General pharmacological propertiesof Sho-seiryu-to (TJ-19) extracts

The general pharmacological properties of TJ-19 extracts were orally investigated in various experimental animals. TJ-19 extracts showed no effect on general behavior and on central nervous system such as spontaneous locomotor activity, proconvulsant and anti-convulsant responses, analgesic activity, body temperature and hexobarbital sleeping time at all doses of 0.5, 1 and 2 g/kg in mice. Further, TJ-19 extracts showed no effect on contractile responses of isolated guinea pig ileum induced by acetylcholine, histamine and BaCl2 at concentrations of 10(-6), 10(-5), and 10(-4) g/ml. TJ-19 extracts, however, increased the respiratory rate, heart rate, blood pressure, systolic pressure, diastolic pressure, and decreased the blood flow in dogs at all doses of 0.5, 1 and 2 g/kg via duodenal administration. Further, TJ-19 extracts decreased the interval of PR and QT of EKG parameters in dogs at doses of 1 and 2 g/kg. TJ-19 extracts increased the intestinal transport of charcoal meal in rats at doses of 1 and 2 g/kg. TJ-19 increased the urinary Na+ excretion at all doses of 0.5, 1, and 2 g/kg, and increased the urinary K+ and Cl- excretion at 1 and 2 g/kg, although it showed no effect on urine volume output in rats. These data suggest that TJ-19 stimulates the sympathetic nervous system function at a pharmacological dose of under 0.5 g/kg, and has possibility to increase the intestinal peristalsis and urinary electrolyte excretion at higher doses.     

Should we tell them when their blood pressure is up?

We carried out two studies to determine the effects of feedback on subsequent blood pressure and heart rate readings in subjects without significant cardiovascular abnormalities. In both studies the subjects were randomly assigned to be told that their blood pressure was normal or was high or to receive no feedback at all; 3 minutes later another reading was taken and correct feedback provided. Study 1 was done in 114 patients who attended a family practice teaching unit for an office visit; subjects taking cardioactive medication or with chronically elevated blood pressure (diastolic pressure more than 95 mm Hg) or known low pressure (diastolic pressure less than 60 mm Hg) were excluded. Half of the subjects received feedback from a nurse and the other half from a physician. We found no effect of type of feedback or type of practitioner on subsequent readings. No adaptation of diastolic blood pressure or heart rate took place, whereas a similar rest period in the laboratory consistently triggers cardiovascular adaptation. Given the field nature of the study it was not clear whether the intervention was not powerful or whether the practitioner-patient interactions diffused the effects of an otherwise powerful intervention. Therefore, a second study with the same design was carried out in a controlled laboratory setting with 61 university students who believed they were in the adaptation phase of an experimental stress protocol. The subjects did not interact with the experimenter, who provided only the initial feedback, via intercom. The findings replicated those of study 1: type of feedback had no significant effect on subsequent blood pressure levels, and all types of feedback prevented cardiovascular adaptation. We recommend that patients be allowed to rest alone for at least 10 minutes before blood pressure is measured. Our findings suggest that practitioners need not be concerned about telling normotensive or borderline hypertensive patients that their blood pressure is elevated.     

Blood pressure reduction by fish oil in adult rats with established hypertension--dependence on sodium intake.

The effects of fish oil combined with dietary sodium restriction on blood pressure and mesenteric vascular resistance were examined in a series of experiments with adult normotensive (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Rats were fed normal or low sodium diets containing fish oil, olive oil or safflower oil. Small but significant reductions of blood pressure (measured directly in conscious rats) were seen in SHRSP but not in WKY after 8 weeks on a fish oil/low sodium diet, compared with rats fed olive or safflower oil diets with normal sodium content. This antihypertensive effect was not dependent on neurally mediated vasoconstriction but was associated with a reduction of basal resistance in the blood-perfused mesenteric artery. Subcutaneous injection of fish oil reduced blood pressure in adult SHRSP on a normal sodium diet. However, there was a further fall in blood pressure when sodium intake was reduced. The results indicate the antihypertensive effect of fish oil can be enhanced by restricting sodium intake.     

Parental responsiveness is feminized after neonatal castration in virgin male prairie voles, but is not masculinized by perinatal testosterone in virgin females

We previously found a large sex difference in the parental responsiveness of adult virgin prairie voles (Microtus ochrogaster) such that most males are spontaneously parental, whereas most females are not. Because this sex difference is independent of the gonadal hormones normally circulating in adult virgin voles, the present study examined whether perinatal hormones influence the development of this sex difference. Males were treated prenatally (via their pregnant dam) with both the androgen receptor blocker flutamide (5 mg/day/dam) and the aromatase inhibitor ATD (1 mg/day/dam), or oil, for the last 2 weeks of gestation. Half of the subjects from each group were castrated on the day of birth and the other half received a sham surgery. As adults, intact males were castrated and all males received a silastic capsule filled with testosterone. Prenatal treatment with flutamide and ATD had no effect on males' behavior toward pups, but neonatal castration significantly reduced the percentage of males acting parentally. In a second experiment, females were exposed to testosterone propionate (TP; 50 microg/day/dam) or oil via their dam during the last 2 weeks of gestation. For the first neonatal week, half of the females from each group were injected with TP (1 mg/day) and the other half oil. As adults, females were ovariectomized and half from each group received a testosterone-filled capsule and the other half received an empty capsule. None of the perinatal TP treatments increased females' parental responsiveness, although females from all groups that received testosterone capsules as adults were highly parental. Therefore, although postnatal testicular hormones are necessary for high parental responsiveness in males, the behavior of females is not influenced by perinatal exposure to testosterone.     

The effect of dietary alteration of prostaglandin synthesis on blood pressure and the reversal of hypertension in the one-kidney, one-clip rat

This study examined the effect of diet-induced changes in prostaglandin synthesis on systolic blood pressure in one-kidney, one clip (1k, 1C) hypertensive rats and on the fall in blood pressure after unclipping. It tested the hypothesis that inhibition of prostaglandin synthesis exacerbates hypertension in this model and prevents complete reversal after unclipping. Rats with sustained hypertension within 8 weeks of renal artery clipping were fed synthetic diets supplemented to 20% of total energy with either safflower oil (linoleic acid) or a mixture of cod liver oil (90%) (containing eicosapentaenoic acid) and linseed oil (10%) (containing linolenic acid) for 4 weeks. The latter oil mixture resulted in a predictable reduction in kidney PGE2 and 6-keto PGF1 alpha (hydrolysis product of PGI2), aortic 6-keto PGF1 alpha and serum TXB2. However, at the end of 4 weeks dietary treatment there were no differences in systolic blood pressure between the two diet groups, and the blood pressure fall 24 hours after unclipping was similar. These findings therefore do not support a role for prostanoids in the maintenance or reversal of 1K, 1C hypertension.     

Tonic and phasic stimulus control of blood pressure responses using opposing unconditional stimuli

The transswitching paradigm was used in the present study to investigate the effects of tonic (long duration) environmental stimuli paired with opposing unconditional stimuli on human blood pressure. Sixty volunteers participated for two sessions, one week apart. Subjects were presented with a pseudorandom sequence of four trials of red lights (five minutes each) and four trials of blue lights (five minutes each) within each session. All subjects received the cold pressor test during the red lights. During the blue lights, half the subjects received warm water and the other half received a neutral temperature water. Subjects received the presentations of the water in one of three methods: as determined by the experimenter, preceded by a warning signal, or self-administered. The results indicated that conditional and unconditional responses during the red lights were progressive increases in blood pressure. During the blue lights associated with warm water, conditional and unconditional responses were often progressive decreases in blood pressure. The method of administration of the water affected the magnitude of the unconditional responses. Evidence for phasic stimulus control was not as unequivocal as tonic stimulus control. The present results indicated that it is possible to modify blood pressure in two directions (increases and decreases) when two high contrast, opposing unconditional stimuli are presented.     

Controlled trial of long term oral potassium supplements in patients with mild hypertension.

A 15 week randomised double blind placebo controlled trial of oral potassium supplements (48 mmol daily) was conducted in 37 patients who had mildly increased blood pressure and a normal dietary intake of sodium. After a two month run in and a one week baseline period the patients were randomly assigned to receive either potassium supplements (n = 18) or placebo (n = 19). By the third week of treatment blood pressure in the actively treated group had decreased significantly compared with that in the placebo group, though the decrease reached its maximum after 15 weeks. Urinary potassium excretion increased significantly in the group who received potassium supplements, but no significant changes were found in plasma sodium and potassium concentrations or in urinary sodium excretion. In a subgroup of 13 patients who underwent a further nine weeks of treatment with oral potassium supplements at half of the previous dose (24 mmol daily) their blood pressure, at the end of this second study period, was still significantly lower compared with their baseline value but not with that of the placebo group. These results show that moderate oral potassium supplements are associated with a long term reduction in blood pressure in patients who have mild hypertension.     

The effect of dietary alteration of prostaglandin synthesis on blood pressure and the reversal of hypertension in the one-kidney, one-clip rat

This study examined the effect of diet-induced changes in prostaglandin synthesis on systolic blood pressure in one-kidney, one clip (1K, 1C) hypertensive rats and on the fall in blood pressure after unclipping. It tested the hypothesis that inhibition of prostaglandin synthesis exacerbates hypertension in this model and prevents complete reversal after unclipping. Rats with sustained hypertension within 8 weeks of renal artery clipping were fed synthetic diets supplemented to 20% of total energy with either safflower oil (linoleic acid) or a mixture of cod liver oil (90%) (containing eicosapentaenoic acid) and linseed oil (10%) (containing linolenic acid) for 4 weeks. The latter oil mixture resulted in a predictable reduction in kidney PGE₂ and 6-keto PGF_1α (hydrolysis product of PGI₂), aortic 6-keto PGF_1α and serum TXB₂. However, at the end of 4 weeks dietary treatment there were no differences in systolic blood pressure between the two diet groups, and the blood pressure fall 24 hours after unclipping was similar. These findings therefore do not support a role for prostanoids in the maintenance or reversal of 1K, 1C hypertension.     

Development of the cerebrospinal fluid in chick embryos. Physicochemical properties.

The development of the physicochemical properties of the cerebrospinal fluid (CSF) was studied in chick embryos from the 9th day of incubation up to hatching. Some of these properties were compared with the corresponding blood or blood plasma properties. During the second half of incubation the CSF pressure rose from 13.2 plus or minus 0.18 mm H2O in 9-day-old embryos to 80.7 plus or minus 0.48 mm H2O just prior to hatching. The critical stages of this development were the 13th to 15th and the 19th to 21st day of incubation. In 13- and 15-day-old embryos, CSF pressure fell sharply after the intracerebral injection of ouabain, but in 19-day embryos it was unaffected. Except for the 15th and 19th incubation day, the CSF pH was always lower than the plasma pH. From the 11th day of incubation up to hatching, the CSF pH fell from 7.36 plus or minus 0.002 to 7.2 plus or minus 0.005. On the 11th and 13th day, specific CSF resistance was higher than plasma resistance, whereas from the 17th incubation day it was significantly lower than the plasma value. During the second half of incubation, specific CSF resistance fell from 1.059 times 10(6) to 0.824 times 10(6) omega mm.m(-1). A difference between the D.C. potential of the venous blood and the CSF appeared for the first time in 15-day-old embryos, the CSF being negative in relation to the blood. By the end of the incubation period this potential difference rose to 10.82 times 0.07 mv.     

The hypertensinogenic activity of 19-nor-deoxycorticosterone in the adrenalectomized spontaneously hypertensive rat

Infusions of 10 or 25 micrograms/day 19-nor-DOC for 2 weeks in adrenalectomized spontaneously hypertensive rats led to significant increases in blood pressure, 55 and 70 mmHg respectively. This study provides further evidence that 19-nor-DOC is a potent hypertensinogenic steroid and that the ADX SHR model is a useful, sensitive bioassay system to test for hypertensinogenic activity.     

Attempts at dietary alteration of prostaglandin pathways in the management of pre-eclampsia

It has been suggested that dietary supplementation with prostaglandin precursors may enhance the synthesis of PGE which lowers vascular sensitivity to increased levels of angiotensin II in pregnancy. Therefore the effect of dietary supplementation with evening primrose oil (linoleic acid and gamma-linoleic acid) in African primigravidae with established pre-eclampsia was studied. Patients were randomly allocated to one of two groups. Group A (23 patients) received 8 capsules/day of evening primrose oil and group B (24 patients) received 8 capsules of placebo. No significant differences were found between the groups in respect to perinatal outcome, blood pressure lowering effect and haematological indices.     

Effect of low-dose aspirin in combination with stable fish oil on whole blood production of eicosanoids

The effect of a combination of aspirin and fish oil on eicosanoids was studied. Four subjects were given 37.5 mg aspirin orally, and 6 weeks later they received a natural, stable fish oil daily for 1 week before taking the same single dose of aspirin. Blood samples for determination of whole blood production of eicosanoids were taken before and after each experimental period. Serum thromboxane A(2)was decreased by 40% (P<0.05) after aspirin alone, but by 62% (P<0.01) after fish oil + aspirin. Serum prostacyclin (measured as 6-keto PGF(1a)) was decreased by aspirin in both cases. The sum of 6-keto PGF(1a)and its equipotent fish oil-derived analogue Delta(17)-6-keto PGF(1a)was reduced after aspirin intake (55%, NS), but after fish oil + aspirin the reduction was smaller (33%, NS). Leukotriene B(4)was increased by 19% (P<0.05) after aspirin, and decreased by 69% (P<0.05) after fish oil + aspirin. A combination of stable fish oil and aspirin thus improves the eicosanoid pattern more than aspirin alone.     

Effects of essential fatty acids on mild to moderate essential hypertension

A double-blind placebo-controlled study with a crossover design was conducted on 25 non-obese black patients with mild-moderate uncomplicated essential hypertension. They were randomly assigned into two groups. After having received placebo capsules for 4 weeks, they received dietary supplementation with either Efamol-marine (containing desaturated n-6 and n3 essential fatty acids), or sunflower seed and linseed oil capsules for 12 weeks. Thereafter a second 4 weeks placebo phase and a subsequent second 12-week active phase were entered into during which a crossover of the dietary supplementation of the groups was brought about. The mean systolic blood pressure of patients receiving Efamol-marine was significantly lowered after 8 and 12 weeks, while those receiving sunflower/linseed oil supplementation had no significant reduction of blood pressure. This observation may indicate that defective desaturation of the essential fatty acids by the enzyme delta-6-desaturase, could play an important role in the etiology of essential hypertension.     

Effects of dietary linoleic acid on blood pressure and renal function in subtotally nephrectomized rats

The effect of a high linoleic acid diet on blood pressure, renal function, and urinary prostaglandin excretion was studied in rats with decreased renal mass. Subtotally nephrectomized (5/6 nephrectomy) male rats received either a 15% linoleic acid (high linoleic acid, HLA) diet containing 20% safflower oil or a 0.28% linoleic acid (low linoleic acid, LLA) diet containing 20% coconut oil. Sham-operated rats were also placed on either HLA or LLA diet. The subtotal nephrectomized rats developed similar degrees of hypertension during the first 3 weeks after subtotal nephrectomy. However, 4 weeks after subtotal nephrectomy, the rats on HLA diet had significantly lower blood pressure than the rats on LLA diet [HLA 152 +/- 3 (mean +/- SE) mm Hg versus LLA 171 +/- 3 mm Hg]. This difference persisted until termination of the experiment at 7 weeks after subtotal nephrectomy (HLA 159 +/- 7 mm Hg versus LLA 192 +/- 6 mm Hg). The GFR measured 7 weeks after subtotal nephrectomy was significantly lower in both of the subtotally nephrectomized groups. However, the HLA subtotal nephrectomized rats had significantly higher GFR than the LLA-treated rats (HLA 0.23 +/- 0.05 ml/min 100 g versus LLA 0.12 +/- 0.02 ml/min/100 g, P less than 0.05). There was no difference in the GFR or blood pressure in the sham-operated rats treated with HLA or LLA diet. PGE2 excretion was lower in the two groups of subnephrectomized rats, but there was no difference between the HLA and LLA treated rats. Urinary 6-ketoPGF1 alpha was not decreased by subtotal nephrectomy and there was no difference between the dietary groups. However, TXB2 excretion was higher in the groups with subtotal nephrectomy, but there was no difference between the two dietary groups. In conclusion, the HLA diet attenuates the rise in blood pressure after subtotal nephrectomy in the rat and preserves renal function. There was no difference in urinary excretion of PGE2, 6-keto-PFG1 alpha, or thromboxane B2 between the two dietary groups.     

Effects of decylubiquinone (coenzyme Q10 analog) supplementation on SHRSP

Decylubiquinone treatment in vitro has demonstrated a potent inhibitor effect on reactive oxidative species production. However, the effectin vivo has not been demonstrated yet. Thus, rats SHRSP male were divided in two groups: treated and controls (n=6, each). The treated group received 10 mg/Kg(-)/body weight of decylubiquinone diluted in coconut oil by oral gavage during four weeks. Control rats just received the vehicle. Body weight, diuresis, food and water intake, systolic blood pressure, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, blood glucose levels and malondialdehyde were determined. There were a significant (p<0.05) reduction on systolic blood pressure, plasma malondialdehyde, total cholesterol and LDL-cholesterol in the treated group. Additionally, HDL-cholesterol also increased significantly. However, body weight, diuresis, food and water intake, blood glucose levels and triglycerides did not alter after treatment. Thus, decylubiquinone can be a new antihypertensive, hypolipidemic and antioxidant agent on the prevention and treatment of diseases linked to oxidative stress.     

Dietary administration of eicosapentaenoic and linolenic acid increases arterial blood pressure and suppresses vascular prostacyclin synthesis in the rat

The role of the ‘prostacyclin-thromboxane system’ in the regulation of arterial blood pressure was investigated in rats receiving diets which contained different amounts of eixosapentaenoic (EPA) and linolenic acid (LNA). Forty rats were divided into five groups of 8 animals, each group receiving 25 energy (en) % as fat. All diets contained equal amounts of linoleic acid (5 en%) and oleic acid (5 en%). In the control group I, the remaining 15 en% of fat were given as saturated fat. Two groups of animals received cod liver oil as a source for EPA in amounts of 2.5 (group II)_and 5 en% (group III) while the two remaining groups were given diets supplemented with linseed oil as a source for LNA in amounts of 2.5 (group IV) and 5 en% (group V), respectively. After six weeks of feeding period the animals were sacrificed and portions of their isolated aorta incubated in Tris buffer (pH 9.3) for determination of prostacyclin (PGI₂)-like activity. Arterial blood pressure was uncharged in group I animals, but significantly increased in all rats receiving dietary EPA or LNA supplements. This rise is arterial blood pressure was associated with a marked suppression of the appearance of PGI₂-like activity in the incubation buffer while platelet thromboxane release during blood clotting was unchanged. Our results show that dietary adminis- tration of EPA and LNA increases arterial blood pressure in the rat and that this effect is associated with a suppressed generation of vasodilator prostacyclin by vascular tissue.     

Chronopharmacology of Captopril plus Hydrochlorothiazide in Hypertension: Morning Versus Evening Dosing

Blood pressure follows a strong circadian rhythm in normotensive people and in patients with primary hypertension. This may have several implications for antihypertensive therapy, including the time of dosing. For this reason we studied the influence of different dosing times on the antihypertensive effect over 24 h using ambulatory blood pressure monitoring (ABPM). We studied 13 male patients with moderate hypertension with controlled blood pressure over 12 months under a fixed combination of captopril and hydrochlorothiazide. The dosage of the combination therapy was then halved and given as one evening and then as one morning dose, each for 3 weeks. The combination therapy given twice daily showed a good 24-h antihypertensive effect after 12 months of treatment. During the following 6 weeks the mean 24-h blood pressure did not increase under half dosage, irrespective of whether under evening or morning dosing. However, mean daytime values (systolic and diastolic) of ABPM were significantly higher with evening dosing when compared both with full dosage and with half dosage given in the morning. The mean arterial blood pressure over 24 h showed the same differences as systolic and diastolic blood pressure, whereas heart rate was not significantly different between the three therapeutic regimens. ABPM seems to be an ideal method for chronopharmacological investigations under everyday conditions. Our study demonstrated significant differences in daytime blood pressure but not in 24-h blood pressure between morning and evening dosing of a fixed antihypertensive combination therapy.     

Comparison of the mineralocorticoid activity of 19-oxygenated and 19-nor derivatives of deoxycorticosterone.

19-Nordeoxycorticosterone (19-nor-DOC) is a mineralocorticoid with several unresolved physiologic questions. First, is 19-nor-DOC synthesized in the kidney from a circulating adrenocortical precursor (19-oicdeoxycorticosterone [19-oic-DOC] or 19-oxodeoxycorticosterone [19-oxo-DOC])? Second, does 19-nor-DOC, synthesized in the kidney, have mineralocorticoid activity or is it excreted in the urine without biologic activity? To answer this question, we administered two of the putative 19-nor-DOC precursors (19-oxo-DOC and 19-oic-DOC) to adrenalectomized rats and measured the formation of 19-nor-DOC and bioactivity as the urinary Na+ to K+ ratio. Each of the 10-microgram steroid treatments produced an elevation of urinary-free 19-nor-DOC (0 to 2 hours), whereas at the 1-micrograms dose only 19-oic-DOCA produced an increased UF 19-nor-DOC. None of the treatments led to an increase of conjugated 19-nor-DOC except 10 microgram 19-oic-DOCA. Increased mineralocorticoid activity (decreased urinary Na+ to K+ ratio) was produced by aldosterone, 1 and 10 micrograms 19-nor-DOC, and 10 micrograms 19-oic-DOCA over the same time period. An anti-mineralocorticoid effect (increased urinary Na+ to K+ ratio) was produced by 1 microgram 19-oxo-DOC. Urinary-free 19-nor-DOC, but not conjugated 19-nor-DOC, correlated with the urinary mineralocorticoid effect (decreased Na+ to K+ ratio). These data support the contention that 19-oic-DOC is the circulating 19-nor-DOC precursor and that, at least at the higher dose, it has a mineralocorticoid action on the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronopharmacology of Captopril plus Hydrochlorothiazide in Hypertension: Morning Versus Evening Dosing

Blood pressure follows a strong circadian rhythm in normotensive people and in patients with primary hypertension. This may have several implications for antihypertensive therapy, including the time of dosing. For this reason we studied the influence of different dosing times on the antihypertensive effect over 24 h using ambulatory blood pressure monitoring (ABPM). We studied 13 male patients with moderate hypertension with controlled blood pressure over 12 months under a fixed combination of captopril and hydrochlorothiazide. The dosage of the combination therapy was then halved and given as one evening and then as one morning dose, each for 3 weeks. The combination therapy given twice daily showed a good 24-h antihypertensive effect after 12 months of treatment. During the following 6 weeks the mean 24-h blood pressure did not increase under half dosage, irrespective of whether under evening or morning dosing. However, mean daytime values (systolic and diastolic) of ABPM were significantly higher with evening dosing when compared both with full dosage and with half dosage given in the morning. The mean arterial blood pressure over 24 h showed the same differences as systolic and diastolic blood pressure, whereas heart rate was not significantly different between the three therapeutic regimens. ABPM seems to be an ideal method for chronopharmacological investigations under everyday conditions. Our study demonstrated significant differences in daytime blood pressure but not in 24-h blood pressure between morning and evening dosing of a fixed antihypertensive combination therapy.