Hideoki Okabayashi

Effect of Decreased Dopamine Synthesis on the Development of Hypertension Induced by Salt Loading in Spontaneously Hypertensive Rats

To clarify role of dopamine in the development of hypertension, the effect of a dopamine synthesis inhibitor on blood pressure and urinary output of catecholamines was investigated in spontaneously hypertensive rats (SHR) fed with high sodium diet. Rats were orally given carbidopa, an inhibitor of peripheral DOPA decarboxylase, or the vehicle for 4 weeks. Carbidopa administration accelerated significantly the development of hypertension as compared to the control SHRs with the vehicle. Carbidopa administration resulted in a significant decrease of urinary excreted sodium, urinary dopamine and renal content of dopamine. Conversely, carbidopa administration resulted in a significant increase of urinary excreted norepinephrine, urinary epinephrine and renal content of norepinephrine as compared with control SHRs. These results suggest that decreased dopamine synthesis in kidneys and probably other peripheral tissue accelerates the development of hypertension, mediated by a decrease of natriuresis and an enhancement of sympatho-adrenomedullary activity. Dopamine plays an important role in its protective action against the development of hypertension enhanced by salt loading, and decreased dopaminergic mechanisms accelerated hypertension in SHR.

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.

Involvement of Dopamine in Development of Hypertension in Spontaneously Hypertensive Rat: Effect of Carbidopa, Inhibitor of Peripheral DOPA Decarboxylase

The demonstration of acceleration of hypertension was investigated in spontaneously hypertensive rats (SHR) treated with carbidopa, inhibitor of peripheral dopa decarboxylase. Oral administration of carbidopa to young SHR for 4 weeks accelerated significantly (P less than 0.05) development of hypertension as compared to SHR treated with vehicle. Urinary excretion of dopamine (DA) (P less than 0.01) and renal content of DA (P less than 0.02) were significantly decreased by carbidopa treatment. Urinary excretion of sodium (P less than 0.05) was significantly decreased and renal content of norepinephrine (NE) (P less than 0.01) was significantly increased by carbidopa. Urinary excretion of NE and epinephrine (E) did not change during the experimental period. Negative correlation between systolic blood pressure and urinary excretion of sodium (P less than 0.05) or dopamine (P less than 0.01) and positive correlation between systolic blood pressure and renal content of NE (P less than 0.05) were significantly observed in both groups of SHR treated with carbidopa and with vehicle for 4 weeks. These results suggest that decreased DA biosynthesis in peripheral tissues accelerates development of hypertension mediated by decrease of natriuresis and enhanced release of NE in the kidneys of SHR. DA plays an important role in regulation of blood pressure, and reduced dopaminergic mechanisms enhance blood pressure in SHR.

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.