The hypotensive effect of prostaglandin E1 on hypertensive cases of various types

Intravenous administration of 50 μg of prostaglandin E₁ (PGE₁) induced a fall of the blood pressure in the patients with hypertension. It included essential, renal, renovascular hypertension and hypertensions associated with Takayasu's arteritis, primary aldosteronism, pheochromocytoma and anephric Kimmelstiel-Wilson syndrome. PGE₁ at dose of 50 μg had little effect on the blood pressure in normotensives. The pattern and the degree of lowering blood pressure were not specific for each type of hypertension. The antihypertensive effect of PGE₁ on essential hypertension was conspicuous in advanced cases.A clinical application of PGE₁ to manage severe hypertension was discussed.     

Role of prostaglandis in the control of renin secretion in the dog (II)

Infusion of prostaglandin E₁ (PGE₁) into the renal artery of anesthetized dogs (1.03 μg/min) caused increases in urine flow rate (V), renal plasma flow (RPF) and renin secretion rate without any change in mean arterial blood pressure (MABP), whereas infusion of prostaglandin F₂α (PGF_2α), (1.03 μg/min) caused no consistent change in V, RPF, or renin secretion rate. Infusion of prostaglandin E₂ (PGE₂) (1.03 μg/min) into the renal artery of “non-filtering” kidneys caused renin secretion rate to rise from 567.7 ± 152.0 U/min(M ± SEM) during control periods to 1373.6 ± 358.5 U/min after 60 minutes of infusion of PGE₂ (P < 0.01), without significant change in MABP (P > 0.1). The data suggest that PGE₁ and PGE₂ play a role in the control of renin secretion. The data further suggest that PGE may control renin secretion through a direct effect on renin-secreting granular cells.     

The Angiotensin Infusion Test and Peripheral Venous Renin Activity

Forty hypertensive patients were studied to examine the assumption that the angiotensin pressor dose reflects endogenous renin activity. Peripheral renin activity was assayed by the method of Boucher et al.⁴ Sensitivity to the infusion of synthetic angiotensin II was determined as suggested by Kaplan and Silah.¹Sixteen patients with essential hypertension with normal renal angiography required 3.8 ng. angiotensin/kg./min. to raise the diastolic pressure 20 mm. Hg. All but one were sensitive to angiotensin infusion of less than 5 ng./kg./min. Renin activity was normal in all except in one sensitive subject. Angiotensin infusion response and mean renin activity in 13 patients with essential hypertension with abnormal renal angiography were similar to that of the first group. The pressor dose in 11 renovascular hypertensives was 9.8 ng./kg./min. All but three had elevated plasma renin activity.Our results suggest that: (1) the angiotensin infusion test is suitable for differentiating patients with true renovascular hypertension from those with essential hypertension with or without associated renal artery disease; (2) the angiotensin pressor dose correlates with the level of peripheral venous renin activity (p < 0.01).     

Impaired renal production of prostaglandin E2: A newly identified lesion in human essential hypertension

To test the hypothesis that impaired renal prostaglandin production may accompany the hypertensive state, we have measured urinary PGE₂ by radio-immunoassay in 52 normotensive and 50 hypertensive subjects. PGE₂ levels were lower in females, and were not affected by Na⁺ intake or age. Patients with essential hypertension had significantly lower PGE₂, particularly those with low-renin hypertension. Forty percent of the hypertensives excreted less than 70 ng/24 hr, values never observed in normotensives except after receiving indomethacin, a well-known prostaglandin synthetase inhibitor. It appears that impaired renal prostaglandin production is commonly encountered in patients with essential hypertension, perhaps contributing to their increased renal resistance. The data further suggest a role for renal prostaglandins in the pathogenesis of low-renin hypertension.     

Prostaglandins and renin release: III. Effects of PGE1, E2 F2α and D2 on renin release from rabbit renal cortical slices

We have investigated the direct effects of prostaglandins E₁, E₂, F_2α and D₂ on renin release from rabbit renal cortical slices. Prostaglandin E₁ (PGE₁) was the most potent stimulant of renin release, while PGE₂ was 20–30 fold less active. PGF_2α was found not to be an inhibitor of renin release as reported by others, but rather a weak agonist. PGD₂ up to a concentration of 10 μg/ml had no activity in this system. That the stimulation of renin release by PGE₁ is a direct effect is supported by the finding that PGE₁-induced release is not blocked by L-propranolol or by Δ^5,8,11,14-eicosatetraynoic acid (ETYA), a prostaglandin synthesis is inhibitor. The fatty acid precursor of PGE₁, Δ^8,11,14-eicosatrienoic acid, also stimulated renin release, an effect which was blocked by ETYA. In addition to the above findings, ethanol, a compound frequently used to dissolve prostaglandins, was shown to inhibit renin release.     

New aspects on primary aldosteronism

The adrenal cortex synthesizes and releases steroid hormones, mainly mineralocorticoids and glucocorticoids. There is a functional zonation of the adrenal cortex and steroid synthesis is thoroughly regulated. Overproduction of aldosterone, primary aldosteronism, may be much more common than previously known and may be responsible for 10% of essential hypertension. Primary aldosteronism is characterized by autonomous production of aldosterone, suppressed renin activity, hypokalemia, and hypertension. The two most common forms are unilateral adenoma and bilateral hyperplasia. In spite of thorough clinical workup and careful histopathology it is often difficult to differentiate between adenoma and hyperplasia. The gene CYP11B2 encodes the steroid synthesizing enzymes for aldosterone production, while the genes CYP17 and CYP11B1 are needed for cortisol production. Most normal controls show expression of CYP11B2 in zona glomerulosa. Expression of CYP11B1 and CYP17 is seen in zona fasciculata and reticularis, whereas the expression of CYP21 is present in all three cortical layers. Adenomas from patients with primary aldosteronism show considerable variation in the expression of CYP11B2. Adenomas from patients with Cushing's syndrome have a strong expression of CYP11B1 and CYP17. In a patient material of 29 cases of primary aldosteronism, 4 patients had small nodules detected with expression of CYP11B2 gene. These nodules were not visualized on CT, whereas adrenal masses seen on CT in these patients showed CYP11B1 and CYP17 gene expression. This suggests that these small nodules are responsible for the aldosterone production and this is characteristic of nodular hyperplasia in patients with primary aldosteronism. In conclusion, this method to visualize mRNA gene expression of steroidogenic enzymes, and especially expression of CYP11B2, has increased the knowledge of adrenal pathophysiology. The results emphasize the value to include functional studies (venous sampling and/or scintigraphy) in the preoperative work up of patients with primary aldosteronism.     

Nocturnal blood pressure in normotensive subjects and those with white coat,primary, and secondary hypertension.

OBJECTIVE--To compare the mean nocturnal blood pressure of patients with various forms of renal and endocrine hypertension with that in patients with primary and white coat hypertension, and normal blood pressure. DESIGN--Ambulatory monitoring of blood pressure over 24 hours in a prospective study. SETTING--Two German centres for outpatients with hypertension and kidney diseases. SUBJECTS--176 normotensive subjects, 490 patients with primary hypertension including mild and severe forms, 42 with white coat hypertension, 208 patients with renal and renovascular hypertension, 43 with hypertension and endocrine disorders, and three with coarctation of the aorta. MAIN OUTCOME MEASURES--Fall in nocturnal blood pressure. RESULTS--Blood pressure in normotensive subjects fell by a mean of 14 mm Hg (11%) systolic and 13 mm Hg (17%) diastolic overnight (2200 to 0600). The falls in patients with primary and white coat hypertension were not significantly different. In all patients with renal and renovascular hypertension, however, the fall was significantly reduced (range of fall from 3/3 mm Hg to 7/9 mm Hg). In patients with hypertension and endocrine disorders the pattern of night time blood pressure was not uniform: patients with hyperthyroidism, primary hyperaldosteronism, and Cushing''s syndrome had significantly smaller reductions in blood pressure (6/8, 4/7, 3/6 mm Hg, respectively). In patients with phaeochromocytoma the mean night time blood pressure increased by 4/2 mm Hg. In patients with hypertension, primary hyperparathyroidism, and unoperated coarctation of the aorta the falls in blood pressure were normal. CONCLUSIONS--In normotensive subjects and those with primary hypertension there is usually a reduction in blood pressure at night. In all renal forms of secondary hypertension and in most endocrine forms the reduction in blood pressure is only a third to a half of normal. Patients with primary hyperparathyroidism and unoperated coarctation of the aorta show a normal reduction.     

Effect of celecoxib on the antihypertensive effect of losartan in a rat model of renovascular hypertension

Certain nonsteroidal anti-inflammatory drugs have been reported to elevate blood pressure in some hypertensive patients, who are either untreated or treated with antihypertensive agents. This study was undertaken to determine the effect of a selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, on the antihypertensive effects of the angiotensin II type 1 receptor (AT1) antagonist, losartan potassium. We studied the effect of oral treatment with losartan (30?mg/kg), celecoxib (3?mg/kg), and their combination on the mean arterial blood pressure (MAP), plasma renin activity (PRA), and plasma prostaglandin E2 (PGE2) in male Sprague-Dawley rats with renovascular hypertension (RVH) induced by partial subdiaphragmatic aortic constriction. Treatment was continued for 7 days after aortic coarctation. Aortic coarctation led to significant increases in the MAP, PRA, and plasma PGE2. In RVH rats, losartan treatment caused a significant decrease of MAP with a significant increase in both plasma PGE2 and PRA. Celecoxib caused a nonsignificant change in MAP with a significant decrease in the raised levels of plasma PGE2 and PRA. Concomitant administration of celecoxib and losartan did not significantly affect the lowering effect of losartan on MAP with a subsequent significant decrease in the plasma PGE2 and PRA in RVH rats. Therefore, celecoxib could be used in renin-dependent hypertensive patients who receive losartan, without fear of a rise in their blood pressure.     

Relationship Between Hyperuricemia and Chronic Kidney Disease

Because approximately 70% of uric acid is excreted from the kidney, hyperuricemia occurs when renal function deteriorates. Until now, it has not been clear if the hyperuricemia seen in such renal diseases plays a role in the progression of renal disease. However, recent clinical studies show that the serum uric acid value is closely associated with hypertension in hyperuricemic patients (cross-sectional study), and also with the onset of hypertension (longitudinal study). Furthermore, one interesting report shows that treatment of hyperuricemia with allopurinol lowers blood pressure in juvenile essential hypertension patients with hyperuricemia. In addition, it is well known that hyperuricemia is closely associated with chronic kidney disease (CKD), is a risk factor for renal insufficiency in general populations, and is a poor prognostic factor of renal function in patients who also have IgA nephropathy. On the other hand, in intervention studies on hyperuricemia, the treatment of hyperuricemia with allopurinol in CKD has resulted in a fall in blood pressure and inhibition of the progression of renal damage. Conversely, the cessation of allopurinol treatment in CKD was followed by a rise in blood pressure and the development of renal damage. Furthermore, the rise of blood pressure and development of renal damage following cessation of allopurinol treatment are only seen in patients not receiving angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). This suggests that the renin angiotensin (RA) system plays an important role in the development of hypertension and renal damage from hyperuricemia.     

Relationship between hyperuricemia and chronic kidney disease

Because approximately 70% of uric acid is excreted from the kidney, hyperuricemia occurs when renal function deteriorates. Until now, it has not been clear if the hyperuricemia seen in such renal diseases plays a role in the progression of renal disease. However, recent clinical studies show that the serum uric acid value is closely associated with hypertension in hyperuricemic patients (cross-sectional study), and also with the onset of hypertension (longitudinal study). Furthermore, one interesting report shows that treatment of hyperuricemia with allopurinol lowers blood pressure in juvenile essential hypertension patients with hyperuricemia. In addition, it is well known that hyperuricemia is closely associated with chronic kidney disease (CKD), is a risk factor for renal insufficiency in general populations, and is a poor prognostic factor of renal function in patients who also have IgA nephropathy. On the other hand, in intervention studies on hyperuricemia, the treatment of hyperuricemia with allopurinol in CKD has resulted in a fall in blood pressure and inhibition of the progression of renal damage. Conversely, the cessation of allopurinol treatment in CKD was followed by a rise in blood pressure and the development of renal damage. Furthermore, the rise of blood pressure and development of renal damage following cessation of allopurinol treatment are only seen in patients not receiving angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). This suggests that the renin angiotensin (RA) system plays an important role in the development of hypertension and renal damage from hyperuricemia.     

Renal vein plasma adenosine 3',5'-cyclic monophosphate in renovascular hypertension.

The concentration of plasma adenosine 3'',5''-cyclic monophosphate (cyclic AMP) and plasma renin activity (PRA) were measured concomitantly in blood from both renal veins and in arterial blood in 22 hypertensive patients. In the nine patients with true renovascular hypertension the concentration of plasma cyclic AMP was greater in the venous effluent of the kidney affected by the renal artery stenosis than in that of the unaffected or less affected kidney. The arteriovenous difference in cyclic AMP concentration was less on the affected side in all but one patient. The arteriovenous differences in PRA identified the affected kidney as the source of hyper-reninemia and showed that renin release from the other kidney was suppressed. In the 13 patients with hypertension associated with but unrelated to renal artery stenosis there were no consistent patterns of cyclic AMP concentration or PRA in the venous effluent of the kidneys or of their arteriovenous differences. In renovascular hypertension the venous effluent of the kidney affected by renal artery stenosis contains not only more renin but also more cyclic AMP, owing to either increased cyclic AMP production or decreased excretion or extraction of cyclic AMP by the affected kidney. This unilateral increase in cyclic AMP concentration may become a complementary diagnostic feature of true renovascular hypertension.     

Renin--angiotensin antagonists and the regulation of blood pressure.

The role of the renin--angiotensin system in the regulation of blood pressure in dogs and in human subjects was assessed by the use of the nonapeptide converting enzyme inhibitor (CEI), permitting the following conclusions: 1) In the normal, sodium replete dog, the renin--angiotensin system plays little role in the regulation of blood pressure. 2) As sodium depletion progresses, the renin--angiotensin system becomes increasingly important in the maintenance of blood pressure. In the markedly hypovolemic animal, blocking the conversion of angiotensin I to angiotensin II leads to prolonged hypotension of shock-like levels. 3) The renin--angiotensin system is responsible for the initiation of renovascular hypertension. Blood pressure does not rise during chronic renal artery constriction when the generation of angiotensin II is prevented by the CEI. Although angiotensin II is essential for the initiation of the elevated blood pressure, the renin--angiotensin system plays a decreasing role in the maintenance of the chronic hypertension as sodium and water are retained, and plasma volume increases. 4) In congestive failure induced in the conscious dog by circulatory impairment, the renin--angiotensin--aldosterone system plays an essential role in the compensatory response. During chronic administration of the CEI, the animal cannot compensate even for a relatively mild degree of constriction, and remains hypotensive. In the dog with congestive failure, as in the dog with renovascular hypertension, plasma renin activity (PRA) and plasma aldosterone are elevated early in the syndrome; during this phase, injection of the nonapeptide produces a marked drop in blood pressure. With the retention of sodium and water, and expansion of plasma and extravascular fluid volumes, PRA and plasma aldosterone return to control levels in the new steady state. The inhibitor no longer produces a drop in blood pressure. Thus, the sequential changes in the renin--angiotensin--aldosterone system are remarkably similar in renovascular hypertension and congestive failure. 5) In the normal, salt replete human subject the renin--angiotensin system plays little role in the regulation of blood pressure either in the recumbent or upright posture. However, with relatively mild sodium depletion, the CEI transiently lowers blood pressure even in the recumbent subject. In the absence of angiotensin II such sodium-depleted subjects are unable to compensate when tilted upright, and faint within minutes.     

Inhibition of the Prostaglandin Transporter PGT Lowers Blood Pressure in Hypertensive Rats and Mice

Inhibiting the synthesis of endogenous prostaglandins with nonsteroidal anti-inflammatory drugs exacerbates arterial hypertension. We hypothesized that the converse, i.e., raising the level of endogenous prostaglandins, might have anti-hypertensive effects. To accomplish this, we focused on inhibiting the prostaglandin transporter PGT (SLCO2A1), which is the obligatory first step in the inactivation of several common PGs. We first examined the role of PGT in controlling arterial blood pressure blood pressure using anesthetized rats. The high-affinity PGT inhibitor T26A sensitized the ability of exogenous PGE₂ to lower blood pressure, confirming both inhibition of PGT by T26A and the vasodepressor action of PGE₂ T26A administered alone to anesthetized rats dose-dependently lowered blood pressure, and did so to a greater degree in spontaneously hypertensive rats than in Wistar-Kyoto control rats. In mice, T26A added chronically to the drinking water increased the urinary excretion and plasma concentration of PGE₂ over several days, confirming that T26A is orally active in antagonizing PGT. T26A given orally to hypertensive mice normalized blood pressure. T26A increased urinary sodium excretion in mice and, when added to the medium bathing isolated mouse aortas, T26A increased the net release of PGE₂ induced by arachidonic acid, inhibited serotonin-induced vasoconstriction, and potentiated vasodilation induced by exogenous PGE₂. We conclude that pharmacologically inhibiting PGT-mediated prostaglandin metabolism lowers blood pressure, probably by prostaglandin-induced natriuresis and vasodilation. PGT is a novel therapeutic target for treating hypertension.     

Effects of prostaglandins E1 and E2 on the in vitro production of immunoglobulin by human peripheral blood lymphocytes

The effects of PGE₂ and PGEl on the response of human peripheral blood lymphocytes to Pokeweed mitogen were studied.Addition of PGE2 inhibited IgM production. This effect was augmented by treating the lymphocytes with 2.0 ug/ml of Indomethacin. Addition of PGE, alone had little effect but augmentation of IgM production was seen in cultures where the lymphocytes had been treated with Indomethacin and PGEl then added. The results suggest that PGE₁/E₂ have a small but measurable effect on in vitro IgM production.     

The role of renal metabolism of PGE2 in determining its activity as a renal vasodilator in the dog

Since the mammalian renal cortex avidly metabolizes prostaglandin E₂ (PGE₂), we examined the importance of renal metabolism of PGE₂ in determining its renal vascular activity in the dog. We used 13, 14 dihydro PGE₂ (DHPGE₂) as a model compound to study this because DHPGE₂ retains similar activity to the parent prostaglandin, PGE₂, but is a poorer substrate than PGE₂ for both the metabolism and the cellular uptake of the prostaglandins. Using dog renal cortical slices, we found that under similar experimental conditions, PGE₂ was metabolized several-fold faster than DHPGE₂. Both prostaglandins were metabolized to the 15 keto 13, 14 dihydro PGE₂, which was positively identified using GC-MS. In vivo, we infused increasing concentrations of DHPGE₂ into the renal artery of dogs and measured renal hemodynamic changes using radioactive microspheres. DHPGE₂ was a potent renal vasodilator beginning at an infusion rate of 10⁻⁹g/kg/min. When compared to PGE₂, DHPGE₂ was about 10 times more potent in affecting renal vasodilation. The intrarenal redistribution of blood flow towards the inner cortex seen with DHPGE₂ was identical to that seen with PGE₂. We conclude that renal catabolism of PGE₂ is very important in limiting the in vivo biological activity of PGE₂, but regional differences in metabolism of PGE₂ within the cortex are an unlikely determinant of the pattern of redistribution of renal blood flow.     

Blood Angiotensin II Levels of Normal and Hypertensive Subjects

A specific radioimmunoassay for angiotensin II has shown that its normal concentration in arterial blood is 2·4±1·2 (S.D.) mμg./l00 ml.; the venous level is consistently below this value, being usually 50–75% of it. Definite rises in blood angiotensin II levels were found in some patients with hypertension, both essential and secondary to renal disease. Extremely low levels were observed in two anephric women, and in one patient with Conn''s syndrome. This radioimmunoassay offers a valuable alternative to renin bioassay in evaluation of the role of the renal pressor system in clinical disorders associated with hypertension and aldosteronism.     

Effect of prostaglandin A1 infusion in hypertensive patients with renal artery stenosis

Clinical data, arteriographic findings, peripheral and renal vein plasma renin activity (PRA) studies and responses to prostaglandin A₁ infusion are presented from observations in seven hypertensive patients with renal artery stenosis. PGA₁ infusion caused an increase in PRA and urine sodium excretion but no significant change in blood pressure. Exaggerated increases in PRA were observed in five patients. With cessation of PGA₁ infusion PRA returned toward pre-infusion levels. In two patients bilateral renal and peripheral vein PRA's were determined before and during PGA₁ infusion. PGA₁ caused a greater increase in renal vein PRA than in peripheral vein PRA indicating a direct enhancement of renin secretion. These studies indicate possible relationships between the vasoactive prostaglandins and the renin-angiotensin system in the pathogenesis of hypertension due to renal artery stenosis.     

Urinary 6-keto PGF1α and PGE2 in two kidney-one clip hypertension in the rat

The 24 hour urinary excretion of 6-keto PGF_1α and PGE₂ was compared in 2 kidney-1 clip rats developing hypertension within 12 weeks of renal artery clipping with rats remaining normotensive over this period. Although systolic blood pressure was markedly elevated in the hypertensive (210 ± 5.1 mm Hg), in contrast with the normotensive (141 ± 1.9 mm Hg) group, urinary levels of 6-keto PGF_1α (26.1 ± 3.4 and 22.1 ± 2.7 ng/24h, respectively) and PGE₂ (52.8 ± 28 and 53.3 ± 10.8 ng/24h) were not significantly different. Treating the 2 kidney-1 clip normotensive group with indomethacin (3.0 mg/kg, by intraperitoneal injection) twice-weekly for 3 weeks reduced 6-keto PGF_1α excretion from 22.1 ± 2.7 to 8.4 ± 2.2 ng/24h (P < 0.002) and PGE₂ from 53.3 ± 10.8 to 8.7 ± 1.8 ng/24h (P < 0.002) but did not change blood pressure when compared with a similar group given buffer vehicle only. These findings do not support a role for renal prostaglandins in 2 kidney-1 clip hypertension in the rat.     

Influence of dietary polyunsaturated fatty acids on renal & aortic prostaglandin synthesis in 1 kidney 1 clip goldblatt hypertensive rats

To study the influence of dietary modification on prostaglandin synthesis and on blood pressure regulation, the effects of dietary enrichment with linolenic or linoleic acid was compared with standard rat chow in 3 groups of 13 rats before and after renal artery constriction and contralateral nephrectomy. Before renal artery constriction 4 weeks supplementation with 40 en% linseed oil (53% linolenic acid) increased renal linolenic acid, decreased arachidonic acid, and suppressed synthesis of 6-keto-PGF_1α and PGE₂ by renal homogenates (33% and 38% respectively, p<0.01) compared with standard diet. Rats fed on 40 en % sunflower seed oil (63% linoleic acid) increased renal prostaglandin synthesis (p<0.05) compared with linseed oil, but not compared with standard diet. Seven weeks after renal artery constriction renal and aortic 6-keto-PGF_1α and PGE₂ were suppressed 30% to 50% (p<0.05) by linseed oil supplements compared with sunflower seed oil and standard diets. In the sunflower seed oil group aortic 6-keto-PGF_1α correlated (r = 0.75, p<0.02) with final systolic blood pressure. Final systolic blood pressures were similar in linseed oil (152.9 mmHg ± se 3.3, sunflower oil (155.1 ± se 6.6) and standard diet group (159.0 ±se 4.2). Thus dietary linseed oil suppressed renal and aortic prostaglandin synthesis but did not accentuate renal hypertension, and linoleic acid supplementation did not protect against 1 kidney 1 clip renal hypertension.     

Atrial natriuretic peptides in man

Research on the physiological role of atrial peptides in man is limited, and the potential for these peptides, or more stable analogues, in therapeutics is uncertain. It is clear, however, that plasma levels of immunoreactive atrial natriuretic peptide (IR-ANP) are increased in volunteers taking a high sodium diet, and are elevated in patients with heart failure, chronic renal failure, and primary aldosteronism. There is suggestive evidence that IR-ANP levels are increased also in essential hypertension, although overlap with normotensives is considerable. Injection or infusion of atrial peptides into man results in a diuresis, an increased output of urine electrolytes, a fall in blood pressure and a rise in heart rate, suppression of aldosterone and sometimes of renin also, and stimulation of norepinephrine. In essential hypertensives, urinary effects may be greater than in normotensives. Heart failure patients show a rise in cardiac output and falls in both systemic and pulmonary arterial pressure. Over the next few years and especially if specific antagonists can be developed, the physiologic and pathophysiologic roles of atrial peptides in normal man and in clinical disorders should be clarified. It is possible that stable analogues of atrial peptides will find a place in the treatment of cardiac failure, renal failure, and perhaps hypertension.