There have been major advances in our understanding of regulation of cerebral circulation under normal conditions, and of cerebral vascular changes during hypertension. In relation to physiological mechanisms, nitric oxide (NO), or an NO-containing substance, appears to play an important role in regulation of cerebral blood flow, including coupling of metabolism and blood flow. ATP-sensitive potassium channels are a major mechanism that mediates cerebral vasodilatation during several pharmacological and physiological stimuli, including hypoxia. In relation to hypertension, potent mechanisms protect the cerebral circulation during chronic hypertension. Vascular hypertrophy also protects cerebral vessels during hypertension by reducing wall stress and by attenuation of increases in pressure in the microcirculation. Vascular remodeling, which results in reduction in external diameter of cerebral vessels, appears to be the dominant structural change in cerebral arterioles during hypertension. Endothelial dysfunction may play a key role in cerebral vascular complications of hypertension. It is now thought that hypertensive encephalopathy is produced by dysfunction of the endothelial blood-brain barrier. Endothelial dysfunction in chronic hypertension also results in abnormal vasomotor regulation. Cerebral vascular muscle also may be dysfunctional in hypertension, as responses to activation of ATP-sensitive potassium channels appear to be impaired. Several mechanisms may predispose to stroke as a complication of hypertension. Endothelial dysfunction may lead to vasospasm, for example, when platelets are activated. Collateral circulation in the cerebrum is impaired by hypertension. Mean pressure is higher in arterioles in the brain stem than in cerebral cortex, which may predispose to hemorrhage in the brain stem. (Hypertens Res 1993; 16: 225-231)

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Variations of blood pressure (BP) and heart rate (HR) were evaluated in patients with essential hypertension (EH) under the conditions of low salt and high salt intake. Fourteen patients with EH were hospitalized and consecutively kept on a daily salt intake of 3 and 20g for 1 week each. Variations in BP were measured at intervals of 15 or 30min using automatic noninvasive BP recorders. Urinary excretion of norepinephrine (UNEV) was also measured serially. The patients whose mean BP was increased more than 10% by salt loading were classified as salt sensitive hypertensives (SS; n=6), while the rest were defined as salt resistant hypertensives (SR; n=8). In SR, averages of both systolic and diastolic blood pressure at night were significantly lower than those during the daytime for both low salt and high salt conditions. UNEV in SR was also decreased significantly at night in both conditions. In SS, however, the nocturnal fall in blood pressure was not significant during salt loading. Furthermore, in SS, UNEV was not decreased significantly during the night in either condition. These results suggest that salt loading in addition to incomplete inhibition of the sympathetic nervous system at night may be involved in the absence of a nocturnal decrease in BP in patients with salt sensitive hypertension. (Hypertens Res 1993; 16: 233-237)

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In the present study, we evaluated the hemodynamic and metabolic profiles derived from oral administration of the angiotensin converting enzyme inhibitor, delapril 50mg/kg/day, and the non-peptide angiotensin II type I (AT₁) receptor antagonist, TCV-116 1mg/kg/day, for five days, to try to discriminate AT₁ receptor-related responses from the depressor properties of chronic treatment with delapril in spontaneously hypertensive rats (SHRs). Both TCV-116 and delapril oral administrations significantly decreased blood pressure without any changes in heart rate. Delapril induced dipsogenic response and natriuresis associated with augmentation of urinary catecholamine excretion, while TCV-116 did not cause any changes in these variables. Neither delapril nor TCV-116 changed urinary excretion of prostaglandin (PG) E2 and 6-keto PG F_1α. We also examined the effects of centrally administered angiotensin converting enzyme inhibitor and AT₁ receptor antagonist to determine the central role of these drugs.Either the active metabolite of delapril, delapril-M1 1 mg/kg/day, or the active form of TCV-116, CV-11974 0.1mg/kg/day, were administered intracerebroventricularly for five days. Both treatments significantly decreased the blood pressure, in association with augmentation of the baroreceptor reflex control of heart rate, in response to phenylephrine injection. These findings suggest that the depressor properties of orally administered delapril are more complex than those of TCV-116, while central blockade by both angiotensin converting enzyme and AT₁ receptor decreases blood pressure in part through baroreceptor sensitization. (Hypertens Res;1993 16: 239-246)

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Endothelin (ET) has been postulated to be hypertensinogenic through its potent and long-lasting vasoconstriction. Whether sustained increase in plasma ET levels causes hypertension remains to be clarified. We investigated the effects of chronic infusion of ET-1 on blood pressure, relevant to the plasma levels in normal Wistar rats. Synthetic ET-1 was administered intravenously using osmotic minipumps at a rate of 16μg/kg/day for 4 weeks. Systolic blood pressure, heart rate, and plasma ET-1 levels were determined before and after the infusion. After one-week infusion, both plasma ET-1 levels and systolic blood pressure were significantly higher than those in the control group. The systolic blood pressure showed a sustained elevation over a period of 2 weeks and then started to decrease gradually to the control levels, while plasma ET-1 levels remained elevated. There were no significant differences in heart rate and body weight between the ET-infusion and control groups. These results suggest that even a mild increase in plasma ET-1 levels could cause elevation of blood pressure. However, normalization of systolic blood pressure despite the sustained increase in plasma ET-1 levels after chronic infusion suggests that an increase in plasma ET-1 levels alone is not sufficient to cause chronic elevation of blood pressure in normal rats. (Hypertens Res 1993; 16: 247-251)

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To further clarify the role of renal kininases in various hypertensive diseases, daily urinary excretions of total kininase, kininase I, kininase II and neutral endopeptidase 24.11(NEP) were examined in patients with essential hypertension (EHT), primary aldosteronism (PA) and Cushing's syndrome. In this study, a new method for the simultaneous determination of human urinary kininase I, II and NEP activities was employed. Total kininase and NEP levels in EHT (579.7 ±79.3, 358.8±53.4μg/min/day), PA (928.8 ±212.8, 278.5±24.4) and Cushing's syndrome (605.7±25.3, 359.9±78.4) were significantly higher than in normotensives (NT: 261.9±29.6, 151.4±10.2). Kininase I levels in PA (100.1±23.4μg/min/day) and Cushing's syndrome (76.6±12.7), but not in EHT (71.8 ±11.5), were significantly higher than in NT (38.2±4.2). Kininase II was significantly higher than in NT (72.2±10.2), only in Cushing's syndrome (137.9±2.4), and levels in EHT (131.1±22.0) and PA (126.7±23.7) were not. Unexpectedly, these three kininases accounted for 62% of total kininase in PA, and almost 100% of total kininase in EHT, Cushing's syndrome and NT. These findings suggest that: 1) NEP may play a major role in the metabolism of renal kinins in man. 2) NEP in EHT, NEP and kininase I in PA and NEP, and kininase I and II in Cushing's syndrome are increased. 3) An unknown kininase, different from these three kininases, may exist in PA. 4) Enhanced renal kininases may play an important role in disorders of renal water-sodium metabolism and blood pressure in these hypertensive diseases by regulating the metabolism of intrarenal kinins. (Hypertens Res 1993; 16: 253-258)

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Based on radio-ligand binding assays, most of the α_2B-adrenoceptors in rat kidney are found in the proximal tubules and are of the α_2B-adrenoceptors subtype. To determine more accurately the distribution of the α_2B-adrenoceptors in the rat kidney, we studied the expression of α_2B-adrenoceptors mRNA in rat kidney slices and microdissected nephron fragments using reverse transcription-polymerase chain reaction (RT-PCR) technique. Sprague-Dawley rat kidney was dissected into cortex, outer medulla and inner medulla. Total RNA was prepared from the kidney slices. Microdissected single nephron segments about 1mm in length were transferred to tubes containing lysis buffer. RT-PCR was performed using a GeneAmp RNA PCR kit from Perkin-Elmer Corporation. The PCR primers were designed based on the sequences of the third cytoplasmic loop of the rat α_2B-gene. After the PCR, the products were analyzed by agarose gel electrophoresis. The specificity of PCR amplified products was examined by restriction endonuclease digestion and internal oligonucleotide hybridization. Our results indicate that α_2B-adrenoceptors mRNA is expressed in rat kidney cortex, outer medulla and inner medulla. Microdissection and RT-PCR showed that α_2B-adrenoceptor mRNA was expressed in the proximal straight tubules (S₃), cortical and medullary thick ascending limbs of Henle (CTALH, MTALH) and cortical and outer medullary collecting tubules (CCT, OMCT). (Hypertens Res 1993; 16: 259-263)

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The aim of the present study was to investigate the participation of the celiac artery vascular bed in the hypertension of spontaneously hypertensive rats (SHR). In conscious SHR and normotensive control rats (NCR), celiac blood flow and arterial pressure were measured with an implanted electromagnetic flow probe and an indwelling arterial catheter. Celiac peripheral resistance (CeR) was calculated as arterial pressure divided by celiac flow. The relative increase of celiac resistance in SHR compared with NCR was less than the increase in total peripheral resistance. That is, participation of CeR in the hypertension was below the average for the whole body. The decrease in local conductance (inverse of resistance) in SHR compared with NCR was calculated to be about 5% of that of total conductance. The contribution of CeR to the hypertension was thus quantitatively about 5%. Ganglionic blockade with hexamethonium bromide decreased CeR more markedly in SHR than in NCR, which suggests an important role of sympathetic nerves in the increased CeR in SHR. ( Hypertens Res 1993; 16: 265-268)

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We investigated the expression of Na, K-ATPase α and β isoform mRNAs in spontaneously hypertensive rat (SHR) hearts, aortae and kidneys, compared with findings in normotensive Wistar-Kyoto rat (WKY), to obtain insight into the role of these isoforms in the development of hypertension in SHR. We used 4-, 8-, and 16-week-old SHR and WKY. Systolic blood pressure was recorded by tail sphygmomanometry. The expression of Na, K-ATPase α and β isoform mRNAs was analyzed by Northern blot hybridization, using isoform specific cDNA probes. In the ventricles, pre-hypertensive 4-week-old SHR showed a significant 3 to 4-fold increase in the α1 and α2 isoform mRNA accumulation compared with age-matched WKY. The α3 isoform mRNA expression was detected only in 4-week-old SHR hearts. The pattern of β1 mRNA expression resembled that of α1 or α2 mRNAs, and a significant 7-fold increase was observed in 4-week-old SHR compared with age-matched WKY. In the aortae, the α1 and α2 isoform mRNAs were expressed, and 4-week-old SHR exhibited a significant 5-fold increase in the α1 and α2 isoform mRNA levels compared with age-matched WKY. In the kidneys, only the α1 isoform mRNA was expressed, and that of SHR showed a significant 2-fold increase compared with age-matched WKY. We conclude that the expression of Na, K-ATPase α and β isoform mRNAs is significantly increased in the hearts, aortae and kidneys of SHR before the onset of hypertension. These findings suggest that, in this model, the altered expression of Na, K-ATPase gene is an early, if not a primary, event in the development of hypertension. (Hypertension Res 1993; 16: 269-274)

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