Renovascular Hypertension Group Research Articles

Abstract 12477: ER Stress Chop Depletion in Endothelial Cells Protects From Renovascular Hypertension Pathogenesis

Introduction: Renovascular hypertension poses a significant risk for cardiovascular diseases, with endoplasmic reticulum (ER) stress playing a critical role in their development. However, the specific impact of ER stress-induced C/EBP homologous protein (CHOP) expression in endothelial cells on renovascular hypertension-induced cardiovascular complications remains unexplored. This study investigates the effects of disrupting ER stress CHOP in endothelial cells on microvascular dysfunction associated with renovascular hypertension. Hypothesis: We hypothesize that deleting ER stress CHOP in endothelial cells (EC) can mitigate renovascular hypertension-induced vascular endothelial dysfunction. Methods: Eight-week-old male and female mice (CHOP flx/flx and EC CHOP-/- ) were divided into eight groups: control groups undergoing a sham operation for 4 weeks and renovascular hypertension groups subjected to 2-kidney-1-clip (2K1C) surgery for 4 weeks. Body weight, blood pressure, running performance, cardiac hypertrophy and fibrosis, lung edema, inflammation, vascular endothelial function, and signaling were assessed. Results: Male and female CHOP flx/flx mice subjected to 2K1C for four weeks exhibited hypertension, cardiac hypertrophy and fibrosis, lung edema, impaired running performance, and endothelium-dependent vascular relaxation dysfunction. In contrast, male and female EC CHOP-/- mice subjected to 2K1C for four weeks were protected against the pathogenesis of renovascular hypertension. Furthermore, mesenteric resistance arteries from CHOP flx/flx mice displayed reduced endothelial nitric oxide synthase (eNOS) phosphorylation, while EC HOP-/- mice showed no such effect. Conclusions: These findings emphasize the significance of targeting ER stress CHOP in endothelial cells of male and female mice to protect against the development and pathogenesis of renovascular hypertension.

Hibiscus attenuates renovascular hypertension-induced aortic remodeling dose dependently: the oxidative stress role and Ang II/cyclophilin A/ERK1/2 signaling.

Introduction: The high levels of angiotensin II (Ang II) can modify the vascular tone, enhance vascular smooth muscle cells (VSMCs) proliferation and hypertrophy and increase the inflammatory cellular infiltration into the vessel wall. The old herbal nonpharmacological agent, Hibiscus (HS) sabdariffa L has multiple cardioprotective impacts; thus, we investigated the role of HS extract in amelioration of renovascular hypertension (RVH)-induced aortic remodeling. Materials and methods: Thirty-five rats (7/group) were randomly allocated into 5 groups; group: I: Control-sham group, and RVH groups; II, III, IV, and V. The rats in RVH groups were subjected to the modified Goldblatt two-kidneys, one clip (2K1C) for induction of hypertension. In group: II, the rats were left untreated whereas in group III, IV, and V: RVH-rats were treated for 6weeks with low dose hibiscus (LDH), medium dose hibiscus (MDH), and high dose hibiscus (HDH) respectively. Results: We found that the augmented pro-contractile response of the aortic rings was ameliorated secondary to the in-vivo treatment with HS dose dependently. The cyclophilin A (CyPA) protein levels positively correlated with the vascular adhesion molecule-1 (VCAM-1) and ERK1/2, which, in turn, contribute to the reactive oxygen species (ROS) production. Daily HS intake modified aortic renovation by enhancing the antioxidant capacity, restraining hypertrophy and fibrosis, downregulation of the metastasis associated lung adenocarcinoma transcript (MALAT1), and cyclophilin A (CyPA)/ERK1/2 levels. Discussion: Adding to the multiple beneficial effects, HS aqueous extract was able to inhibit vascular smooth muscle cell proliferation induced by 2K1C model. Thus, adding more privilege for the utilization of the traditional herbal extracts to attenuate RVH-induced aortopathy.

Evaluation of Regional Myocardial Work Indices in Pediatric Essential and Renal or Renovascular Hypertension.

Myocardial work (MW) is an index of LV function based on pressure-strain loops and brachial cuff pressure measurement. MW has been proposed as more sensitive than conventional functional parameters, as it accounts for afterload and myocardial deformation. However, many studies have been limited to assessment of global MW indices, neglecting regional differences in cardiac associated with hypertension and consequent cardiac remodeling. We aimed to quantify regional MW in pediatric hypertension and compare the findings in renal or renovascular hypertension (RHTN) with essential hypertension (EHTN). We retrospectively assessed conventional markers of LV function, and both global and regional MW indices in 78 patients (49 males, 15.4 ± 2.94 years) with EHTN and RHTN. Peak systolic strain (PSS) in the basal septal segment was significantly impaired in patients with RHTN compared to EHTN (-13.00% [-15.50%; -13.00%] vs. -15.00% [-17.50%; -13.50%], P = 0.034). Similarly, basal septal MW indices were significantly elevated in patients with EHTN compared to RHTN, including MW efficiency (MWE) (95.0% [93.0%; 98.0%] vs. 94.0% [89.0%; 95.0%], P = 0.004) and constructive work (CW) (1700 mm Hg% (409 mm Hg%) vs. 1520 mm Hg% (336 mm Hg%), P = 0.037). Wasted work (WW) was significantly elevated in the RHTN group (79.0 mm Hg% [28.5 mm Hg%; 104 mm Hg%] vs. 105 mm Hg% [62.0 mm Hg%; 164 mm Hg%], P = 0.010). Significant differences in basal septal PSS and MW indices were observed between EHTN and RHTN. These findings highlight the usefulness of regional MW indices in assessing disease and may help differentiate between etiologies of pediatric hypertension.

GONADOECTOMY REDUCED THE DEGREE OF DEVELOPMENT OF RENOVASCULAR HYPERTENSION IN FEMALE RATS CAUSED BY STOP OF HIGH-SALT DIET

Objective: Excessive dietary salt intake is associated with an increased risk for hypertension. However, more research on measurement, storage and kinetics of sodium on blood pressure and sex hormones is required for dietary salt restrictions. The aim was to study the influence of gonadoectomy and stop of the high-salt diet on the development of renovascular hypertension (RVH) in female rats. Design and method: Was used the model of RVH 1 kidney 1 clip (1K1C) on female Wistar rats. All manipulations with animals were carried out according to the Council Directive 86/609/EEC principles. Gonadoectomized and normal rats of 8 weeks old (eight groups) were used. |There were two control groups: one with gonads © and one without (OvE). 4 groups out of remaining 6 groups of rats, had a high salt diet (4%). All rats from 6 groups the Goldblatt’s (1K1C) surgery was subjected. We had two groups with RVH with normal diet (0,25 % NaCl - RVH and OvE-RVH; two groups with high salt diet - RVH-HS and OvE-RVH-HS; and two groups with high salt diet, which was stop in two weeks after the Goldblatt’s (1K1C) surgery: RVH-ChHS and OvE-RVH-ChHS. In all animals the systemic blood pressure (mBP), diastolic (dBP), systolic (sBP) pressure, left ventricular pressure (LVP) and heart rate was directly measured. Left ventricular hypertrophy (LVH) was calculated as (LVweight)/(rat b.w.)*100%. Results: In all RVH groups, with and without gonads, the systemic arterial hypertension was developed. The most level of RVH was in RVH-ChHS rats: mBP - 145,7 ± 9,5 mmHg, dBP - 123,5 ± 10,4 mmHg, LVH - 0,214 ± 0,013 %. Ovariectomy leads to significant (p < 0,05) decrease in the degree of development of RVH. In OvE-RVH-ChHS was mBP 122,2 ± 6,3 mmHg, dBP 94,0 ± 6,0 mmHg and LVH 0,182 ± 0,009 %. Conclusions: Changing the diet from high salt to normal during the development of renovascular hypertension in female rats leads to an increase in the degree of disease. This effect was not observed in gonadoectomized female rats.

RENOVASCULAR HYPERTENSION-INDUCED CARDIAC CHANGES IN A RAT MODEL: FEASIBILITY OF CONVENTIONAL AND RECENT ECHOCARDIOGRAPHY

Objective: Renovascular hypertension (RH) is a major cause of secondary hypertension, and hypertension eventually led to cardiac remodeling in patients. Hypertension leads to concentric left ventricle hypertrophy, while hypervolemia originated from renal failure leads to eccentric hypertrophy. Both mechanisms occur in RH which results in complex cardiac remodeling. Uraemic cardiomyopathy results from RH is characterized by diastolic dysfunction, but traditional echocardiography was limited in evaluating the diastolic function due to unknown hemodynamic and morphologic status. Recently, non-invasive intraventricular pressure gradient (IVPG), a preload-independent diastolic function parameter, was established and showed higher sensitivity to evaluate diastolic dysfunctions, particularly during cardiomyopathy. However, no previous studies highlighted the feasibility of the IVPG in the diagnosis of RH. Design and method: Twelve rats were received subtotal nephrectomy in 1 week to produce progressive renal failure as the RH group. The other twelve rats were sham-operated as a control group. Conventional and color M-mode echocardiography was performed for isoflurane-anesthetized rats at 2nd, 4th, 6th, and 8th weeks post-operation. IVPG was evaluated based on the Euler equation. Results: Hypertension, polyuria and hypervolemia were observed in RH group from the 2nd, 4th, and 8th week, respectively. Marked left ventricle hypertrophy was evidenced at 6th (1.32 ± 0.28 vs 1.09 ± 0.09, p = 0.016) and 8th-week post-operation (1.34 ± 0.28 vs 1.16 ± 0.09, p = 0.014) that was more prominent in the posterior papillary muscle. Peak mitral E velocity in RH rats was higher than control at the 8th week (106.35 ± 16.04 vs 91.23 ± 10.82, p = 0.031). In contrast, tissue Doppler index, total IVPG, basal IVPG, and mid-to-apical IVPG showed no difference between groups throughout the experiment. Conclusions: Hypervolemia and RH lead to unclassified geometry in RH-associated cardiac remodeling. Blood pressure change precedes the change of preload during the development of RH cardiac remodeling.

Abstract 13777: Coexisting Metabolic Syndrome Inhibits Myocardial Mitophagy in Renovascular Hypertensive Pigs, Aggravating Cardiac Injury and Dysfunction

Introduction: Subjects with renovascular hypertension (RVH) often manifest with metabolic syndrome (MetS), increasing risk for heart failure, yet the mechanisms underlying cardiac injury remain unknown. Reduced mitophagy and accumulation of impaired mitochondria have been linked to progression of heart failure. Hypothesis: We hypothesized that superimposition of MetS on RVH in swine inhibits myocardial mitophagy, aggravating mitochondrial damage, cardiac injury and dysfunction. Methods: Pigs were studied after 16 weeks of RVH (renal artery stenosis) with or without diet-induced MetS, and Lean controls (n=6 each). Cardiac function was assessed in vivo (multidetector-CT), and cardiac mitochondrial structure, function, mitophagy, and myocardial fibrosis ex vivo. Results: MetS groups developed obesity, whereas RVH groups developed hypertension (Table). Mitochondrial matrix density and ATP production were lower and H2O2 production higher in both RVH groups vs. Lean and MetS (Fig. AB). However, MetS+RVH failed to activate mitophagy and downregulate myocardial expression of mitophagy-related microRNAs achieved by Lean+RVH (Fig. CD). Myocardial expression of the mitophagy marker PTEN-induced kinase (PINK)-1 inversely correlated with myocardial fibrosis (R 2 =0.195, p=0.031). Cardiac fibrosis, hypertrophy, and diastolic dysfunction (decreased E/A ratio) were greater in MetS+RVH vs. Lean+RVH (Table, Fig. E). Conclusions: MetS aggravates myocardial mitochondrial damage and dysfunction in swine RVH. MetS+RVH failed to activate mitophagy, resulting in greater cardiac remodeling, fibrosis, and diastolic dysfunction. Mitochondrial injury and impaired mitophagy may constitute important mechanisms and potential therapeutic targets to ameliorate cardiac structural damage and dysfunction in patients with coexisting MetS and RVH.

Myrtus communis improves cognitive impairment in renovascular hypertensive rats.

Myrtus communis has anti-inflammatory, neuroprotective and anticholinesterase activities yet there have been limited studies examining effects of Myrtus communis on cognitive functions. This study investigated the possible effects of Myrtus communis on changes in the cognitive functions of experimental renovascular hypertensive rats. Fifty-six Wistar-Albino rats were equally divided into 4 groups; sham-operated control, renovascular hypertension (RVH), ramipril (RVH + Ram) and Myrtus communis extract (RVH + MC) treatment groups. Goldblatt's 2-kidney 1-clip (2K1C) method was used to induce RVH. At the end of 9 weeks of treatment, after blood pressure recording, the animals underwent new object recognition test and Morris water maze (MWM) task. Following these tests, blood brain barrier (BBB) integrity was examined in 6 animals from each group. In the others after decapitation, osteopontin and interleukin (IL)-10 levels were measured in blood samples; while matrix metalloproteinase (MMP)-13, sodium potassium adenosine triphosphatase (Na+,K+-ATPase), cluster of differentiation (CD) 36, amyloid beta (Aβ), neprilysin levels, and acetylcholinesterase (AChE) activity were investigated in hippocampal tissues. In RVH group, high systolic blood pressure decreased serum IL-10 levels, increased serum osteopontin levels and also impaired BBB permeability. Hippocampal MMP-13, CD36, Aβ, neprilysin levels and AChE activities were elevated, while there were decreases in Na+,K+-ATPase levels. In new objet recognition test, discrimination index (DI) was determined as lower in saline-treated RVH group compared to control animals. In MWM training trail, 4th day performance in finding platform was significantly reduced in saline-treated RVH group compared to control group. RVH also decreased the time spent in target quadrant in probe test of MWM task compared to control group. In both of the treatment groups, all biochemical parameters were restored in parallel with improvement in the behavioral test performances. The results of this study suggest that Myrtus communis extract may improve the cognitive dysfunctions in hypertension through antihypertensive, anti-inflammatory and anticholinesterase activities.

Abstract 063: Urinary Mitochondrial DNA Copy Number Identifies Renal Mitochondrial Injury in Renovascular Hypertensive Patients Undergoing Renal Revascularization

Background: We have previously shown in patients with renovascular hypertension (RVH) that elevated urinary mtDNA copy numbers represent surrogate markers of renal mitochondrial injury. Revascularization with percutaneous transluminal renal angioplasty (PTRA) can lead to acute renal reperfusion injury. However, whether PTRA induces renal mitochondrial injury remains unknown. Methods: We prospectively measured urinary copy number of the mtDNA genes cytochrome-c oxidase-3 (COX3) and NADH dehydrogenase subunit-1 (ND1) by qPCR in 5 RVH patients before and 24hrs after PTRA. Five additional patients were treated before and during PTRA with the mitoprotective drug elamipretide (ELAM, 0.05 mg/kg/hr IV infusion). Healthy volunteers (HV) served as controls (n=5). Results: Baseline blood pressure was similarly elevated in both RVH groups, and eGFR lower than HV (Table). Baseline urinary COX3 and ND1 levels were similarly higher in both RVH groups compared with HV (Fig. A), and directly correlated with serum creatinine levels (R 2 =0.74, p=0.001 and R 2 =0.45, p=0.033, respectively). Over 3 months, eGFR increased only in ELAM-treated patients (Fig. B). Furthermore, the rise in urinary mtDNA 24hrs after PTRA was blunted in PTRA+ELAM versus PTRA+Placebo, and inversely correlated with the change in eGFR of 3 months after PTRA (Fig. C). Conclusion: PTRA induces an acute rise in urinary mtDNA levels, likely reflecting renal mitochondrial injury due to reperfusion injury that inhibits renal recovery. Mitoprotection in this cohort limited PTRA-associated mitochondrial injury and improved renal outcomes after revascularization.

Role of renin–angiotensin aldosterone system on short-term blood pressure variability in hypertensive patients

ABSTRACTThe relationship between the renin–angiotensin aldosterone system and short-term blood pressure variability has not been well elucidated. Here, we investigated whether blood pressure variability determined by ambulatory blood pressure monitoring differed among patients with primary aldosteronism (PA), renovascular hypertension (RVHT), and essential hypertension (EHT). We examined 25 patients with PA, 28 patients with RVHT, and 18 patients with EHT. Ambulatory blood pressure monitoring was conducted in all patients. Short-term blood pressure variability was evaluated by calculating the standard deviation (SD), coefficient of variation (CV), and average real variability (ARV) of 24-h, daytime, and nighttime blood pressure values. Day–night differences in blood pressure were also determined. The mean 24-h systolic blood pressure (SBP) and the mean diastolic blood pressure (DBP) in the PA and RVHT groups were found to be comparable to those in the EHT group. The SD, the CV, nor the ARV of the 24-h, daytime, and nighttime blood pressures showed any significant differences among the three groups. The day–night differences in blood pressure were comparable among the three groups. The short-term blood pressure variabilities evaluated by ambulatory blood pressure monitoring were comparable among the patients with EHT, RVHT, and PA. The results suggest that the renin–angiotensin aldosterone system may contribute little to short-term blood pressure variability in individuals with hypertension.

Estrogen receptor agonists alleviate cardiac and renal oxidative injury in rats with renovascular hypertension

ABSTRACTAlthough endogenous estrogen is known to offer cardiac and vascular protection, the involvement of estrogen receptors in mediating the protective effect of estrogen on hypertension-induced cardiovascular and renal injury is not fully explained. We aimed to investigate the effects of estrogen receptor (ER) agonists on oxidative injury, cardiovascular and renal functions of rats with renovascular hypertension (RVH). Female Sprague-Dawley rats were randomly divided as control and RVH groups, and RVH groups had either ovariectomy (OVX) or sham-OVX. Sham-OVX-RVH and OVX-RVH groups received either ERβ agonist diarylpropiolnitrile (1 mg/kg/day) or ERα agonist propyl pyrazole triol (1 mg/kg/day) for 6 weeks starting at the third week following the surgery. At the end of the 9th week, systolic blood pressures were recorded, cardiac functions were determined, and the contraction/relaxation responses of aortic rings were obtained. Serum creatinine levels, tissue malondialdehyde, glutathione, superoxide dismutase, catalase levels, and myeloperoxidase activity in heart and kidney samples were analyzed, and Na+, K+-ATPase activity was measured in kidney samples. In both sham-OVX and OVX rats, both agonists reduced blood pressure and reversed the impaired contractile performance of the heart, while ERβ agonist improved renal functions in both the OVX and non-OVX rats. Both agonists reduced neutrophil infiltration, lipid peroxidation, and elevated antioxidant levels in the heart, but a more ERβ-mediated protective effect was observed in the kidney. Our data suggest that activation of ERβ might play a role in preserving the function of the stenotic kidney and delaying the progression of renal injury, while both receptors mediate similar cardioprotective effects.

Regular swimming exercise performed either before or after the induction of renovascular hypertension alleviates oxidative renal injury in rats

Epidemiological studies have shown that regular exercise and increased aerobic fitness are associated with a decrease in allcause mortality and morbidity, including diseases related with high blood pressure. However, whether exercise has an antiinflammatory impact on the pathogenesis of hypertension was not elucidated yet. In the present study, to investigate the potential protective and therapeutic effects of exercise training (swimming for 30 min/day, 5 days/week for 9 weeks) on renovascular hypertension (RVH) 10-week-old male Wistar albino rats were divided into 4 groups as sham-operated sedentary control group, sedentary group with RVH (2-Kidney, 1-Clip Goldblatt) and two exercised RVH groups, which had 9-week training either before the surgery or after the surgery. Systolic blood pressures (SBP) were measured by the tail-cuff method on a weekly basis and at the end of 12 weeks, rats were decapitated to obtain kidneys. SBP were significantly higher in the sedentary RVH group than the control group, whereas in the trained RVH group measurements were not different than those of the control animals. In the renal tissues of the sedentary RVH group, malondialdehyde and myeloperoxidase levels were increased with a concomitant decrease in glutathione levels, while in the trained RVH group the levels were not different than those of the control group. Moreover, in the trained RVH group, superoxide dismutase and catalase levels measured as antioxidant parameters, were also significantly increased as compared with those of the sedentary RVH group. Current results demonstrate that regular moderate training controls high blood pressure in RVH, while RVH-induced oxidative damage in renal tissue is ameliorated through the modulation of oxidant-antioxidant balance. Exercise training does not only improve the circulatory functions, but it also initiates an anti-inflammatory process to defend against the angiotensin-II-induced renal injury. Keywords: Exercise, hypertension, kidney, oxidative stress

Cardiac Function In Renovascular Hypertensive Patients With and Without Renal Dysfunction

Hypertension impairs left ventricular (LV) diastolic and systolic function, which might be aggravated by inflammation or neurohumoral activation. We hypothesized that LV diastolic dysfunction is more common in patients with renovascular hypertension (RVHT) compared with essential hypertension (EHT). Hypertensive patients who underwent both renal imaging to exclude RVHT and cardiac echocardiography within a 3-year period were identified retrospectively. Patients with significant renovascular disease were included in the RVHT group (n = 75); those without significant renovascular disease were included in the EHT group (n = 69). Cardiac function and structure were compared. Baseline renal function was preserved (serum creatinine ≤ 2mg/dl) in EHT patients and impaired (serum creatinine > 2mg/dl) in only 9 RVHT patients. RVHT patients had higher systolic blood pressure, E/e' ratio, and greater prevalence of concentric hypertrophy but lower estimated glomerular-filtration-rate (eGFR) compared with EHT patients. Increased prevalence of LV diastolic dysfunction remained statistically significant in patients with RVHT after multivariable adjustment for age, sex, blood pressure, eGFR, diabetes, smoking, and statin use, with a relative risk (95% CI) for abnormal E/e' of 1.70 (95% confidence interval = 1.05-2.90; P = 0.03) compared with EHT. RVHT patients with severe renal dysfunction showed greater impairments in cardiac systolic and diastolic function compared with those in EHT patients or preserved renal function RVHT patients. Among hypertensive patients undergoing echocardiography, cardiac structure and diastolic function are impaired in RVHT patients compared with EHT patients and remain different after adjustment for multiple significant covariables. When associated with significant renal dysfunction, RVHT aggravates LV hypertrophy and both systolic and diastolic dysfunction. Hence, identification of RVHT and renal dysfunction warrants development of targeted management strategies.

Phase‐contrast MRI‐based elastography technique detects early hypertensive changes in ex vivo porcine aortic wall

To measure the elastic properties of ex vivo porcine aortas in control and hypertensive groups using a phase contrast magnetic resonance imaging (MRI)-based elastography technique. Female domestic pigs were randomized to a normal control group (N; n=5) or a renovascular hypertension group (HT; n=5) for the duration of 3 months. Mean arterial pressure was significantly higher in the hypertension group than in the control group (173+/-12 vs. 115+/-11 mmHg, P<or=0.05). The animals were euthanized after 3 months of hypertension and abdominal aortas harvested. The ex vivo aortic samples were then examined using a phase-contrast MRI-based elastography technique. The Young's modulus-wall thickness product, a reflection of vascular stiffness, was significantly higher in the hypertension group than in the control group (0.571+/-0.080 vs. 0.419+/-0.026, P<0.05). Histological analysis and staining confirmed increased intima-media thickness and collagen content in the hypertensive aorta, while elastin staining showed no difference. The current study shows that MR elastography offers a method to study the physiologic changes in the arterial wall secondary to early hypertension.

MYOCARDIAL IMAGING WITH 123I-METAIODOBENZYLGUANIDINE IN ESSENTIAL HYPERTENSION AND RENOVASCULAR HYPERTENSION

Iodine-123 metaiodobenzylguanidine (MIBG) myocardial imaging is considered to reflect cardiac sympathetic function. We performed myocardial MIBG scintigraphy and echocardiography in 27 patients with essential hypertension (EHT), 7 patients with renovascular hypertension (RVHT), and 8 normotensive subjects (NT) to investigate alterations in MIBG myocardial imaging in the presence of hypertension and left ventricular hypertrophy (LVH). EHT were divided into two groups based on LV wall thickness; EHT with LVH group (≥13 mm, n = 15) and EHT without LVH group (<13 mm, n = 12). The delayed uptake of MIBG was decreased, and the washout rate of MIBG was greater in the EHT with LVH group than EHT without LVH group or NT group. The washout rate was correlated with LV mass and LV diastolic function (as assessed by mitral flow). In RVHT group, the MIBG washout rate increased even without LVH, compared with NT and EHT without LVH groups. In summary, the washout rate of MIBG increased in parallel with the development of LVH in EHT and increased independently of the LV mass in RVHT. Cardiac sympathetic function could be altered in hypertensive LVH and in renovascular hypertension.

The effect of non-antihypertensive doses of angiotensin converting enzyme inhibitor on myocardial necrosis and hypertrophy in young rats with renovascular hypertension.

In renovascular hypertensive rats, low doses of angiotensin converting enzyme (ACE) inhibitors have been found to prevent myocardial hypertrophy independent of blood pressure level. This finding would suggest humoral rather than mechanical control of myocyte growth. The aim of this study was to examine the effect of nonantihypertensive doses of ACE inhibitor on myocardial hypertrophy and necrosis in hypertensive rats. Renovascular hypertension (RHT) was induced in four-week-old Wistar rats. Twenty-eight animals were treated for four weeks with three doses of ramipril (0.01, 0.1 or 1. 0 mg/kg/day, which are unable to lower blood pressure. Fourteen animals were not treated (RHT group). A sham operated, age/sex-matched group was used as control (n = 10). Myocardial histology was analysed in 3 microm thick sections of the ventricle stained with either haematoxylin-eosin, reticulin silver stain or Masson's trichrome. There was a significant correlation between systolic blood pressure and left ventricular to body weight ratio in both sets of animals: untreated plus controls and ramipril-treated rats. ACE inhibition prevented myocyte and perivascular necrosis and fibrosis in a dose-dependent manner. We conclude that myocardial hypertrophy in rats with renovascular hypertension is directly related to arterial pressure, and that this relationship is not affected by nonantihypertensive doses of ACE inhibitor. Myocardial necrosis/fibrosis and coronary artery damage induced by angiotensin II are prevented by ACE inhibitor in a dose-dependent manner, despite the presence of arterial hypertension.

EFFECT OF RENOVASCULAR HYPERTENSION ON CORONARY VASCULAR RESPONSIVITY IN CONSCIOUS DOGS

637 Hypertension is associated with a decreased ability of the coronary vasculature to dilate. Whether this is due to increased vasoconstrictor mechanisms or decreased vasodilatory mechanisms is not known. To examine the hypothesis that a dysfunctional endothelium may contribute to this, we compared the effects of blocking the endothelial-dependent vasodilator, nitric oxide (NO) in normotensive dogs to dogs with renovascular hypertension (RVH). Six dogs were chronically instrumented to measure left ventricular systolic and diastolic pressures, maximal rate of rise of LVP, heart rate, mean aortic pressure, and circumflex flow velocity (CFV). After normotensive studies were concluded, RVH was induced in 3 dogs by reducing left renal artery blood flow by 60% causing MAP to rise from 89±6 to 114±7 mmHg. Endothelial NO production was blocked in the normotensive state with 75 mg nitro-L-arginine (L-NA), i.c. Responses to intracoronary (i.c.) norepinephrine(NE), terbutaline (TRB), isoproterenol (ISO), and acetylcholine (ACh) were examined. The following data was collected and are expressed as% change in CFV from basal levels. TableTableThe similar responses observed in the Normotensive+L-NA and RVH groups suggests that the altered coronary vascular responsiveness observed in hypertension involves coronary vascular endothelial damage.

Prevention of angiotensin II induced myocyte necrosis and coronary vascular damage by lisinopril and losartan in the rat

The aims were to determine: (1) if angiotensin converting enzyme (ACE) inhibition and angiotensin II receptor blockade can prevent angiotensin II induced coronary vascular damage; (2) if the cardioprotective properties of ACE inhibition are dose dependent; and (3) if the cardioprotective properties of ACE inhibition are independent of its ability to prevent the conversion of angiotensin I to angiotensin II. Control rats and rats with either renovascular hypertension or continuous angiotensin II infusion (150 ng.min-1) for 14 d were subdivided into nine groups as follows: unoperated and untreated controls (n = 5); untreated renovascular hypertension (n = 8); untreated angiotensin II (n = 9); a renovascular hypertension group receiving one of the following doses of lisinopril 20 (n = 8), 2.5 (n = 4), and 0.6 (n = 6) mg.kg-1.d-1; a renovascular hypertension group receiving losartan (7.5 mg.d-1, n = 4); and an angiotensin II group receiving either the high dose of lisinopril (n = 6) or losartan (n = 4). Treatment was started one day before initiation of renovascular hypertension and angiotensin II infusion and continued throughout the study period. The number and size of necrotic areas and numbers of damaged coronary vessels were determined in sections of right and left ventricular tissue. Both coronary vascular injury and myocyte injury induced by angiotensin II were prevented by losartan. In renovascular hypertension, the lowest dose of lisinopril prevented vascular and attenuated myocyte damage but to a lesser degree than the higher doses. The cardioprotective ability of ACE inhibition is primarily the result of its ability to prevent the conversion of angiotensin I to angiotensin II. Angiotensin II related cardiomyocyte necrosis and coronary vascular damage are angiotensin type 1 receptor mediated and completely preventable with the receptor antagonist losartan. The ability of ACE inhibition to prevent this damage is dose dependent and primarily related to the degree to which the inhibitor can prevent the conversion of angiotensin I to angiotensin II.

Exaggerated blood pressure response to angiotensin II in patients with Cushing's syndrome due to adrenocortical adenoma.

We studied the roles played by the renin-angiotensin system in inducing hypertension in nine patients with Cushing's syndrome (CS) resulting from adrenocortical adenoma, and compared them with those in patients with primary aldosteronism (PA), renovascular hypertension (RVH) and essential hypertension (EH). In the CS group, each parameter, including serum potassium, plasma renin activity, plasma aldosterone, deoxycorticosterone and corticosterone concentrations, is within the normal range. However, plasma renin activity in the CS group was lower than that in the RVH group but higher than that in the PA group, and plasma aldosterone concentration was lower than that in each RVH or PA group. These findings indicated that the CS group had a different type of hypertension from that in either RVH or PA, in which the renin angiotensin system or mineralocorticoids play an important role in hypertension. Meanwhile, captopril (50 mg) administration either with or without indomethacin pretreatment decreased the mean blood pressure in the CS group, although captopril failed to change it in the PA group or in normal subjects. Furthermore, the pressor response to exogenous angiotensin II in the CS group was higher than that in the RVH or EH group, but was not different from that in the PA group. Thus, the hypertension in patients with CS due to adrenocortical adenoma appears to be mediated through a change in the renin-angiotensin system in the form of exaggerated pressor responses to angiotensin II.

Effect of isobaric hyperoxemia on erythropoietin secretion in hypertensive patients.

We assessed the influence of hyperoxemia on erythropoietin secretion in patients with various etiological forms of arterial hypertension (essential, n = 15; renoparenchymal, n = 16; renovascular, n = 15) and in 15 healthy subjects. On the first day of the study, blood was withdrawn at 1-hour intervals for the estimation of erythropoietin during a total of 6 hours and at 2-hour intervals for the assessment of PO2. Three days later the same parameters were assessed again at identical time intervals, but the subjects were breathing pure oxygen during the first 2 hours. Breathing with pure oxygen resulted in a significant increase of blood PO2 (184.85 +/- 4.47 versus 85.92 +/- 2.28 in essential, 185.21 +/- 5.52 versus 84.55 +/- 3.04 in renoparenchymal, and 181.7 +/- 3.14 versus 87.49 +/- 2.25 in renovascular hypertension groups and 189.84 +/- 5.2 versus 85.89 +/- 1.73 mm Hg in healthy subjects; P < .001 in all groups). Baseline plasma erythropoietin was not different among the groups (29.33 +/- 4.14 in essential, 24.56 +/- 3.09 in renoparenchymal, and 27.77 +/- 3.29 in renovascular hypertension groups and 24.23 +/- 2.70 mU/mL in the control group). The pattern of erythropoietin decline was different in the groups of hypertensive patients. In patients with essential hypertension, unlike in healthy subjects and patients with other etiological forms of arterial hypertension, only a very short-term suppression of erythropoietin levels was observed during hyperoxemia. No significant changes in blood pressure during breathing with pure oxygen were found in any of the studied groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Excess prevalence of supraaortic artery lesions in renovascular hypertension: an arteriographic study.

High renin or renovascular hypertension (RVH) has been associated with a higher risk of stroke than low-to-normal renin hypertension. Our present purpose was to investigate the angiographic prevalence and distribution of lesions of the supraaortic arteries in a series of consecutive patients with RVH compared with control patients with low-to-normal renin primary hypertension (PH). Thirty-two consecutive hypertensives (21 females, 11 males, aged 23-72 years) were investigated by renal and aortic arch digital subtraction arteriography (DSA). None of them had any history or symptoms of cerebrovascular disease. In each, the presence and severity of lesions at 17 different segments of the supraaortic arteries were evaluated and a score for supraaortic lesions was then calculated based on the number and severity of lesions. RVH was diagnosed in 16 patients with renal artery stenoses and normalization of blood pressure after percutaneous transluminal renal angioplasty (PTRA) (n = 12) or surgery (n = 4). The cause of renal artery obstruction was fibrodysplasia in 5 patients (31%) and atherosclerosis in 11 (69%). PH was diagnosed in 16 patients based on a normal renal DSA and exclusion of all other possible causes of hypertension. The RVH and PH groups were similar with respect to age, sex, body mass index, diabetes, smoking habits, serum triglycerides, cholesterol, and blood pressure values, and differed only in plasma renin activity (6.0 +/- 1.7 ng AngI/ml/h in RVH vs. 1.4 +/- 0.3 in PH, mean +/- SEM, p = 0.008). The score for supraaortic arterial lesions was significantly higher in RVH than in PH (181 +/- 32 vs. 17 +/- 9, p = 0.001). This difference was also evident when the five patients with fibrodysplasia were compared with five age- and sex-matched PH patients. The sites most frequently involved were the carotid artery bulb and the internal carotid artery sinus. At each affected site the score was higher for RVH than for PH. For the same demographic features and risk profile, RVH was associated with a higher prevalence and severity of supraaortic artery lesions than PH.