Iwao Ikegaki

Chronic intracerebroventricular infusions of endothelin elevate arterial pressure in rats

We investigated the effects of intracerebroventricular infusions of endothelin on cardiovascular and endocrinological responses using conscious, unrestrained rats. Chronic intracerebroventricular infusions of endothelin, 10 pmol/h for 7 days, elevated arterial pressure significantly on days 5, 6 and 7 of the infusion, compared with intracerebroventricular infusions of the vehicle. Heart rate decreased from day 1 of the infusion of endothelin until the end of the experiment. The urinary excretion of norepinephrine increased on day 3 and epinephrine increased on days 3, 4 and 5 of endothelin infusion. The urinary excretion of arginine vasopressin increased on day 5, 6 and 7 of the infusion. These findings suggest that chronic intracerebroventricular infusions of endothelin elicit elevations in arterial pressure and that the initiation of blood pressure rises can be related to sympathetic activation although the actual role for the pressor responses has been played by the released arginine vasopressin.

The effects of insulin and insulin-like materials in the brain on central cardiovascular regulation : with special reference to the central effects of sodium chloride

The present study investigated the roles of insulin on central cardiovascular regulation. When rats were fed with a high-salt diet for 4 weeks, hypothalamic and pituitary contents of insulin-like immunoreactive substance (ILI) significantly decreased. The plasma concentration of ILI remained unaltered, however. Intracerebroventricular injections of insulin significantly decreased both the blood pressure and the heart rate, with corresponding decreases in renal sympathetic nervous activity in urethane-anesthetized rats. Microinjections of insulin into the ventromedial nucleus in the hypothalamus caused greater vasodepression and bradycardia compared with the intracerebroventricular injections. Intracerebroventricular infusions of insulin inhibited the pressor effects of simultaneously-infused hypertonic saline, and the digitalis-like immunoreactivity in both the plasma and the hypothalamus were significantly decreased by the insulin. These results indicate that ILI in the brain affects the central cardiovascular regulation through the suppression of both sympathetic nervous system activity and the release of digitalis-like substances. These mechanisms may operate particularly during a sodium load.

Inhibitory roles of the hypothalamic atrial natriuretic polypeptide on the vasopressin release in the sodium-loaded rats.

Implication of the brain atrial natriuretic polypeptide on the vasopressin release was investigated using rats fed with a high-sodium containing diet. Sodium loading increased not only the blood pressure but also the urinary output of vasopressin significantly. The plasma vasopressin concentration increased about 10 times after the intracerebroventricular injections of angiotensin II. Thereby, magnitude of the response was significantly smaller in the rat fed with a high sodium diet than in rats with the regular-diet. The hypothalamic content of both vasopressin and atrial natriuretic polypeptide was significantly larger in the high-salt group than the regular-salt. The intraventricular injections of atrial natriuretic polypeptide abolished the vasopressin release induced by the intraventricular injections of angiotensin II. These results indicate that the vasopressin production in the hypothalamus is increased, but the release is relatively suppressed in the sodium-loaded rats, and that increased hypothalamic atrial natriuretic polypeptide is involved in the suppression of the vasopressin release and in decreasing their sodium appetite to avoid the high sodium environment.

Digitalis-like substance is produced in the hypothalamus but not in the adrenal gland in rats

We studied the role of the adrenals on the plasma levels and urinary output of the digoxin-like immunoreactivity in order to elucidate the interrelationship between the adrenals and hypothalamic digoxin-like immunoreactivity. Urine was collected for 24 h 6 days after the bilateral adrenalectomy and then rats were killed by decapilation. Urinary excretion of digoxin-like immunoreactivity did not differ significantly between the sham-operated and adrenalectomized groups, regardless of sodium intake. Plasma levels did not change significantly with sodium-loading, and adrenalectomy did not significantly affect the plasma concentrations of the immunoreactivity. However, bilateral adrenalectomy increased the content of digoxin-like immunoreactivity in the hypothalamus significantly in both rat groups fed with a regular (P < 0.05) and a high-salt (P < 0.02) diet. However, when the levels were measured only 16 h after bilateral adrenalectomy, both plasma and hypothalamic contents were significantly higher in the high-salt than the regular-salt group. The correlation between the plasma and hypothalamic content was significant (P < 0.01). These results strongly suggest that digoxin-like immunoreactivity is produced in the hypothalamus but not in the adrenals, and that the adrenal glands influence the turnover of the hypothalamic endogenous digitalis-like substance.

Brain renin-angiotensin system and the hypothalamic, digitalis-like Na+, K+-ATPase inhibitor in rats.

Since angiotensin (ang) II blockers attenuate the centrally-induced pressor responses to a Na+, K+-ATPase inhibitor, ouabain, a brain renin-ang system is assumed to be involved in this pressor mechanism. Centrally-induced pressor responses to hypertonic saline were also blocked with ang II blockers. Thereby, the increase in the plasma level of digoxin-like immunoreactivity was abolished with simultaneous infusions of an ang II analogue or atrial natriuretic polypeptide (ANP). These results indicate that the pressor responses to sodium salts are mediated via inhibition of the brain Na+, K+-ATPase, and that the brain renin-ang system is involved in this mechanism. We noted the existence of a digoxin-like immunoreactive substance (DLI) containing neurons in the hypothalamus (PVN, SON) with the fibers densely distributed in the AV3V area including OVLT, SFO and the median eminence, an area where receptors for ang II are also distributed (1,2). Since pressor responses to intracerebroventricular (ICV) infusions of hypertonic NaCl are abolished with ICV pretreatment with ang II blockers, a brain renin-ang system may be involved in this mechanism. We then searched for a possible relationship between the central effects of NaCl, a brain renin-ang system and an endogenous Na+, K+-ATPase inhibitor in the hypothalamus.

Sympatholytic effects of the intravenously injected alpha1-adrenergic blocker, bunazosin, in anaesthetized rats

Cardiovascular regulation during alpha 1-adrenergic blocker-induced vasodepression was investigated in urethane-anaesthetized rats. Intravenous (i.v.) injections of bunazosin, an alpha 1-blocker, elicited depressor responses which were accompanied by corresponding decreases in both heart rate and abdominal sympathetic discharge, dose-dependently. Those responses were not affected by the bilateral sino-aortic de-afferentation. Assuming that the site of action is in the central nervous system, bunazosin was injected intracerebroventricularly (i.c.v.). It produced hypotension accompanied by decreases in heart rate and abdominal sympathetic nerve activity. The magnitude of the responses was greater when bunazosin was injected i.c.v. than when injected i.v. Since these results indicated that the central alpha 1-adrenergic receptors mediate vasopressor responses, the effects of i.c.v. injections of an alpha 1-agonist, phenylephrine was explored. It elicited vasopressor responses accompanied by corresponding increases in heart rate and abdominal sympathetic nerve activity. Furthermore, i.c.v. pretreatment with bunazosin abolished the vasopressor responses to i.c.v. injections of phenylephrine. These results indicate that central alpha 1-adrenergic receptors mediate vasopressor responses and that i.v. injections of alpha 1-blockers affect the central alpha 1-receptors, to produce a decrease in sympathetic nerve activity. Consequently, alpha 1-adrenergic blockers decrease blood pressure not only by peripheral vasodilation but also by inhibition of the sympathetic outflow in rats.

DIGOXIN‐LIKE IMMUNOREACTIVITY INCREASES WITH INTRAVENOUS INFUSION OF SALINE IN RATS

1. The effects of sodium‐loading on releases of endogenous digitalis‐like substance were investigated by measuring digoxin‐like immunoreactivity (DLI) during intravenous infusions of isotonic (0.15 mol/L) and hypertonic (1 mol/L) saline in anaesthetized rats. Plasma DLI was measured after death by a digoxin‐radioimmunoassay.

Interaction of Noradrenaline and Dopamine in Patients with Essential Hypertension or with Pheochromocytoma

To analyse the interaction of noradrenaline (NA) and dopamine (DA) release, the present study compared urinary outputs of total NA and DA as well as plasma levels of total NA and DA in normotensive (NT) subjects, in patients with essential hypertension (EHT) and in a patient with pheochromocytoma. Significant correlations between total NA and DA in urine were observed in NT subjects, in patients with EHT and in a patient with pheochromocytoma. A significant correlation was observed in plasma total NA and DA of blood collected from several veins except for the tumor vein, by indwelling catheter, in a patient with pheochromocytoma. These results suggest that DA is released from sympathetic nerve terminals in response to an augmented release of NA.

INTRACEREBROVENTRICULAR INFUSIONS OF INSULIN INCREASE VASOPRESSIN RELEASE IN RATS

1. The role of cerebral insulin or insulin‐like immunoreactive substance (ILI) on arginine–vasopressin (AVP) release using rats was investigated. Feeding rats with a high salt diet for 4 weeks significantly decreased the contents of ILI in both the hypothalamus and pituitary gland. Intracerebroventricular infusions of insulin (4 and 40 μg/min for 30 min) increased plasma AVP concentrations dose‐dependently without hypoglycaemia, but decreased hypothalamic and pituitary contents of AVP.