were measured on cross-sectioned arteries. The media thickness, luminal radius and the ratio between media thickness and luminal radius (m/r ratio) were then calculated for a standardized condition, assuming a smooth and circular internal elastic membrane, in which the arteries were compared. The m/r ratio was markedly reduced in the most proximal as well as in more distal arterial segments of the treated animals when compared with untreated rats of corresponding age and category. The quotient was somewhat reduced also when compared with normotensive controls (WKY) although the systolic blood pressure in younger treated rats was not fully normalized. The results may suggest that the present treatment influences the arterial walls not only by reducing the pressure load but also through pressure-independent mechanisms.     

Hepatic arteries in normotensive and spontaneously hypertensive rats. A morphometric study

The media thickness (m), luminal radius (r) and m/r ratio were determined in the hepatic arterial trunk and in intra-hepatic arterial branches as was the number of arteries per cm2 sectioned liver tissue in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto controls (WKY). The cross-sectional vessel parameters were calculated for a standardized condition, in which the internal elastic membrane is smooth and circular. Both intra-hepatic arterial branches and the hepatic arterial trunk showed significantly higher m/r ratios in SHR than in WKY controls. The luminal radius of the hepatic arterial trunk was larger in SHR than in WKY (P less than 0.05). The number of arteries per cm2 sectioned liver tissue was greater in SHR (P less than 0.05). It is suggested that the consequences of the increased m/r ratio in hepatic arteries of SHR are counteracted to some extent by an increased vascularization, but that during hypovolaemia and compensatory vasoconstriction, a greater decrease in hepatic arterial blood flow occurs in SHR than in WKY.     

复方降压片对高血压大鼠冠状动脉壁肥厚和储备力下降的影响

目的 研究复方降压片对高血压大鼠冠状动脉壁肥厚和储备力下降的影响。方法 4w大鼠设4组：分别为自发性高血压大鼠(SHR)组、SHR口服复方降压片组、SHR口服卡托普利组和正常血压大鼠(WKY)组，饲养12w。冠脉最大血流量用离体心脏灌注法测定。结果 复方降压片能显著降低SHR收缩压、冠状动脉横截面积，提高最大冠状动脉流量，与卡托普利相似。复方降压片能降低SHR的左心室重与体重比，但仍然显著高于WKY组和口服卡托普利组。结论 复方降压片能预防SHR冠状动脉壁肥厚、储备力下降，减轻左心室肥厚；冠状动脉血流储备力的损害程度和左心室肥厚程度不平行。     

Quantitative image analysis of choroid and retinal vasculature in SHR: a model of cerebrovascular hypertensive changes?

Retinal and choroids arteries changes were investigated ophthalmoscopically and with morphometric techniques in spontaneously hypertensive rats (SHR) of 26 weeks either untreated (control animals) or treated for 12 weeks equi-hypotensive doses of the Ca2+ antagonist nicardipine or of the non-dihydropyridine type vasodilatator hydralazine. Retinal and choroid arteries hypertensive changes were compared with those affecting pial and intracerebral arteries of frontal lobe. Ophthalmoscopic analysis revealed in control SHR a rarefaction of capillaries and a decrease of their length and area. Treatment with nicardipine and to a lesser extent with hydralazine countered ophthalmoscopic changes noticeable in SHR. Morphometric analysis revealed thickening of the wall and luminal narrowing of retinal, choroids, pial, and intracerebral arteries. Anti-hypertensive treatment decreased thickening of the arterial wall and increased luminal narrowing of different arteries investigated. Nicardipine was more effective than hydralazine in countering arterial hypertensive changes in SHR and displayed a vasodilatory activity on small sized retinal and cerebral arteries, that represent a vascular segment not sensitive to hydralazine. Comparative evaluation of the wall-to-lumen ratio revealed a similar pattern between retinal and intracerebral arteries, but not between other arteries investigated. This suggests that analysis of retinal arteries may be predictive of brain intracerebral arteries changes in hypertension.     

Impaired collateral artery development in spontaneously hypertensive rats

OBJECTIVE: To determine whether collateral artery development is impaired in spontaneously hypertensive (SHR) relative to normotensive (WKY) rats. METHODS: Sequential mesenteric arteries were ligated to create a collateral pathway responsible for the perfusion of approximately 50 first-order arterioles. Collateral development was assessed by measurement of in vivo arterial diameter before and 1 week after ligation. Histological and morphometric measurements were made from cross-sectional preparations of these arteries to evaluate intimal and medial cell numbers and medial area. eNOS expression was evaluated with Western blotting. RESULTS: One week after arterial ligation, collateral diameter was increased more in WKY than SHR both absolutely (137 +/- 9.1 versus 99 +/- 8.6 microm) and relative to same-animal controls (38 +/- 5.5% versus 13 +/- 7.1%). At the time of model creation, blood flow was elevated to comparable levels in both WKY and SHR, and wall shear rate in the SHR collateral was greater than both the SHR control and WKY collateral arteries. Endothelial cell number in arterial cross-section was increased in collaterals by 80% in WKY and only 22% in the SHR. eNOS expression was increased in the WKY (128%) but not in the SHR collateral. CONCLUSIONS: For equivalent arterial occlusion, the data demonstrate that collateral development is suppressed in the SHR as indicated by luminal expansion. This impairment of luminal expansion is associated with a decreased endothelial proliferation and the lack of an increase in eNOS expression.     

Enhanced vascular tone in the renal vasculature of spontaneously hypertensive rats

The renal microvascular responses of Wistar-Kyoto and spontaneously hypertensive rats to changes in perfusion pressure were compared using a juxtamedullary nephron microvascular preparation perfused in vitro with a physiological salt solution containing 5% albumin. In the spontaneously hypertensive rats, the internal diameters of arcuate and interlobular arteries and the proximal and distal afferent arterioles averaged 307 +/- 26, 52 +/- 2, 24 +/- 0.9, and 22 +/- 1.2 microns, respectively, at 80 mm Hg. They were 18-35% smaller (p less than 0.05) than the corresponding vessels measured in Wistar-Kyoto rats. In low calcium media, the arcuate and interlobular arteries and the proximal and distal afferent arterioles of spontaneously hypertensive rats exhibited a greater dilation than the vessels of Wistar-Kyoto rats. These observations suggest that the diameters of the preglomerular vasculature of the spontaneously hypertensive rats are reduced because of an elevated vascular tone rather than structural changes narrowing the lumen of these vessels. These results suggest that enhanced vascular tone in the preglomerular vasculature of juxtamedullary nephrons may contribute to the elevated renal medullary vascular resistance and resetting of the pressure-natriuretic relation previously observed in spontaneously hypertensive rats.