Despite many previous studies, the mechanism of glucocorticoid-induced hypertension remains unknown. The present review will introduce the results of our studies on this subject in patients with Cushing's syndrome and in experimemtal animals. Our studies indicate that the following multiple factors are involved in glucocorticoid-induced hypertension in humans and animals: 1) activation of the renin-angiotensin (R-A) system due to an increase in plasma renin substrate (PRS); 2) reduced activity of depressor systems, including the kallikrein-kinin (K-K) system, prostaglandins (PGs), and the endothelium-derived relaxing factor nitric oxide (NO); and 3) increased pressor responses to angiotensin II (Ang II) and norepinephrine. Furthermore, our in vitro studies have revealed that the number of Ang II type 1 receptors of vascular smooth muscle cells (VSMCs) is significantly increased by glucocorticoids. It is concluded that the pathogenesis of glucocorticoid-induced hypertension is multi-factorial, involving the various mechanisms described above. (Hypertens Res 1996; 19: 1-8)

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To examine the influence of hypertension on cardiovascular variability in elderly subjects, we measured spontaneous beat-to-beat blood pressure (BPV) and heart rate variability (HRV) in elderly subjects with or without hypertension at rest and during tilting. The study group consisted of 23 community-dwelling, male elderly subjects (aged 62-75 years) and was divided into two groups, i.e., a hypertensive group (HT group; n=11) and normotensive group (NT group; n=12). According to the modeling and decomposing algorithm of an autoregressive process, we estimated the component power of low-frequency (LF; 0.03-0.15Hz) and high-frequency components (HF; respiratory frequency) of BPV and HRV by power spectral analysis. We also measured plasma norepinephrine (PNE) levels in the two groups at rest and during tilting. In the HT group, we found that the amplitude of LF-BPV was greater (p<0.05) and its relative change by postural tilting was smaller (p<0.05) than those in the NT group. We found no significant difference in the amplitude of LF-HRV and HF-HRV between the two groups, and found no significant response of the amplitude of LF-HRV and HF-HRV to postural tilting. We also found no differ ence in PNE level between the two groups at rest or during tilting. These results suggest that the regulatory function of sympathetic vasomotor activity assessed by power spectral analysis of BPV is altered in hypertensive elderly subjects, although the influence of hypertension on the autonomic control of the heart is less dominant in the elderly. (Hypertens Res 1996; 19: 9-16)

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Renal papillary plasma flow was tested during acute increases and decreases of perfusion pressure using the ¹²⁵I-labelled albumin technique. Increases of pressure were attained through ligation of carotid arteries; decreases of pressure through modest hemorrhage. In 12 control rats with blood pressure of 144mmHg, the papillary plasma flow averaged 21.5ml per 100g papilla per min. In 12 rats after ligation of carotid arteries, blood pressure rose from 143mmHg to 172, a 20% increase. The papillary plasma flow in these rats with acute hypertension averaged 17.9ml per 100g papilla per min, a 17% decrease (p<0.025). In another 12 rats after bleeding 1% of body weight over a period of 10min, blood pressure dropped from 146mmHg to 104, a 29% decrease. The papillary plasma flow in these rats with acute hypotension averaged 26.0ml per 100g papilla per min, a 21% increase (p<0.025). The decrease in papillary plasma flow during acute hypertension strongly suggests an increased vascular resistance of the descending vasa recta, while the increase in papillary plasma flow during acute hypotension suggests that vasodilatation occurred in these vessels. This dilatation may be produced by the local release of prostaglandins or other vasoactive substances. Thus, the renal papilla appears to "overshoot" its autoregulation of plasma flow, with actual reduced flow during an acute blood pressure rise and increased flow during an acute blood pressure fall, an enigmatic over-compensation. (Hypertens Res 1996; 19: 17-22)

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Studies have suggested that endothelin-1 (ET-1) activates cellular contraction and proliferation in rat vascular smooth muscle cells (VSMC). We examined whether an ET_A receptor antagonist, BQ-123, inhibits the following cellular actions of ET-1 in rat VSMC: cytosolic free calcium ([Ca²⁺]i) mobilization, cellular contraction, mitogen-activated protein (MAP) kinase activation, [³H]thymidine incorporation, and MTT reduction. [Ca²⁺]i was measured by the fluorescent method. MAP kinase activity was measured by the phosphorylation of a synthetic peptide of a specific substrate for MAP kinase. The specificity of BQ-123 for ET-1-activated MAP kinase was checked by Western blotting analysis. [³H]thymidine incorporation and MTT reduction studies were performed using the cells incubated for 12h with serum-free medium containing effectors. BQ-123 inhibited ET-1 receptor binding and blocked [Ca²⁺]i mobilization, cellular contraction, MAP kinase activation, [³H]thymidine incorporation, and MTT reduction in response to ET-1. BQ-123 did not affect the arginine vasopressin (AVP)- and angiotensin II (Ang II)-induced increases in [Ca²⁺]i mobilization or in MAP kinase activity. Preincubation with BQ-123 did not enhance its inhibitory effects but these effects of BQ-123 were diminished by washing after preincubation. Receptor studies revealed that the washing procedure decreased the inhibitory effect of BQ-123 on ET-1 binding to receptors. These results indicate that BQ-123 is a potent and specific ET_A receptor antagonist that blocks the ET-1-induced cellular contraction and proliferation in rat VSMC. (Hypertens Res 1996; 19: 23-30)

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Although calcium antagonists reduce systemic blood pressure, the effects of calcium antagonists on renal preglomerular and postglomerular microcirculation have been suggested to differ. In the present study we examined the vasodilator action of dihydropyridine-type calcium antagonists, including nifedipine, nicardipine, amlodipine, and efonidipine, on afferent and efferent arterioles during angiotensin II (A-II)-and norepinephrine (NE)-induced renal vasoconstriction. Isolated perfused hydronephrotic kidneys were used to directly visualize renal microcirculatory response to calcium antagonists. Both A-II and NE caused marked vasoconstriction of afferent (A-II, 27±2% decrement; NE, 28±2% decrement) and efferent arterioles (A-II, 25±4% decrement; NE, 22±2% decrement). The subsequent addition of nifedipine, nicardipine, and amlodipine reversed the afferent arteriolar vasoconstriction in a dose-dependent manner, and elicited complete vasodilation at 10^-6M. In contrast, efferent arteriolar vasoconstriction was relatively refractory to the dilator action of these calcium antagonists; maximal dilation observed at 10^-6M was 21±1% (A-II) and 22±3% (NE) for nifedipine, 25±3% (A-II) and 20±6% (NE) for nicardipine, and 39±6% (A-II) and 37±3% (NE) for amlodipine. In striking contrast, efonidipine dilated not only afferent arterioles, but also efferent arterioles in a dose-dependent manner. At 10^-6M, efonidipine completely inhibited the afferent (A-II, 89±7% reversal; NE, 99±8% reversal) and efferent arteriolar vasoconstriction (A-II, 93±4% reversal; NE, 87±9% reversal). These findings clearly demonstrate that calcium antagonists dilate the afferent arteriole. Unlike the effects on the afferent arteriole, efferent arteriolar responsiveness to calcium antagonists differ, depending on the type of calcium antagonist. The efonidipine-induced efferent arteriolar vasodilation is probably not related to voltageoperated calcium channels, and may act, in concert with blood pressure lowering effect, to ameliorate glomerular capillary hypertension. (Hypertens Res 1996; 19: 31-36)

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To determine whether improvement of insulin resistance decreases blood pressure as well as obesity, metformin (100mg/kg/d) or vehicle was administered for 20 weeks to 12-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) rats (n=10 each), a newly developed animal model of non-insulin-dependent diabetes mellitus (NIDDM) with mild obesity, hyperinsulinemia, and hypertriglyceridemia. Oral administration of metformin ameliorated glucose intolerance and attenuated the insulin response to glucose loading (2g/kg, i.p.), as evidenced by a decrease in the area under the curve for glucose and insulin at 24 weeks by 19% and 37%, respectively. At 21 weeks, systolic blood pressure was significantly lower in the metformin group than in controls (130±1.9 vs. 143±2.7mmHg, p<0.01), despite no difference in body weight. Subsequently, blood pressure tended to be slightly but insignificantly lower in the metformin group, and body weight was significantly lower in the metformin group (532±9.8 vs. 587±10.3g at 31 weeks, p<0.01). Metformin treatment also lowered the level of serum triglycerides (9.4±0.6 vs. 13.2±0.5mmol/l, p<0.01) and the plasma norepinephrine concentration (4, 222±373 vs. 7, 548±1, 058pg/ml, p<0.01). These results suggest that metformin-induced improvement of insulin resistance in obese rats with NIDDM may lower blood pressure, as well as decrease sympathetic activity and reduce body weight. (Hypertens Res 1996; 19: 37-41)

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Nowadays practical antihypertensive therapy involves not only simple normalization of blood pressure but also a reduction of the risks of cardiovascular disease. In this multicenter open-label study, the long-term effects of doxazosin, an α₁-adrenergic receptor blocker, on serum lipids were prospectively investigated in 253 patients with essential hypertension. They were treated with doxazosin for 1 year. The averaged blood pressure was maintained at levels lower than 150/90mmHg throughout 1 year, but heart rate did not increase. After 3 months of doxazosin therapy, total and low density lipoprotein-cholesterol levels in serum were significantly reduced by 3.3% and 3.4%, respectively, and these levels were maintained throughout the study period. This effect of doxazosin on serum lipids was especially prominent in patients with hypercholesterolemia. In addition, the lipid profile of these patients was favorably altered even when other antihypertensive drugs or lipid-lowering drugs had already been used or were used concurrently. These results constitute useful information for physicians who treat hypertension with α₁-blockers to reduce the overall risk of cardiovascular disease. (Hypertens Res 1996; 19: 43-49)

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To search for the genes that determine the level of blood pressure, we performed linkage analyses using rat microsatellite markers in two sets of F₂ rats derived from two hypertensive rat strains and one normotensive rat strain. In the first F₂ progeny obtained from spontaneously hypertensive rats and Wistar-Kyoto rats, it was found that two different loci cosegregated with blood pressure. One was γ-crystallin locus on rat chromosome 9, which has a hypertensive effect, and the other was peroxisomal 3-keto acyl-CoA thiolase locus on rat chromosome 8, which has a hypotensive effect. Then, we studied the same loci in second F₂ progeny obtained from Dahl/Iwai salt-sensitive rats and Wistar-Kyoto rats. It was found that the locus located on rat chromosome 8 also had a hypotensive effect, although the others were not cosegregated with blood pressure in this cross. We suggest that a new locus for hypertension is located on rat chromosome 9 and that a locus on rat chromosome 8 has a common effect that makes blood pressure decrease in different hypertensive strains. (Hypertens Res 1996; 19: 51-56)

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