Akira Nanbu

Enhanced Production of Nitric Oxide May Be Involved in Acute Hypotension During Maintenance Hemodialysis

To investigate the possible involvement of endogenous nitric oxide (NO) in acute hypotension during maintenance hemodialysis, we measured the plasma concentration of the nitrate anion NO3-, a stable metabolite of NO, in 19 patients undergoing hemodialysis. We analyzed heart rate variability to estimate the relationship between autonomic nervous activity and NO production, low-frequency/high-frequency components (L/H) as a parameter of cardiac sympathetic activity, and high-frequency power as a parameter of cardiac vagal activity. Six patients developed severe hypotension (a change in mean blood pressure during dialysis > or = 20 mm Hg), four patients developed mild hypotension (a change in mean blood pressure < or = 19 mm Hg and > or = 1 mm Hg), and nine patients did not develop hypotension. The plasma levels of NO3- before dialysis were markedly elevated in the severely hypotensive group compared with the patients who showed no hypotension (566+/-122 micromol/L v 133+/-38 micromol/L; P < 0.01), and this difference disappeared midhemodialysis and after hemodialysis. The plasma concentration of NO3- before dialysis was significantly associated with both the change in mean blood pressure during dialysis (r= -0.735; P = 0.003) and the mean blood pressure after dialysis (r = -0.675; P = 0.0015). The L/H ratio was inhibited before or after dialysis in the severely hypotensive group compared with the nonhypotensive group, and hypotension during dialysis was correlated with the inhibited L/H ratio before (r = 0.784; P = 0.001) or after (r = 0.822; P = 0.001) dialysis. Plasma NO3- concentrations were correlated with the L/H ratio before (r = -0.553; P = .014) or after (r = -0.546; P = 0.015) dialysis. These results suggest that inhibited sympathetic activity is one of the causes of acute hypotension during dialysis, and the enhanced production of NO is involved in this inhibition of the sympathetic activity in patients having a hypotensive episode during dialysis. The plasma concentration of NO3- before dialysis may be a predictor of the risk of hypotension during dialysis in patients with end-stage renal disease.

Benzamil blockade of brain Na+ channels averts Na+-induced hypertension in rats

To determine the possible involvement of brain amiloride-sensitive Na+channels in Na+-induced hypertension, we investigated the effects of benzamil hydrochloride, a specific blocker of these Na+channels, on the acute pressor mechanisms of intracerebroventricular infusion of hypertonic NaCl and the continuous pressor mechanisms of Na+-induced chronic hypertension, such as deoxycorticosterone acetate-salt hypertensive or stroke-prone spontaneous hypertensive rats, and of non-Na+-induced hypertension, such as renovascular hypertensive rats. Intracerebroventricular preinjection with benzamil (1 or 10 nmol/kg) abolished the increase in mean arterial pressure, heart rate, abdominal sympathetic discharge, and plasma vasopressin concentration induced by an acute increase in cerebrospinal Na+ concentrations at intracerebroventricular infusion of 1.5 M hypertonic NaCl. Continuous intracerebroventricular infusion of benzamil (1 or 10 nmol ⋅ kg-1 ⋅ day-1) for 7 days attenuated Na+-induced chronic hypertension in both deoxycorticosterone acetate-salt and stroke-prone spontaneous hypertensive rats, accompanied by reduction of urinary excretion of vasopressin and norepinephrine but not in renovascular hypertensive rats. Intravenous infusion of benzamil (10 nmol ⋅ kg-1 ⋅ day-1) for 7 days affected neither arterial pressure nor urinary excretion of vasopressin and norepinephrine in either model of hypertension. Benzamil-blockable brain amiloride-sensitive Na+ channels are expected to function as one of the Na+receptors in the brain and to be involved in the pressor mechanism of Na+-induced hypertension.To determine the possible involvement of brain amiloride-sensitive Na+ channels in Na(+)-induced hypertension, we investigated the effects of benzamil hydrochloride, a specific blocker of these Na+ channels, on the acute pressor mechanisms of intracerebroventricular infusion of hypertonic NaCl and the continuous pressor mechanisms of Na(+)-induced chronic hypertension, such as deoxycorticosterone acetate-salt hypertensive or stroke-prone spontaneous hypertensive rats, and of non-Na(+)-induced hypertension, such as renovascular hypertensive rats. Intracerebroventricular preinjection with benzamil (1 or 10 nmol/kg) abolished the increase in mean arterial pressure, heart rate, abdominal sympathetic discharge, and plasma vasopressin concentration induced by an acute increase in cerebrospinal Na+ concentrations at intracerebroventricular infusion of 1.5 M hypertonic NaCl. Continuous intracerebroventricular infusion of benzamil (1 or 10 nmol.kg-1.day-1) for 7 days attenuated Na(+)-induced chronic hypertension in both deoxycorticosterone acetate-salt and stroke-prone spontaneous hypertensive rats, accompanied by reduction of urinary excretion of vasopressin and norepinephrine but not in renovascular hypertensive rats. Intravenous infusion of benzamil (10 nmol.kg-1.day-1) for 7 days affected neither arterial pressure nor urinary excretion of vasopressin and norepinephrine in either model of hypertension. Benzamil-blockable brain amiloride-sensitive Na+ channels are expected to function as one of the Na+ receptors in the brain and to be involved in the pressor mechanism of Na(+)-induced hypertension.

Endogenous nitric oxide production is augmented as the severity advances in patients with liver cirrhosis.

1 Since endothelium‐derived nitric oxide (NO) is a potent vasodilator and degraded into nitrous ions, we measured the serum nitrate ion (NO3−) and the amount of urinary excretions of NO3− as an index for endogenous NO to ascertain whether NO formation is augmented in patients with chronic liver diseases. 2 Using inpatients suffering from chronic liver diseases, serum levels and urinary excretions of NO3− were measured by using high‐performance liquid chromatography with an anion exchange column. 3 Among the four patient groups of normal controls, and those with chronic liver diseases such as chronic active hepatitis, compensated cirrhosis, and decompensated cirrhosis the serum level of NO3− showed the highest level in a patient group with decompensated cirrhosis. The amount of urinary excretion of NO3− was significantly increased in both groups of patients with liver cirrhosis compared with the control group and patients with chronic active hepatitis. Patients with chronic active hepatitis did not show any difference between the normal control group. The amount of urinary excretion of NO3− correlated significantly and negatively with the level of serum albumin (P<0.05) and counts of platelets (P< 0.01) in patients with compensated cirrhosis. 4 These findings suggest that the production of endogenous NO is augmented in patients with liver cirrhosis, particularly in a decompensated subgroup. Increases in the production of endogenous NO correspond to the progress of liver cirrhosis, but not in patients with chronic hepatitis.

Eicosapentaenoic Acid Stimulates Nitric Oxide Production And Decreases Cardiac Noradrenaline In Diabetic Rats

1. The aim of the present study was to investigate whether long‐term oral administration of eicosapentaenoic acid increases nitric oxide (NO) production and affects cardiac sympathetic activity in rats with diabetes mellitus.

Serum hepatocyte growth factor as a possible indicator of arteriosclerosis

Objective To investigate the possible involvement of hepatocyte growth factor in arteriosclerotic lesions, by studying the relationship between serum concentrations of hepatocyte growth factor and grades of retinal arteriosclerosis. Methods We measured the blood pressure, body mass index, serum concentrations of total cholesterol, highdensity lipoprotein cholesterol, triglycerides, creatinine, uric acid, total protein, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, γ-glutamyltranspeptidase, alkaline phosphatase, and hepatocyte growth factor, erythrocyte counts, hemoglobin concentration, and hematocrit levels of 112 adults. Serum concentrations of hepatocyte growth factor were measured by a specific enzyme-linked immunosorbent assay. For each subject, photographs of both optic fundi were taken, and the grade of arteriosclerotic changes in the retinal arteries was evaluated according to Scheies classification. Results Individuals with more advanced grades of arteriosclerotic changes had higher serum hepatocyte growth factor values (grade 0, 0.056 ± 0.004 ng/ml, n = 86; grade 1, 0.132 ± 0.026 ng/ml, n = 17, P < 0.01, versus grade 0; grade 2–3, 0.271 ± 0.023 ng/ml, n = 9, P < 0.01, versus grades 0 and 1). The serum hepatocyte growth factor concentrations were also correlated significantly to the serum uric acid concentrations (r = 0.230, P = 0.015) and erythrocyte counts (r = 0.299, P = 0.001), but not to the systolic and diastolic blood pressures, and other physical and humoral parameters. Conclusions Serum hepatocyte growth factor levels are thought to indicate the presence or development of arteriosclerotic lesions and may be a useful biochemical parameter for estimating the development of systemic arteriosclerosis irrespective of blood pressure levels.

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.

Sodium intake regulates renin gene expression differently in the hypothalamus and kidney of rats

Objective To elucidate the different effects of sodium intake on renin messenger RNA (mRNA) in the hypothalamus and the kidney and to investigate the role of hypothalamic renin in sodium-induced hypertension. Design and methods We investigated the expression of the renin gene in the hypothalamus and the kidney of rats with altered sodium intake and those administered either deoxycorticosterone acetate (DOCA) or sodium. Diets containing a high (8% NaCl), normal (2% NaCl), or low (0.2% NaCl) amount of sodium were administered to 12-week-old male Wistar rats for 10 days or 8 weeks before the rats were killed. Male Wistar rats administered either DOCA or 1% NaCl were killed 2 weeks (during the prehypertensive stage) or 6 weeks (during the hypertensive stage) after the start of treatment. The hypothalamus and kidneys were excised for extraction of total RNA. Competitive polymerase chain reaction of renin mRNA and deletion-mutated renin RNA was performed, and the renin mRNA concentration was calculated. Results A high sodium intake for 10 days increased the renin mRNA in the hypothalamus; the hypothalamic renin mRNA had not been suppressed after 8 weeks of a high sodium intake despite the lowering in renal renin mRNA. Renin mRNA levels in the hypothalamus were not suppressed either in the prehypertensive or in the hypertensive stage in rats treated with DOCA or sodium, or both, although the renal renin mRNA was reduced in rats administered DOCA or sodium, or both, compared with that in sham-treated control rats, during both stages. Conclusions The expression of the renin gene is regulated differently in the rat hypothalamus from that in the kidney. The constant expression of the renin gene in the hypothalamus during a chronic high sodium load might be related at least in part to the mechanism of the activated brain renin–angiotensin system in sodium-induced hypertension.

Inverse association of Chlamydia pneumoniae infection with high blood pressure in Japanese adults

To determine whether Chlamydia pneumoniae (C. pneumoniae) infection is associated with hypertension in Japanese adults, we measured serum levels of IgA (a marker of reinfection) and of IgG (a marker of previous infection) antibodies to C. pneumoniae by enzyme-linked immunosorbent assay in 112 adults including normotensive and untreated hypertensive subjects and in 117 hypertensive subjects who had been receiving treatment for more than 3 years. In 112 adults, positivity rate for IgA was lower (P < .01) in hypertensive than in normotensive or borderline hypertensive subjects. Positivity rates for IgA and IgG together, which indicate persistent infection of C. pneumoniae, were lower (P < .01) in hypertensive than in normotensive subjects. IgA levels were inversely correlated with systolic blood pressure (SBP) (r = 0.530, P = .0001) and with diastolic blood pressure (DBP) (r = 0.398, P = .0001). In the 117 hypertensive subjects treated with medication, positivity rate for IgA was lower (P < .01) in subjects with poor control than in those with good control. Positivity rates for IgA and IgG together were lower (P < 0.01) in the poor control group than in the good or fair control groups. IgA levels were correlated inversely with SBP and DBP. In both 112 adults and 117 hypertensive patients, levels of SBP or DBP were inversely associated with positivity rates for IgA and IgG together in multiple logistic regression analysis. The results suggest an inverse relationship between high blood pressure and C. pneumoniae infection in Japanese adults.

ANTI-OBESITY AND ANTI-DIABETIC EFFECTS OF CARTEOLOL IN NON-INSULIN-DEPENDENT DIABETIC MICE

1. When carteolol, a β‐adrenergic blocker, was administered to KK‐Ay/Ta Jcl mice that are obese and develop spontaneously non‐insulin dependent diabetes, their increase in bodyweight was arrested from the age of 16 weeks. Since their intake of food and water was not influenced by carteolol treatment, compared with the control KK‐Ay/Ta Jcl mice, abolition of the weight gain might be attributed to increased energy metabolism.

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.