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.     

Atrial natriuretic factor inhibits the sympathetic nervous activity in one-kidney, one-clip hypertension in the rat

The one-kidney, one-clip model of rat hypertension was found to have an increased natriuresis following chronic infusion of atrial natriuretic factor (ANF). We have now found that this natriuretic effect of ANF is associated with a suppression of the initially elevated urinary excretion of norepinephrine and epinephrine and increase of the excretion of the main dopamine metabolite-dihydroxyphenylacetic acid as well as of the urinary dopamine to norepinephrine ratio. These data are compatible with the hypothesis that ANF suppresses the increased sympathetic activity in this model of hypertension and this action combined with opposite changes of dopamine may contribute to the natriuretic effect of ANF.     

Plasma active and acid-activatable renin during the development of one-kidney, one-clip and two-kidney, one-clip hypertension in the rabbit.

Systolic blood pressure in the central ear artery of eight rabbits increased by 21 mmHg (1 mmHg = 133.32 Pa) over 40 days following renal artery clipping and contralateral nephrectomy (one-kidney, one-clip). Plasma active and acid-activatable (pH 2.8) renin did not change significantly. Similar data were obtained from a group of 12 rabbits following renal artery clipping alone (two-kidney, one-clip) except that blood pressure in this group increased for 26 days but then declined until 40 days. Two animals with one-kidney, one-clip hypertension and three rabbits with two-kidney, one-clip hypertension had large increases in plasma active and inactive renin levels, which followed a more exaggerated rise in blood pressure than in the previous two groups. Forty days after unilateral renal artery clipping, the unclipped kidney was removed in 10 animals with two-kidney, one-clip hypertension. A further increase in blood pressure (+29%) occurred in seven of the animals but no change in plasma active or inactive renin. Results were compared with two groups of control animals, a unilateral nephrectomy group and a laparotomy group. None of the surgical procedures used produced a consistent pattern of change in the relative amounts of active and inactive renin in plasma. No marked changes in sodium, potassium, or water balance occurred in any group of animals.     

The effect of inhibition of prostaglandin synthesis on plasnta renin activity and blood pressure in essential hypertension

The influence of oral indomethacin treatment (75 mg daily for a week) on urinary excretion of prostaglandin (PG) F_2α, plasma renin activity (PRA), blood pressure (BP) and electrolyte excretion (Na⁺ and K⁺) was studied in 21 patients with untreated essential hypertension (9 women and 12 men, aged from 40 to 45 years). PGF_2α excretion and PRA were markedly suppressed by indomethacin in both sexes. A close correlation was found between the decreases in PGF_2α excretion and PRA. 13,14dihydro-15keto-PGF_2α (a metabolite of PGF_2α) excretion also tended to be lowered during the indomethacin treatment. BP tended to increase but urine volume and electrolyte excretion were unchanged during the indomethacin period. The results suggest that in essential hypertension inhibition of the PG synthesis causes a concomitant suppression in PRA and may slightly increase BP.     

Failure of naloxone to influence surgical reversal of two-kidney, one-clip hypertension in the rat

The rapid fall in blood pressure after removal of the constricting clip in two-kidney one-clip (2K-1C) hypertension in the rat is not fully explained by inhibition of the renin-angiotensin system or change in sodium balance. It has been postulated that compounds released in the renal venous effluent following unclipping of 2K-1C rats have a central opiate-like action and endogenous opioids are recognized to have profound hypotensive properties. To investigate this, we removed the clip from, or performed a sham operation in, early phase (less than 6 weeks) 2K-1C hypertensive rats during an infusion of naloxone, an opioid antagonist, or vehicle alone. The infusion of naloxone did not affect the pattern of blood pressure fall in either unclipped or sham-operated rats. Both naloxone-treated and control groups were similarly normotensive at 24 hr postoperation, the MAP being significantly lower than in the sham-operated groups, which regained previously hypertensive levels. Heart rate was unchanged 24 hr postoperatively in all groups. Morphine-induced bradycardia and hypotension were significantly reduced by naloxone infusion. Thus, naloxone infusion had no effect on blood pressure or heart rate in either the sham-operated or the unclipped groups, indicating that endogenous opioids do not have a major role in the reversal of renovascular hypertension under these circumstances.     

Vascular smooth muscle membrane potential in rats with early and chronic one-kidney, one-clip hypertension

It has been suggested that the cell membrane of vascular smooth muscle in one-kidney, one-clip hypertension, and other forms of volume-dependent, low-renin hypertension, is partially depolarized due to the effects of a circulating ouabain-like factor, and that this depolarization is an important mechanism of the hypertension. Levels of circulating ouabain-like factors in early stages of volume-dependent hypertension are reported equal to, or greater than, those in chronic hypertension. Therefore, we measured intracellular membrane potential (Em) in vitro (37 degrees C, physiological salt solution) in vascular smooth muscle of the caudal artery from normotensive control rats (1K) and rats in the early and chronic stages of one-kidney, one-clip hypertension (1K1C). In 20 chronic 1K1C (4-6 weeks of systolic pressure greater than 140 mm Hg) the resting Em's (M +/- SEM) were -46.7 +/- 0.7 mV, compared to -50.9 +/- 0.6 for 20 1K (P less than 0.01). The delta Em due to 1 mM ouabain was attenuated in 10 1K1C compared to 11 1K (+5.4 +/- 0.9 and +10.0 +/- 0.7 mV, respectively; P less than 0.01). The Em's of the two groups after ouabain were the same. In contrast, in 16 early 1K1C rats (less than 7 days hypertension, average 3 days) compared to 15 appropriate 1K, there were no significant alterations in resting Em (-50.1 +/- 0.4 mV, compared to -50.5 +/- 0.5, respectively) and there were no differences in ouabain response. These results suggest a temporal dissociation between levels of humoral inhibitors and depolarization, and between depolarization and hypertension, and thus fail to support the hypotheses that there are casual relationships between these variables in volume-dependent, low-renin hypertension.     

Role of sodium balance on maintenance of blood pressure in the chronic phase of two-kidney, one-clip hypertension

Blood pressure and sodium balance have been studied after unclipping, nephrectomy and sham operation of ischemic kidney in the chronic phase (16 weeks) of two-kidney, one clip hypertension. In hypertensive rats the fractional excretion of sodium was 85.5 +/- 2.3% and blood pressure (BP) was significantly increased (187.1 +/- 4.5 mmHg, p less than 0.001). Removal of either the constricting clip or ischemic kidney induced a decrease of BP to normal level whereas sham operation did not produce any change. However, rats submitted to these three experimental manipulations showed, at 1, 2, 3 and 4 days, and at 3 weeks, similar changes in sodium excretion. In the groups with unclipping or nephrectomy of ischemic kidney, water intake was less and urine volume smaller than in the sham operated group. These results suggest that a positive sodium balance is not important to maintain hypertension at this stage and that changes in sodium balance, after both unclipping and nephrectomy of ischemic kidney, have no influence in BP normalization.     

The effect of dietary alpha-bromopalmitate on blood lipids in the rat

When alpha-bromopalmitate was fed to rats for 9-30 days, the level of serum triacylglycerol increased up to 2-fold over the concentration of controls. alpha-Bromopalmitate treatment had no effect on concentration of complex lipids in liver, while the triacylglycerol level in heart was significantly enhanced. From metabolic studies using isolated hepatocytes and liver microsomes, it is suggested that the increased serum triacylglycerol level after alpha-bromopalmitate feeding is mainly due to reduced fatty acid oxidation in both liver and peripheral tissues, and to a lesser extent, to inhibited fatty acid uptake and esterification.     

Influence of dietary vitamin E on prostaglandin biosynthesis in rat blood

A vitamin E (-tocopherol) deficient diet stimulated prostaglandin biosynthesis in coagulating rat blood. Prostaglandins were extracted from serum, purified and bioassayed. The identity of prostaglandin E₂ was confirmed by gas chromatography-mass spectrometry. Withholding vitamin E from the diet caused a marked increase in PGE₂ and a lesser increase in PGF₂ production in serum. In rats maintained on diets containing different concentrations of vitamin E, serum concentrations of PGE₂ and PGF₂ were inversely related to serum concentrations of -tocopherol. These data suggest that in vivo -tocopherol inhibits the endogenous conversion of arachidonic acid into PGE₂ and PGF₂. The possibility that -tocopherol may inhibit the formation of endoperoxide intermediates of PGE₂ and PGF₂ biosynthesis and subsequent induction of platelet aggregation is discussed.     

Changes in hemodynamic and neurohumoral control cause cardiac damage in one-kidney, one-clip hypertensive mice

Sympathovagal balance and baroreflex control of heart rate (HR) were evaluated during the development (1 and 4 wk) of one-kidney, one-clip (1K1C) hypertension in conscious mice. The development of cardiac hypertrophy and fibrosis was also examined. Overall variability of systolic arterial pressure (AP) and HR in the time domain and baroreflex sensitivity were calculated from basal recordings. Methyl atropine and propranolol allowed the evaluation of the sympathovagal balance to the heart and the intrinsic HR. Staining of renal ANG II in the kidney and plasma renin activity (PRA) were also evaluated. One and four weeks after clipping, the mice were hypertensive and tachycardic, and they exhibited elevated sympathetic and reduced vagal tone. The intrinsic HR was elevated only 1 wk after clipping. Systolic AP variability was elevated, while HR variability and baroreflex sensitivity were reduced 1 and 4 wk after clipping. Renal ANG II staining and PRA were elevated only 1 wk after clipping. Concentric cardiac hypertrophy was observed at 1 and 4 wk, while cardiac fibrosis was observed only at 4 wk after clipping. In conclusion, these data further support previous findings in the literature and provide new features of neurohumoral changes during the development of 1K1C hypertension in mice. In addition, the 1K1C hypertensive model in mice can be an important tool for studies evaluating the role of specific genes relating to dependent and nondependent ANG II hypertension in transgenic mice.     

Influence of dietary vitamin E on prostaglandin biosynthesis in rat blood.

A vitamin E (alpha-tocopherol) deficient diet stimulated prostaglandin biosynthesis in coagulating rat blood. Prostaglandins were extracted from serum, purified and bioassayed. The identity of prostaglandin E2 was confirmed by gas chromatography-mass spectrometry. Withholding vitamin E from the diet caused a marked increase in PGE2 and a lesser increase in PGF2alpha production in serum. In rats maintained on diets containing different concentrations of vitamin E, serum concentrations of PGE2 and PGF2alpha were inversely related to serum concentrations of alpha-tocopherol. These data suggest that in vitro alpha-tocopherol inhibits the endogenous conversion of arachidonic acid into PGE2 and PGF2alpha. The possibility that alpha-tocopherol may inhibit the formation of endoperoxide intermediates of PGE2 and PGF2alpha biosynthesis and subsequent induction of platelet aggregation is discussed.     

The effect of inhibition of prostaglandin synthesis on ovarian hypertrophy in the rat.

Aspirin and indomethacin, inhibitors of prostaglandin biosynthesis, were utilized to determine the role of prostaglandins (PGs) in ovarian weight gain in rats following unilateral ovariectomy or treatment with PMSG. After unilateral ovariectomy, the compensatory ovarian hypertrophy was 185-0% compared with 139-8% and 97-5% in rats treated with indomethacin and aspirin, respectively. The adrenal weights in rats treated with aspirin were also reduced significantly. Administration of PGE2 or PGF2alpha with aspirin reversed the effect of aspirin on the adrenals but had no effect on the ovarian weight. Indomethacin and aspirin treatment of animals injected with PMSG also reduced the ovarian weight gain. If 100 mug PGE2 were given twice daily, this effect was reversed in both groups but thrice daily administration had no effect on rats receiving aspirin. In PMSG-treated rats, 100 mug PGF2alpha twice daily did not reverse the effect of indomethacin and aspirin, and actually enhanced the effect of aspirin.     

Effects of minoxidil on blood pressure and cardiac hypertrophy in two-kidney, one-clip hypertensive rats

Rats made severely hypertensive by renal arterial clipping were treated for 24 days with the arterial vasodilator minoxidil (40, 80, and 120 mg/L drinking water). In all three treated groups of animals, blood pressure initially decreased markedly and to a similar extent. Subsequently partial tolerance developed to the antihypertensive effects of minoxidil. All three doses induced hypertrophy of the right ventricle to a similar degree. In contrast, the hypertension-induced hypertrophy of the left ventricle was further increased in a dose-dependent fashion by minoxidil.     

Reduction of blood pressure and increased diuresis and natriuresis during chronic infusion of atrial natriuretic factor (ANF Arg 101-Tyr 126) in conscious one-kidney, one-clip hypertensive rats

Conscious one-kidney, one-clip hypertensive rats and their normotensive controls were infused during 7 days with synthetic ANF (Arg 101-Tyr 126) at 100 ng/hr/rat (35 pmol/hr/rat) by means of osmotic minipumps. The basal blood pressure of 193 +/- 6 mmHg gradually declined to 145 +/- 6 mmHg at day 4 after the infusion was started. No changes in blood pressure were observed in ANF-infused normotensive rats. A significantly higher diuresis and natriuresis was observed in ANF-infused hypertensive rats when compared to the non-treated hypertensive group. No such changes were observed in ANF-treated normotensive animals. No differences in PRA were seen in any group. Atrial immunoreactive ANF was significantly lower in one-kidney, one-clip rats than in the normotensive animals, but whether this is the reflection of an increased release in the circulation remains to be elucidated. It is suggested that the hypotensive response of one-kidney, one-clip animals to ANF may be secondary to a dual mechanism, vasodilatation and volume depletion.     

Steroid-independent effect of gonadotropins on prostaglandin synthesis in rat Graafian follicles

The content of prostaglandins of the E-group (PGE) or F-group (PGF) was determined by radioimmunoassay in rat ovaries and in homogenates of cultured Graafian follicles. Intraperitoneal administration of luteinizing hormone (NIH-LH-S18; 10 μg/rat) at 9.00 h on any day of the estrous cycle caused an increase in ovarian PGE content within 5 h. The response was greatest on the day of proestrus (940% rise), i.e. when the ovary contains large follicles, and least at metestrus (80%). Follicles explanted from proestrous rats before the preovulatory gonadotropin surge responded to addition of LH (1–5 μg/ml) to the culture medium with a 10 to 30-fold increase in PGE and a 5-fold increase in PGF accumulation over a 5-h-period. Follicle stimulating hormone (NIH-FSH-S9; 10 μg/ml) caused a similar rise in follicular PGE accumulation, even after treatment of the FSH preparation with excess of an antiserum to the β-subunit of LH. Stimulation of follicular PG accumulation was unimpaired during suppression of progesterone and estrogen synthesis by aminoglutethimide. It is concluded that these steroids play no part in the mediation of the LH-effect on follicular prostaglandin formation.     

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.     

Effects of hydralazine on blood pressure, pressor mechanisms, and cardiac hypertrophy in two-kidney, one-clip hypertensive rats

In 2-kidney, 1-clip hypertensive rats, the time course of changes in blood pressure (BP), heart rate, activity of the sympathetic nervous system and the renin-angiotensin system, plasma and blood volumes, left ventricular (LV) and right ventricular (RV) weight, and LV dimensions were evaluated during treatment with hydralazine 80 and 120 mg/L drinking water for 2 days or 1, 2, 3, 5, and 8 weeks. Hydralazine induced initially a clear antihypertensive effect (mean BP from 170-180 down to 135-145 mmHg (1 mmHg = 133.32 Pa], subsequently tolerance developed. Heart rate, plasma catecholamines, and the blood pressure response to hexamethonium were not affected by treatment. Significant increases in plasma renin activity occurred during the initial 1-3 weeks of treatment. Plasma and blood volumes showed only small increases with prolonged treatment. RV weight and LV internal diameter showed significant increases at 3, 5, and 8 weeks of treatment, LV weight at 5 and 8 weeks. LV wall thickness did not change significantly. Thus, treatment with the arterial vasodilator hydralazine causes both RV hypertrophy and eccentric LV hypertrophy. Intravascular volume expansion, associated possibly with redistribution of blood volume to the central compartment, may play a major role in these cardiac effects. Increased renin release but not a generalized increase in sympathetic tone may play a role in the development of tolerance to the antihypertensive effect.