In vitro prostaglandin (PG) and thromboxane B2 (TXB2) formation by isolated glomeruli from normotensive (N) and two-kidney, one-clip hypertensive (2K,1C) rats was determined. When calculated on the basis of glomerular protein content, PGE2, 6-keto-PGF1 alpha and TXB2 production of glomeruli from clipped kidneys was significantly greater than PG and TXB2 formation of glomeruli from the untouched kidneys. When PG and TXB2 formation was calculated per amount of glomeruli, only PGE2 formation was found to be significantly greater in clipped kidneys. No severe damage of glomerular structure was found in the kidneys when studied by light microscopy. In additional in vivo studies, the effect of the cyclooxygenase inhibitor indomethacin on blood pressure and glomerular filtration rate (GFR) was evaluated. Following indomethacin GFR in 7 of 13 clipped kidneys of 2K,1C rats decreased from 363 +/- 77 to 188 +/- 51 microliter/100 g body wt, whereas six kidneys developed anuria. No effect of cyclooxygenase inhibition on GFR was found in N rats and in untouched kidneys of 2K,1C rats. Mean arterial blood pressure in 2K,1C hypertension fell significantly, from 158 +/- 10 to 135 +/- 7 mmHg, after cyclooxygenase inhibition. No effect was seen in N rats. The data suggest that increased glomerular PG formation in the clipped kidneys of 2K,1C rats is involved in the pathogenesis of hypertension in this animal model.

In vitro formation of prostaglandins (PG) E₂, F_2α, 6-keto-F_1α, and thromboxane B₂ (TxB₂) by glomeruli from rats with reduced renal mass (RRM) were evaluated by radioimmunoassay. Four weeks following ablation of renal mass, PGE₂, PGF_2α, and TxB₂ production by glomeruli from RRM rats was significantly greater, when compared with glomerular PG and TxB₂ production of sham-operated control (C) rats. The effect of cyclooxygenase inhibition with indomethacin and the selective inhibition of thromboxane formation with UK 38485 on glomerular filtration rate (GFR) was investigated in experiments in vivo. In RRM rats indomethacin reduced GFR from 212 ± 17 to 138 ± 14 μl/100 g/body weight (p < 0.05) without effect on C rats. Thromboxane synthesis inhibition with UK 38485, however, increased GFR significantly in RRM rats (221 ± 26 to 303 ± 21; p < 0.05). The data suggest that vasodilatory PGs and TxB₂ modulate GFR in rats with ablation of renal mass.

Orocecal transit time was determined by the lactulose hydrogen breath test in nine healthy volunteers after administration of placebo, loperamide (16 mg per os), and loperamide (16 mg per os) followed by oral naloxone at doses of 16 and 32 mg. The four tests were performed in double-blind conditions and in random sequences. Transit time (mean, SD) after loperamide (128.8 min, 32.9) was significantly increased (P less than 0.05) compared with placebo (85.5 min, 35.7), loperamide followed by naloxone 16 mg (88.8 min, 46.2), and loperamide followed by naloxone 32 mg (84.4 min, 40.6). These results show that the peripheral opioid agonist loperamide delays orocecal transit in healthy subjects and that naloxone per os at adequate doses antagonizes this effect.

The intrinsic in vitro production of prostaglandins (PGs) E2, F2 alpha, 6-keto-F1 alpha, and thromboxane B2 (TxB2) and the conversion of exogenous substrate to PGs and TxB2 by isolated human glomeruli was demonstrated, 6-keto-PGF1 alpha was the major product. This was observed under basal conditions and following incubation with exogenous substrate. Indomethacin (Indo; 10(-4 M) inhibited the conversion of arachidonic acid to PGs and the release of [1-14C]-labeled products from human glomeruli by about 80%. The addition of angiotensin II (AII) to the isolated glomeruli produced, under basal conditions, an almost selective stimulation of 6-keto-PGF1 alpha. Following the prelabeling of glomeruli with 1-14C-arachidonic acid, the increase of glomerular PG formation after AII was added was also only significant for 6-keto-PGF1 alpha. When glomeruli were preincubated with large amounts of non-radiolabeled substrate. AII stimulated PGE2 and 6-keto-PGF1 alpha formation significantly. The data demonstrate PG formation in isolated human glomeruli and show an interaction between AII and the prostaglandin system in this tissue. This interrelationship might have physiologic consequences in the regulation of glomerular hemodynamics.

The effect of dietary sodium intake (5 days' low salt, 4 days' high salt) on 24-h urinary prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) excretion, blood pressure (BP), and plasma renin activity (PRA) was evaluated in 16 patients with essential hypertension. Sodium restriction significantly increased urinary PGE2 excretion (p less than 0.05) from 151 +/- 76 to 328 +/- 94 ng/24 h, while high salt intake reduced renal PGE2 production to 114 +/- 41 ng/24 h (p less than 0.05). There was a moderate but not significant increase in urinary PGF2 alpha excretion on the low salt regimen, which was reversed under high salt diet. Systolic and diastolic blood pressure fell from 162 +/- 11 to 145 +/- 10 mm Hg, i.e., 102 +/- 6 to 90 +/- 9 mm Hg on low sodium intake (35 mEq/day) and returned to levels close to control after 4 days on a high salt diet (250 mEq/day). Under low salt conditions, PRA increased significantly (p less than 0.001) from 0.83 +/- 0.33 to 2.82 +/- 1.12 ng AI/ml/h and fell to 0.45 +/- 0.31 ng AI/ml/h on high salt regimen (p less than 0.001). The results demonstrate that dietary sodium chloride intake modulates renal PGE2 production in patients with essential hypertension. The depressed PGE2 production under high salt conditions may play a role in regulation of renal vascular resistance and influence sustainment of chronic hypertension disease.