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Na+-K+ cotransport was measured in 21 hospitalized geriatric patients, all recovering from hip surgery. Twelve of these had hypertension, and the other 9 were the control group. Although both groups were comparable for age, blood pressure was significantly different. Mean cotransport values in red blood cells showed no significant difference between the two groups. While Na+-K+ cotransport activity may be hereditary, the authors do not feel the test may be used as a genetic marker for hypertension.

Calcium channel blockers seem to be particularly suitable for elderly hypertensive patients since these agents do not cause salt and fluid retention, postural hypotension, sedation, depression, or biochemical abnormalities. Moreover, their use is compatible with several common diseases of old age, such as diabetes, obstructive lung disease, and peripheral vascular disease. We recently conducted a study in 21 patients (average age, 79 +/- 2 years) who completed an eight-week trial with 20-mg nifedipine tablets taken twice daily. Mean blood pressure decreased from 191 +/- 2/96 +/- 2 mm Hg to 151 +/- 4/80 +/- 3 mm Hg. In 15 patients (71 percent), blood pressure decreased to less than or equal to 160/90 mm Hg; in four additional patients (19 percent), diastolic blood pressure decreased by 15 to 25 percent. Thus, there was a sustained lowering of blood pressure in 90 percent of the participants receiving nifedipine monotherapy. A review of recent studies in elderly hypertensive patients revealed similarly favorable results with calcium channel blockers given alone or in combination with other agents. The accumulating data suggest that these compounds may offer a useful new approach to the treatment of hypertension in old age. However, in these studies, the number of patients and the duration of follow-up need to be extended to confirm the favorable impression obtained thus far.

An unusual case of prostatic carcinoma presenting as severe obstructive jaundice is reported. After treatment with stilbestrol and bilateral orchidectomy, liver function tests became normal and lung metastases disappeared. During a second episode of jaundice due to serum hepatitis, liver function deteriorated following stilbestrol administration, and the drug was temporarily discontinued. The patient has been followed up for three years and liver function tests remain normal.

The acute and chronic renal handling of salt was evaluated in age matched Sabra hypertension-prone (SBH) and hypertension-resistant (SBN) rats. Acute oral (4 ml/100 g) and intravenous (3.3 ml/100 g) isotonic saline loading in unanesthetized normotensive animals maintained on normal diet elicited a significantly lesser diuretic and natriuretic response in SBH than in SBN. Intermittent studies in metabolic cages in rats aged 5 to 21 weeks showed that both strains consumed similar amounts of salt but that SBH excreted significantly less urinary sodium than SBN (F = 40, p less than 0.001). Twenty four hour clearance studies showed a similar filtered sodium load in the two strains but a lower total and fractional sodium excretion in SBH, suggesting increased tubular reabsorption. Under conditions of water diuresis, free water clearance was similar in the two strains, suggesting the site for disparate tubular sodium handling to be distal to the thick medullary ascending limb of the loop of Henle. Acute oral saline loading and long term studies in metabolic cages in rats prepared with deoxycorticosterone-acetate (doca) and salt showed no significant differences in sodium excretion between hypertensive SBH and normotensive SBN. These findings indicate disparate renal sodium handling between SBH and SBN rats, already apparent before the onset of hypertension, which dissipates during doca-salt treatment.

The effect of hypertension, which is known to enhance atherosclerosis, on acid esterase activity of rat aortic wall was studied histochemically. The purpose was to test our notion that atherogenesis depends on the balance between supply of lipids to the arterial smooth muscle cells and the lysosomal esterase activities. Hypertension was produced in rats by unilateral nephrectomy and administration of desoxycorticosterone acetate and sodium chloride. The animals reacted with varying degrees of hypertension. In rats with hypertension of a sufficiently high degree and of long duration, inhibition of aortic acid esterase activities occurred. No inhibition of these enzymes occurred in the other organs examined.

Plasma levels of immunoreactive ACTH, corticosterone (CS), and PRL in two-kidney, one clip (2K1C) hypertensive SABRA, hypertension-prone (SBH), hypertension-resistant (SBN), and normotensive SABRA rats were compared under both quiescent conditions and after acute (2 min) cold water stress. Serum levels of CS were higher in 2K1C hypertensive compared with normotensive SABRA rats under both quiescent and stressful conditions. Circulating levels of ACTH and PRL were similar in both groups under quiescent conditions. Resting circulating levels of CS were higher in the SBH rats compared with SABRA or SBN rats. Serum PRL levels were similar in SBH and SABRA rats under both quiescent and stressful conditions. Resting PRL levels in the SBN rats were lower compared with the SABRA rats. Resting serum levels of ACTH and CS in the SBN rats were similar to those found in the SABRA rats. After stress exposure serum ACTH and CS levels were elevated in all groups. Serum PRL levels in SBN rats were not affected by stress, unlike the marked elevation seen in the other groups. Our study demonstrates increased secretion of CS in both 2K1C hypertensive and SBH rats under quiescent conditions. Both 2K1C hypertensive and SBH rats have normal hormonal capacity to respond to stress. SBN rats exhibited reduced PRL secretion under both quiescent and stressful conditions. It is suggested that abnormal activity of the hypothalamic-pituitary-adrenal system may play a role in the pathogenesis of 2K1C and genetic hypertension as well as in resistance to hypertension.

Sodium and potassium ion transport systems were studied in erythrocytes from spontaneously hypertensive Okamoto rats (SHR), hypertension-prone Sabra rats (SbH), and one-kidney one-clip Goldblatt hypertensive rats, and compared with Wistar-Kyoto normotensive rats (WKY), hypertension-resistant Sabra rats (SbN), and sham-operated Wistar rats. We observed the following: (1) An increased net potassium influx and a reduced net sodium extrusion occurred in SHR. The increased potassium influx was inhibited by ouabain, indicating an increased sodium ion pump activity. Bumetanide-sensitive sodium extrusion was lower in SHR than it was in WKY, indicating abnormally low outward sodium-potassium cotransport fluxes. (2) Passive sodium ion permeability was increased in SbH compared with SbN. Cotransport was normal in SbH rats. (3) Sodium-potassium cotransport and passive permeability were normal in renovascular hypertension. (4) After a chronic or acute sodium load, the sodium content increased in erythrocytes from SHR and SbH but not in those of normotensive or renal hypertensive rats. It appears therefore that erythrocyte membrane abnormalities leading to an increased intracellular sodium concentration are only present in genetic hypertension. The reduction of outward sodium-potassium cotransport observed in SHR is identical to that previously reported in human essential hypertension, suggesting that it may be considered as a genetic marker.

To determine whether the increased renal synthesis of thromboxane (Tx)A2 found in genetically hypertensive rats also occurred in rats with a sodium-dependent form of hypertension, the urinary excretion of 6-keto-prostaglandin F1 alpha (6KPGF1 alpha) and of TxB2 was measured by a sensitive and specific radioimmunoassay in hypertension-prone (SBH), -resistant (SBN) and unselected (SB) female rats of the Sabra strains. Rats of the three strains were studied before (9 weeks of age) and after five weeks of deoxycorticosterone (DOCA)-salt treatment. Before treatment, the urinary 6KPGF1 alpha did not differ among the three strains while a higher TxB2 excretion was seen in the SBN rats. After treatment, the urinary excretion of TxB2 increased significantly in SBH and SB but not in SBN rats, while the urinary 6KPGF1 alpha remained unchanged in SBH, increased moderately in SB and markedly in SBN controls. Consequently, DOCA-salt-induced changes in blood pressure and in urinary 6KPGF1 alpha observed in the three strains of rats were inversely related (r = -0.78; P less than 0.001). It is concluded that the high blood pressure developed after DOCA-salt treatment in SBH rats is more likely to depend upon a defect in the renal production of prostacyclin rather than upon an increased synthesis of thromboxane A2.

By selective inbreeding of the Hebrew University Sabra rat, we have obtained a hypertension prone (H) and a hypertension resistant (N) substrain. The criteria for selection was the blood pressure response to DOCA-salt. The outstanding element of our model is the N rat with its remarkable resistance to hypertension. When compared to H, the N rat presents the following characteristics: 1. The blood pressure of experimentally naive N rats is significantly lower at comparable ages, in both sexes. 2. N rats are resistant to both DOCA-salt and renal clip hypertension. 3. In the medulla oblongata (MO) of N rats, the noradrenaline (NA) content is significantly higher and the activity of tyrosine hydroxylase is significantly lower. 4. In the MO of N rats, the sensitivity of the NA dependent cAMP generating system is significantly decreased. 5. In the atrium of N rats, the NA content is significantly higher, and is unaffected by DOCA-salt treatment. The results suggest that genetic differences in catecholamine metabolism may account for the disparate susceptibility to hypertension of the two strains.

Comparative studies on nine genetic hypertensive rat strains [two stroke-prone spontaneously hypertensive rats (SHRSP) and Dahl salt-sensitive (DS) strains, and one strain each of spontaneously hypertensive rats (SHR), Lyon hypertensive rats (LH), Milan hypertensive strain (MHS), genetically hypertensive rats (GH) and Sabra hypertensive rats (SBH)] and their respective controls [two Dahl salt-resistent (DR) strains and one strain each of Wistar-Kyoto rats (WKY), Lyon normotensive rats (LN); Lyon low blood pressure rats (LL), Milan normotensive strain (MNS), genetically normotensive rats (GN) and Sabra normotensive rats (SBN) and their original strain, Sabra rats (SB)], in groups consisting of 6-10 males from each strain, were carried out at 10-12 weeks of age under the same experimental conditions. After checking the developmental course of blood pressure and changes in body weight, they were killed at 12 weeks of age for blood analysis and organ-weight examinations. The SHRSP and SHR showed markedly higher blood pressure levels and earlier blood pressure rises in comparison with other hypertensive strains, although they had higher blood pressure than their respective controls. Among various organ weights examined, all hypertensive strains commonly showed increases in left ventricular weight in proportion to blood pressure rises. Kidney weights were significantly decreased only in MHS compared with MNS, while they were either unchanged or significantly greater in other hypertensive strains. Weights of adrenal glands were greater in the two strains of DS and in LH than in their respective control strains. These comparative data indicate possible differences in the pathogenic mechanism involved in these genetic hypertensive rat strains.

Catecholamine and vasopressin content were studied in discrete brain nuclei of the Sabra strain of hypertension prone (SBH) and resistant (SBN) rats. Higher concentrations of dopamine, norepinephrine and epinephrine were observed in the median eminence of SBN compared to SBH or controls (SB) rats. Dopamine and epinephrine levels were higher in the lateral septal nucleus of SBH rats as compared to SBN or SB. Vasopressin content in discrete regions along the hypothalamo-pituitary axis was elevated in both SBH and SBN as compared to SB, but were especially elevated in the SBH group. The catecholamine and vasopressin changes found in SBH are different than those described in other genetically hypertensive rats indicating a difference in either the pathogenesis or central response to hypertension of this strain.

The effects of chronic dietary salt-loading and nifedipine therapy on hypertension-prone (SBH), -resistant (SBN) and parental (SB) Sabra rats were investigated. Salt diet for 12 weeks resulted in a sustained hypertension and heart hypertrophy only in SBH. Nifedipine therapy (300 p.p.m. = 300 mg/kg of food) introduced after week 7 on a salt diet, achieved small changes in salt-loaded SBN and SB rats, but resulted in a marked decrease in blood pressure in SBH rats within 1 week and in a regression of cardiac hypertrophy. Plasma renin activity rose slightly in nifedipine treated SB and SBN rats, but decreased significantly in treated SBH rats. Histopathological investigations revealed hypertensive vasculopathy in three out of nine untreated SBH rats, whereas there were no morphological changes in the treated rats.

Norepinephrine and epinephrine concentrations in the caudal and rostral part of the nucleus tractus solitarii (NTS) and in locus coeruleus (LC) of Sabra hypertension prone (SBH) rats are 2-4-fold higher than in the parent Sabra (SB) strain; SB rats have higher concentrations than the Sabra hypertension resistant (SBN) rats. Dopamine concentrations were higher in SBH as compared to SB and SBN rats only in the caudal NTS. Vasopressin concentrations in the NTS of SBH were 3-fold higher than the levels found in SB or SBN rats. These data suggest that catecholamines and vasopressin in specific brainstem nuclei are involved in either the pathogenesis or central response to hypertension in SBH rats.

The efficacy and safety of cilazapril monotherapy was evaluated in a multicenter, open-label, ascending-dose titration study in 83 elderly essential hypertensive patients. After a four-week, single-blind, placebo run-in period, patients received 1 mg of cilazapril once daily for the first four weeks. This dose was then increased to 2.5 mg once daily for the next four weeks for patients whose pre-dose sitting diastolic blood pressure was above 90 mm Hg. Similarly, at Week 8 the dose was increased in such patients from 1 to 2.5 mg or from 2.5 to 5 mg once daily. A 12-hour blood pressure profile was performed on the first day of active treatment and of each dose increase. Mean decrease of sitting diastolic blood pressure from baseline (102.7 +/- 0.4 mm Hg) at Week 12 was 13.3 +/- 1.1 mm Hg (p less than 0.001). Seventy-five percent of patients had a decrease of 10 mm Hg or more from baseline sitting diastolic blood pressure, and in 60 percent sitting diastolic blood pressure normalized. Unexpectedly large decreases of blood pressure after the first dose were seen only in three patients and none had clinical symptoms. Fourteen patients (16.9 percent) reported adverse events, but most of these were judged unlikely to be related to therapy. Four patients with predisposing underlying diseases experienced potentially serious adverse events (angina pectoris, myocardial infarction, arrhythmia, and blood pressure elevation) whose relationship to therapy was judged remote or only possible. There was no particular pattern of changes in laboratory values. The results indicate that cilazapril is an effective, safe, and well-tolerated antihypertensive drug for the elderly.

A rise in erythrocyte Na+ content secondary to a sodium rich diet has been observed in genetically hypertensive Rats and in Rats with a predisposition to develop hypertension under the influence of Na+ loading. In contrast, such a rise is absent in Rats with a genetic resistance to the development of hypertension. Hence, the determination of erythrocyte Na+ after exposure to a sodium load may permit the characterization of primary hypertension.

Hypertension was induced in rats (Hebrew University strain) by three different procedures: (1) deoxycorticosterone acetate (DOCA)--salt treatment; (2) unilateral renal artery clip or (3) chronic salt-loading. Noradrenaline (NA) and dopamine (DA) distribution in different brain areas was assayed following induction of hypertension. NA content increased significantly in various areas: the increase of NA in the pons-medulla was common to all procedures inducing hypertension. NA content increased also in the mesencephalon, the hypothalamus and the rest of the forebrain (DOCA--salt hypertension), in the mesencephalon, the hypothalamus and the cortex (in renal clip hypertension). No significant changes in DA content were observed in any region of the brain following induction of hypertension by the three different methods. In two substrains, selected from the Hebrew University strain, for their respective sensitivity (H) or immunity (N) to hypertension induced by DOCA--salt treatment, there were no significant increases in NA or DA in any part of the brain following DOCA--salt treatment. Comparison of NA concentrations in these strains showed that NA was significantly higher in the pons-medulla of the untreated N strain rats than in the medulla of untreated H strain or in untreated rats of the original strain (Hebrew University). A model is presented suggesting that central NA-containing neurons plays a major role in controlling hypertension.

Cerebral and renal alpha 2-adrenoceptors, modulated in vitro by sodium ions, are implicated in the control of sympathetic activity and of sodium reabsorption, respectively. The aim of the present study was to investigate the effect of high (8%) versus normal (0.2%) sodium diet on cerebral and renal alpha-adrenoceptors of Sabra hypertensive (SBH) and normotensive (SBN) rats. After two or five weeks of high sodium diet alpha 2-adrenoceptor density was increased in the renal cortex of SHB and SBN rats. In contrast, cerebral alpha 2-adrenoceptor densities were markedly decreased in SBN but unchanged in SBH rats. Blood pressure increased only after five weeks of high sodium diet, in SBH and to a lesser extent in SBN rats. The change in alpha 2-adrenoceptor densities thus preceded the blood pressure elevation. The dietary sodium-induced increase in renal alpha 2-adrenoceptor densities which precedes the blood pressure elevation does not appear to be a genetic marker of hypertension. Conversely, the marked decrease of cerebral alpha 2-adrenoceptors in SBN rats may represent an adaptative change in sympathetic activity responsible for the resistance to the development of salt-induced hypertension.

The effect of desoxycorticosterone (DOC)-NaCl treatment upon sympathetic neuronal uptake of norepinephrine (uptake1) was evaluated in strains of hypertension-resistant (SBN) and -prone (SBH) rats. Uninephrectomized animals were given either a placebo pellet sc and tapwater (untreated) or a 25-mg DOC pellet and 1% NaCl. Four weeks later, tail systolic pressure was significantly higher in DOC-NaCl SBH, 183 +/- 3 mm Hg, than SBN, 141 +/- 2 (P less than 0.01). [3H]Norepinephrine (NE) uptake was determined in heart slices of all four groups by incubation in Krebs buffer at 37 degrees C for 20 min at several concentrations. Preliminary studies confirmed that this is a measure of uptake1. Heart slices of DOC-NaCl-treated SBN and SBH rats had significantly reduced NE uptake at concentrations of 10-80 nM (P less than 0.01); there was no significant difference between SBN and SBH in this regard. Untreated SBH rats have been shown to have a defect in baroreflex regulation when normotensive. The results raise the possibility that the greater increase in arterial pressure caused by DOC-NaCl in SBH compared to SBN may be related to both the inborn difference in reflex function and an acquired reduction in inactivation of norepinephrine by sympathetic neuronal uptake.

The effect of nifedipine monotherapy, retard tablets, 20 mg bid, was evaluated in 23 hypertensive patients, mean age, 79 +/- 2 years. Twenty-one patients completed an eight-week study. Blood pressure (BP) decreased to 160/90 mm Hg in 15 patients; in four additional patients diastolic BP dropped by 15% to 28%. In a subset of five patients with isolated systolic hypertension, a significant reduction in systolic BP was noted. Side effects were relatively mild and only two patients discontinued the study. The results suggest that nifedipine monotherapy offers an alternative, logic, therapeutic approach to hypertension in the elderly.

Baroreflex control of heart rate in response to phenylephrine was studied in conscious Sabra hypertension-prone (SBH) rats, at a prehypertensive stage, and hypertension-resistant (SBN) rats. Baroreflex sensitivity as determined from the slope of the relationship of mean arterial blood pressure and heart period was significantly lower in SBH rats (0.58 +/- 0.06 versus 1.71 +/- 0.11 ms/mmHg in SBN rats, P less than 0.01) before the development of hypertension. Sympathetic nerve blockade with guanethidine (15 mg/kg) significantly reduced the slope of the mean arterial blood pressure-heart period relationship in SBN rats to 0.45 +/- 0.05 ms/mmHg (P less than 0.01) and increased the pressor response to phenylephrine, without having any effect on these parameters in SBH rats. Atropine methyl nitrate (1 mg/kg) abolished reflex vagal bradycardia in response to phenylephrine in both groups of rats. This suggests that SBH rats are unable to withdraw the sympathetic cardiac component of the baroreflex in response to a pressor stimulus and appear to rely only on increased vagal activity to effect bradycardia.

The elimination of an acute oral saline load is markedly blunted in adult Sabra hypertension-prone (SBH) rats compared with hypertension-resistant Sabra normotensive (SBN) rats. Within 2 h, urinary output and the excretion of sodium and potassium are significantly reduced, while urine osmolality is markedly elevated in SBH rats. The long-term administration of nifedipine, 20-30 mg/kg body weight enhanced the diuretic and natriuretic response to saline loading in members of both strains. The effect was significantly more pronounced in SBH, especially in adult animals where the diuretic and natriuretic response averaged 150 and 130% of control, while in SBN the enhanced response was 50 and 20%, respectively. As a result of the disparate effect of nifedipine in the two strains, the blunted response of SBH was abolished. The mechanism of the preferential response to nifedipine of SBH rats remains to be determined.

The renal handling of water by SBH and SBN rats was evaluated under basal conditions and following various intervention procedures. During 17 weeks of unrestricted water intake, SBH rats drank less water and excreted less urine with a higher osmolality than SBN. The differences in urine volume and osmolality persisted during 2 weeks of paired water intake. Acute water loading elicited comparable dilution of the urine in the two strains. Water deprivation for 48 h resulted in a marked rise in urine osmolality, which tended to be higher in SBN. Administration of exogenous vasopressin in water loaded animals caused a similar rise in urine osmolality. Papillary solute and urea content was higher in SBH than in SBN, but comparable in water loaded animals. The results show that although SBH differ from SBN rats in the handling of water under basal conditions, their renal diluting and concentrating capacity is comparable at extreme conditions. GFR and RBF were equal in both strains. The data suggest that SBH rats have increased renal water reabsorption as compared to SBN, which may be mediated by ADH, PG or other mechanisms. This characteristic may be related to their propensity to develop hypertension.

The activity of renal Na-K-ATPase was compared in hypertension-prone (SBH) and hypertension-resistant (SBN) Sabra rats on regular sodium intake and 2-3 weeks after a high sodium diet. ATPase activity was determined in single nephron segments by a micromethod. The activity profile was found to be similar in the two substrains on both regimens. Following high sodium intake there was a significant increment of Na-K-ATPase activity which was limited to the medullary thick ascending limb in the two substrains. The results clearly indicate a lack of relationship between renal Na-K-ATPase activity and proneness or resistance to hypertension in this experimental model.

The long-term antihypertensive effect of combined nifedipine and propranolol therapy was assessed in an open trial in 26 hypertensive patients (19 men, seven women, mean age 53 years). On propranolol alone (160 to 240 mg/day), the patients' average sitting blood pressure was 192 +/- 5/114 +/- 2 mm Hg. Propranolol was continued in a fixed dose and nifedipine was added in a dose that was gradually increased from 30 to 90 mg/day to achieve blood pressure (BP) values below 160/95 mm Hg. Twenty-two patients remained on the combined regimen for 14 to 30 weeks. Their BP decreased to 136 +/- 3/84 +/- 2 mm Hg on an average daily dose of 59.5 mg nifedipine. Seventeen of the 22 subjects were subsequently treated sequentially with propranolol alone, combined therapy, and nifedipine alone, to assess the relative efficacy of each mode of therapy. The combined regimen was found to be more effective than either drug alone. Side effects occurred in 13 of 26 patients. Four dropped out 4 to 11 weeks after starting nifedipine because of either intolerable flushing (2), allergic rash (1), or headache (1). Nine subjects experienced mild reactions that were well tolerated. It is concluded that the combined use of propranolol and nifedipine is effective in the long-term treatment of moderately severe hypertension and offers an alternative therapeutic approach that deserves further evaluation.

Sodium ions and guanyl nucleotides play an important role in increasing alpha 2-adrenoceptor densities in cerebral and renal cortex of normotensive rats. The in vitro effect of Na+ and GTP was investigated on cerebral and renal alpha-adrenoceptors in hypertensive (SBH, salt-sensitive) and normotensive (SBN, salt-resistant) Sabra rats. In SBH and SBN rats, guanyl nucleotides increased cerebral and renal high-affinity alpha 2-adrenoceptor densities. Sodium ions, in contrast, markedly increased cerebral and renal high affinity alpha 2-adrenoceptor densities only in SBH rats. Under these conditions, alpha 1-adrenoceptor densities were unchanged. Thus, although Na+ and GTP both increase alpha 2-adrenoceptor densities, these agents appear to mediate their regulatory effects via different membrane components. Moreover, the absence of sodium regulation of alpha 2-adrenoceptors in SBN rats may be responsible for the resistance to salt-induced hypertension.

The renal handling of an oral isotonic saline load was studied in hypertension-prone (SBH), hypertension-resistant (SBN) and the parental Sabra (SB) rats. The diuretic and natriuretic response of SBH rats was unequivocally diminished, thus lending further support to the concept of impaired salt handling in hypertension.

Salt consumption was compared in two strains of rats, selected for their disparate proneness (strain "H") or resistance (strain "N") to Doca-salt hypertension. NaCl intake was similar in "H" and "N" rats prior to an following administration of Doca, while their respective blood pressures at the end of this experiment was 178 +/- 5mm Hg vs. 134 +/- 3 mm Hg. Thus, disparate responses of the blood pressure to Doca in the two strains cannot be ascribed to differences in salt intake. In another study, salt preference was tested in "H" and "N" rats by two-bottle self-selecting technique. Before Doca, saline preference in "H" rats averaged 60.3 +/- 5.8% of total daily fluid consumption, vs 18 +/- 4.2% in "N" rats. Following Doca treatment for 3 weeks the respective values were 96 +/- 1.7% vs 67 +/- 6.6%. Thus Doca treatment enhanced salt appetite in both strains, but salt preference remained significantly higher in the "H" rats. The increased susceptibility to hypertension and enhanced salt appetite in the "H" rat, corroborates similar reports in the Okamoto "SH" rat. In the Brookhaven "S" rat, however, susceptibility to hypertension is associated with salt avoidance. The conflicting data do not support a unified concept of a genetically determined link between salt appetite and proneness to hypertension.

Several studies have suggested a correlation between sodium accumulation and the development of hypertension. However, the mechanisms whereby sodium is able to increase blood pressure remain unclear. In the present study, alpha-adrenoceptors and noradrenaline contents have been studied in the cerebral cortex, hypothalamus and medulla oblongata in the Sabra rat strain in order to define their role in the resistance or sensitivity to sodium-induced hypertension. Alpha-Adrenoceptors were defined using the selective ligands 3H-prazosin and 3H-rauwolscine for alpha 1- and alpha 2-adrenoceptors, respectively. Under normal sodium diet, alpha 2-adrenoceptor density was higher in cerebral cortex and lower in hypothalamus and medulla oblongata of SBN (salt-resistant) compared to SBH (salt-sensitive) rats. Five weeks of high sodium intake induced a decrease in alpha 2-adrenoceptor density in cerebral cortex and an increase in hypothalamus only in SBN rats. These changes abolished the differences between SBH and SBN rats observed with a normal sodium diet. No changes in density and affinity of alpha 2-adrenoceptors were observed in medulla oblongata of SBN and SBH rats. Density and affinity of alpha 1-adrenoceptors were similar in SBN and SBH rats in all the tissues studied and they were unaffected by the high sodium diet. Noradrenaline contents in cerebral cortex, hypothalamus and medulla oblongata were also similar in the two rat substrains under normal sodium diet, but high sodium intake induced a decrease cerebrocortical noradrenaline content only in SBN rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of the present study was to investigate the effect of high (8%) versus normal (0.2%) sodium diet on cerebral and renal alpha-adrenoceptors of Sabra hypertensive (SBH) and normotensive (SBN) rats. Cerebral alpha 2-adrenoceptor densities were higher in SBN than in SBH rats. In contrast, renal alpha 2-adrenoceptor density was higher in SBH than in SBN rats. No difference in alpha 1-adrenoceptor densities was observed between the two strains. After 2 and 5 weeks of high-sodium diet, alpha 2-adrenoceptor densities were increased in renal cortex of SBH and SBN rats. In contrast, cerebral alpha 2-adrenoceptor densities were markedly decreased in SBN but not in SBH rats. alpha 1-Adrenoceptor densities were unchanged by high salt intake. Blood pressure increased only after 5 weeks of high-sodium diet, markedly in SBH and to a lesser extent in SBN rats. The variation in alpha 2-adrenoceptor densities thus preceded the blood pressure elevation. The dietary sodium-induced increase in renal alpha 2-adrenoceptor densities observed both in SBH and SBN rats does not appear to be a genetic marker of hypertension. In contrast, the marked decrease in cerebral alpha 2-adrenoceptors in SBN rats may represent an adaptative change in sympathetic activity responsible for the resistance to the development of salt-induced hypertension.

The metabolism of phosphoinositides, a class of membrane lipids that appears to be intimately involved in the regulation by the membrane of the intracellular Ca2+ level, has been reported to be modified in the erythrocyte of the spontaneously hypertensive rat (SHR and SHR/SP). In order to elucidate the link between the phosphoinositide alteration and hypertension, the metabolism of phosphoinositides was studied in human essential hypertension and in Sabra rats under various patho-physiological conditions. Experiments were performed in vitro on isolated ghost membranes by measuring the radioactivity incorporated into triphosphoinositides (PI-P2) and diphosphoinositides (PI-P) following the incubation of membranes with [gamma 32P]-ATP. 32P-PI-P2, in moderate untreated essential hypertensive controls (n = 31) was higher than in normotensives (n = 30) (1.18 +/- 0.06 vs 0.92 +/- 0.04, 32P nmol/15 min/mg prot, p less than 0.005); 32P-PI-P2 and 32P-PI-P in hypertensive patients treated with beta-blocking agents (n = 20) did not differ from the values observed in untreated hypertensives. In Sabra rats, 32P-PI-P2 values were 0.79 +/- 0.03 and 1.32 +/- 0.08 for SbN and SbH, respectively (8-11 animals per group); difference was significant. 32P-PI-P values varied similarly. Both 32P-PI-P2 and 32P-PI-P did not change significantly when animals were fed a high sodium diet or were injected with DOCA, though such treatments rose the blood pressure. Our data indicate that the modification of phosphoinositide metabolism that we observed both in rat and human hypertension is not a consequence of the blood pressure elevation, but may be considered as an intrinsic membrane defect. Changes in the phosphoinositide metabolism may therefore be associated with the functional and structural alterations concerning the transmembrane Na+ and Ca2+ fluxes which may be of pathogenic importance.

The Sabra hypertension resistant rats (SBN) have an outstanding ability to maintain normal blood pressure when exposed to procedures that ordinarily cause hypertension in normal rats. The following findings may be relevant to resistance to hypertension of these rats: 1) In SBN rats, cardiac norepinephrine content is not affected by DOCA-salt treatment. Since depletion of cardiac norepinephrine is an index of cardiac adrenergic nerve overactivity, the results suggest an attenuated cardiac sympathetic nerve activity in these rats. 2) In SBN rats, the sensitivity of the baroreflex control of the heart is markedly increased compared with other strains. Reduction of baro-receptor sensitivity by aortic-baroreceptor deafferentation renders them susceptible to DOCA-salt hypertension. The results suggest a strong relationship between baroreflex supersensitivity and resistance to hypertension in these rats. 3) The amount of alpha 2 adrenoreceptor densities in cerebral and renal cortical membranes of normal rats increased in vitro, in the presence of sodium and guanyl nucleotide (GTP). In SBN rats, the effect of sodium is markedly attenuated compared with SBH, while response to GTP is identical in the two strains. The demonstration of a similar pattern of response in the Dahl rats suggests that alpha 2 adrenoreceptor may be involved in the sensitivity or resistance to salt induced hypertension.