Hypotensive responses to centrally administered taurine in DOCA-salt hypertensive and spontaneously hypertensive rats

The present study was designed to investigate the short-term effects of intracerebroventricularly-administered taurine in DOCA-salt hypertensive (DOCA), spontaneously hypertensive (SHR) and their respective normotensive control rats anesthetized with urethane. Blood pressure, heart rate and sympathetic nerve activity were consistently decreased following the injection of taurine 150 micrograms per rat in hypertensive rats as well as in normotensive controls of the two groups. Percent changes from the baselines in blood pressure, heart rate and sympathetic nerve activity were significantly larger in DOCA-salt hypertensive rats than those in sham operated rats. In contrast, percent changes in blood pressure and sympathetic nerve activity were not significantly different between spontaneously hypertensive rats and normotensive wistar kyoto rats. These result show that the responses of blood pressure, heart rate and sympathetic nerve activity to intracerebroventricular taurine are different between spontaneously hypertensive rats and DOCA-salt hypertensive rats. It appears that augmented vasodepressor responses to taurine in DOCA-salt hypertensive rats, as compared to spontaneously hypertensive rats, are due to enhanced inhibition of the sympathetic outflow.     

The Effects of Dietary Potassium on Vascular and Glomerular Lesions in Hypertensive Rats

The present study examines the effects of dietary potassium (K) on hypertensive glomerular and vascular lesions in deoxycorticosterone acetate and salt induced (DOCA-salt) and two kidney one clip (2K1C) hypertensive as well as normotensive control rats. Animals received a regular (0.28% K), high (1.1% K) or low (0.07% K) potassium diet for 6 weeks. In control rats, low K diet significantly increased systolic blood pressure (SBP) (p<0.05). In DOCA-salt rats, high K diet did not modify SBP or glomerular and vascular lesions while low K diet significantly increased premature death in these rats. In 2K1C rats, dietary K did not alter the blood pressure, but percentage media area (% media) of intramyocardial arteries, percentage of glomerular lesions, and renal arterial and arteriolar lesion scores were lower in high K diet rats than regular and low K diet rats (p<0.05). This study is the first demonstration that high K diet can protect against vascular and glomerular lesions in a non salt-loaded hypertensive model. The beneficial effects of dietary K on vascular lesions are at least in part independent of changes in blood pressure, and may be renin related.     

Depressor effects of captopril in DOCA-salt hypertensive rats: role of vasopressin

Oral administration of the angiotensin I-converting enzyme inhibitor captopril produced a substantial reduction of blood pressure in DOCA-salt hypertensive rats. After oral administration of captopril (30 mg/kg), mean blood pressure decreased from 172 +/- 11 to 148 +/- 9 mmHg (P less than 0.01) in one hour and its antihypertensive effects lasted for the next seven hours. Plasma vasopressin levels showed a marked elevation in DOCA-salt hypertensive rats compared with control values (22 +/- 5 versus 5 +/- 3 pg/ml). This increase in vasopressin was significantly reduced by captopril from 25 +/- 5 to 8 +/- 6 pg/ml. In addition, whole body vascular reactivity to norepinephrine was examined. Responsiveness was at first attenuated but returned to control value in spite of reduction of both plasma vasopressin and blood pressure. Thus, captopril reduces blood pressure in DOCA-salt hypertensive rats and the fall in blood pressure is accompanied by reduction of plasma vasopressin and attenuation of vascular reactivity.     

Folate supplementation during pregnancy improves offspring cardiovascular dysfunction induced by protein restriction

Dietary protein restriction in the rat compromises the maternal cardiovascular adaptations to pregnancy and leads to raised blood pressure and endothelial dysfunction in the offspring. In this study we have hypothesized that dietary folate supplementation of the low-protein diet will improve maternal vascular function and also restore offspring cardiovascular function. Pregnant Wistar rats were fed either a control (18% casein) or protein-restricted (9% casein) diet +/-5 mg/kg folate supplement. Function of isolated maternal uterine artery and small mesenteric arteries from adult male offspring was assessed, systolic blood pressure recorded, and offspring thoracic aorta levels of endothelial nitric oxide (NO) synthase mRNA measured. In the uterine artery of late pregnancy dams, vasodilatation to vascular endothelial growth factor was attenuated in the protein-restricted group but restored with folate supplementation, as was isoprenaline-induced vasodilatation (P<0.05). In male offspring, protein restriction during pregnancy led to raised systolic blood pressure (P<0.01), impaired acetylcholine-induced vasodilatation (P<0.01), and reduced levels of endothelial NO synthase mRNA (P<0.05). Maternal folate supplementation during pregnancy prevented this elevated systolic blood pressure associated with a protein restriction diet. With folate supplementation, endothelium-dependent vasodilatation and endothelial NO synthase mRNA levels were not significantly different from either the control or protein-restricted groups. Maternal folate supplementation of the control diet had no effect on blood pressure or vasodilatation. This study supports the hypothesis that folate status in pregnancy can influence fetal development and, thus, the risks of cardiovascular disease in the next generation. The concept of developmental origins of adult disease focuses predominately on fetal life but must also include a role for maternal cardiovascular function.     

Morin attenuates blood pressure and oxidative stress in deoxycorticosterone acetate-salt hypertensive rats: a biochemical and histopathological evaluation

The present study was designed to evaluate the antihypertensive and antioxidant effect of morin, a flavonoid against deoxycorticosterone acetate (DOCA)-salt induced hypertension in male Wistar rats. Hypertension was induced in uninephrectomized rats (UNX) by weekly twice subcutaneous injection of DOCA (25mg/kg) and 1% NaCl in the drinking water for six consecutive weeks. The DOCA-salt hypertensive rats showed significant (P < .05) increase in the systolic and diastolic blood pressure, heart rate, water intake and organ weights (kidney, heart, aorta and liver). DOCA-salt hypertensive rats also showed significant (P < .05) increase in the levels of thiobarbituric acid reactive substances, lipid hydroperoxides and conjugated dienes in plasma and tissues (kidney, heart, aorta and liver), and significant (P < .05) decrease in the body weight, nitrite and nitrate levels in plasma and heart. Furthermore, the activities of enzymic antioxidants such as superoxide dismutase, catalase and glutathione peroxidase in erythrocyte and tissues and the levels of non-enzymic antioxidants such as reduced glutathione, vitamin C and vitamin E in plasma and tissues were significantly (P < .05) decreased in DOCA-salt rats. Morin supplementation (50mg/kg) daily for six weeks brought back all the above parameters to near normal level. The above findings were confirmed by the histopathological examination. No significant (P < .05) effect was observed in UNX-rats treated with morin (50mg/kg). These results suggest that morin acts as an antihypertensive and antioxidant agent against DOCA-salt induced hypertension.     

Vasopressin response in collecting ducts of rats resistant to mineralocorticoid hypertension.

In previous studies we found that vasopressin stimulation of both cyclic AMP (cAMP) formation in cortical collecting tubules (CCT) and sodium reabsorption in isolated perfused kidneys was markedly exaggerated in rats with mineralocorticoid hypertension. In the present study, we tested the response (cAMP accumulation) of cortical and outer medullary collecting tubules (OMCT) to vasopressin in two rat models that are resistant to deoxycorticosterone acetate (DOCA)-induced hypertension, the Wistar-Furth strain and NaCl-deficient rats. The blood pressure of normal outbred Wistar rats rose to hypertensive levels (systolic pressure more than 165 mm Hg) during a 5-week treatment with DOCA (10 mg/week) and 1% saline to drink. Significant hypertrophy of the heart and kidneys was also observed. Vasopressin (10(-8) M)-induced cAMP formation was enhanced 3.4-fold in the CCT (OMCT unchanged) of hypertensive rats compared with normotensive controls. Significant hypertrophy (as indexed by tubule diameter) of the CCT but not the OMCT was also observed in DOCA-salt hypertensive rats. Restriction of dietary NaCl (0.13% in chow, tap water to drink) completely prevented DOCA-induced hypertension, organ and CCT hypertrophy, and enhancement of vasopressin-stimulated cAMP formation in the CCT. In Wistar-Furth rats, DOCA-salt treatment did not alter blood pressure or cause significant organ hypertrophy. However, DOCA-salt treatment enhanced vasopressin-stimulated cAMP formation by 4.1-fold in CCT of Wistar-Furth rats, with significant tubular hypertrophy in the CCT but not the OMCT. We conclude that DOCA-induced hypertension and changes in CCT function are dependent on excess dietary NaCl.(ABSTRACT TRUNCATED AT 250 WORDS)     

Decreased density of vascular receptors for atrial natriuretic peptide in DOCA-salt hypertensive rats

We have previously found that vascular receptors for atrial natriuretic peptide (ANP) in the rat are down-regulated by volume expansion. For this reason vascular ANP receptor density and affinity were examined in a model of volume-expanded hypertension, the deoxycorticosterone acetate (DOCA)-salt hypertensive rat. The density of mesenteric vascular ANP binding sites was decreased in DOCA-salt hypertensive rats from a control value in uninephrectomized rats of 203 +/- 25 fmol/mg protein to 60 +/- 13 fmol/mg protein (p less than 0.01). The sensitivity of norepinephrine-precontracted aorta to ANP was significantly reduced in DOCA-salt hypertensive rats (p less than 0.001). DOCA-salt hypertensive rats infused intravenously for 4 days with ANP, 100 to 300 ng/hr, did not experience a lowering of blood pressure, in contrast to the significant reduction in blood pressure seen in two-kidney, one clip Goldblatt hypertensive rats similarly infused. In the latter there was no natriuretic response to ANP, while in the DOCA-salt hypertensive rats natriuresis occurred without lowering of blood pressure. In the DOCA-salt hypertensive rats plasma ANP concentration was increased to 68 +/- 8 fmol/ml from 10 +/- 1 fmol/ml in uninephrectomized rats. In conclusion, raised ANP concentration in plasma of volume-expanded hypertensive rats (DOCA-salt hypertension) may result in decreased density of ANP vascular receptors. These results suggest that a decrement in the number of ANP receptors may be a cause of decreased sensitivity of vascular responses to ANP in vitro and resistance to the blood pressure-lowering action of ANP in vivo.     

Alterations in circulating levels and cardiovascular tissue content of neuropeptide Y-like immunoreactivity during the development of deoxycorticosterone acetate-salt hypertension in the rat.

OBJECTIVE: To investigate the modification of plasma and tissue neuropeptide Y-like immunoreactivity (NPY-li) concentrations, in relation to blood pressure and plasma catecholamine levels, during the development of deoxycorticosterone acetate (DOCA)-salt hypertension. METHODS: Mean arterial pressure (MAP), heart rate, tissue and plasma NPY-li levels, and aortic norepinephrine and epinephrine plasma levels were measured in conscious DOCA-salt hypertensive rats treated for 1, 2 and 3 weeks, and in their respective normotensive controls. RESULTS: Both norepinephrine and NPY-li plasma levels increased significantly in parallel with blood pressure during DOCA-salt treatment, so that MAP was significantly correlated with plasma norepinephrine and NPY-li levels in hypertensive rats. Plasma NPY-li levels were also correlated with norepinephrine levels only in hypertensive rats, but were correlated with epinephrine levels only in normotensive animals. Tissue NPY-li content was lower in the mesenteric artery and heart ventricles after 1-3 weeks of DOCA-salt treatment, but the content in the adrenal gland was not significantly different from that in normotensive rats. CONCLUSIONS: In DOCA-salt hypertensive rats, increased plasma NPY-li levels originate primarily from the sympathetic nerves, since those levels were correlated exclusively with circulating norepinephrine levels and they were associated with a reduction in NPY-li content of the heart and mesenteric artery. It is thus possible that the enhanced release of NPY-li from sympathetic nerves could contribute to the rise in blood pressure and to the maintenance of hypertension in this experimental model.     

Effects of chronic dietary lithium on phosphatidylinositol pathway in heart and arteries of DOCA-salt hypertensive rats

The sensitivity of the phosphatidylinositol (PI) pathway was evaluated in slices of atria (A), ventricles (V), and mesenteric artery (MA) in normotensive (NT) and DOCA-salt hypertensive (DOCA-HT) rats. During norepinephrine (NE) activation, the PI reactivity was two to three times greater in A, V, and MA of HT rats compared to NT rats. The long-term (2 weeks) administration of dietary lithium (Li) reduced the activation of PI by NE in left A and right V but caused no changes in MA of HT rats. The Li-treated hypertensive rats were also characterized by a lower systolic blood pressure and a lower ratio of ventricular weight/body weight. Plasma epinephrine (E) levels that were higher in HT rats were normalized in DOCA-HT + Li-treated rats, while the NE levels remained elevated in the DOCA-HT + Li group.     

Effect of DOCA-salt treatment duration and anteroventral third ventricle lesions on a plasma-borne sodium pump inhibitor in rats

We determined the effect of plasma obtained from rats treated with DOCA-salt for 6 and 28 days on sodium pump activity, measured as ouabain-sensitive Rb+ uptake in tail arteries from these rats. The effect of an electrolytic lesion in the area of the anteroventral third cerebral ventricle (AV3V) before DOCA-salt treatment was investigated in relation to the ability of plasma to inhibit vascular Na+ pump activity. Systolic blood pressures, plasma sodium and potassium concentrations, body weights and haematocrit were also measured. Six days after DOCA-salt treatment, there was a 22% suppression of vascular Na+ pump activity in these rats. This suppression was due to a plasma factor since plasma from these rats produced a similar degree of suppression in arteries isolated from untreated control rats. Furthermore, tail arteries from DOCA-salt rats treated for 6 days displayed normal Na+ pump activity when incubated in plasma from control rats or in Krebs-Henseleit buffer. There was no elevation of systolic blood pressure at the end of 6 days of treatment with DOCA-salt. Placement of an electrolytic brain lesion in the AV3V area before treatment with DOCA-salt abolished the ability of plasma to inhibit the vascular Na+ pump. Treatment with DOCA-salt for 28 days resulted in a significant increase in systolic blood pressure, a decrease in plasma potassium concentration, and a significant increase in vascular Na+ pump activity (26%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of salt, race, and hypertension on reactivity to stressors

Blood pressure and heart rate reactivity to a psychological stressor and to a cold pressor test were examined in a group of 51 normotensive and 37 unmedicated hypertensive men. All were studied twice, once while the participants were maintained on a moderately high salt (200 meq sodium/day) diet and once while the participants were maintained on an extremely low salt (10 meq sodium/day) diet. Dietary salt had no effect on blood pressure or heart rate responses to the two stressors. The systolic and diastolic responses of the white participants to the psychological stressor were greater than those of the black participants (both p less than 0.05); however, there was no difference between blacks and whites in reactivity to the cold pressor challenge. As compared with the normotensive group, the hypertensive group reacted to the psychological stressor with increased responses in systolic blood pressure, diastolic blood pressure, and heart rate (all p less than 0.05). The hypertensive group also hyperresponded in terms of the systolic pressure response to the cold pressor task (p less than 0.05). Plasma norepinephrine and epinephrine responses were not significantly different across the two diets, races, or diagnoses.     

Myocardial fibrosis and diastolic dysfunction in deoxycorticosterone acetate-salt hypertensive rats is ameliorated by the peroxisome proliferator-activated receptor-alpha activator fenofibrate, partly by suppressing inflammatory responses associated with the nuclear factor-kappa-B pathway

OBJECTIVES: We sought to clarify that a peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activator inhibits myocardial fibrosis and its resultant diastolic dysfunction in hypertensive heart disease, as well as to investigate whether inflammatory mediators through the nuclear factor (NF)-kappa-B pathway are involved in the effects. BACKGROUND: Patients with hypertensive heart disease often have diastolic heart failure without systolic dysfunction. Meanwhile, it has been well established in atherosclerosis that PPAR-alpha activation negatively regulates early inflammation. In hypertensive hearts, however, it is still unclear whether PPAR-alpha activation inhibits inflammation and fibrosis. METHODS: Twenty-one rats were randomly separated into the following three groups: deoxycorticosterone acetate (DOCA)-salt hypertensive rats treated with a PPAR-alpha activator, fenofibrate (80 mg/kg/day for 5 weeks); DOCA-salt rats treated with vehicle only; and uni-nephrectomized rats as normotensive controls. RESULTS: Fenofibrate significantly inhibited the elevation of left ventricular end-diastolic pressure and the reduction of the magnitude of the negative maximum rate of left ventricular pressure rise and decline, corrected by left ventricular pressure (-dP/dt(max)/P), which are indicators of diastolic dysfunction. Next, fenofibrate prevented myocardial fibrosis and reduced the hydroxyproline content and procollagen I and III messenger ribonucleic acid expression. Finally, inflammatory gene expression associated with NF-kappa-B (interleukin-6, cyclooxygenase-2, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1), which is upregulated in DOCA-salt rats, was significantly suppressed by fenofibrate. Activation of NF-kappa-B and expression of I-kappa-B-alpha in DOCA-salt rats were normalized by fenofibrate. CONCLUSIONS: A PPAR-alpha activator reduced myocardial fibrosis and prevented the development of diastolic dysfunction in DOCA-salt rats. The effects of a PPAR-alpha activator may be mediated partly by prevention of inflammatory mediators through the NF-kappa-B pathway. These results suggest that treatment with PPAR-alpha activators will improve diastolic dysfunction in hypertensive heart disease.     

INCREASED ARGINASE ACTIVITY IN AORTA OF MINERALOCORTICOID-SALT HYPERTENSIVE RATS

The present study was designed, first to investigate aortic arginase activity during the development and the establishment of mineralocorticoid-salt (DOCA-salt) hypertension, and second, to determine the relationship between arginase activity and blood pressure by giving a protein-supplemented diet (50% casein) known to increase hepatic arginase activity. Our results showed that aortic arginase activity in established hypertension of DOCA-salt rats was higher than in normotensive rats. The protein-supplemented diet (50% casein) accelerated the development of DOCA-salt hypertension. There was a positive correlation between arginase activity and the level of blood pressure in these DOCA-salt hypertensive rats fed 50% casein but not in DOCA-salt hypertensive rats on a normal (20% casein) diet. In normotensive rats, the protein-supplemented diet decreased aortic arginase activity and produced no change in systolic blood pressure. Our data suggest that aortic arginase activity is modified in established DOCA-salt hypertension and could participate in the physiopathology of arterial hypertension.     

Hypotensive action of taurine in DOCA-salt rats--involvement of sympathoadrenal inhibition and endogenous opiate

We studied the roles of the sympathoadrenal system and endogenous opiate in the antihypertensive effects of supplementation of dietary taurine, a sulfur amino acid, in deoxycorticosterone acetate (DOCA)-salt rats. Supplementation of 1% taurine in drinking water for 2 weeks was found to prevent the increase in systolic blood pressure of DOCA-salt rats (116 +/- 2 vs 138 +/- 2 mmHg, p less than 0.01), but failed to effect the systolic blood pressure of vehicle-treated control rats (115 +/- 2 vs 112 +/- 3 mmHg), taurine supplementation restored to normal increased plasma norepinephrine (326 +/- 32 vs 531 +/- 67 pg/ml, p less than 0.01) and epinephrine (204 +/- 19 vs 304 +/- 43 pg/ml, p less than 0.05) concentrations in DOCA-salt rats, but had no effect on norepinephrine (346 +/- 23 vs 338 +/- 33 pg/ml) or epinephrine (198 +/- 17 vs 224 +/- 26 pg/ml) concentrations in control rats. Accordingly, the increased epinephrine content in the adrenals of DOCA-salt rats was normalized with the supplementation of taurine, associated with a markedly increased adrenal taurine content. In conscious rats, moreover, intraperitoneal injection of naloxone (2 mg/kg), a specific opiate antagonist, increased systolic blood pressure only in taurine-supplemented DOCA-salt rats. Evidence presented suggests, therefore, that both the suppression of the increased sympathoadrenal activity and the activation of endogenous opiate might contribute to the antihypertensive effect of taurine in DOCA-salt rats.     

Increased arginase activity in aorta of mineralocorticoid-salt hypertensive rats

The present study was designed, first to investigate aortic arginase activity during the development and the establishment of mineralocorticoid-salt (DOCA-salt) hypertension, and second, to determine the relationship between arginase activity and blood pressure by giving a protein-supplemented diet (50% casein) known to increase hepatic arginase activity. Our results showed that aortic arginase activity in established hypertension of DOCA-salt rats was higher than in normotensive rats. The protein-supplemented diet (50% casein) accelerated the development of DOCA-salt hypertension. There was a positive correlation between arginase activity and the level of blood pressure in these DOCA-salt hypertensive rats fed 50% casein but not in DOCA-salt hypertensive rats on a normal (20% casein) diet. In normotensive rats, the protein-supplemented diet decreased aortic arginase activity and produced no change in systolic blood pressure. Our data suggest that aortic arginase activity is modified in established DOCA-salt hypertension and could participate in the physiopathology of arterial hypertension.     

High calcium diet augments vascular potassium relaxation in hypertensive rats.

The effects of increased dietary calcium on the development of hypertension and vascular smooth muscle responses were studied in spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. Both hypertensive and normotensive animals were divided into two groups; the calcium content of the normal diet was 1.1% and that of the high calcium diet 3.1%. During the 12-week study, calcium supplementation significantly attenuated the increase in systolic blood pressure in the hypertensive rats but did not affect blood pressure in the normotensive rats. The contractile responses of endothelium-denuded mesenteric arterial rings to potassium chloride were similar in all study groups. The contractions to norepinephrine were not altered by the high calcium diet either, but smooth muscle sensitivity to this agonist was lower in the normotensive than in the hypertensive rats. Potassium relaxation was used to evaluate the activity of vascular smooth muscle Na+,K(+)-ATPase. The maximal rate of potassium relaxation was fastest in the normotensive groups but was also clearly faster in calcium-treated hypertensive rats when compared with hypertensive rats on a normal diet. Platelets were used as a cell model for the analysis of intracellular free calcium concentration, which was measured by the fluorescent indicator quin-2. Intracellular free calcium was significantly reduced in the hypertensive rats by calcium supplementation and was not affected in the normotensive rats. In conclusion, a reduction of intracellular free calcium concentration indicating improved calcium regulation and a concomitant alteration in vascular relaxation probably reflecting increased activity of smooth muscle Na+,K(+)-ATPase may contribute to the blood pressure-lowering effect of a high calcium diet.     

Diuretic and Natriuretic Responses to Anf in the Presence and Absence of Renal Nerves in Doca-Salt Hypertensive Rats

To determine if renal nerves contributes in the renal response to atrial natriuretic factor (ANF) in DOCA-salt hypertensive rats, diuretic and natriuretic responses to ANF were measured in Inactin (0.1 g/kg, i.p) anesthetized rats with unilateral renal denervation. Rats were assigned to either a control group (108±6 mmHg), or one of two DOCA-salt groups (injected with deoxycorticosterone acetate, DOCA, 25 mg/week, and given 0.9% saline to drink for 4 weeks); a) DOCA-salt group (137±6 mmHg) and b) DOCA-salt-BPC group (with blood pressure controlled at the level of the femoral artery (102±3 mmHg) by an occluder on the abdominal aorta proximal to the right renal artery). Urine flow and sodium excretion in response to ANF infusion (0.3 μg/min/kg) were measured from intact and denervated kidneys of control and DOCA-salt treated rats.

ANF infusion produced a significant increase in diuresis and natriuresis in all three groups of rats. Urine flow and sodium excretion in response to ANF were significantly less in the intact kidney but not the denervated kidneys of the DOCA-salt rats compared to control rats. These results indicate that renal nerves contribute to the blunted renal responses to ANF in DOCA-salt rats. Renal responses also were significantly smaller in both intact and denervated kidneys of DOCA-salt-BPC rats (in which arterial pressure was reduced) compared to DOCA-salt rats. Overall, these results indicate that both renal nerves and arterial pressure determine the natriuretic and diuretic actions of ANF in DOCA-salt hypertensive rats.     

A comparison of the action of atriopeptin III on renal function in normal and DOCA-salt hypertensive rats

Administration of atriopeptin III (125, 250 and 500 ng/kg, intravenously) into pentobarbitone anaesthetized normotensive and DOCA-salt hypertensive rats had no effect on blood pressure or renal haemodynamics. Urine flow and absolute and fractional sodium excretion were increased by 48-90% from the lowest to the highest dose of atriopeptin III in the normotensive group, but were increased by over twice these amounts in the DOCA-salt hypertensive rats. Fractional lithium excretion and calculated proximal tubular fluid reabsorption were unaffected by the peptide in the normotensive rats, but in the hypertensive group atriopeptide III increased fractional lithium excretion by 25-50% and decreased proximal tubular reabsorption to a similar extent. Beyond the proximal tubule there were similar increases in fractional and absolute fluid handling in both groups of rats. These results demonstrated that in DOCA-salt hypertension there was increased sensitivity to the natriuretic activity of atriopeptin III which appeared to result from an increased responsiveness of the proximal tubule.     

Estrogen Metabolite 2-methoxyestradiol Prevents Hypertension in Deoxycorticosterone Acetate-salt Rats

Purpose

Our early work showed that the estrogen metabolite 2-methoxyestradiol (2ME) inhibits proliferation of vascular smooth muscle cells (SMCs) and vascular contractility through an endothelium-dependent mechanism. The aim of this study was to examine whether 2ME prevents the development of hypertension in rats.

Methods

A hypertensive model was established in uninephrectomized rats using deoxycorticosterone acetate (DOCA)-salt. Blood pressure in response to 2ME (treatment up to 10 weeks or single bolus) was monitored.

Results

Our results showed that systolic blood pressure, as measured by tail-cuff plethysmography, was significantly increased in conscious rats treated with DOCA-salt for 3–10 weeks. Co-treatment with 2ME (100–300 μg/kg), but not dimethyl sulfoxide (DMSO), completely prevented the increase in blood pressure of DOCA-salt rats. After 10-week treatment, the mean arterial blood pressure (MABP) of anesthetized rats measured using PowerLab Data Acquisition System was: 84?±?16 mmHg in normotensive control rats and 150?±?9 mmHg in DOCA-salt rats, which was similar to that of DMSO-treated rats. Treatment with 2ME at low or high doses reduced MABP of DOCA-salt rats close to that of control normotensive rats. In addition, MABP of hypertensive DOCA-salt rats was significantly reduced in response to a single injection of 2ME. Delayed administration of 2ME reduced the further increase of blood pressure in DOCA-salt rats. However, inhibition of 2ME production by entacapone did not significantly affect blood pressure in either control or DOCA-salt rats.

Conclusions

2ME treatment prevents the development of hypertension in DOCA-salt rats, implicating a therapeutic potential of 2ME in hypertension treatment.     

Potassium supplementation reduces clinic and ambulatory blood pressure in elderly hypertensive patients.

OBJECTIVES: To determine the effects of potassium chloride 60 mmol/day supplementation on clinic and 24-h ambulatory blood pressure values in elderly untreated hypertensive patients. DESIGN: A double-blind randomized placebo-controlled crossover study lasting 8 weeks, following a 4-week run-in period. SETTING: Outpatient clinic in a district general hospital. PATIENTS: Eighteen untreated elderly hypertensive patients (mean age 75 years, range 66-79) with a systolic blood pressure of > or = 160 mmHg and/or a diastolic blood pressure of > or = 95 mmHg were recruited from the clinics of local general practitioners and from the current hospital outpatient department. Patients had not received any antihypertensive medication for at least 4 weeks before entry into the study. INTERVENTIONS: Before entry into the study, the daily dietary electrolyte intake of each individual was established and this was maintained during the run-in and intervention periods. Following a 4-week run-in period patients received potassium supplements or matching placebo, each for 4 weeks. MAIN OUTCOME MEASURES: The within-patient changes in clinic and 24-h ambulatory blood pressures at the end of each intervention period. RESULTS: After 4 weeks potassium supplementation compared with placebo there was a significant fall in supine clinic blood pressure, standing and 24-h ambulatory systolic blood pressure. There was no significant change in clinic standing diastolic blood pressure, 24-h ambulatory diastolic blood pressure or pulse rate. Plasma renin activity increased and body weight fell after potassium supplementation. Twenty-four-hour urinary potassium rose significantly, whereas urinary sodium excretion was unchanged. CONCLUSIONS: A 60-mmol daily supplement of potassium chloride reduces clinic and 24-h ambulatory blood pressure in elderly hypertensive patients.