Essential hypertension (EH) is a progressive rise in blood pressure (BP) with age for which there is no obvious cause. Its unique clinical marker is the high BP itself. No other abnormality appears to be common to all hypertensive patients. Our understanding of the mechanisms that keep BP high has improved considerably and a number of clues to potential causes have been found. High BP arises from the interactions between an organism's attributes and environmental factors. The former may include abnormal transmembrane ion transport systems. There are a number of hypotheses postulating how abnormal sodium or calcium metabolism causes increased systemic vascular resistance through altered vaso-active responses, structural changes in the vasculature, or both. (Hypertens Res 1994; 17: 149-155)

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Antihypertensive therapy can prevent stroke. This has been shown in patients with severe as well as mild hypertension, and in young, middle-aged, and elderly hypertensive patients. However, although prevention of stroke ranks very high among the proven benefits of antihypertensive therapy, there are several aspects of this benefit that deserve discussion. These include: 1) the benefits on fatal and non-fatal strokes, respectively; 2) the possibly greater benefits resulting from a greater reduction in blood pressure than the reduction achieved in most trials; 3) the relative benefits on haemorrhagic and thrombotic strokes, respectively; 4) the effects of antihypertensive therapy in patients with a previous stroke; and 5) the efficacy of different antihypertensive drugs on stroke prevention. (Hypertens Res 1994; 17: 157-160)

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A large body of epidemiological evidence demonstrates that the rate of cerebrovascular events is directly related to clinic blood pressure values. Although highly statistically significant, however, the relationship is not very close, which implies that within a general trend several patients with a lower blood pressure suffer from a stroke whereas other patients with a higher blood pressure do not. Whether and to what extent the ability to predict the future occurrence of stroke can be increased is discussed in this paper, which considers three main possibilities: (1) genetic factors that make some populations and individuals more prone to the occurrence of a cerebrovascular event for a given systolic or diastolic blood pressure, (2) risk factors other than hypertension (e.g. smoking) interacting in a positive fashion to increase the stroke risk profile, and (3) evaluation of blood pressure by ambulatory monitoring rather than by "clinic" measurements. This last possibility is supported by studies that show that the end organ damage associated with hypertension is more closely related to 24-hour average than to clinic blood pressure and that the relationship becomes closer if 24-hour blood pressure variability is also taken into accout. It is more specifically supported by evidence that 24-hour blood pressure values correlate more than clinic blood pressure with cerebrovascular damage, provided that the damage is quantified on an almost continuous scale by nuclear magnetic resonance rather than being expressed as an all-or-none clinical event. Improving prediction of future occurrence of stroke also improves efficacy of therapeutic intervention, thus having a great practical relevance. To date it would appear that the greatest protection against cerebrovascular events is obtained by removal of risk factors other than hypertension and by effective control of 24-hour blood pressure. Although the matter is still controversial, this should include a reduction in nighttime blood pressure at least in patients with no major organ damage. (Hypertens Res 1994; 17: 161-163)

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Using ryanodine and verapamil, we compared the effects of dietary salt on the relative contribution of sarcoplasmic reticulum (SR) Ca²⁺ release and gated Ca²⁺ entry to arterial contractions induced by norepinephrine (NE) in Dahl salt-sensitive (DS) and salt-resistant (DR) rats. Aortic rings freshly excised from 14DS rats and 13DR rats that had been on low- (0.3%) or high- (8%) NaCl diets for 4 weeks were superfused with physiological saline and isometric tension was measured. The inhibition of the NE (3×10^-8M) -induced contraction of aortic rings by ryanodine (3μM) was significantly greater in DR rats on the low-salt diet than in those on the high-salt diet (p<0.02), but there was no such difference in DS rats. The inhibition of the NE-induced contraction of aortic rings by verapamil (10μM) was significantly greater in DS rats on the high-salt diet than in those on the low-salt diet (p<0.02), but there was no such difference in DR rats. These observations suggest that the effects of dietary salt on gated Ca entry and SR Ca release in NE-induced contraction differ between DS and DR rats. They also suggest that gated Ca²⁺ entry might play an important role in Ca²⁺ control and that the mechanism by which Ca release from SR is reduced might be impaired, or that the ryanodine receptor might be altered in these tissues of salt-fed DS rats. These changes might lead to an elevation of intracellular calcium and contribute to the mechanism of hypertension. (Hypertens Res 1994; 17: 165-171)

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To assess the chronic antihypertensive and renal protective effects of losartan, a specific angiotensin II receptor antagonist, in the remnant kidney model of chronic renal failure, we administered losartan alone or in combination with enalapril, for 14 days to 5/6-nephrectomized spontaneously hypertensive rats (SHR). Eight-week-old SHR underwent 5/6 nephrectomy. One week after the operation, low-dose or high-dose losartan alone (1 or 10mg/kg/day), or a combination of high-dose losartan and enalapril (6 mg/kg/day) was administered intraperitoneally via an osmotic minipump for 14 days. Low-dose Losartan only slightly attenuated the increase in blood pressure. High dose losartan completely blocked the increase in blood pressure throughout the experiment. Simultaneous administration of enalapril did not modify the antihypertensive effects of losartan. Furthermore, high-dose losartan with enalapril, and low- dose or high-dose losartan alone significantly decreased urinary protein excretion to the same extent. These effects were sustained for the entire experiment and were not associated with any significant changes in body weight, fluid intake, urine volume, urinary electrolyte excretion, or serum creatinine. These results suggest that losartan might have a renal protective effect independent of its systemic antihypertensive action. In addition, they suggest that the antihypertensive and renoprotective effects of ACE inhibitors in this rat model are mainly due to inhibition of angiotensin II production rather than to stimulation of the kallikrein-kinin system or the vasodilator prostaglandins. (Hypertens Res 1994; 17: 173-178)

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We investigated the reported differences in the modulating effect of sodium on renal α₂-adrenoceptor binding between inbred Dahl Salt-Sensitive (S/JR) and Salt-Resistant (R/JR) Rats. Saturation binding of [³H]rauwolscine to renal α₂-adrenoceptors and its displacement by epinephrine were performed in the absence and presence of NaCl, GppNHp, or MgCl₂ in S/JR and R/JR rats. We omitted sucrose in our buffers which preserves endogenous catecholamines in renal membranes. MgCl₂ but not NaCl or GppNHp decreased the apparent density and affinity of renal α₂-adrenoceptors for [³H]rauwolscine in both strains. NaCl and GppNHp reduced and MgCl₂ increased the affinity of renal α₂-adrenoceptors for epinephrine in both strains. There were no differences in the modulating effects of sodium on renal α₂-adrenoceptor binding between the two strains except for the higher receptor density in S/JR than in R/JR rats. These data suggest that the difference in renal α₂-adrenoceptors between S/JR and R/JR is not due to alterations which affect receptor protein structure or interaction with G proteins. Thus, future investigations should be directed at the regulation of the receptor gene expression. (Hypertens Res 1994; 17: 179-185)

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To elucidate the genetic alterations of gene expression and regulation of the type 1 angiotensin II receptor (AT₁), we measured the relative levels of mRNAs of AT_1A receptor and AT_1B receptor subtypes in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The effect of treatment with a selective AT₁ receptor antagonist, TCV-116 (1mg/kg/day for a week), on the levels of mRNAs of AT₁ receptor subtypes was also studied. The relative levels of AT_1A and AT_1B receptor mRNAs in the adrenal gland, heart, aorta, and kidney were measured by a sensitive reverse transcriptase-polymerase chain reaction method. AT_1A receptor mRNA was predominantly expressed in the heart and kidney, but AT_1B receptor mRNA was dominant in the adrenal gland in both strains. AT_1A and AT_1B receptor mRNAs were equally expressed in the aorta. There were no significant differences between WKY and SHR in the levels of AT_1A and AT_1B receptor mRNAs except for aortic AT_1B receptor mRNA, which was expressed less in SHR. There were no differences between WKY and SHR in the effect of an AT₁ receptor antagonist, TCV-116, on the levels of AT_1A and AT_1B receptor mRNAs in those four organs. TCV-116 administration reduced the expression of AT_1A receptor mRNA in the heart and aorta, and reduced the expression of AT_1B receptor mRNA in the adrenal gland and heart. These results indicate that the expression of genes for AT_1A and AT_1B receptor subtypes is regulated in a tissue-specific manner in both strains. (Hypertens Res 1994; 17: 187-192)

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Problem: The phorbol ester-induced contractile response of blood vessels from spontaneously hypertensive rats (SHR) is greater than that from normotensive Wistar-Kyoto rats (WKY), which suggests that protein kinase C activity is abnormally high in vascular smooth muscle from SHR. However, the role of the overlying endothelium in these responses has not been tested. Hypothesis: The response of vascular smooth muscle to protein kinase C activation is influenced by the presence of the endothelium. Methods: We examined the isotonic contraction of aortic rings (with or without endothelium) from 12-14-week-old SHR and WKY in response to KCl, norepinephrine, and the phorbol ester PDBu (with and without staurosporine). We also tested these responses in the presence of L-NMMA. Results: PDBu (1nM-1 mM) dose-dependently increased contractile force, with an EC₅₀ of 100nM. Aortic rings from SHR were more sensitive than those from WKY at all doses tested. Removal of the endothelium abolished this difference: the sensitivity of aortic rings from WKY increased and the contractility of rings from SHR decreased. Preincubation with L-NMMA (10^-5M) for 20min also abolished the difference in contractile response in the same fashion. The response to norepinephrine was increased by L-NMMA in both SHR and WKY. Conclusions: The difference between SHR and WKY in phorbol ester-induced contraction of aortic rings is due to a difference in endothelial cell function, rather than to a difference in vascular smooth muscle. We suggest that PKC may mediate the release from endothelial cells of a vasodilator, which may be nitric oxide. This effect may be abnormally weak in the endothelium of SHR. (Hypertens Res 1994; 17: 193-197)

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We studied the effects of direct blockade of angiotensin II by a non-peptide angiotensin II receptor (AT₁) antagonist, losartan, on development of cardiovascular hypertrophy in salt-loaded Dahl salt-sensitive (DS) rats. Six-week-old male DS rats were fed a 4% NaCl diet and were simultaneously treated with one of two doses of oral losartan for 7 weeks. Vehicle-treated rats were given tap water alone. Blood pressure and body weight were monitored. The low-dose of losartan (30 mg/kg/day; n=12) blunted the rise in tail-cuff systolic blood pressure only transiently and did not reduce the left ventricular mass (ratio of left ventricular weight/body weight), when compared to the vehicle control (n=12). The high dose of losartan (100mg/kg/day; n=6) blunted the rise in blood pressure; however, left ventricular mass was not significantly lower in rats given the high dose of losartan than in those given vehicle (n= 12). The pressor response to intravenous angiotensin II was greatly suppressed in salt-loaded DS rats treated with 30mg/kg/day of losartan. These results suggest that losartan has minor hypotensive effects without reducing cardiovascular hypertrophy in DS rats fed a 4 % NaCl diet. We conclude that angiotensin II blockade has only minor effects on hypertension and cardiovascular hypertrophy in salt- loaded DS rats, and that the renin-angiotensin system may play no major role in the development of cardiovascular hypertrophy in DS rats on a moderately high-salt diet. (Hypertens Res 1994; 17: 199-203)

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