Advanced Stages Of Hypertension Research Articles

Max Solomonovich Kushakovsky. Life and work

Born on 1 December 1922 in the small Ukrainian town of Zvenigorodka, Cherkasy region; died on 11 Juni 2002 in Saint Petersburg.
 In 1947, M.S. Kushakovky graduated from the Military Medical Academy with merits, and his name was among the first to be put on Academy's marble plaque of honor after the war. At the beginning of 1951, M.S. Kushakovky defended his PhD. thesis on the topic Hemodynamic disorders and the condition of the precapillary bed in advanced stages of hypertension (on the issue of adaptive mechanisms). In September 1960 he received the academic title of Associate Professor. At the department, he was in charge of the clinical department, conducted practical classes with students of the 3rd and 6th years of the Military Medical Academy, lectured for military doctors of advanced courses on various sections of internal diseases, functional diagnostics of diseases of the heart and blood vessels. In 1965, the doctoral dissertation was successfully defended. In total, he published 17 monographs (including reprints) and more than 220 articles. Max Solomonovich was a member of the editorial boards of the journals Arterial Hypertension and Bulletin of Arrhythmology. For a long time, Max Solomonovich was a board member of the therapeutic and cardiological societies of Leningrad and St. Petersburg. Prof. M.S. Kushakovsky was a scientific advisor for 30 PhD students. In 2001, he was awarded the title of "Honorary Doctor" of the St. Petersburg Medical Academy of Postgraduate Education, as well as the title of "Honorary Cardiologist of Russia".
 In 2003, the Department of Cardiology of St. Petersburg Medical Academy of Postgraduate Education was named after him. Since 2011, after the merger of St. Petersburg Medical Academy of Postgraduate Education and Leningrad Sanitary and Hygienic Medical Institute, the combined Department of Hospital Therapy and Cardiology has born his name.

Suppression of β1-Adrenoceptor Autoantibodies is Involved in the Antiarrhythmic Effects of Omega-3 Fatty Acids in Male and Female Hypertensive Rats.

The arrhythmogenic potential of β1-adrenoceptor autoantibodies (β1-AA), as well as antiarrhythmic properties of omega-3 in heart diseases, have been reported while underlying mechanisms are poorly understood. We aimed to test our hypothesis that omega-3 (eicosapentaenoic acid-EPA, docosahexaenoic acid-DHA) may inhibit matrix metalloproteinase (MMP-2) activity to prevent cleavage of β1-AR and formation of β1-AA resulting in attenuation of pro-arrhythmic connexin-43 (Cx43) and protein kinase C (PKC) signaling in the diseased heart. We have demonstrated that the appearance and increase of β1-AA in blood serum of male and female 12-month-old spontaneously hypertensive rats (SHR) was associated with an increase of inducible ventricular fibrillation (VF) comparing to normotensive controls. In contrast, supplementation of hypertensive rats with omega-3 for two months suppressed β1-AA levels and reduced incidence of VF. Suppression of β1-AA was accompanied by a decrease of elevated myocardial MMP-2 activity, preservation of cardiac cell membrane integrity and Cx43 topology. Moreover, omega-3 abrogated decline in expression of total Cx43 as well as its phosphorylated forms at serine 368 along with PKC-ε, while decreased pro-fibrotic PKC-δ levels in hypertensive rat heart regardless the sex. The implication of MMP-2 in the action of omega-3 was also demonstrated in cultured cardiomyocytes in which desensitization of β1-AR due to permanent activation of β1-AR with isoproterenol was prevented by MMP-2 inhibitor or EPA. Collectively, these data support the notion that omega-3 via suppression of β1-AA mechanistically controlled by MMP-2 may attenuate abnormal of Cx43 and PKC-ε signaling; thus, abolish arrhythmia substrate and protect rats with an advanced stage of hypertension from malignant arrhythmias.

Ser-Tyr and Asn-Ala, vasorelaxing dipeptides found by comprehensive screening, reduce blood pressure via different age-dependent mechanisms.

To understand the changes in physiological responses due to aging, a number of bioactive probes based on different signal transduction pathways are necessary. In this study, we comprehensively and systematically investigated changes in blood vessel function with age using a 336-dipeptide library.In the early stage of hypertension, the most potent vasorelaxant dipeptide was Ser-Tyr (SY) in the mesenteric artery isolated from spontaneously hypertensive rats (SHR). SY-induced vasorelaxation and anti-hypertensive effects were blocked by L-NAME, an inhibitor of nitric oxide synthase (NOS), suggesting that SY activates the NO system. On the other hand, the patterns of dipeptides with vasorelaxation activity in early and advanced stages of hypertension were different. In the advanced stage, the most potent vasorelaxing dipeptide was Asn-Ala (NA). Orally administered NA (1.5 mg/kg) reduced the blood pressure in the advanced stage, at which drugs were sometimes less effective, and the anti-hypertensive effects lasted for 6 hr. The NA-induced vasorelaxation and anti-hypertensive activity was blocked by lorglumide, an antagonist of the cholecystokinin CCK1 receptor, suggesting that NA activated the CCK system.Taken together, in the early and advanced stages of hypertension, SY and NA exhibited vasorelaxing and anti-hypertensive effects via the NO and CCK systems, respectively.

Impaired Glymphatic Transport in Spontaneously Hypertensive Rats.

The glymphatic system is a brainwide CSF transport system that uses the perivascular space for fast inflow of CSF. Arterial pulsations are a major driver of glymphatic CSF inflow, and hypertension that causes vascular pathologies, such as arterial stiffening and perivascular alterations, may impede the inflow. We used dynamic contrast-enhanced MRI to assess the effect of hypertension on glymphatic transport kinetics in male young and adult spontaneously hypertensive (SHR) rats compared with age-matched normotensive Wistar-Kyoto rats (WKY). We anesthetized the rats with dexmedetomidine/isoflurane and infused paramagnetic contrast (Gd-DOTA) into the cisterna magna during dynamic contrast-enhanced MRI to quantify glymphatic transport kinetics. Structural MRI analysis showed that cerebroventricular volumes are larger and brain volumes significantly smaller in SHR compared with WKY rats, regardless of age. We observed ventricular reflux of Gd-DOTA in SHR rats only, indicating abnormal CSF flow dynamics secondary to innate hydrocephalus. One-tissue compartment analysis revealed impeded glymphatic transport of Gd-DOTA in SHR compared with WKY rats in both age groups, implying that glymphatic transport, including solute clearance from brain parenchyma, is impaired during evolving hypertension in young SHR, an effect that worsens in states of chronic hypertension. The study demonstrates the suppression of glymphatic clearance in SHR rats and thus offers new insight into the coexistence of hypertension and concomitant vascular pathologies in Alzheimer's disease. The study further highlights the importance of considering the distribution of tracers in the CSF compartment in the analysis of the glymphatic system.SIGNIFICANCE STATEMENT The glymphatic system contributes to the removal of amyloid β from the brain and is disrupted in Alzheimer's disease and aging. Using a rat model of hypertension, we measured gross CSF flow and tracked glymphatic influx and efflux rates with dynamic contrast-enhanced MRI, showing that glymphatic transport is compromised in both early and advanced stages of hypertension. The study provides a new perspective on the importance for brain metabolite and fluid homeostasis of maintaining healthy blood vessels, an increasingly pertinent issue in an aging population that in part may explain the link between vascular pathology and Alzheimer's disease.

Bioactive Compounds and Antihypertensive Activity of Extracts of Hibiscus sabdariffa L

Introduction: systemic arterial hypertension (SAH) is the main risk factor for the developing of cardiovascular disease, which the leading cause of death worldwide. One of the best ways to control blood pressure (BP) levels is the combination of lifestyle changes and drug therapy. However, pharmacotherapy is expensive and produces adverse reactions. Thus, it is necessary to find cheap, safe and effective alternative treatments. Hibiscus sabdariffa L. (HS) is a plant that is traditionally used in some countries to treat SAH, which has given rise to various investigations to determine their compounds and their antihypertensive activity. Aim: the present article aims at reviewing the reports that support the antihypertensive activity of extracts from HS in animal and human models Conclusions: the information collected from scientific literature suggests that HS extracts have antihypertensive effects in animals and humans, especially in early stages; however, more studies in advanced stages of hypertension are needed.

Is antioxidant therapy effective for advanced hypertension and renal injury?

nappropriate augmentation of reactive oxygen species(ROS) production reduces the bioavailability of anti-oxidant defenses [1,2] and plays a pivotal role in thepathophysiology of hypertension and renal injury [3–5].Experimental studies have indicated that enhanced ROSproduction is involved in vascular remodeling and endo-thelium dysfunction during the development of hyperten-sion [6]. Earlier clinical studies have also suggested a strongassociation between lower antioxidant levels and cardio-vascular risks [7].To date, much effort has been directed toward thebenefits of antioxidant therapy. Clinical studies, includingthe Cambridge Heart Antioxidant Study [8] and the Anti-oxidant Supplementation in Atherosclerosis PreventionStudy [9], have shown the beneficial effects of antioxidanttherapy for cardiovascular events. Large epidemiologicalstudies have also reported that dietary intake of anti-oxidants inverselycorrelateswithhypertension[9,10].Simi-larly, treatment with ascorbic acid significantly improvedSBP and DBP in mild-to-moderate hypertensive patients[11]. In experimental models of hypertension, vitamin Calone or in combination with vitamin E increased thesynthesis of nitric oxide and reduced blood pressure[12,13]. Furthermore, an antioxidant rich diet was shownto relieve hypertension and reduces renal immune cellinfiltration [14]. By contrast, many clinical trials failed todemonstrate any beneficial effects of antioxidant therapyon blood pressure [15–17] and cardiovascular events[18–20]. For example, the Heart Protection Study Collabo-rative Group studied high-risk individuals and showed thatalthoughantioxidantvitaminsupplementationsubstantiallyincreased blood vitamin concentrations, it did not produceany significant reductions in the incidence of any type ofcardiovascular disease [19].In this issue of Journal of Hypertension, the article‘Superoxide dismutase mimetic, tempol, aggravates renalinjury in advanced-stage stroke-prone spontaneouslyhypertensive rats’ by Sugama et al. [21] shows that anti-oxidanttherapywithasuperoxidemimetic,tempol,didnotreduce blood pressure in salt-loaded old stroke pronespontaneously hypertensive rats (SHRSP). The authors alsoshowed that although tempol effectively reduced oxidativestress in the kidney, it actually exacerbated the progressionof proteinuria and histological damage, such as glomerulo-sclerosis and interstitial fibrosis. These data suggestthat alternative pathways that are ROS-independent areinvolved in the pathogenesis of the advanced stage ofhypertension and renal injury in SHRSP. It is also possiblethat oxidative stress is merely a consequence of the acti-vation of these alternative pathways. However, Park et al.[22] had performed similar experiments in SHRSP andshown that long-term treatment with tempol from earlystages of hypertension did attenuate the progression ofhypertension through the prevention of vascular remodel-ing, and that this was associated with decreased vascularsuperoxide production and increased plasma antioxidantlevels.Thus, thequestion arisesastowhyantioxidanttherapiesshow such conflicting results in clinical and experimentalstudies [23]. Importantly, it is clear from the clinical studiesthatdosedifferencesdonotseemtoberesponsibleforsuchdiscrepant results [23]. One possible explanation for thediscrepancy in these studies is the different stage of hyper-tension and renal injury. In both clinical and experimentalstudies,beneficialeffectsofantioxidantsweremostlyfoundwhen interventions were started at an early stage. Forexample, Park et al. [22] administered tempol from an earlyage and showed an attenuation in the development ofhypertension in SHRSP, whereas Sugama et al. [21] failedto observe a blood pressure-lowering effect of tempolif treatment started at an advanced hypertensive stage.Inatomi et al. [24] have also shown that in patients withmild cardioembolic stroke, treatment with an antioxidant,edaravone, resulted in early functional improvement, butthese effects were not observed in late stages.Thefindingthatantioxidanttherapieshavenobeneficialeffects on advanced hypertension, as well as cardiovas-cular and renal diseases, suggest a potentialinvolvement of

Renal denervation in the treatment of drug-resistant hypertension: current knowledge and future perspectives

Resistant hypertension remains a challenging issue even for modern medicine. Therefore, research is focusing on the development of new technologies to optimize the treatment of this condition. It has been demonstrated that the dysfunction of the sympathetic nervous system is crucial in the development and maintenance of advanced stages of hypertension. Based on these findings, clinical trials have recently shown that catheter-based percutaneous renal denervation therapy is safe and effective in the treatment of resistant hypertension. This review discusses the current scientific knowledge of renal denervation therapy in resistant hypertension, including the different methods that have been described in the literature so far, as well as limitations of the available data. Furthermore, new potential targets for this fascinating therapy will be addressed.

Efficacy of renal denervation with a standard EP catheter in the 24-h ambulatory blood pressure monitoring—long-term follow-up

Resistant hypertension (HTN), defined as ambulatory blood pressure (BP) above 140/90 mmHg in spite of the concurrent use of three or more antihypertensive drugs, is a serious global health issue. It has been estimated that it may affect 20% to 30% of the HTN population [1]. Only about 30% of these patients are actually adequately controlled according to the target BP. A critical factor in resistant HTN is the hyperactivity of the sympathetic nervous system, which increases progressively and in parallel with HTN stages, indicating that more advanced stages of HTN have a greater adrenergic activity [2]. Recent research could show that catheter-based renal sympathetic denervation is effective in BP lowering in patients with resistant hypertension [3–7]. Usually, a special ablation catheter (Symplicity®, Flex-Catheter, Medtronic/Ardian Inc. USA) is used for this purpose. We could recently show that sympathetic denervation with a standard electrophysiology (EP) catheter is also effective in reduction of blood pressure during 3month follow-up (FU) [7]. The aim of this study was to evaluate the efficacy (measured in the 24-h ambulatory BPmonitoring) and safety of renal sympathetic denervation by using a standard EP catheter during long-term FU (12 months) with a larger group of patients. Therefore, 30 patients with drug-resistant hypertension despite treatment with at least four antihypertensive drugs (mean 6) were treated with RF ablation of the renal artery for sympathetic denervation. Baseline evaluation of patients included physical examination, review of medications, basic blood chemistries (including serum creatinine and proteinuria), and 24-h ambulatory BP measurement. All patients have had secondary forms of hypertension excluded. Baseline parameters and comorbidity of patients are shown in Table 1. The method of the ablation procedure with a standard EP catheter has been previously described indetail [7]. In brief, renal artery stenosiswas excludedby renal angiogram via femoral access. After this, a standard steerable radiofrequency (RF) ablation catheter with a 7-French diameter (Marinr®; Medtronic Inc., Minneapolis, MN, USA) was introduced into both renal arteries, consecutively. We applied six low-power RF applications along the length of each renal artery to create lesions (up to 1 min each). Energy delivery was titrated up to a maximum of 8–13 watts under continuously monitoring of impedance and temperature. During RF ablation, we administered intravenous unfractionated heparin with an activated clotting time target range between 250 and 300 s. Aspirin (100 mg per day) was given at least for 3 months following the procedure. Since RF ablation was accompanied by diffuse visceral abdominal pain, patients received intravenous analgesia (fentanyl at doses up to 0.15 mg and midazolam at doses up to 4 mg). The final renal angiogram at procedure termination showed only renal artery irregularities which were not flow limiting. The median fluoroscopy time in our study was 7.5±3.4 min. We did not observe any complications or side effects during FU. The mean reduction of 24-h ambulatory BP was −15.5 mmHg in systolic BP (p=0.01) and −3.4 mmHg in diastolic BP (p=0.03) at 1 month (n=30), −25.5 mmHg in systolic BP (p=0.0001) and −10.9 mmHg in diastolic BP (p=0.01) at 3 months (n=30), −24.1 mmHg in systolic BP (p=0.0003) and −10.6 mmHg in diastolic BP (p=0.002) at 6 months (n=20), and −15 mmHg in systolic BP (p=0.04) and −4.3 mmHg in diastolic BP (not significant) at 12 months (n=10). The results are shown in Fig. 1. In six patients the number of different drugs could be reduced (−1 in five patients, −2 in one patient) and in one patient the medication increased from 5 to 6 different drugs at 6-month FU. All other patients received unchanged doses of antihypertensive drugs. Serum creatinine and proteinuria as markers of renal function remained stable in the FUperiod. Renal duplex sonography performed at 3 and at 12 months revealed no renal artery stenosis or other abnormalities in all patients. The blood-pressure-lowering in our study was a little less than described in the Symplicity HTN trials that found a reduction in officebased BP of −32/−12 mmHg after 6 months [8] and −27/−17 mmHg after 12 months [3]. However, these differences might be due to methodical aspects. In contrast to the measurement of office-based BP by the Symplicity HTN-1 and HTN-2 investigators, we used 24-h ambulatory BP measurements for our analysis, possibly depicting more real life proportions of blood-pressure-lowering. In fact, the 24-h BP monitoring, which was available in 20 patients of the Symplicity HTN-2 trial at 6 months, showed only a decrease of −11/−7 mmHg from baseline to 6 months follow-up [8], underscoring the efficacy of our approach. Furthermore, after 6 months, 80% of our patients were responders to our treatment, defined by a reduction in BP of 10 mm Hg ormore, which is comparable with the response rate of 84% in the HTN-2 trial. However, we recognize that the small number of patients, especially

Increased Indexes of Thrombin Activation in Advanced Stages of Hypertension

Background: The hemostatic system plays an important role in thrombotic lesions, which can complicate the clinical course of hypertensive patients. The aim of this study was to verify a possible activation of the blood clotting processes, the evaluation of two markers of thrombin activation in 62 hypertensive patients, with and without vascular complications, compared with a control group. Methods and Results: In 22 patients with newly diagnosed uncomplicated essential hypertension, in 40 hypertensive patients with clinically evident vascular complications (20 patients with controlled blood pressure and 20 with uncontrolled and high blood pressure) and in 20 normotensive sex- and age-matched subjects, two indexes of thrombin generation and action, namely prothrombin fragment 1 + 2 (F1 + 2) and fibrinopeptide A (FPA) were evaluated. The observed values show an increase of the F1 + 2 levels in patients with overt vascular complications; those with higher blood pressure, moreover, showed FPA levels higher than those with controlled blood pressure. Conclusions: These results seem to indicate that plasma F1 + 2 levels are significantly elevated, as a marker of a thrombosis-prone status, in patients with organic damage. Successively, with progress of hypertension and increasing blood pressure, the evidence of elevated FPA levels seems to indicate a clear prethrombotic situation which could turn into a thrombotic state.

Future prospects for calcium antagonists.

In hypertensive disease, calcium antagonists (CA) affect the limiting step of increased vascular resistance. In the future, it is likely that the use of calcium antagonists will be extended to the early stage of hypertension, which is characterised predominantly by preglomerular vasoconstriction and only discrete impairment of renal function. In the advanced stages of hypertension they will be used to prevent vascular remodelling and to limit renal and cardiac tissue damage. By preventing excessive calcium overload, calcium antagonists preserve tissue integrity and reverse the progression of specific vascular pathologies such as arteriosclerosis and microangiopathy through mechanisms independent of their blood pressure-lowering effect. The protective effect demonstrated by nifedipine against toxic and radiation-induced changes in nonvascular tissue in animal models merits specific attention.

The pathophysiology of hypertension. Differences between young and elderly patients.

While structural and functional signs of a genetic predisposition to hypertension may sometimes be detected in the juvenile cardiovascular system, the borderline phase characteristic of young hypertensive patients is often dominated by a 'hyperkinetic' circulatory state. The modest pressure elevation is then mainly due to an increase in cardiac output and accentuated responses to neurohormonal stimuli. During the development of established hypertension, cardiac output gradually returns to normal and the high pressure state is largely a result of chronically elevated systemic resistance with cardiovascular 'structural upward resetting'. Signs of increased neurohormonal influences usually become less prominent. In general, the chronic high pressure state tends to accelerate ordinary cardiovascular aging, and therefore the advanced stages of primary hypertension are characterised by considerable interstitial infiltration with consequent wall stiffening and reduced aortic 'Windkessel' function. This further enhances the end-systolic afterload for the left ventricle, while at the same time myocardial strength and coronary reserve tend to decline. Age-related reductions in barostat function, reflex efficiency, and renal excretory capacity are also accentuated, and endothelial function suffers. Thus, the cardiovascular system in elderly hypertensive patients is generally characterised by pronounced and apparently poorly reversible structural changes. Nevertheless, recent studies indicate that even late phases of hypertension in elderly patients may respond favourably to treatment. This may predominantly reflect the high risk of serious cardiovascular damage in the elderly, but also that therapeutic intervention is able to reverse the structural changes observed in the advanced stages of hypertension.

Does Isovolumic Relaxation Time Reflect the Severity of Left Ventricular Hypertrophy in Patients with Essential Hypertension?

To elucidate whether the isovolumic relaxation time (IRT) reflects the severity of left ventricular hypertrophy, IRT and left ventricular mass index (LVMI) were measured in 43 patients with essential hypertension and in 17 normotensive controls. The hypertensive patients were subdivided into three groups based on interventricular septal thickness (IVST) and left ventricular posterior wall thickness (PWT), determined echocardiographically, and clinical symptoms. IVST and PWT in group 1 patients (n = 10) were less than 10 mm, IVST and/or PWT in group 2 (n = 23) were 10 mm or greater, and the hypertensive patients in group 3 (n = 10) were in class III of the New York Heart Association Classification of hypertension. The IRT was prolonged in accordance with the increase in LVMI in groups 1 and 2. Though the LVMI showed no significant difference between normotensive controls and group 1, the IRT was significantly longer in group 1 patients (p < 0.05). The LVMI was markedly greater in group 3 than in group 2 (p < 0.01), but the IRT showed no significant difference. This finding indicates that there might be a limit of IRT prolongation associated with myocardial hypertrophy due to essential hypertension. In conclusion, IRT reflects the severity of left ventricular hypertrophy in patients with mild to moderate essential hypertension, but does not in advanced stages of hypertension.

Renal function, plasma renin, and spontaneous diuresis in an advanced stage of hypertension in rats.

Relationship of renal function and plasma renin level to a spontaneous diuresis in an advanced stage of hypertension was examined in the stroke-prone spontaneously hypertensive rats (SHRSP). For a comparison, it was also investigated in 2 kidney 1 clip (1CR) and 2 kidney 2 clip (2CR) models of renovascular hypertensive rats. The spontaneous diuresis was usually associated with an elevation of plasma renin level and an impairment of renal function in SHRSP and 1CR. In SHRSP, renal plasma flow showed an inverse correlation to the plasma renin level. The diuresis, however, is not prerequisite to the increase in plasma renin or to the renal impairment, since the latter changes were not always accompanied by diuresis. No correlations were found between these factors in 2CR. Remittent diuresis was observed in many 2CRs and 2 SHRSPs with normal renal function, indicating that renal damage underlies the continuous progression of the diuresis observed in most cases of SHRSP and 1CR. Both sodium and potassium balances tended to be negative in 1CR and 2CR in the diuretic phase, whereas potassium alone showed this tendency in SHRSP. The negative balances, if any, were not due to an excessive loss of the electrolytes but attributed mainly to a decrease in intake. The critical level of blood pressure for the spontaneous diuresis was highest in SHRSP and lowest in 1CR. It is probable that an interaction and cooperation between high blood pressure, impaired renal function and high plasma renin participate in the mechanism of the spontaneous diuresis during the development of malignant phase of hypertension of the rat.

Catecholamine turnover changes in hypothalamus and dorsal midline area of the caudal medulla oblongata of spontaneously hypertensive rats

The central noradrenaline (NA) and adrenaline (A) turnover in 15–16-week-old stroke prone, spontaneously hypertensive (sp-SH) female rats in an advanced stage of hypertension was found to differ from that of normotensive Wistar-Kyoto (WKy) control rats. The catecholamine (CA) levels were measured after inhibition of dopamine-β-hydroxylase (DBH) or of phenylethanolamine- N-methyltransferase (PNMT). In the hypertensive rats the dopamine (DA) and NA levels and the NA turnover were reduced in the hypothalamus, while in the dorsal part of the caudal medulla oblongata NA levels and A turnover were reduced. Changes in hypothalamic DA and NA mechanisms and in A mechanisms in medulla oblongata may therefore be of importance in the blood pressure regulation of sp-SH rats.

Low renin hypertension.

Low renin hypertension probably does not represent a clinical entity. In many patients with low renin hypertension blood pressure is normalized by treatment with diuretics only; in these patients a (genetic?) sensitivity to salt might play a predominant role in the pathogenesis of hypertension and renin suppression. In another group of patients renin suppression appears to be secondary to the hypertensive process. This is indicated by the observation that prevalence of low renin hypertension increases with age and that it is more frequent in advanced stages of hypertension. Also a diminished sympathetic tone might play a part in the renin unresponsiveness. Finally, although no positive evidence was found, the possibility cannot be excluded that, at least in some cases, a mineralocorticoid other than aldosterone is involved. Neither in normotensive subjects nor in hypertensive patients, both with normal and with low plasma renin was a correlation between plasma renin concentration and plasma aldosterone concentration following stimulation by upright posture found. More detailed studies will be necessary to clarify the relationship between the renin-angiotensin system and aldosterone secretion during upright posture, in particular in patients with low renin hypertension.

Plasma renin and vascular complications in substrains of the spontaneously hypertensive rat, with a reference to water and electrolyte balance.

The stroke-prone and stroke-resistant substrains of the spontaneously hypertensive rat (SHR) were employed for an evaluation of possible role of reninangiotensin system and of water and electrolyte balances in inducing hypertensive vascular lesions. Serial study on plasma renin level and vascular changes did not support the hypothesis that plasma renin is a major risk factor in the development of cardiovascular complications. The high plasma renin level seen in advanced stages of hypertension appeared to be a result of severe vascular damages, indicating malignant transformation of hypertension. In this state, water turnover was enhanced without any abnormality in electrolyte balances. A possible mechanism involved in the malignant course of hypertension is discussed.

Pathogenesis of cerebral hemorrhages in experimental hypertension in rabbits with particular reference to acute vascular lesions (fibrinoid necrosis) of small arteries and arterioles.

The effect of salt, high blood pressure and renal factors on the development of acute vascular lesions of small arteries and arterioles and cerebral hemorrhages was studied in rabbits through production of hypertension by means of unilateral or bilateral renal injuries. 1 . Massive cerebral hemorrhages were induced in animals with bilateral renal injuries and these were never induced in animals with one ischemic and the other intact kidneys even during advanced stage of hypertension. 2. Animals died, due to cerebral hemorrhages usually accompanied with marked high blood pressure during the advanced stage. However, cerebral hemorrhages were induced in animals with blood pressure less than 120 mmHg as well as in those with higher blood pressure during the early stage after renal manipulation. 3. Among acute arterial lesions, the most prominent lesion consisted of the fibrinoid necrosis of small arteries and arterioles with a wide distribution. The vessels of gastro-intestinal tract especially those of stomack were predominantly vulneable. 4. Fibrinoid necrosis of small arteries and arterioles in the brain was found all of the experiments with cerebral hemorrhages. The incidence of the acute arterial lesion in the brain and other tissues was higher in experimental groups in which cerebral hemorrhages developed. These results convince that the fibrinoid necrosis of small arteries and arterioles in the brain is the primary vascular lesion responsible for cerebral hemorrhages. 5. The incidence of the fibrinoid necrosis in small vessels was not related with the grade of high blood pressure especially during the early stage of hypertension. It was not clear, however, how much the high blood pressure itself contributed to the development of the acute arterial lesion during the advanced stage of hypertension. 6. Renal factors played a great role in producing the acute arterial lesion (fibrinoid necrosis). A renal factor other than renin seemed to be responsible for the acute arterial lesion and cerebral hemorrhages. The acute arterial lesion was induced in animals with one ischemic and the other intact kidneys during the early stage of hypertension. But, it was scarcely produced during the advanced stage of hypertension. Bilateral renal injuries (two ischemic kidneys or one ischemic kidney after one nephrectomy) enhanced the development of the acute arterial lesion. 7. High salt intake augumented the incidence of the acute arterial lesion.

Electron microscopic studies on the adrenal medulla and adrenal cortex of hypertensive rats. 1. Spontaneously hypertensive rats.

Spontaneously hypertensive rats (OKAMOTO and AOKI) (SHR) in the prehypertensive stage (40-60 days after birth), initial stage of hypertension (4-6 months after birth) and advanced stage of hypertension (more than one year after birth) were used in an electron microdscopic study of the fine structure of the zona fasciculata of the adrenal cortex and the noradrenaline storing cells of the adrenal medulla and compared with normal control rats of corresponding ages. The following results were obtained. 1. The number of noradrenaline storing granules within the adrenal medullary cells and the number of vesicles representing the postsecretory state were signiflcantly larger in the SHR than in normal rats at each stage. On ultra-thin slices, the number of granules was about I .3 times the control and the number of vesicles about 1.4-2.6 times the control. The granules revealed variations in size. 2. The cells In the zona fasciculata of SHR showed an increase in the number of RNA granules and mitochondria as compared with normal rats at each stage. An increase in number and distention of the smooth surfaced endoplasmic reticulum was pronounced, and closely resembled the finding recognized following ACTH administration. 3. The cells in the zona glomerulosa of SHR at initial stage of hypertension showed a slight increase in the number of mitochondria as compared with normal rats. Morphological changes in the zona reticularis were not recognized through electron microscopy at each stage.

Histometric and histochemical studies of the hypothalamo-hypophyseal neurosecretory system of spontaneously hypertensive rats and rats with experimental hypertension.

Histometric and histochemical studies were performed on the two hypothalamic neurosecretory nuclei (i.e., the supraoptic and paraventricular nuclei) and a few other hypothalamic nuclei in spontaneously hypertensive rats (S.H. rats) and in rats with various forms of experimental hypertension. 1. The following results were obtained in the histometric study. (1) The cellular and nuclear size of the nerve cells of the supraoptic nucleus was significantly greater in the S.H. rats than in the controls throughout the pre-hypertensive, initial and advanced stages of hypertension. In the advanced stage cells were 30% and nuclei 20% larger than normal ; in the pre-hypertensive stage 17% and 12% and in the initial stage 7% and 8% larger, respectively. The nuclear and cellular size of the nerve cells in the supraoptic nucleus tended to be greater than normal in the rats with DOCA-hypertension and with renal infarction hypertension, although the number of cases examined, was too small (3 cases) to be significant. (2) The paraventricular nucleus of the S.H. rats showed nearly the same results as the supraoptic nucleus with significant differences except for the nuclear size in the pre-hypertensive stage. The cells were 14-19% larger than normal in all the stages, the nuclei less than 11% larger than normal. In the rats with experimental hypertension cellular and nuclear size tended to be greater than in the controls, but the number of cases examined was small (3 cases). (3) The cellular size of the nerve cells in the ventromedial nucleus in these hypertensive animals remained normal. 2. The following results were obtained in the histochemical study of neurosecretory material. The amount of neurosecretory material in the hypothalamic neurosecretory nuclei and posterior pituitary of most of these hypertensive animals was not very different from that in the controls, although it was more prominent in some.

On histochemical studies of the various organs of spontaneously hypertensive rats.

Spontaneously hypertensive rats (OKAMOTO and AOKI) were sacrificed in the pre-hypertensive stage (40 to 60 days after birth), initial stage (5 to 7 months after birth) or advanced stage of hypertension (13 to 17 months after birth). Twenty-one kinds of enzyme activity were examined histochemical in the adrenals, thyroid, kidneys, heart, liver and pancreas, and noradrenalin reaction was also applied to the adrenal medulla. Each positive finding in spontaneously hypertensive rats was obtained by comparing it with the reaction of the same sex normotensive Wistar strain rats with almost the same survival duration. 1) Glucose-6-phosphate dehydrogenase and triphosphopyridine nucleotide diaphorase activity increased in the zona fasciculata and reticularis of the adrenal cortex of spontaneously hypertensive rats with dominant elevation of the former activity in the middle and outer part of the fascicular zone from the pre-hypertensive stage. More prominent increase was observed after the incidence of hypertension. 2) The noradrenalin-storing cell islets in the adrenal medulla of spontaneously hypertensive rats indicated a stronger reaction with about twice the mean dimensional ratio to the whole adrenal medulla in all stages than was found in normotensives. 3) Acid phosphatase activity in the follicular cells of the thyroid in spontaneously hypertensive rats was elevated from the pre-hypertensive stage. 4) Adenosine triphosphatase activity of the renal interlobular arteries of spontaneously hypertensive rats showed an increase in about half the cases in the pre-hypertensive stage and in all cases after the incidence of hypertension. 5) Glucose-6-phosphate dehydrogenase and triphophopyridine nucleotide diaphorase activity in the zona glomerulosa of the adrenal cortex of spontaneously hypertensive rats rose after the incidence of hypertension, though the latter activity showed only a slightly in-creasing tendency. 6) Increase of adenosine triphosphatase activity in the walls of renal interlobular arteries and vasa afferens of spontaneously hypertensive rats was detected in all cases after the incidence of hypertension. 7) Gradual elevation of monoamine oxidase activity in the heart muscle of spontaneously hypertensive rats occurred after the incidence of hypertension. 8) No constant difference was found in the results of other kinds of enzyme histochemical comparisons of adrenals, thyroid, kidneys or heart, or in the enzyme histochemistry of the liver or pancreas, either. 9) From the above-mentioned evidence, it may be assumed that there exists from the pre-hypertensive stage in spontaneously hypertensive rats, an increase of (1) glucocorticoids synthesis in the adrenal cortex ; (2) either synthesis of noradrenalin, or retention of it in the adrenal medulla ; (3) secretory activity of the thyroid and (4) the contracting tendency of the renal vessels of medium caliber. In addition, after the incidence of hypertension, elevation of (5) aldosterone synthesis in the zona glomerulosa of the adrenal cortex ; (6) the contraction of the renal vessels and (7) the catecholamine metabolism, primarily the oxidative deamination in the heart muscle is also indicated.