Yukio Yamori

Norepinephrine Metabolism in Brainstem of Spontaneously Hypertensive Rats

Concentrations of norepinephrine in lower brainstem and hypothalamus of genetically hypertensive rats are significantly lower than in control rats. There is a concomitant reduction (50 percent) in aromatic L-amino acid decarboxylase but not in tyrosine hydroxylase activity. A possible relation of this central catecholamine deficiency to the hypertension is discussed.

Effect of antihypertensive therapy on lysine incorporation into vascular protein of the spontaneously hypertensive rat

Young spontaneously hypertensive rats (SHR) were either treated with hydralazine or hexamethonium or splanchnicotomized, so that the development of hypertension was effectively arrested for two weeks. The rate of incorporation of 3H-lysine into non-collagenous proteins in vivo of the heart, aorta and mesenteric arteries was determined in the treated SHR, as well as control SHR and normal Wistar/Kyoto (WK) rats. The lysine incorporation into the non-collagenous protein of mesenteric arteries was increased in 8-week-old SHR as compared with WK rats. Teh elevated lysine incorporation in the SHR was abolished by treatment with hexamethonium or by splanchnicotomy, but was not affected by treatment with hydralazine. It is suggested that sympathetic innervation is important fot the increased synthesis of vascular non-collagenous protein during the early hypertensive phase in the SHR.

Effects of l‐dopa and inhibitors of decarboxylase and monoamine oxidase on brain noradrenaline levels and blood pressure in spontaneously hypertensive rats

Acute administration of l‐dopa (200 mg/kg) resulted in a significant decrease in blood pressure of the spontaneously hypertensive (SH) rat. Simultaneous treatment with a peripheral decarboxylase inhibitor (3,4‐dihydroxyphenyl‐2‐hydrazino‐2‐methylpropionic acid; MK 485) potentiated this effect while treatment with a decarboxylase inhibitor that penetrates the central nervous system (4‐bromo‐3‐hydroxybenzyloxyamine; NSD 1055) tended to block the effect of l‐dopa. In general, only treatments that increased brainstem noradrenaline were effective in reducing blood pressure. In young SH rats chronic treatment with l‐dopa and a peripheral decarboxylase inhibitor significantly retarded the development of hypertension over four weeks. Treatment of SH rats with 3 daily doses (100 mg/kg each) of p‐chlorophenylalanine resulted in a complete loss of 5‐hydroxy‐tryptamine and a slight reduction of noradrenaline in the brainstem. The blood pressure of these animals was slightly increased over that of the control SH rats. Treatment of several groups of SH rats with a monoamine oxidase inhibitor (pargyline) in various combinations with l‐dopa and a peripheral decarboxylase inhibitor resulted in a wide range of noradrenaline levels in the brainstem. There appeared to be a highly significant inverse correlation between brainstem noradrenaline and blood pressure. The findings are consistent with central noradrenergic modulation of blood pressure in the rat.

Effect of tissue norepinephrine depletion by 6-hydroxydopamine on blood pressure in spontaneously hypertensive rats

Abstract Blood pressure was studied in normotensive and spontaneously hypertensive rats (SHR) in which catecholamine depletion had been produced by 6-hydroxydopamine. After i.v. administration of 80–200 mg/kg 6-hydroxydopamine, norepinephrine (NE) levels in heart, spleen, and kidney were markedly reduced (14–66% of control value) while brain NE remained unchanged. These doses did not affect development of hypertension in SHR or the blood pressure in normotensive control rats during a 20 day period of study. A transient decrease of blood pressure was observed acutely (1–3 days) after an 80 mg/kg dose in normotensive and hypertensive animals. Depletion of NE in the brainstem (to 33–42% of control value) after intraventricular injection of 6-hydroxydopamine, 50–300 μg, had no effect on blood pressure of SHR and normotensive rats. It is concluded that only a small portion of tissue NE content is sufficient for development and maintenance of hypertension in the SHR.

The hypotensive effect of centrally administered tyrosine

Intraventricular injection of 15 microgram L-tyrosine results in a significant reduction in blood pressure in the spontaneously hypertensive rat. An increase in the turnover of norepinephrine as indexed by MOPEG-SO4 is observed concurrently. The data are consistent with the previously suggested depressor role of certain central noradrenergic neurons.

Sodium and Other Dietary Factors in Experimental and Human Hypertension: The Japanese Experience

Stroke is the most preponderant cause of death in Japan, while myocardial infarction is the first cause of death in Western countries. Epidemiologic studies have indicated that stroke incidence in Japan, which is closely related to hypertension itself, is rather inversely correlated with serum cholesterol levels that are generally far lower than those of the populations in Western countries; the mean of the various populations in Japan is mostly below 200 mg/dl. Since the stroke incidence is higher in rural inhabitants in Japan who are taking less cholesterol and protein, but excess salt (the mean daily intake is mostly over 12 g, not infrequently over 20 g), salt excess seems to be more closely related to high stroke incidence.

Pathophysiological Role of Taurine in Blood Pressure Regulation in Stroke-Prone Spontaneously Hypertensive Rats (SHR)

Stroke-prone spontaneously hypertensive rats (SHRSP), which were established by selective breeding (Yamori et al., 1974a; Okamoto et al., 1974), develop severe hypertension and cerebrovascular lesions in more than 90% of the population (Yamori et al., 1976). These SHRSP, as well as spontaneously hypertensive rats (SHR), are regarded as the best models to date for studies on the pathogenesis and prevention of the spontaneously developing hypertensive diseases observed in man (Yamori and Okamoto, 1974; Folkow et al., 1973).

Biomembrane Abnormalities in Spontaneous Hypertension

Recent studies on spontaneously hypertensive rats (SHR) [1] and strokeprone SHR (SHRSP) [2] have brought us both good news and bad news [3]. The bad news is that hypertension and stroke are definitely determined by genetic factors [4]. On the other hand, the good news is that hypertension and stroke can be prevented by modifying environmental factors or by preventive treatments, even if genetic predisposition is strong [3, 5, 6].

Experimental and Epidemiological Studies on the Relation of Trace Elements in the Pathogenesis and Prevention of Cardiovascular Diseases

Review of previous experimental and epidemiological studies indicated some relationship of water quality with cardiovascular mortalities and the possible involvement of selenium in cardiomyopathy and of cadmium in hypertension. Present studies on rat models for hypertension, stroke and atherosclerosis revealed significant alterations in plasma and some organ contents of magnesium (Mg) among macroelements and of zinc (Zn) among microelements so far examined, suggestive of the possible involvement of these minerals in hypertension mechanisms, especially in its intracellular processes in addition to causative and preventive roles of macroelements such as sodium (Na), potassium (K) and calcium (Ca) that have been experimentally proven by our previous studies. In our world-wide epidemiological studies on cardiovascular diseases and nutrition, 24 hour urinalysis data of 5 Chinese populations showed not only correlation of Na but also inverse correlations of Ca and Mg with blood pressure. Moreover, comparative analysis on water quality in 6 populations with high and low cardiovascular mortalities has demonstrated Ca and/or Mg contents are obviously higher in those with low risks.

Is Biomembrane Abnormality a Pathogenic Factor or a Genetic Marker of Hypertensive Diseases

The establishment of the strains of spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) indicates that genetic factors are important in the pathogenesis of hypertension and hypertensive diseases such as stroke. Among various characteristics observed in SHR and SHRSP, the membrane abnormality noted in erythrocytes may be related to a fundamental fault in hypertension or considered as a genetic marker of hypertensive diseases. We have therefore sought to analyze characteristics of various membranes (erythrocytes, platelets, and synaptosomes) by different methods (membrane viscosity by a microviscosimeter, membrane permeability of lipophilic ions by a newly developed biomembrane-permeability detector, osmotic fragility by a coil-planet centrifugation) in SHRSP, SHR, and their normotensive control Wistar-Kyoto (WK) strain, as well as in men with or without family history of stroke. Moreover, the changes in synaptosomal membrane potential induced by depolarization with various potassium ion concentrations were determined, using a fluorochrome as an indicator. Norepinephrine uptake into and release from synaptosomes were also quantitatively estimated.