Altered regulation of renin secretion by insulinlike growth factors and angiotensin II in diabetic rats.

The etiology of the low renin state in DM is not clear. To assess the role of certain growth and regulatory factors in this process, we studied the effects of insulin, IGF-I, and IGF-II on the renin-angiotensin system in normal and 8-wk STZ-induced diabetic rats. Renin secretion was studied both in static incubations and by perifusion of rat renal cortical slices. In diabetic rats, both plasma renin activity (0.65 +/- 1.6 vs. 4.0 +/- 1.2 ng ANG I.ml-1.h-1) and tissue renin concentrations (27 +/- 5 vs. 51 +/- 8 ng ANG I.mg tissue-1.h-1) were reduced. Insulin (0.1-1.0 mu/ml) and IGF-I (10(-9) to 4 x 10(-9) M) stimulated renin secretion in normal tissue (control, 95 +/- 3%; insulin [0.5 mu/ml], 134 +/- 7%; IGF-I [4 x 10(-9) M], 149 +/- 7%). IGF-I stimulated renin secretion in perifusions as early as 30 min, whereas IGF-II had no effect. However, in diabetic renal tissue, neither insulin (0.1-1.0 mu/ml) nor IGF-I (10(-9) to 4 x 10(-9) M) had an effect on renin. This lack of effect was overcome by adding up to 100-fold higher concentrations of these growth factors. ANG II (10(-10) M-10(-8) M) had an exaggerated inhibitory effect on renin secretion in diabetic tissue. This study suggests that the low renin state in DM may be explained by the enhanced inhibitory effect of ANG II and the resistance to the secretogogue actions of insulin and IGF-I.

Renin response to 12-hydroxyeicosatetraenoic acid is increased in diabetic rats.

Eicosanoids (prostaglandins) can alter renin secretion and angiotensin (ANG) II action. We have studied the effects of both prostacyclin and a lipoxygenase (LO) product, 12-hydroxyeicosatetraenoic acid (12-HETE), on renin in normal and streptozotocin-induced diabetic rats. 12-HETE is not only a potent inhibitor of basal renin secretion but also a key mediator of ANG II-induced renin inhibition. We have also examined the effects of ANG II on 12-HETE formation in normal and diabetic animals. Both plasma (3.9 +/- 0.9 vs. 0.8 +/- 0.1 ng ANG I.ml-1.h-1, P < 0.01) and tissue (38 +/- 6 vs. 21 +/- 2 ng ANG I.mg tissue-1.h-1, P < 0.05) renin activity levels were markedly reduced in diabetic animals. Iloprost (10(-6) mol/l), a stable analog of prostacyclin, had similar stimulatory effects on renin secretion in both normal and diabetic tissues, but the response was enhanced by LO inhibition in diabetic tissue. 12-HETE (10(-7) mol/l) had an exaggerated effect on renin inhibition in diabetic tissue (78 +/- 2% normal vs. 65 +/- 4% diabetic, P < 0.05). Similarly, ANG II (10(-8) mol/l) inhibition of renin was significantly enhanced in diabetic rats (P < 0.001). However, ANG II did not produce an exaggerated increase in 12-HETE in diabetic renal tissue. Insulin reversed the inhibitory effects of ANG II on renin in normal rats, but it blunted the effect of ANG II in diabetic rats. These studies suggest that, while the capacity of renal cortical tissue to synthesize 12-HETE in response to ANG II is not altered, 12-HETE and ANG II actions are exaggerated in diabetes, and this may contribute to reduced renin production.

Role of extra- and intracellular calcium and calmodulin in renin release from rat kidney.

Renin release from the juxtaglomerular cell appears to be inversely related to calcium concentration. We studied the role of Ca+2 to confirm recent findings and to further explore the role of intracellular calcium as well as the calcium-calmodulin system in renin release. A rat renal cortical slice preparation was used. Isoproterenol (10(-6) M) caused significant stimulation of renin release, whereas angiotensin (AII; 5 X 10(-5) M) suppressed basal as well as isoproterenol-stimulated renin release. Removal of calcium from the buffer reversed AII suppression of renin release. Nifedipine (10(-5) M), a specific calcium channel blocker, induced a marked increase in basal renin release. TMB-8, an inhibitor of intracellular calcium release, also caused a dose-related increase in basal renin release. The calmodulin antagonists trifluoperazine and calmidazolium both caused significant dose-related increases; however, calmidazolium was a more potent stimulator. Low extracellular calcium or nifedipine concentrations did not alter isoproterenol-induced renin release. Isoproterenol further stimulated renin release in the presence of trifluoperazine and calmidazolium. These results suggest that acute beta-adrenergic stimulation of renin in independent of changes in levels of extracellular and intracellular calcium and calmodulin. These studies provide further evidence that unlike most other secretory systems, the reduction of intracellular calcium or inhibition of the calcium-calmodulin system in the juxtaglomerular cells of the kidney acts as a secretogogue.

Androgen induction of steroid 5 alpha-reductase may be mediated via insulin-like growth factor-I.

The action of added insulin-like growth factor-I (IGF-I) and dihydrotestosterone (DHT) on steroid 5 alpha-reductase (5 alpha R) activity was studied using primary cultures of rat or human scrotal skin fibroblasts. Agents were added to cultured cells (2 x 10(5) cells) for 2 days, and enzyme activity was measured by the percent conversion of [3H] testosterone to DHT over a 4-h period in the absence of fetal calf serum or other growth factors. DHT, but not testosterone, at 10(-7) M significantly increased 5 alpha R activity (rat, 1.5 +/- 0.3% to 3.0 +/- 0.4%; human, 7.6 +/- 1.7% to 11.4 +/- 2.9%; P < 0.01). IGF-I (10(-9)-6.4 x 10(-9) M), but not IGF-II (10(-9)-10(-8) M) or insulin (10(-9)-10(-7) M), increased enzyme activity in a dose-related fashion [i.e. 1.5 +/- 0.5 to 10 +/- 2 in rat and 6.0 +/- 1.1 to 9.8 +/- 1.6% (P < 0.01) in human cells]. No change in cell numbers was observed in any experiment. Since the effect of IGF-I was about 100 times that of androgen, we studied the possibility that androgen induction of the enzyme activity could be via IGF-I production. Addition of a monoclonal antibody against IGF-I significantly reduced the effect of DHT, and simultaneous addition of a specific IGF-I receptor antibody blocked the expected induction of 5 alpha R activity (control, 4.9 +/- 0.5; DHT, 8.0 +/- 1.9; DHT plus IGF-I receptor antibody, 3.7 +/- 0.4%). No effect on 3 alpha-reduction of [3H]DHT to 3 alpha-androstanediol was detected in separate experiments. These studies indicate that IGF-I may be an important regulator of skin 5 alpha R activity and, thus, may influence DHT formation. The previously known androgen induction of this peripheral steroidogenic enzyme may be via paracrine/autocrine production of an IGF-I-type growth factor.

Role of atrial natriuretic factor in renin release.

Atrial natriuretic factor (ANF) was studied for its effect on renin release by rat renal cortical slices. ANF (rat) alone (10(-9)-10(-6) M) had no effect on basal renin release, but significantly (P less than 0.001) potentiated angiotensin II (AII) inhibition of renin secretion in doses as low as 10(-9) M. ANF also potentiated the inhibitory effect of AII on 8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (which alters intracellular calcium) and calmidazolium (a calmodulin blocker) effects on renin release. ANF did not inhibit the action of isoproterenol, which probably acts through cAMP, at doses below micromolar concentrations. Large, probably pharmacological amounts (greater than 10(-6) M) produce some inhibition. Since AII action on renin is associated with increases in intracellular calcium, our studies suggest that ANF acts by altering the intracellular calcium-calmodulin-mediated steps of AII action on this tissue and not via cAMP.

Angiotensin feedback inhibition on renin is expressed via the lipoxygenase pathway.

Angiotensin II (AII) action on adrenal and smooth muscle cells is mediated via mechanisms that include changes in calcium flux and phosphoinositide hydrolysis. Phosphoinositide metabolism results in the release of arachidonic acid, a precursor of both the cyclooxygenase (CO) and lipoxygenase (LO) pathway. The effects of both LO and CO inhibitors on AII action were studied using both static incubations and perifusions of rat renal cortical slices. 12-Hydroperoxyeicosatetraenoic acid and its stable metabolite 12-hydroxyacid mimicked the inhibitory actions of AII on renin. A specific CO blocker did not alter AII inhibition of renin and a 5-LO blocker U60,257 was also ineffective, whereas the LO blockers BW755c, phenidone, and baicalein all eliminated or interfered with the action of AII on renin. All inhibition in the presence of a LO blocker was restored by adding nanomolar concentrations of 12-hydroperoxyeicosatetraenoic acid. LO inhibitors were specific for blocking AII, as they did not interfere with potassium (K+)-induced renin inhibition. These results imply that 12 and/or 15 products of the LO pathway are involved in AII action.

Tumor necrosis factor and interleukin-1 may regulate renin secretion.

Cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1) are not only immunoregulatory polypeptides, but may have endocrine functions. We have studied the direct effects of recombinant and purified TNF and IL-1 on renin secretion using both static incubations and perifusions of rat renal cortical slices. Ultrapure human IL-1 (hIL-1) at concentrations as low as 5 U/ml (3 X 10(-12) M) significantly stimulated renin secretion (control, 98 +/- 4%; hIL-1, 153 +/- 13%; P less than 0.01). TNF similarly induced renin release [control, 97 +/- 6%; TNF (10 U/ml), 151 +/- 13%; P less than 0.005]. TNF and recombinant human IL-1 beta (rhIL-i beta) also blocked the inhibitory actions of angiotensin-II (AII) on renin release [control, 100 +/- 3%; AII (2 X 10(-7) M), 80 +/- 5%; AII plus TNF (20 U/ml), 102 +/- 7%; AII plus rhIL beta (10 U/ml), 106 +/- 6%; both P less than 0.02 vs. AII]. A cyclooxygenase (CO) blocker, meclofenamate (M), which does not significantly alter basal renin release, attenuated the TNF- and rhIL-1 beta-induced renin secretion [TNF (20 U/ml), 132 +/- 11%; TNF plus M (5 X 10(-5) M), 100 +/- 3% (P less than 0.01); rhIL-1 beta (10 U/ml), 135 +/- 9%; rhIL-1 beta plus M, 105 +/- 10% (P less than 0.05)]. The stimulatory effects of TNF and IL-1 on renin were reversible. These results suggest that IL-1 and TNF are renin secretagogues and can also block the inhibitory actions of AII on renin. Since the effect of TNF and IL-1 on renin can be blocked by a (CO) inhibitor, the studies indicate a role of prostaglandins in their action. Therefore, locally produced TNF and IL-1 may play an important paracrine role in regulation of the renin-angiotensin system.

A 12-lipoxygenase product of arachidonate metabolism is involved in angiotensin action on renin release.

Angiotensin II (AII) action is coupled to the hydrolysis of phospholipids resulting in the formation of arachidonic acid, the precursor of both prostaglandins, and hydroxyeicosatetraenoic acids (HETEs). Since 12-HETE is not only a major arachidonate lipoxygenase (LO) product in the kidney, but is also a potent inhibitor of renin release, we studied the role of AII on renin inhibition and 12-HETE formation using rat renal cortical slices and isolated juxtaglomerular-like cells. In both preparations, 12-HETE was produced in a basal state. AII significantly inhibited renin release (control 100 +/- 3%, AII (10(8) M) 79 + 4%, P less than 0.01) and stimulated 12-HETE formation in slices (control 106 +/- 6%, AII 10(-8) M 177 +/- 18%, P less than 0.01) and in an enriched juxtaglomular cell preparation (control 96 +/- 3%, AII 10(-8) M 130 +/- 6%, P less than 0.001). A specific cyclooxygenase blocker, meclofenomate, or 5-LO blocker, U60,257, did not alter basal or AII-induced renin inhibition or 12-HETE formation by slices. The LO blockers BW755c, at 10(-5) M, or baicalein, 10(-6) M, did not significantly alter basal renin or 12-HETE levels, but BW755c at 10(-4) M, significantly stimulated basal renin (131 +/- 4%) and decreased basal 12-HETE levels (72 +/- 5%). However, both BW755c and baicalein blunted AII-induced renin inhibition (AII, 10(-8) M 70 +/- 3%, AII + BW755c, 10(-5) M 85 +/- 4%, P less than 0.02, AII + baicalein, 10(-6) M, 90 +/- 4%, P less than 0.005) and AII mediated 12-HETE formation (AII, 10(-8) M 150 +/- 5%, AII + BW755c, 10(-5) M 117 +/- 8%, P less than 0.02, AII + baicalein, 10(-6) M 110 +/- 3%, P less than 0.005). These results suggest that AII inhibition of renin is not mediated by the cyclooxygenase or 5-LO pathway, but rather by the 12-LO pathway. These findings reveal a new action for 12-LO products which may play a pivotal role in stimulus secretion coupling of renin secretion.

Epidermal growth factor is a potent inhibitor of renin secretion.

Epidermal growth factor (EGF) is not only a cell mitogen but a potent vasoconstrictor that shares many properties with angiotensin II. Because EGF is localized in the kidney, we have studied the direct effects of EGF on renin secretion using both static incubations and perifusions of rat renal cortical slices. EGF at 5 x 10(-9) M significantly inhibited renin secretion in static incubations (control, 100 +/- 3%; EGF, 72 +/- 3%; p < 0.001). When added to perifusions, EGF acted rapidly, reducing renin secretion at the earliest time period (10 minutes). Similarly, transforming growth factor-alpha, which can bind to the EGF receptor, also inhibited renin secretion (control, 92 +/- 8%; transforming growth factor-alpha [2 x 10(-9) M], 63 +/- 4%; p < 0.02). Because both prostaglandins and lipoxygenase products of arachidonic acid have been shown to play a role in some EGF-mediated actions, we examined these possible mechanisms of EGF action. Meclofenamate, a cyclooxygenase blocker, and BW755c and baicalein, both lipoxygenase blockers, were studied. None of these agents altered EGF-mediated renin inhibition. EGF action has also been coupled to the stimulation of tyrosine kinase activity; therefore, we examined the effects of the tyrosine kinase inhibitors genistein and quercetin. Both genistein (10(-5) M) and quercetin (10(-5) M) abolished the inhibition of renin by EGF (control, 100 +/- 3%; EGF, 82 +/- 4%; EGF plus genistein, 110 +/- 7%; p < 0.01; EGF, 75 +/- 4%; EGF plus quercetin, 92 +/- 4%; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Ouabain is a potent inhibitor of aldosterone secretion and angiotensin action in the human adrenal.

Digitalis glycosides and a putative ouabain-like substance act by inhibiting Na,K-adenosine triphosphatases and could regulate aldosterone secretion. We studied the effects of ouabain on basal and angiotensin II (AII)-induced aldosterone in rat and human adrenal glomerulosa cells. In the rat, ouabain at doses as high as 10(-4) mol/L had no effect on basal aldosterone secretion, but caused a dose-related inhibition of AII and ACTH secretion. In human glomerulosa cells, ouabain was 1000 times more potent on both basal and AII stimulation, with action at 10(-8) mol/L. The effect of ACTH was also blunted by 10(-8)-10(-7) mol/L ouabain. However, the effect of potassium (8.7 mmol/L) on aldosterone was not altered by these doses of ouabain. These results suggest that nanomolar levels of ouabain can reduce aldosterone secretion from human zona glomerulosa cells.

Inactive renin and prostaglandin E2 production in hyporeninemic hypoaldosteronism.

To ascertain whether inactive renin (IR) might predominate in the syndrome of hyporeninemic hypoaldosteronism (HH) and whether the production of prostaglandin E2 (PGE2), a potent stimulus for renin release, might be decreased, we measured PRA, active renin (AR), and IR by the acid activation method and urinary PGE2 in 10 patients with HH. In contrast to uniformly low levels of PRA (0.6 +/- 0.2 ng/ml . h) and AR (2.7 +/- 0.6), IR was either normal or elevated (14.7 +/- 2.2 in HH; 11.8 +/- 1.1 in 28 normal subjects) and the IR to AR ratio was markedly increased (8.5 +/- 2.0 vs. 3.4 +/- 0.5; P < 0.05). Urinary PGE2 was decreased in 4 patients but was in the normal range in 5 other patients with HH. In 16 human volunteers, PG inhibition with indomethacin led to a significant decrease in AR (P < 0.05) but not in IR, and the IR to AR ratio increased 2-fold (P < 0.02). The data suggest that HH is a disease involving the defective conversion of IR to AR rather than impaired total renin production. In some patients, PG deficiency may contribute to the development of HH.

Inhibition of testosterone metabolism in the human prostate.

PIP: The conversion of carbon-14-testosterone (T) to 5alpha-dihydrotestosterone (DHT) and androstanediol (A-diol) was studied in vitro using a crude homogenate of prostate from patients with benign prostatic hypertrophy. Under standard conditions, the mean conversion to DHT was 70 + or -1 (standare error, SE)% and to A-diol 14 + or -1 (SE)%. Addition of various antiandrogens and other substances decreased the T to DHT conversion to 0-55% and the T to A-diol to 0-10%. The most potent inhibitors were desoxycorticosterone and progesterone. Estradiol-17beta, cyproterone acetate, medrogestone, medroxyprogesterone acetate, estriol and 4'-nitro-3'trifluoromethylisobutyramilide were also effective inhibotors. To determine whether this effect might be significant in vivo, similar conversion studies were carried out on prostatic tissue obtained from 3 patients who had received oral medrogestone for 1-2 weeks. T to DHT was reduced to 12.2 + or -2.8 (SE)% and T to A-diol to 6.5 + or -1.0 (SE)%. The ability of such compounds to inhibit DHT formation represents 1 mode of action which may account at least in part for their efficacy in the treatment of benign prostatic hypertrophy.^ieng

Evidence that specific dopamine-1 receptor activation is involved in dopamine-induced renin release.

Direct effects of dopamine on renin release were examined using static incubations and perifusions of rat renal cortical slices. Dopamine (10(-5)M) significantly stimulated renin release compared with control. To determine which receptors are involved in dopamine-elicited renin release, studies were performed with specific dopamine-1 and dopamine-2 receptor agonists and antagonists, as well as with alpha- and beta-adrenergic antagonists. Fenoldopam, a dopamine-1 receptor agonist, dose dependently stimulated renin secretion both in static incubations and perifusions; whereas quinpirole (10(-7)-10(-5)M), a dopamine-2 receptor agonist, was ineffective. Phentolamine (10(-4)M), an alpha-adrenergic antagonist, did not alter dopamine- or fenoldopam-induced renin release. Similarly, propranolol, a beta-blocker, did not interfere with the renin stimulation of dopamine (10(-5)M) or fenoldopam (10(-6)M) incubations or perifusion experiments; whereas propranolol significantly blocked isoproterenol action. SCH 23390 (10(-5)M), a specific dopamine-1 antagonist, blocked dopamine- and fenoldopam-induced renin. In contrast, pimozide, a dopamine-2 receptor antagonist, was ineffective. These studies indicate that dopamine is a direct renin secretogogue, and its effects seem to be mediated by specific dopamine-1 receptor activation, as neither alpha- nor beta-adrenergic blockers nor dopamine-2 receptor antagonists altered dopamine actions. The results suggest that dopamine produced locally in the kidney may stimulate renin secretion directly by dopamine-1 receptor activation.

Effect of dopamine2 blockade on renal function under varied sodium intake.

This study explored the role of the dopamine-2 receptor (DA2) in the control of renal blood flow (RBF) and the influence of variations in sodium intake. These relationships have not been previously defined in man. Seven normotensive male subjects underwent a low dose dopamine (DA) infusion (1 microgram/kg.min) for 3 h, known to activate both DA1 and DA2 receptors. The effect of DA2 receptor on renal hemodynamics was studied using a relatively specific DA2 blocker [domperidone (DOM); 60 mg, orally] alone and with a DA infusion. Systemic and renal hemodynamics parameters were measured noninvasively. Urinary prostacyclin was measured in 3-h urine specimens, obtained during the DA infusion. The DA infusion increased RBF and prostacyclin during both normal and high salt diets, but this effect was attenuated on a low salt diet. DOM alone significantly reduced basal RBF during normal (1304 +/- 48 vs. 1175 +/- 45 mL/min.1.73 m2; P < 0.01) and low salt diets (1402 +/- 80 vs. 1220 +/- 101 mL/min.1.73 m2; P < 0.02), but was without effect during high sodium intake. DOM had no effect on prostacyclin excretion at any level of salt intake. These results suggest that both DA1 and DA2 are activated in renal vessels by DA, and that DA2 receptors play a role in the renal vasodilating action of DA. Changes in sodium balance alter the actions of the two receptors (DA1 and DA2) in a coordinated fashion in the regulation of RBF.

The inhibitory role of 12- and 15-lipoxygenase products on renin release.

Release of arachidonic acid from membrane phospholipids is a limiting step in the synthesis of both cyclooxygenase products and lipoxygenase products. The direct effects of prostacyclin and some lipoxygenase products on renin release were studied using rat renal cortical slices. Prostacyclin, at concentrations of 10(-5) M, stimulated renin secretion, but this effect was short-lived. Leukotrienes or their precursor, 5-hydroperoxyeicosatetraenoic acid, did not affect basal renin release. In contrast, 10(-9) M 12-hydroperoxyeicosatetraenoic acid and 10(-8) M 12-hydroxyeicosatetraenoic acid were potent inhibitors of renin secretion. Similarly, 15-hydroperoxyeicosatetraenoic acid and its hydroxy derivative, 15-hydroxyeicosatetraenoic acid, at somewhat higher molar concentrations (10(-6) M) also reduced basal renin. These studies confirm prostacyclin as a potential renin secretagogue; however, its action in vitro is transient, probably because of its rapid degradation. Our studies provide new evidence that products of the 12-lipoxygenase and 15-lipoxygenase pathways, reported to be present in renal vascular tissue, are potent inhibitors of renin secretion and much more active on a molar basis on renin secretion than is prostacyclin. These studies suggest the potential presence of a dual system of stimulation and suppression that may regulate renin secretion in normal and clinical states.

Cortisol production by testicular tumors in a patient with congenital adrenal hyperplasia (21-hydroxylase deficiency).

Bilateral testicular tumors are known to occur in congenital adrenal hyperplasia, but their steroidogenic properties are not well studied. We have recently demonstrated steroid 11 beta-hydroxylase activity in these tumors from a 27-yr-old patient with documented salt-losing congenital hyperplasia (21-hydroxylase deficiency). Spermatic venous blood obtained at operation contained 3.6-5 ng/ml cortisol, as measured by specific RIA after Sephadex LH-20 chromatography. In contrast, the peripheral venous cortisol level was 0.64 ng/ml. The presence of 11 beta-hydroxylase activity was demonstrated by the in vitro conversion of [3H]deoxycorticosterone to [3H]corticosterone in tumor tissue. The conversion ratio of deoxycorticosterone to corticosterone was 4.3% and 7.07%/mg tissue in the tumor tissue, whereas in normal testicular tissue, it was less than 1%. The radiochemical identity of corticosterone was confirmed by rechromatography on Sephadex LH-20, coelution with added [14C]corticosterone, and a constant 3H to 14C ratio after acetylation and thin layer chromatography. The tumor cells grown in primary culture produced steroids and responded to ACTH and hCG. Electron microscopy of the tumor revealed a large number of mitochondria containing electron dense granules. Light microscopy was compatible with Leydig cell tumor. In conclusion, testicular tumors in association with congenital adrenal hyperplasia have morphological features of Leydig cells but have the capability of 11 beta-hydroxylation and cortisol production, properties which are unique to adrenocortical tissue. These findings suggest that they originate from pluripotential cells in the testicles. Regression of these tumors has been reported with optimal biochemical control of the disease.

Magnesium deficiency produces insulin resistance and increased thromboxane synthesis.

Evidence suggests that magnesium deficiency may play an important role in cardiovascular disease. In this study, we evaluated the effects of a magnesium infusion and dietary-induced isolated magnesium deficiency on the production of thromboxane and on angiotensin II-mediated aldosterone synthesis in normal human subjects. Because insulin resistance may be associated with altered blood pressure, we also measured insulin sensitivity using an intravenous glucose tolerance test with minimal model analysis in six subjects. The magnesium infusion reduced urinary thromboxane concentration and angiotensin II-induced plasma aldosterone levels. The low magnesium diet reduced both serum magnesium and intracellular free magnesium in red blood cells as determined by nuclear magnetic resonance (186 +/- 10 [SEM] to 127 +/- 9 mM, p < 0.01). Urinary thromboxane concentration measured by radioimmunoassay increased after magnesium deficiency. Similarly, angiotensin II-induced plasma aldosterone concentration increased after magnesium deficiency. Analysis showed that all subjects studied had a decrease in insulin sensitivity after magnesium deficiency (3.69 +/- 0.6 to 2.75 +/- 0.5 min-1 per microunit per milliliter x 10(-4), p < 0.03). We conclude that dietary-induced magnesium deficiency 1) increases thromboxane urinary concentration and 2) enhances angiotensin-induced aldosterone synthesis. These effects are associated with a decrease in insulin action, suggesting that magnesium deficiency may be a common factor associated with insulin resistance and vascular disease.

A 12-lipoxygenase product, 12-hydroxyeicosatetraenoic acid, is increased in diabetics with incipient and early renal disease.

Earlier studies in diabetic animal models or ex vivo from diabetics suggest a deficiency in prostacyclin (PGI2) production and an increase in an alternate arachidonic acid metabolite, 12-hydroxyeicosatetraenoic acid (12-HETE), which stimulates angiogenesis, mitogenesis, and inhibits renin secretion. We studied the urinary excretion rate of 6-keto-PGF1 alpha (a stable metabolite of PGI2) and 12-HETE in controls and 42 noninsulin-dependent diabetes mellitus (NIDDM) patients with normal renal function and those with micro- or macroalbuminuria/hyporeninemic hypoaldosteronism (HH). The 2 eicosanoids were measured in urine using previously described high pressure liquid chromatography and RIA methods. Normal subjects and patients with NIDDM and microalbuminuria were infused with low dose calcium infusions that stimulate prostacyclin production in normal subjects. The PGI2 excretion rate of NIDDM patients with normal renal function was not different from that of controls (143 +/- 17 vs. 118 +/- 34 ng/g creatinine), but was reduced in those with microalbuminuria (75 +/- 10) and in macroalbuminuria patients (48 +/- 7; P < 0.01). In contrast, 12-HETE was increased in diabetics with normal renal function as well as in those with micro- or macroalbuminuria patients (69 +/- 18 vs. 250 +/- 62 vs. 226 +/- 60 and 404 +/- 131 ng/g creatinine; P < 0.01). Calcium did not stimulate PGI2, but increased 12-HETE in diabetics with microalbuminuria in contrast to levels in normal subjects. HH patients excreted less PGI2 (as previously reported), but had increased 12-HETE. HETE/PGI2 ratios further demonstrated these changes in the various groups. In a nondiabetic hypertensive microalbuminuria group, 12-HETE excretion was normal (73 +/- 28 ng/g creatinine). We conclude that the lipoxygenase product 12-HETE is increased early in the diabetic process, whereas PGI2 production is progressively impaired in NIDDM. These changes may play a role in the vascular disease of diabetes and partially explain the HH syndrome.

Active and inactive renin in low renin states: studies in human plasma.

Low PRA and active renin (AR) may be accompanied by low inactive renin (IR), indicating impaired renin production, or by normal or elevated IR, suggesting defective conversion to AR. To explore these possibilities, plasma AR and IR (acid activation method) were measured in normal volunteers and in patients with low PRA. All low renin states showed significant low PRA and AR when compared to normals; on the other hand, IR was 11.8 +/- 1.1 ng/ml.h in normals; low in primary aldosteronism (2.1 +/- 0.5 ng/ml.h) and anephric subjects; normal in low renin essential hypertension (7.5 +/- 1.3 ng/ml.h), nondiabetic hyporeninemic hypoaldosteronism (9.4 +/- 1.6 ng/ml.h) and diabetic hyporeninemic hypoaldosteronism (17.3 +/- 2.5 ng/ml.h); and significantly elevated in diabetics with nephropathy (21.0 +/- 1.6 ng/ml.h). The acute iv infusion of 2 liters saline in normal subjects did not decrease IR (11.8 +/- 2.0 vs. 13.0 +/- 1.8 ng/ml.h) despite a reduction in PRA and AR of 50-75%. These data indicate that in cases of primary aldosteronism and in anephric subjects both AR and IR are decreased, suggesting a decrease in total renal synthesis or release, whereas in low renin essential hypertension, nondiabetic hyporeninemic hypoaldosteronism, diabetic hyporeninemic aldosteronism, and diabetics with nephropathy AR is low and IR is normal or high, suggesting the possibility of impaired conversion to AR.

Comparison of dopamine and fenoldopam effects on renal blood flow and prostacyclin excretion in normal and essential hypertensive subjects.

We recently reported that a low dose dopamine (DA) infusion in normal subjects increased renal blood flow (RBF) via prostacyclin (PGI2) formation without changes in PGE2 levels. The present study explores whether this mechanism is mediated by the DA1 receptor and evaluates the effect of DA on RBF and PGs in subjects with essential hypertension (EH). A low dose of DA (1 microgram/kg.min), which previously did not alter hemodynamics in normal subjects was infused into eight patient with EH to determine the role of DA stimulation in hypertensives. To assess the effect of DA1 stimulation, fenoldopam, a selective DA1 agonist, was infused (0.1 microgram/kg.min) into 10 normal and 10 hypertensive patients. Fenoldopam, unlike DA, significantly decreased diastolic blood pressure in hypertensives (96 +/- 3 to 85 +/- 2 mm Hg; P less than 0.01) along with a significant increase in pulse rate (68 +/- 2 vs. 73 +/- 2 beats/min; P less than 0.01). RBF measured by para-aminohippurate clearance increased only in normals during fenoldopam infusion from 1185 +/- 71 to 1533 +/- 84 L/min.m2 (PGI(2)01), and this was associated with an increase in PGI2 (6-keto-PGF1) excretion (149 +/- 19 vs. 214 +/- 32 ng/g creatinine; P less than 0.02). These effects of fenoldopam were similar to DA effects on RBF and PGI2 excretion in normals. In contrast, in hypertensive subjects, neither fenoldopam (867 +/- 113 vs. 1054 +/- 177 L/min.m2; P greater than 0.1) nor DA (1098 +/- 85 vs. 1061 +/- 101 L/min.m2; P greater than 0.1) increased RBF. Similarly, neither the DA nor the fenoldopam infusion stimulated PGI2 excretion in the hypertensives. The fenoldopam infusion in the hypertensives produced a significant natriuresis (22 +/- 3 to 49 +/- 9 mmol/3 h; P less than 0.05). Similar effects on Na+ excretion in this group were noted during DA infusion (17 +/- 3 to 36 +/- 3 mmol/3 h; P less than 0.05), suggesting that DA-induced natriuresis is not directly linked to DA-induced changes in RBF or PG excretion. The present study shows that in normal subjects, fenoldopam, a specific DA1 agonist, like DA, stimulates renal PGI2 release and RBF. In contrast, neither DA nor fenoldopam alters PGI2 or RBF in patients with EH, suggesting an alteration of dopaminergic tone in some hypertensives that is characterized by a defect in DA1 receptor sensitivity.