Dopaminergic modulation of salt sensitivity in patients with essential hypertension.

The present study was designed to investigate the possible role of dopaminergic mechanisms in contributing to the pathogenesis of hypertension in salt sensitive patients. Eighteen patients with essential hypertension were studied while under a diet ranging from low salt to high salt, which enabled a classification in "salt-sensitive" (SS) and "nonsalt-sensitive" (NSS) groups based on a tentative criteria of a 10% increase of mean blood pressure with high salt diet. The SS patients showed reduced urinary excretion of sodium as compared with that from NSS patients. Urinary norepinephrine excretion in all patients with salt loading was suppressed, but urinary excretion of epinephrine showed a tendency to increase in SS patients after salt loading. Urinary excretion of dopamine increased in NSS patients with salt loading, but did not change in SS patients. To further evaluate the role of dopaminergic mechanisms in salt-sensitive hypertension, metoclopramide, a dopamine antagonist, was injected intravenously to all patients. With salt loading, plasma aldosterone levels increased after injection of metoclopramide in NSS patients, but did not change in SS patients. These results suggest that salt-sensitive hypertension is modulated by dopaminergic activity, which in turn is attenuated in SS patients. Decreased dopaminergic activity induced sodium retention both by a direct effect on the kidney as well as indirectly via relatively increased aldosterone secretion. Both mechanisms would help to increase intravascular volume and blood pressure in salt-sensitive hypertension.

[Effect of imipenem/cilastatin combined with vancomycin for MRSA infection].

Therapeutic efficacy of the combined regimen, imipenem/cilastatin (IPM/CS) plus vancomycin (VCM), was examined in a total of 13 patients infected with MRSA (10 patients with pneumonia, 2 with sepsis and 1 with urinary tract infection). Based on the results of determination of FIC indices, in vitro combined effects were synergistic in 4 strains and additive in 3 strains. There was, however, no apparent correlation between the in vitro combined effect in terms of FIC index and clinical outcome. No side effects or abnormal laboratory findings were observed. The average daily doses of IPM/CS and VCM were 1.2 g and 1.25 g and the average administration periods were 17.5 and 14.9 days, respectively. The present results suggested that simultaneous use of IPM/CS and VCM at the standard doses could yield an enhancement of both bacteriological and clinical efficacies in treatment of the patients with MRSA infection.

Role of renal nerves and dopamine on prostaglandin E release from the kidney of rats.

The aim of the study is to investigate the role of renal nerves and dopamine (DA) on urinary excretion of prostaglandin E (PGE) released from kidney with or without salt loading in rats. After excessive intake of high Na, urinary excretions of PGE and DA enhanced as compared with those of basal Na. In rats with renal denervation, urinary excretion of PGE and norepinephrine decreased in salt loading, and urinary Na excretion increased. Urinary PGE excretion was also enhanced by treatment of bromocriptine accompanying with augmented natriuresis. Urinary PGE excretion was suppressed by treatment of carbidopa, which also suppressed the urinary excretion of DA. These results suggest that the renal adrenergic nerve and tubular DA in kidney play an important role on the release of PGE and that these mechanisms in PGE release from kidney augment in salt loading.

[The effect of dopaminergic antagonists on plasma aldosterone in normal subjects and patients with hypopituitarism].

Although angiotensin II, ACTH and potassium are generally acknowledged as major factors in regulating the influences on aldosterone secretion, it has recently been reported that dopamine is a potent inhibitor of aldosterone secretion in man and animals. In the present study, we investigated the effect of two kinds of dopaminergic receptor antagonists, metoclopramide and sulpiride, on plasma aldosterone concentration (PAC) and serum prolactin (PRL) in man. Normotensive volunteers and patients with hypopituitarism were injected with metoclopramide (10 mg i.v.) or sulpiride (10 mg i.m.). In normal volunteers, metoclopramide increased both PAC and PRL levels, and showed a maximum level at 30 minutes after injection. In patients with hypopituitarism, PAC tended to increase without change of PRL, which suggested that the increase in PAC by metoclopramide might have a direct inhibitory effect on the dopaminergic receptor in the adrenal gland. Moreover another antagonist, sulpiride also increased PRL but contrary tended to decrease PAC. These results suggested that PRL responses to both inhibitors were mediated by dopaminergic antagonist activity at the level of pituitary receptors. However dopamine-induced modulation of aldosterone secretion may be different from that of PRL at dopaminergic receptors. These results suggested that modulatory inhibition of aldosterone secretion by dopamine may be affected by difference of affinity of dopamine to receptor as organ specificity, or different affinity of metoclopramide and sulpiride to adrenal dopamine receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive effect of nifedipine and its relationship to severity of hypertension.

The antihypertensive effect of nifedipine (Adalat), a Ca2+-antagonistic drug, was studied in patients with mild or severe hypertension. In both short- and long-term trials, nifedipine exerted a strong hypotensive effect, more pronounced in patients with severe than in cases with mild hypertension. The results of our short-term study showed a positive correlation between the maximum fall in blood pressure induced by nifedipine and pretreatment systolic blood pressure values or the total severity index score of hypertension. In our long-term trial, we also observed a positive correlation between maximum reduction of blood pressure--induced by nifedipine--and pretreatment values. However, no correlation between reduction of blood pressure and total severity index score of hypertension could be established. Our results indicate that nifedipine could be effective in the management of severe hypertension. The hypotensive action of nifedipine, at least partly due to its Ca2+ influx blocking action, suggests that etiologically hypertension may be connected with an abnormal calcium metabolism of the cardiovascular muscle cells.

The role of prostaglandins in the regulation of blood pressure with special reference to vascular reactivity.

The role of prostaglandins (PGs) in the regulation of blood pressure was analysed from the point of view of vascular reactivity to PGs and also of PG-induced modulation of pressor response. The vasodepressor effect of PGE1 was more sensitive in the patients with essential hypertension than in the normotensive subjects. In the normotensive subjects or in rats, pressor response to norepinephrine was modulated by PGE1, enhanced under treatment with indomethacin, an inhibitor of PG biosynthesis, and suppressed under an infusion of PGE1. These results indicate that pressor response to norepinephrine is modulated by exogenous and endogenous PGs. The PG-induced modulation disappeared after chemical sympathectomy, suggesting that the PG-induced modulation of pressor response is regulated by the sympathetic nervous system. In sympathetic neurotransmission, PGs could play an important role in the regulation of norepinephrine release. Renal content of norepinephrine was reduced under treatment with indomethacin, indicating an enhanced release of norepinephrine and an enhanced turnover of norepinephrine in the kidneys under treatment with indomethacin. These results suggest that a deficient state of PG may enhance the pressor response and norepinephrine release. As there is much evidence indicating that the reduction of PG synthesis in patients and animals with hypertension, vascular reactivity to PGs and PG-induced modulation of pressor response may play significant roles in the regulation of blood pressure and could be causal factors of hypertension.

The significance of duration of salt loading on cardiovascular response and urinary excretion of catecholamine in rats.

To analyze the conflicting data on the relationship between sodium intake and catecholamine release, the effect of the duration of high sodium loading on cardiovascular response and catecholamine release was examined in conscious rats. Urinary excretions of norepinephrine (NE), and dopamine (DA) were measured frequently over a 4 week period. Male Wistar rats at 4 weeks of age were given a diet containing either basal (0.3%) or high (3.1%) sodium content. Systolic blood pressure was measured weekly by the tail cuff method. Twenty-four hour urine collections were made for analysis of catecholamines in metabolic cages every other day during the initial 2 weeks and once a week in the following 2 weeks of salt loading. High sodium intake resulted in a rise in blood pressure and a reduction in heart rate. Bradycardia was significant during the initial 2 weeks and not significant during the following 2 weeks after the initiation of salt loading. Urinary excretion of NE did not change during the initial 2 weeks of salt loading but increased significantly following the 2 week period after salt loading. Urinary excretion of DA increased diphasically, showing the first peak at 1 week after salt loading and the second peak at 4 weeks after the initiation of salt loading. These results suggest that the heart rate and urinary excretion of catecholamine are influenced by the duration of salt loading. When we estimate the effect of salt loading on cardiovascular response and urinary excretion of catecholamine, we should draw attention to the importance of the duration of salt loading, because this duration of time further elicites delayed response in the sympathetic nervous system.

The role of brain angiotensin II in the mechanism of the pressor responses to intracisternal injection of hypertonic NaCl in urethane anesthetized rats.

Intracisternal injections of hypertonic NaCl elicited the pressor responses in urethane anesthetized spontaneously hypertensive and normotensive Wistar rats. The intracisternal pretreatment of 1-Sar-8-Ile-angiotensin II, angiotensin II analog, could abolish the pressor responses to intracisternal injections of 5% NaCl in urethane anesthetized spontaneously hypertensive rats, while basal blood pressure was not affected by these pretreatment. Both intracisternal and intravenous administration of captopril, an angiotensin I converting enzyme inhibitor, did not alter the pressor effect of hypertonic NaCl in normotensive rats. Basal blood pressure was lowered by intravenous injection of captopril. The involvement of angiotensin II in the pressor mechanism of hypertonic NaCl was confirmed by the enhanced pressor responses to intracisternal injections of 5% NaCl in urethane anesthetized rats pretreated intracisternally with angiotensin II. These findings suggest that angiotensin II itself could play an important role in the pressor responses to intracisternal injections of hypertonic NaCl without involving a converting enzyme system.

Effect of prostaglandin E1 on renin and aldosterone in hypertensive patients.

The effect of prostaglandin E1 (PGE1) on plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was studied in the hypertensive subjects treated with or without 75 mg indomethacin or 60 mg propranolol for a week. Subsequent to the treatment with indomethacin for a week, PRA and PAC levels were decreased as compared to the control, without changes in the blood pressure and heart rate. During the infusion of PGE1, the blood pressure was decreased and the pulse rate was increased. PRA and PAC levels were also elevated. These changes of parameters were not different between the control and the indomethacin-treated subjects. PRA and PAC were suppressed after the treatment with propranolol. With the infusion of PGE1, the level of PRA was not significantly elevated, while, PAC was significantly increased by the infusion of 100 ng/Kg/min of PGE1. During the infusion of PGE1, the blood pressure was decreased while the pulse rate was increased in the subjects treated with propranolol. However, the elevation of the pulse rate was less remarkable than the control. These data indicate that PGE1 have important roles in the regulation of the release of renin and aldosterone. These findings also suggest that PGE1 may act to stimulate the secretion of aldosterone in man.