Masatoshi Sakamoto

Cardiovascular Regulation by l-Arginine in the Brain of Rats: Role of the Brain Renin-Angiotensin System and Nitric Oxide

The effect of brain L-arginine on arterial pressure was investigated by injecting L- or D-arginine into the cerebral ventricles of male Wistar rats that were anesthetized with urethane. Intracerebroventricular (I.C.V.) injection of 1 micromol L-arginine reduced the arterial pressure and the abdominal sympathetic nervous activity (SNA), whereas the injection of 10 micromol L-arginine induced a transient pressor response and reduced both the heart rate and SNA. Although I.C.V. injection of 1 micromol D-arginine had no effect on cardiovascular function or SNA, injection of 10 micromol of this enantiomer elicited a transient pressor response, similar to that induced by 10 micromol L-arginine, followed by a persistent increase in arterial pressure and a corresponding increase in SNA. I.C.V. pretreatment with the nitric oxide synthase inhibitor N(G)-monomethyl L-arginine abolished the vasodepressor response and reduced the inhibition of SNA induced by I.C.V. injection of 1 micromol L-arginine; such pretreatment increased the arterial pressure, heart rate, and SNA measured 30 min after I.C.V. injection of 10 micromol L-arginine. I.C.V. pretreatment with the angiotensin II type 1 receptor antagonist CV-11974 inhibited the pressor response to 10 micromol L-arginine and the first phase of the pressor response to 10 micromol D-arginine. Intravenous pretreatment with the alpha1-adrenoceptor blocker bunazosin hydrochloride abolished the pressor response to 10 micromol L-arginine and both phases of the pressor response to 10 micromol D-arginine. Brain L-arginine thus appears to exert pressor actions through stimulation of the brain renin-angiotensin system and peripheral SNA. However, these actions may be attenuated by L-arginine-derived nitric oxide.

Lower than normal expression of brain nitric oxide synthase gene in the hypothalamus of deoxycorticosterone acetate-salt hypertensive rats.

Objective To elucidate the role of brain nitric oxide produced by neuronal constitutive nitric oxide synthase in sodium-induced hypertension. Design and methods Diets containing a high (8% NaCl), a medium (2% NaCl), and a low (0.2% NaCl) sodium content were administered to Wistar rats aged 12 weeks for 10 days or 8 weeks until they were killed. Male Wistar rats administered either deoxycorticosterone acetate, 1% NaCl or both and the respective controls were killed 2 weeks (during prehypertensive stage) or 6 weeks (during hypertensive stage) after the start of treatment. The hypothalamus and lower brainstem were excised for extraction of total RNA. Reverse transcription polymerase chain reactions of constitutive nitric oxide synthase messenger RNA and glyceraldehyde-3-phosphate dehydrogenase messenger RNA were performed, and constitutive nitric oxide synthase messenger RNA levels were expressed relative to glyceraldehyde-3-phosphate dehydrogenase messenger RNA levels. Results A high sodium intake for 10 days tended to decrease constitutive nitric oxide synthase messenger RNA levels in the hypothalamus, compared with effect of a low sodium intake. Constitutive nitric oxide synthase messenger RNA levels in the hypothalamus of deoxycorticosterone acetate-salt hypertensive rats were lower than those in the control sham-operated rats. Neither alteration of sodium intake nor administration of deoxycorticosterone with and without sodium affected constitutive nitric oxide synthase gene expression in the lower brainstem. Conclusions Expression of neuronal constitutive nitric oxide synthase gene is downregulated in the hypothalamus of deoxycorticosterone acetate-salt hypertensive rats. This lower than normal expression of neuronal constitutive nitric oxide synthase gene in the hypothalamus could be an adaptive response to sodium-induced hypertension, and suggests that nitric oxide produced by hypothalamic constitutive nitric oxide synthase plays a role in maintenance of blood pressure in relation to sodium balance in rats.

Cerebral ATP-Sensitive Potassium Channels During Acute Reduction of Carotid Blood Flow

The ATP-sensitive potassium channels (KATP) are activated either by a decrease in intracellular ATP content or by a lowering of the ATP-ADP ratio such as during stroke. We studied the role of cerebral KATP on arterial pressure during acute reduction of cerebral blood flow in 12-week-old male Wistar rats anesthetized with urethane by recording arterial pressure and heart rate continuously. After bilateral ligation of the common carotid arteries, glibenclamide, a specific blocker of KATP, was injected intracerebroventricularly into the cerebral lateral ventricle. Glibenclamide elicited a sustained vasopressor response in a dose-dependent manner in rats with bilateral carotid artery ligation (10 nmol, +15 +/- 2 mm Hg; 1 nmol, +5 +/- 1 mm Hg, P < .01 versus vehicle), but hemodynamic alterations were barely recorded with glibenclamide in sham-operated control rats. The abdominal sympathetic discharge was not increased significantly enough to explain the pressor mechanism. Similarly, pretreatments with intravenous injections of bunazosin, an alpha 1-adrenoceptor antagonist, did not affect the pressor response of intracerebroventricular glibenclamide. To investigate the vasopressor mechanism further, we measured plasma and pituitary concentrations of arginine vasopressin and determined the effects of vasopressin receptor antagonists. The intracerebroventricular injections of glibenclamide significantly increased the plasma concentration of vasopressin (P < .05) and significantly decreased the pituitary concentration of vasopressin (P < .05) in rats with bilateral carotid artery ligation. Intravenous pretreatment with the vasopressin V1 receptor antagonist OPC-21268 abolished the vasopressor response to intracerebroventricular glibenclamide (+16 +/- 2 versus +1 +/- 1 mm Hg, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral adenosine triphosphate-sensitive K+ channels may be impaired during acute cerebral ischemia in spontaneously hypertensive rats

To elucidate the role of cerebral adenosine triphosphate (ATP)-sensitive K+ channels (KATP) on arterial pressure regulation during acute cerebral ischemia in spontaneously hypertensive rats (SHR), intracerebroventricular (i.c.v.) injections of either glibenclamide, a specific blocker of KATP, or pinacidil, a KATP opener, were performed in SHR and Wistar-Kyoto rats (WKY). Intracerebroventricular injections of glibenclamide elicited a vasopressor response in WKY with bilateral ligation of the carotid arteries, whereas the response was smaller in SHR. It increased plasma AVP, but decreased pituitary AVP in WKY with ligation, but not in SHR. Systemic administration of an AVP V1 receptor antagonist, OPC-21268, abolished the vasopressor responses to i.c.v. injections of glibenclamide in WKY. Bilateral ligation of the carotid arteries augmented the vasodepressor responses to i.c.v. injections of pinacidil in WKY, but not in SHR. Cerebral KATP may play a role in buffering a rise in arterial pressure by inhibiting the release of AVP from the pituitary glands during acute cerebral ischemia in WKY, but this mechanism might be deranged in SHR, probably due to impaired responsiveness of cerebral KATP to ischemia.

Brain Atrial Natriuretic Peptide Family Abolishes Cardiovascular Haemodynamic Alterations Caused By Hypertonic Saline In Rats

1. Regional haemodynamic alterations caused by hypertonic NaCl solution (Hi‐Salt; 10%, 10 μL) injected intracerebroventricularly (i.c.v.) were investigated by using radioactive microspheres in anaesthetized rats.

ROLE OF CEREBRAL ATP‐SENSITIVE K+ CHANNELS IN ARTERIAL PRESSURE REGULATION DURING ACUTE CEREBRAL ISCHAEMIA IN SHR AND WKY RATS

1. ATP‐sensitive K+ channels (KATP) are activated either by decreased intracellular ATP content or ATP/ADP ratio during ischaemia. We examined the role of a cerebral KATP in arterial pressure regulation during acute cerebral ischaemia using SHR and WKY rats. Thirteen week old male SHR or WKY rats were anaesthetized with urethane, and arterial pressure and heart rate were recorded under an artificial ventilation.