Tetsuhiro Kubota

Effects of thromboxane synthetase inhibitors on aggregation of rabbit platelets

Thromboxane (TX) synthetase activity was selectively inhibited by (E)-3-[4-(1-imidazolylmethyl)phenyl]-2-propenoic acid hydrochloride monohydrate (OKY-046) and sodium (E)-3-[4-(3-pyridylmethyl)phenyl]-2-methyl-propenoate (OKY-1581) (OKYs). Their IC50 for the rabbit platelet enzyme were found to be 11nM and 3nM respectively. Arachidonic acid (AA) or collagen induced platelet aggregation, and generated TXA 2 and prostaglandins (PGs) in rabbit platelets. OKYs inhibited platelet aggregation and TXA2 generation without affecting PGs generation, while aspirin inhibited platelet aggregation, and TXA2 and PGs generation. There was a parallel relation between the degree of inhibition of platelet aggregation and TXA2 generation by OKYs, but the inhibitory effects of aspirin on platelet aggregation was related to that on both TXA2 and PGs generation. However, OKYs and aspirin did not inhibit ADP-induced platelet aggregation which did not involve the generation of TXA2 and PGs. These results suggested that TXA2 generation is related to platelet aggregation induced by AA or collagen, and that the inhibitory effect of OKYs on platelet aggregation is due to the inhibition of TX synthetase.

Acute effects of the calcium antagonist, nifedipine, on blood pressure, pulse rate, and the renin-angiotensin-aldosterone system in patients with essential hypertension

Ten milligrams nifedipine was administered orally to young and old persons with or without hypertension, and the acute effects of nifedipine on the renin-angiotensin-aldosterone system were studied one half to 3 hours later. Nifedipine reduced blood pressure and increased pulse rate in young and old persons with or without hypertension. Simultaneously, nifedipine produced a significant increase of plasma renin activity in young persons with or without hypertension but failed to do so in old persons with or without hypertension. As a result, angiotensin I and II increased significantly in young persons but not in old persons. Hydralazine elevated aldosterone concentration by stimulating the renin-angiotensin system but nifedipine failed to do so despite its effect on the renin-angiotensin system in young individuals. Since calcium is required to secrete aldosterone, it is suggested that nifedipine blocked aldosterone secretion by the agents calcium antagonizing action.

An Elevation of Plasma TSH Concentration in Spontaneously Hypertensive Rats (SHR)

Summary Thyroid activity was tested in two substrains of SHR. Plasma level and pituitary content of TSH increased significantly in both substrains of SHR. As a result, the thyroid weight and thyroidal radioiodine uptake increased significantly. Plasma T3 concentration was decreased in Kyoto sub-strain but was normal in NN substrain, while plasma T4 concentration decreased significantly in both substrains. Since the pituitary content and plasma level of TSH were significantly higher in spite of the normal concentration of plasma T3, it is concluded that the pituitary “hormostat” is set at a higher level at least in the NN substrain of SHR.

Human renin inhibiting dipeptide

KRI-1177, a dipeptide containing nor-statine inhibited renin activity in human and Japanese monkey plasma to a markedly greater extent than that in dog, rabbit and rat plasma. The systemic blood pressure of anesthetized monkeys was lowered by intravenous injections of this compound which also reduced plasma renin activity and concentration of angiotensins. KRI-1177 appears to selectively inhibit primate renin activity, thereby producing hypotension.

Augmentation of prostacyclin and depression of PGE2, PGF2α and thromboxane A2 by TSH in cultured porcine thyroid cells: An important role of prostacyclin in maintaining thyroid cell function

The importance of prostaglandins (PCs) in thyroid physiology has long been a controversial subject. In [l-3] 6-ketoprostaglandin Fr, was isolated and found to be an end-metabolite of the unstable compound, prostacyclin [4,.5]. Prostacyclin producing activity has been reported in many tissues and cells [6-81, and biological significance of prostacyclin in maintaining homeostasis has become apparent. Thromboxane Ba, an end-metabolite of thromboxane Aa, has been isolated [9] and this thromboxane A* seems to play some role to maintain homeostasis. However, prostacyclin and thromboxane Aa producing activities in the thyroid have not been reported and their biological significance needs to be studied. To evaluate the role of endogenous PGs in the regulation of thyroid function, we have estimated prostaglandin Ea (PGE,), prostaglandin Fzor (PGFa,), 6-ketoprostaglandin Fr, and thromboxane Bz (TXBa) and correlations of these PGs and thyroid functions were studied using cultured porcine thyroid cells. Here, we show that in the absence of TSH, the cells are unable to take up iodide or organify it but product; PGE2, PGFzo, and TXBz and that in the presence of TSH, the cells are able to take up iodide and organify it but preferentially produce 6-ketoprostaglandin Fr,, an end-metabolite of prostacyclin.

Congenital Abnormality of Pituitary-Thyroid Axis in Spontaneously Hypertensive Rats (SHR) and Stroke-Prone Rats (SPR):

Summary In an attempt to study whether TSH abnormality was genetically determined in SHR and SPR, plasma T4, T3, TSH and prolactin concentrations were measured in the animals with intervals of 1 to 3 months. Hypertension was found in 6-month-old SHR and SPR, but it was not found in younger animals. In contrast, a decrease of plasma T3 and an increase of plasma TSH were found in 15-day-old SHR. Also, an increase of TSH was found in 1-month-old SPR in spite of normal plasma T3 concentration. These abnormalities in SHR and SPR increased progressively with age. It is suggested that thyroid-pituitary abnormality was genetically determined in SHR and SPR.

Changes in Hormonal Activities Relative to the Severity of Essential Hypertension

ABSTRACT: Endocrine activity in patients with essential hypertension was studied by measuring the urinary excretion of catecholamines, prostaglandin E (PGE) and cyclic adenosine monophosphate (cAMP). Simultaneously, plasma renin activity, concentrations of serum sodium, potassium, blood urea nitrogen (BUN) and creatinine were determined. Systolic blood pressure and BUN increased progressively with age until the sixth decade. Urinary excretion of norepinephrine was correlated with the systolic blood pressure. In contrast, plasma renin activity and urinary excretion of PGE decreased progressively with the increase in systolic blood pressure. Although the cause of essential hypertension is not known, it is suggested that hypertension accelerates the aging process in the kidney and thus decreases renal PGE synthesis. This decrease of PGE in turn causes a reduction of plasma renin activity, possibly either by accelerating the retention of sodium and water or by failing to stimulate renin synthesis. A decrease of PGE may also potentiate the vasopressor action of norepinephrine.

Design and synthesis of an orally potent human renin inhibitor containing a novel amino acid, cyclohexylnorstatine

An orally potent human renin inhibitor (1a) containing a novel amino acid, (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid named cyclohexylnorstatine, has been designed from the angiotensinogen transition-state and synthesized.

Effects of Antihypertensive Treatment on Left Ventricular Hypertrophy in Patients with Essential Hypertension

ABSTRACT: In an attempt to determine which type of antihypertensive drug is more effective in reducing left ventricular hypertrophy (LVH), thiazide, α‐methyldopa, hydralazine and propranolol were administered singly or in combination to patients with essential hypertension, and to spontaneously hypertensive rats (SHR). QRS voltage [S1 + R5(or R6)] in the electrocardiogram (ECG), the cardio‐thorax (C/T) ratio in chest x‐ray films, and the heart weight were used to assess regression of LVH and cardiomegaly. The S1 + R5(or R6) and the C/T ratio were well correlated with the pretreatment systolic blood pressure. Adequate blood pressure control produced regression of S1 + R5(or R6) and the C/T ratio, but the change in QRS voltage remained the earlier and more reliable sign of LVH for evaluating the effectiveness of therapy. The regression of QRS voltage and heart weight occurred regardless of which type of therapeutic drug was used in patients with essential hypertension and in SHR. It is suggested that LVH is directly related to the height of arterial pressure and that lowering of arterial pressure can be followed by regression of ECG‐LVH regardless of the type of depressive drug used.