Angiotensin (Ang) II plays an important role in regulating cardiovascular hemodynamics as well as cardiovascular structure. At least two distinct receptor subtypes of Ang II have been defined on the basis of their differential pharmacological and biochemical properties, and designated as Ang II type 1(AT1) receptor and type 2 (AT2) receptor. Most of the known effects of Ang II in adult tissues are attributable to the AT1 receptor. Recent cloning of the AT2 receptor has revealed a variety of new physiological effects of Ang II. AT1 and AT2 receptors belong to the seven-transmembrane receptor family. However, the function and signaling mechanism of these receptor subtypes are quite different. These receptors seem to exert opposite effects in terms of cardiovascular hemodynamics and cell growth. Growth inhibitory effects of AT2 receptors are unique in that this receptor activates a variety of phosphatases and cross talks with the signaling of other seven-transmembrane, G protein-coupled receptors, as well as other classes of growth factor receptors. We will review recent concepts of the molecular and cellular mechanisms of AT2 receptor action in this article. (Hypertens Res 1999; 22: 67-74)

View full abstract

The effects of a combined therapy with a calcium channel antagonist and αβ-blocker in patients with accelerated-malignant hypertension on blood pressure and renal function were examined. Thirteen patients presented with the clinical features of malignant hypertension (diastolic blood pressure >130 mmHg, retinal damage and progressive renal failure) at our hospital, over the 3 yr period from 1995 to 1997. These patients were treated with both a calcium antagonist, 60-80mg/d dose of long acting nifedipine, and an αβ-blocker, 20mg/d dose of arotinolol, for over 12 mo. At admission, the average blood pressure of the patients was 233±8/144±3mmHg. The level of serum creatinine in these patients was 6.2±1.0mg/dl. Intermittent hemodialysis therapy was introduced in 7 patients. Three days after treatment, blood pressure decreased to 162±4/102±4mmHg. A month later, blood pressure decreased to 148±3/89±2mmHg and serum creatinine levels were 3.6±0.4mg/dl. Renal function in these patients improved, and they completely recovered from renal dysfunction, allowing withdrawal of haemodialysis therapy. One year later, the blood pressure in all of these patients was well controlled and no further renal deterioration was observed, except in one patient. Despite the reduction in blood pressure, one patient was on hemodialysis three times a week after 8 mo of treatment. From these finding, it is concluded that combination therapy with a calcium antagonist and αβ-blocker is effective in both the reduction of highly elevated blood pressure and protection of the kidneys, resulting in amelioration of accelerated-malignant hypertension. (Hypertens Res 1999; 22: 75-80)

View full abstract

Renin-angiotensin system activity has been shown to affect insulin sensitivity. However, the relationship between I/D polymorphism and insulin resistance is controversial. Therefore, we examined the relationship between the ACE genotype and insulin sensitivity in 51 Japanese hypertensive patients using the glucose clamp technique. The ACE genotype distribution in the hypertensive subjects was: 7 subjects with DD, 20 subjects with ID, and 24 subjects with II. Insulin sensitivity in terms of the glucose disposal rate was not significantly different among the three ACE genotypes, although there was a tendency for insulin sensitivity to decrease in the order of II, ID and DD, DD being the lowest. These findings are contrary to previous reports that insulin sensitivity was increased in normotensive subjects with the DD genotype who were Caucasian or African-American. There might be a difference due to race and whether the subjects are hypertensive or obese. We concluded that insulin sensitivity was not different among the ACE genotypes in the Japanese hypertensive subjects, supporting a previous report on the Chinese population. To date, insulin sensitivity has not been found to differ with ACE genotypes in the oriental population. (Hypertens Res 1999; 22: 81-84)

View full abstract

To identify factors that influence changes in the activities of daily living (ADL) assessed by a standardized scoring system, ADL-20, and factors affecting the self-estimate of the changes in ADL, we conducted a 1-yr follow-up study of 1, 163 outpatients aged 50yr or older. The follow-up rate was 83.1%. A decrease in the ADL score was associated with advancing age and a lower prescription rate of β-blockers. Analysis of the modalities of ADL revealed an association between a decreasing mobility score and a lower prescription rate of β-blockers. In patients with impaired ADL at the time of enrollment, worsening of the ADL score was also associated with a lower baseline ADL score and a history of cardiovascular events. The prescription rate of diuretics was lower in patients who exhibited an improvement in ADL score. There was a considerable dissociation between the self-estimate of changes in ADL and the actual change in ADL-20 score. In more than 60% of patients with impaired baseline ADL, the self-estimate of changes was worse than the actual change in the ADL score. The "worse-than-actual" self-estimate of changes in ADL was associated with a higher prescription rate of β-blockers. Thus, a history of cardiovascular events accelerates the aging-related deterioration of ADL. The use of a β-blocker may worsen the self-estimate of the changes in ADL, while the actual ADL is preserved or slightly improved during β-blocker therapy. (Hypertens Res 1999; 22: 85-93)

View full abstract

There are inconsistent reports that the angiotensinogen (ATG) variant Met²³⁵→Thr (T235) allele and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) variants are associated with hypertension and related target organ damage. Both high blood pressure (BP) and abnormal diurnal BP variation patterns are related to target organ damage, but it is not known whether the above genetic variants of the renin-angiotensin system are related to 24h BP and the diurnal BP pattern in Japanese. We studied the association of the ATG T235 allele and ACE D allele with 24h BP and diurnal BP variation in 235 of 262 consecutive untreated (or off medication) elderly Japanese hypertensives who underwent 24h ambulatory BP monitoring. There was no significant association between the T235 or ACE D allele with office BP, but the T235 allele was significantly associated with 24h BP and day BP, and the D allele was significantly associated with increased 24h BP, day BP, and night BP. There were no effects of the T235 or D alleles on any BP parameters. Those with white-coat hypertension had a significantly lower T235 allele frequency (0.68) than those with sustained hypertension (0.79, p=0.010), but the difference in D allele frequency was marginal (0.30 vs. 0.38, p=0.057). In conclusion, in elderly Japanese hypertensive individuals, both the ATG T235 and ACE D alleles are associated with increased 24h BP and day BP, while only the ACE D allele is associated with increased night BP. (Hypertens Res 1999; 22: 95-103)

View full abstract

We sought to clarify the incidence, vessel-size and age distribution of periarteritis nodosa in rats occurring as a vascular lesion in malignant hypertension. Stroke-prone spontaneously hypertensive and stroke-resistant spontaneously hypertensive rat strains were studied, as well as Wistar-Kyoto control rats. Mesenteric arteries and testicular arteries were examined histologically. Additionally, electron microscopy investigation was carried out on one stroke-prone hypertensive rat and one control. Periarteritis nodosa lesions were present in testicular arterioles in 57.1%, and mesenteric arteries in 28.6%, of stroke-prone hypertensive rats aged 9.5 mo. Lesion incidence at these sites was 100% and 60% respectively in 10 stroke-prone rats aged 15.5 mo, and 42.9% and 28.6% in stroke-resistant hypertensive rats aged 22.5 mo. In contrast, the incidence rate was 0% at both sites in stroke-resistant hypertensive rats aged 8 or 14.5 mo, and in control rats aged 9.5 or 25mo. In stroke-prone rats, arteritis lesion counts (mean±SD) in testicular sections were 11.6±17 at age 9.5 mo and 96.3±60.9 at age 15.5 mo. In individual lesion scoring, arteritis was more severe in mesenteric arteries than in testicular arterioles. For arteriolar lesion distribution patterns in testicular sections, partial peripheral, partial peripheral plus central, and circumferential patterns were all noted. In conclusion, periarteritis nodosa in hypertensive stroke-prone rats occurs earlier in testicular arterioles, but attains greater severity in the mesenteric artery. (Hypertens Res 1999; 22: 105-112)

View full abstract

We have previously shown that endothelin-1 (ET-1) modulates mechanical stretch-induced hypertrophic responses such as extracellular signal-regulated protein kinase (ERK) activation in cardiac myocytes. This study was undertaken to elucidate the ET-1-evoked signal transduction pathways leading to ERK activation. ET-1 was added to cultured cardiac myocytes of neonatal rats with or without a variety of inhibitors. ET-1 activated ERKs, which were followed by an increase in protein synthesis, and inhibition of protein kinase C activities by calphostin C completely suppressed the ET-1-induced ERK activation. We next examined whether tyrosine kinases or Ras are involved in ET-1-induced signaling pathways in cardiomyocytes. Pretreatment with a receptor tyrosine kinase inhibitor did not attenuate ET-1-induced activation of ERKs. Also, co-transfection of the dominant-negative mutant of Ras or active mutant of C-terminal Src kinase, a tyrosine kinase which inhibits Src family tyrosine kinases, with hemagglutinin-tagged ERK2 had no effects on ET-1-induced ERK2 activation. On the other hand, blockade of Raf-1 kinase function by overexpression of the dominant-negative mutant of Raf-1 kinase completely inhibited ET-1-induced ERK2 activation. These results suggest that protein kinase C and Raf-1 kinase, but not Src or Ras, are critical to ET-1-induced ERK activation in cardiac myocytes. (Hypertens Res 1999; 22: 113-119)

View full abstract

An AT₁ receptor antagonist, losartan, has been reported to improve survival and quality of life in patients with congestive heart failure as angiotensin converting enzyme inhibitors do. Since many of the patients are normotensive, it may be a drawback if the compound decreases normal blood pressure. In this study, we investigated whether a novel AT₁ receptor antagonist, TA-606, which is more potent than losartan, affects normal blood pressure and its regulatory system in comparison with losartan. TA-606 (30 and 100mg/kg, p.o.) did not change normal blood pressure, whereas losartan (100mg/kg, p.o.) tended to decrease it. Although EXP3174 (1 and 10mg/kg, i.v.), an active metabolite of losartan, suppressed the baroreceptor-heart rate (HR) reflex, 606A (1 and 10mg/kg, i.v.), an active metabolite of TA-606, did not affect it. Since losartan is known to affect the L-glutamate receptor which is part of the central blood pressure regulatory system, we also investigated whether 606A affects L-glutamate receptor binding. We found that 606A did not affect the binding of the L-glutamate receptor, but EXP3174 inhibited the binding with IC₅₀ values of 13.3μM. These findings suggest that, even having the same AT₁ receptor antagonist properties as losartan and EXP3174, TA-606 and its active metabolite do not influence normal blood pressure or its regulatory system. (Hypertens Res 1999; 22: 121-127)

View full abstract

We have reported that diuresis and natriuresis due to increase in renal kinins induced by the neutral endopeptidase 24.11 (NEP) inhibitor were attenuated by nitric oxide (NO) synthase inhibitor. To further clarify the water-sodium excretory mechanism of renal kinins, we estimated NO₂+NO₃ (NO_x) and cGMP in plasma and urine with and without a specific NEP inhibitor, thiorphan. P-aminohippuric acid (PAH) and inulin were injected into male Sprague-Dawley rats. Vehicle (n=8) or thiorphan (30mg/kg, n=10) was injected after the control period. Mean blood pressure (MBP), plasma and urinary PAH, inulin, NO_x and cGMP, urinary volume (UV) and urinary sodium excretion (UNaV) were measured before and after injection of the reagents. MBP, renal plasma flow and glomerular filtration rate were not affected by thiorphan. Plasma NO_x and cGMP with thiorphan did not differ from the vehicle, while urinary NO_x and cGMP increased. None of the variables were affected by vehicle. UV and UNaV were higher with thiorphan than with vehicle. Positive correlation was found between urinary ΔNO_x and ΔcGMP. Each urinary ΔNO_x and ΔcGMP was significantly correlated to both ΔUV and ΔUNaV. Urinary NO_x and cGMP were increased while maintaining correlations to UV and UNaV, but plasma NO_x and cGMP were not affected by thiorphan. This implies that the mechanism of water-sodium excretion induced by NEP inhibitor is mediated by renal NO. Therefore, renal NO may contribute to the diuretic and natriuretic effects of renal kinins. (Hypertens Res 1999; 22: 129-134)

View full abstract

The ouabainlike factor (OLF) is thought to be an important modulator of salt and water metabolism. Plasma OLF could be derived from the central nervous system and/or the adrenal gland. Since the adrenal medulla is of neural origin, the cytology of pheochromocytoma of adrenomedullary origin resembles that of neuronal cells. Ouabainlike immunoreactivity (OLI) is, in fact, present in the adrenal medulla as shown by immunohistochemistry. The plasma levels of catecholamines and OLI were significantly elevated during surgical extirpation of pheochromocytoma in this case. To clarify the origin of circulating OLI in a patient with pheochromocytoma, the relationship between plasma OLI and catecholamines during adrenalectomy was investigated. Plasma catecholamine levels exceeded the normal reference interval, and plasma OLI was positively correlated with the patient′s plasma level of norepinephrine. The peak level during operation was about 10 times higher than the baseline level. Both levels reached a maximum when the tumor was mechanically pressed, and then gradually decreased thereafter. The level of OLI in the tumor was higher than that of the normal adrenal cortex. When OLI in the tumor was characterized by reversed-phase high-performance liquid chromatography, the retention time of OLI corresponded with that of authentic ouabain. These results suggest that the circulating OLI in this patients was derived mainly from the pheochromocytoma of adrenomedullary origin. (Hypertens Res 1999; 22: 135-139)

View full abstract

A 36-yr-old male was found to have renovascular hypertension due to an occluded right renal artery and 70% stenosis in the left renal artery, caused by fibromuscular dysplasia. The right kidney was supplied by collateral blood flow, and secreted more renin than the left kidney. Two differential therapeutic approaches were taken: autotransplantation for the right kidney and percutaneous transluminal renal angioplasty followed by stent implantation for the left. The renovascular hypertension was treated with these therapies, preserving renal function in this patient. (Hypertens Res 1999; 22: 141-143)

View full abstract

Acceptance of the notion that physiologically specific interruption of the renin-angiotensin-aldosterone system (RAAS) is of considerable therapeutic benefit in the treatment of hypertension and congestive heart failure has generated great interest in the search for novel pharmacological inhibitors. The RAAS is expressed at the whole body, organ/tissue and cellular level through the action of the octapeptide angiotensin II (Ang II), the primary effector molecule of the RAAS. The availability of selective, potent, orally active and long-acting nonpeptide Ang II type 1 (AT₁) receptor antagonists provided the opportunity to obtain the benefits of selectively blocking the RAAS at the level of the AT₁ receptor that mediates most, if not all, of the important actions of Ang II, and avoid the nonspecificity of the Ang I converting enzyme (ACE) inhibitors. Losartan was the first, but by no means remained the only nonpeptide AT₁ receptor antagonist. Numerous other "sartans" have emerged in the past several years and successfully completed clinical development. With the exception of Eprosartan, all others, i.e. Candesartan, Irbesartan, Saprisartan, Tasosartan, Telmisartan, Valsartan and Zolasartan, are based on modifications of Losartan's prototypic chemical structure. AT₁ receptor antagonists represent the newest addition to the arsenal of cardiovascular therapeutics. The predominant role of the AT₁ receptor in mediating the pathophysiological role of Ang II underlies the effectiveness of this novel class of agents to lower arterial blood pressure, reduce pre- and afterload, inhibit sympathetic nervous system activity and prevent cardiovascular hypertrophy and cardiac failure induced by inappropriate control of the RAAS. (Hypertens Res 1999; 22: 147-153)

View full abstract

To evaluate the role of losartan on left ventricular (LV) function of hypertensive patients. Hypertensive patients (n=19) underwent evaluation of systolic and diastolic LV function, using radionuclide ventriculography (RVG), before and at 3mo into the treatment with the angiotensin II antagonist losartan. All patients underwent a baseline 12 lead ECG and an echocardiogram (ECHO), which was also repeated at 3mo into treatment. Results are expressed as mean±SEM and statistics were performed using paired t-test. A p value ≤0.05 was considered significant. Treatment with losartan for 3mo had no effect on LV mass measured by echo (141±5 vs. 139±6g/m²). The LV ejection fraction, measured by RVG, was unchanged by treatment when compared to the baseline study (58±2% vs. 57±2%, respectivelly, p=0.49). Considering all patients involved in the study (n=19), the LV "Peak Filling Rate" (PFR), a parameter of diastolic function measured by RVG, was also unchanged by treatment when compared to baseline (2.5±0.2EDV/s vs. 2.5±0.3EDV/s, respectively, p=0.9). However the analysis of those patients with evidence of diastolic dysfunction (n=12) on the baseline RVG (PFR<2.5EVD/s), demonstrated significant improvement of LV filling after therapy with losartan (PFR =1.8±0.1EDV/s vs. 2.3 ±0.2EDV/s, respectively, p=0.05). This change was associated with improvement of symptoms. Our results demonstrated that hypertensive patients with diastolic dysfunction on radionuclide ventriculography have significant improvement of ventricular filling at 3mo into treatment with losartan. (Hypertens Res 1999; 22: 155-159)

View full abstract