Brain natriuretic peptide (BNP) was first identified in the porcine brain and later isolated from porcine, rat, and human hearts. In humans, plasma BNP concentrations are progressively elevated with increasing severity of hypertension, particularly when left ventricular hypertrophy (LVH) is present. This presumably reflects increases in ventricular mass associated with increased synthesis and constitutive secretion of BNP from ventricular tissue. In this respect, plasma BNP may be a marker for hypertensive LVH. Acute administration of BNP induces significant natriuresis and suppresses plasma aldosterone in hypertensive subjects. However, further studies are necessary to clarify the pathophysiological significance of BNP in essential hypertension. (Hypertens Res 1995; 18: 259-266)

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Recent findings have enhanced our understanding of the roles played by the L-DOPA system in the baroreceptor reflex and in blood pressure regulation in the lower brainstem. L-DOPA is probably a neurotransmitter of primary baroreceptor afferents terminating in depressor sites of the nucleus tractus solitarii (NTS). It also seems to be a neurotransmitter in depressor sites of the caudal ventrolateral medulla (CVLM) and in pressor sites of the rostral ventrolateral medulla (RVLM) of normotensive Wistar rats. We have explored whether or not presynaptic and postsynaptic functions of the L-DOPA system in these areas are altered to maintain hypertension in adult spontaneously hypertensive rats, as compared with age-matched Wistar Kyoto rats. In this review article, we survey the roles of the L-DOPA system in the baroreceptor reflex and in blood pressure regulation in the rat lower brainstem. (Hypertens Res 1995; 18: 267-277)

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Angiotensin (Ang) II and atrial natriuretic peptide (ANP) have opposing effects on blood pressure, sympathetic activity, vasopressin and ACTH secretion, salt appetite, and drinking. We observed their interaction by infusing Ang II (7.2nmol/h) into the peritoneum (ip) or into the lateral ventricle (icv) of rats with osmotic minipumps for seven days. At sacrifice, rats receiving Ang II-icv had a systolic blood pressure of 184±3 (SEM) mmHg, those receiving Ang II-ip had 159±5mmHg (p<0.05), while controls had 109±2 and 110±2mmHg, respectively (p<0.05). Drinking and urine volume increased similarly in rats receiving Ang II by either route, while Uosm decreased. Renin (PRA) values were lower (p<0.05) in rats receiving Ang II-icv (0.7±0.2ng Ang l/ml/h) or Ang II-ip (0.9±0.2) than in the respective controls (2.3±0.7 and 2.0±0.3). Plasma ANP values with Ang II-icv (18±1.6pg/ml) or with Ang II-ip (49 ±6) were also lower (p<0.05) than respective controls (89±12, 76±4). Vasopressin (AVP) concentrations in the plasma were not influenced by the regimens. In the brain, the ANP contents in areas of the so-called AV3V-region (organum vasculosum laminae terminalis, preoptic periventricular nucleus, medial preoptic nucleus) were similarly and significantly reduced by both Ang II-icv and Ang II-ip. ANP values were also reduced in the median eminence by both types of Ang II-treatment, while ANP concentrations in the supraoptic nucleus were increased. The data show that Ang II infusions producing a chronic rise in blood pressure exert similar effects on drinking behavior, PRA, and ANP concentrations in blood and brain. The AV3V area may be pivotal to both models. (Hypertens Res 1995;18: 279-284)

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We examined the role of central GABAergic mechanisms in salt-induced hypertension and exaggerated responses to stress in borderline hypertensive rats (BHR), the first offspring of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The studies were done in conscious BHR and WKY on high (H) (8% NaCl) or normal (N) (0.3% NaCl) salt diets for 5 weeks. A high-salt diet elevated arterial pressure (AP) (p<0.01) and augmented pressor responses to shaker stress (p<0.05) in BHR but not in WKY. Intravenous hexamethonium caused a greater decrease in AP in BHR-H than in BHR-N at rest. Muscimol (a GABA agonist) injected into the central ventricle (icv) caused a greater decrease in resting AP (p<0.01) and heart rate (HR) (p<0.05) in BHR-H than in BHR-N. Renal sympathetic nerve activity (RSNA) did not change in BHR-H, but increased (p<0.05) in BHR-N during muscimol-induced hypotension, although the magnitudes of muscimol-induced hypotension were greater in BHR-H than in BHR-N. The increases in RSNA in response to intravenous nitroglycerin were similar in BHR-H and BHR-N. Muscimol attenuated pressor and tachycardic responses to stress more in BHR-H than in BHR-N (p<0.01). Muscimol did not alter AP and HR at rest or their responses to stress in the two groups of WKY. The magnitudes of pressor response to bicuculline (a GABA antagonist) did not differ between the two groups of BHR. These results suggest that a high salt diet may alter the central GABAergic system in BHR, which contributes to salt-induced hypertension and augmented pressor and tachycardic responses to stress. (Hypertens Res 1995; 18: 285-293)

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A significant association between elevations of serum gamma-glutamyl transpeptidase (γ-GTP) levels and those of blood pressure and hypertension has been reported separately in drinkers and nondrinkers. The aim of the present study is to evaluate whether the relationship between serum γ-GTP and the prevalence of hypertension is the same or similar in both drinkers and nondrinkers. The study subjects comprised 4, 920 male nondrinkers, 9, 390 male daily drinkers, 8, 081 female nondrinkers, and 278 female daily drinkers, who were aged 40 to 59 years. The prevalence of hypertension in the male and female daily drinkers was 1.5 and 1.3 times, respectively, higher than in the nondrinkers. Mean systolic blood pressure in the male and female drinkers was 4.4 and 3.1mmHg, respectively, higher than in the nondrinkers. After adjusting for age, body mass index, and serum γ-GTP levels, the differences in the prevalence of hypertension and the mean systolic blood pressure level between the drinkers and nondrinkers decreased to 1.2 times and 2.7mmHg, respectively. Although these small differences remained statistically significant, the association between serum γ-GTP and hypertension appears to be quite similar in both drinkers and nondrinkers, suggesting that hepatic steatosis may play a common, pathogenetic role in the development of hypertension. (Hypertens Res 1995; 18: 295-301)

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The present study was undertaken to compare the effects of first-line antihypertensive drugs in Japanese patients. Four antihypertensive drugs were studied: trichlormethiazide (TCT), nifedipine retard (NIF), atenolol (ATN), and enalapril malate (ENP). Thirty-eight patients (16 men and 22 women; age, 53.3± 8.8 years, mean±SD) were enrolled in the study. After a control period of 2 to 4 weeks, the four drugs were administered according to a randomized, cross-over design, the duration of each treatment period being 8 to 12 weeks. The initial dose of each drug was increased until blood pressure (BP) fell to less than 150/90mmHg. The maximum doses of TCT, NIF, ATN, and ENP were 4, 40, 50, and 20mg/day, respectively. The protocol was completed in 25 of the 38 patients. The BPs (SBP/DBP) at the end of each period were 168±3 (mean±SEM)/105±1 (control), 149±4/98±2 (TCT), 138±3/89±2 (NIF), 151 ±4/94±2 (ATN), and 152±4/97±2mmHg (ENP). The BP during NIF treatment was significantly lower than during the other treatments. This finding suggests that the calcium antagonist had a greater hypotensive effect than the other first-line antihypertensive drugs studied. The subjects seem to more closely resemble black rather than white populations with respect to their response to antihypertensive treatment. (Hypertens Res 1995; 18: 303-305)

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Insulin resistance and hyperinsulinemia have been linked with essential hypertension. Age-associated increases in glucose intolerance and hypertension are also well established. To clarify the influence of aging on the insulin sensitivity, euglycemic hyperinsulinemic glucose clamp technique was carried out in 41 normotensive subjects and 42 patients with essential hypertension. The subjects of these groups were divided into two subgroups: young (<40 years old) and middle-elderly (≥40 years old). Insulin sensitivity was assessed as M-value, the rate at which glucose must be infused to maintain a basal blood glucose level. In normotensive subjects, the young subgroup had a significantly higher M-value than did the middle-elderly subgroup. There was a significant negative correlation between age and M-value in normotensive subjects. On the other hand, there was no significant difference in M-value between the young and middle-elderly subgroups in the patients with essential hypertension. The age did not correlate with M-value in the hypertensive group. The normotensive subjects showed a significantly lower M-value than the hypertensive patients in the young group, but not in the middle-elderly group. These results indicate that 1) insulin sensitivity declines with age in normotensive subjects, and that 2) insulin sensitivity is already diminished in the early stage of hypertension, and no further decrease in insulin sensitivity occurs with aging in essential hypertensive patients. (Hypertens Res 1995; 18: 307-311)

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In order to clarify the mechanism of hypertension induced by a nitric oxide (NO) synthase inhibitor, L-N^G-nitro-L-arginine (LNNA), metabolites of NO, catecholamines, and hemodynamic parameters were measured during 7 days of oral administration of LNNA in rats. Control rats received either L-arginine (L-Arg) or the vehicle. Systolic blood pressure, measured by the tail-cuff method was elevated throughout the period of LNNA administration, but that in the two control groups was not influenced by treatment. Heart rate decreased on the second day only in LNNA-treated rats. Although L-Arg treatment had no influence, LNNA markedly decreased the plasma level and the urinary excretion of nitrate ions (NO₃^-). Urinary excretion of noradrenaline was significantly decreased on the second day of LNNA administration and returned to the control level thereafter. When hemodynamic changes were measured by using radioactive microspheres, LNNA was found to increase blood pressure by markedly increasing total peripheral resistance. Cardiac output was decreased by LNNA. L-Arg, again, did not influence the hemodynamic variables as compared with the vehicle control group. The regional vascular resistance index was increased by LNNA in many tissues and organs, except the brain and the heart. Regional blood flow, on the other hand, was significantly decreased only in the liver and skin by LNNA. The marked reduction in NO₃^- in urine by LNNA-treatments may indicate that the measured NO₃^- is exclusively of endogenous origin, and that inhibition of NO production causes elevation of blood pressure by constricting peripheral arteries. Sympatholytic responses by the baroreceptor reflex were thereby evident only on the second and the third days, which was indicated by bradycardia and suppression of noradrenaline excretion into urine. These results indicate that the inhibition of NO synthase actually decreases production of endogenous NO, and that the hypertension caused by decreases in NO production is due to elevation of total peripheral vascular resistance. (Hypertens Res 1995; 18: 319-324)

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