Attenuation of Angiotensin II- and III-induced Aldosterone Release by Prostaglandin Synthesis Inhibitors

The effect of two prostaglandin synthesis inhibitors, indomethacin and meclofenamate, on angiotensin II (AII)- and III (AIII)-induced aldosterone release was studied in normal and sodium-depleted conscious rats and in adrenal capsular cell suspensions obtained from normal rats. In normal rats, in vivo AII and AIII were equipotent in causing dose-related increases in serum aldosterone concentrations. Indomethacin decreased the basal serum aldosterone levels by 50% and serum renin levels by 43%. In addition, the steroidogenic effects of AII and AIII were reduced by 45 and 63% with 3 mg/kg of indomethacin and 63 and 73% with 10 mg/kg, respectively. In contrast, meclofenamate failed to alter basal serum levels of aldosterone or AII-stimulated aldosterone release but inhibited serum renin levels by 27% and the aldosterone-stimulating effect of AIII by 99%. Indomethacin (3 mg/kg) and meclofenamate (2 mg/kg) inhibited urinary prostaglandin (PG)E(2) and PGF(2alpha) excretion by 63 and 52% and 37 and 31%, respectively. Both inhibitors significantly decreased the adrenal capsular PGE(2) and PGF(2alpha) content and the conversion of [(14)C]arachidonate to [(14)C]PGE(2) and [(14)C]PGF(2alpha). In sodium-depleted rats, indomethacin produced similar effects reducing the control serum aldosterone levels by 29%, AII-stimulated aldosterone by 47%, and completely suppressing the aldosterone response to AIII without altering serum renin activity. In adrenal cell suspensions, similar results were observed with indomethacin inhibiting basal and AII- and AIII-stimulated aldosterone release by 29, 81, and 93%, respectively. Meclofenamate failed to alter basal and AII-stimulated aldosterone release but inhibited that stimulated by AIII by 86%. The present findings suggest that prostaglandins modulate the effects of the renin-angiotensin system by stimulating the release of renin from the kidney and augmenting the steroidogenic effects of AII and AIII in the adrenal cortex.     

Autoregulatory vasodilation enhances renal prostaglandin E2 and associated renin release during arachidonic acid infusion in dogs

To examine whether autoregulatory dilation of preglomerular vessels enhances prostaglandin (PG)E2 and renin release during arachidonic acid infusion, the ureter was occluded or the renal artery constricted in anesthetized dogs. Intrarenal arachidonic acid infusion (40 micrograms X kg-1 X min-1) increased PGE2 release by 41 +/- 17 pmol/min at control pressures and by 149 +/- 60 pmol/min during ureteral occlusion. Arachidonic acid infusion (160 micrograms X kg-1 X min-1) increased PGE2 release by 149 +/- 60 pmol/min at control pressures, by 505 +/- 211 pmol/min during ureteral occlusion and by 581 +/- 201 pmol/min during renal arterial constriction. Thus, PGE2 release during arachidonic acid infusion was trebled by autoregulatory dilation. Arachidonic acid infusion (160 micrograms X kg-1 X min-1) raised renin release by 6 +/- 2 micrograms of angiotensin I per min at control pressures, by 25 +/- 9 micrograms of angiotensin I per min during renal arterial constriction and during ureteral occlusion by 16 +/- 4 micrograms of angiotensin I per min, which was not significantly higher than induced by the lower rate of infusion. Arachidonic acid infusion (160 micrograms X kg-1 X min-1) raised renal blood flow by 54 +/- 5% at control pressures but exerted no vasoactive effect during ureteral occlusion and renal arterial constriction. We conclude that autoregulatory dilation enhances the stimulatory effects of arachidonic acid on renal PG synthesis. Both increased intrarenal PG concentration and autoregulatory dilation may contribute to enhancement of renin release. The stimulatory effects of arachidonic acid on PG synthesis and renin release are independent of the vasoactive effects of arachidonic acid.     

Effects of blockades of alpha and beta adrenoceptors and dopamine receptors on renal nerve stimulation-induced prostaglandin E2 and renin release in anesthetized dogs

Effects of intrarenal infusions of prazosin (0.7 microgram/kg/min), yohimbine (1 microgram/kg/min), propranolol (4 micrograms/kg/min) and sulpiride (20 micrograms/kg/min) on renal prostaglandin (PG) E2 and renin release in response to renal nerve stimulation (RNS) were examined in anesthetized dogs. RNS (2.5-5 Hz, for 10 min) decreased renal blood flow and increased both PGE2 and renin secretion rates. The blood flow response was inhibited by prazosin but not by other antagonists. Prazosin and propranolol, but not yohimbine or sulpiride, attenuated the renin response. However, none of these antagonists affected the PGE2 response. The results suggest that the RNS-induced renin release is mediated by alpha adrenoceptors, which seem to be alpha-1 type, and beta adrenoceptors, but the RNS-induced PGE2 release is not mediated by these adrenoceptors. Renal dopaminergic component may play no significant role in the RNS-induced PGE2 or renin release.     

Glomerular prostaglandin and thromboxane synthesis in rat nephrotoxic serum nephritis. Effects on renal hemodynamics.

Glomerular arachidonate cyclooxygenation by isolated rat glomeruli was assessed in vitro in antiglomerular basement membrane (anti-GBM) antibody-induced glomerulonephritis by radioimmunoassay for prostaglandins (PG) and thromboxane. After a single intravenous injection of rabbit anti-rat GBM serum, we observed enhancement of glomerular thromboxane B2 (TxB2) synthesis as early as 2 to 3 h with smaller increments in PGF2 alpha, PGE2 and 6-keto-PGF1 alpha synthetic rates. On day 2 of the disease, the glomerular synthesis of TxB2 and, to a lesser extent, PGF2 alpha and PGE2 remained enhanced, whereas on days 8, 11, and 14, TxB2 was the only prostanoid synthesized at increased rates. Glomerular TxB2 synthesis correlated with the presacrifice 24-h protein excretion. 60 min after intravenous infusion of anti-GMB serum, glomerular filtration rate (GFR) decreased (0.66 +/- 0.04 to 0.44 +/- 0.03 ml/min per 100 g, P less than 0.05), without a significant change in renal plasma flow (RPF): 1.97 +/- 0.23 to 1.80 +/- 0.23 ml/min per 100 g) and without a change in glomerular PG synthetic rates. At 2 h, GFR and RPF reached a nadir (0.25 +/- 0.04 and 1.3 +/- 0.1 ml/min per 100 g, respectively) coinciding with a fivefold increment in glomerular TxB2. By 3 h GFR and RPF partially recovered to 0.43 +/- 0.07 and 1.77 +/- 0.20 ml/min per 100 g, respectively, P less than 0.05, despite further increments in TxB2 synthesis. This recovery of GFR and RPF coincided with increments in vasodilatory PG, (PGE2 and PGI2). The thromboxane synthetase inhibitor OKY-1581 markedly inhibited platelet and glomerular TxB2 synthesis and preserved GFR at 1, 2, and 3 h. Another thromboxane synthetase inhibitor, UK-38485, also completely inhibited platelet and glomerular TxB2 synthesis and prevented decrements of GFR at 2 and 3 h. A cyclooxygenase inhibitor, ibuprofen, inhibited platelet TxB2 and PGE2 synthesis and significantly reduced glomerular PGE2 but not TxB2 synthesis. In the ibuprofen-treated rats, the partial recoveries of GFR and RPF at 3 h were attenuated. The in vitro glomerular TxB2 synthesis correlated inversely with the presacrifice GFR and filtration fraction. These observations indicate that in anti-GBM nephritis there is enhanced synthesis of TxA2 and PG in the glomerulus that mediate changes in renal hemodynamics.     

Effects of 1-Sar-8-Ile-angiotensin II on urinary prostaglandin excretion in patients with essential hypertension

To investigate the interaction between the renin angiotensin aldosterone system and the renal prostaglandin (PG), urinary excretion of PGE, urinary excretion of main urinary metabolite (MUM) of PGF2a, urinary excretion of aldosterone, and plasma renin activity were measured before and after infusion of 1-Sar-8-Ile-Angiotensin II, a specific competitive inhibitor of angiotensin II, in 18 patients with essential hypertension under normal and low sodium diets. The values of urinary sodium excretion in these patients before the infusion of the peptide were 160.8 +/- 13.3 and 27.0 +/- 2.7 mEq per day on normal and low sodium diet, respectively. On normal sodium diet, urinary excretion of PGE was found to correlate with the level of plasma renin activity before the infusion (r = 0.6977, p less than 0.01), and it was decreased slightly from 0.37 +/- 0.05 ng/min to 0.26 +/- 0.04 ng/min after the infusion of the antagonist. On low sodium diet, urinary excretion of PGE was not significantly changed by the infusion of the peptide and showed no correlation with the level of plasma renin activity before the infusion, while urinary excretion of PGE showed a significant correlation with the excretion of urinary aldosterone (r = 0.6719, p less than 0.02). Excretion of PGF2aMUM decreased after the infusion of this peptide on both sodium diets, but the changes were not statistically significant. The present data suggest that angiotensin II influences the synthesis or release of renal PG in patients with essential hypertension on normal sodium diet, but not when they are on low sodium diet.     

New mechanisms of a positive effect of curantyl in chronic nephritis

The effects of curantyl (dipiridamole) on the excretion of prostaglandins E2 and F2 alpha (PGF2 alpha and PGF2 alpha) and renal hemodynamics (RHD) were studied in patients with hypertensive nephritis in an acute test and during prolonged (up to 21 mos) single-agent therapy. In the acute test curantyl increased PG excretion in 15 out of 18 patients by 86.8 +/- 17.6%, mainly at the expense of PGE2 (133.2 +/- 33.1%), and renal blood flow in 11 out of 12 patients by 32.1 +/- 7.7%. During prolonged therapy curantyl also raised PGE2 excretion and improved RHD (raised renal blood flow, glomerular filtration and decreased renal vascular resistance). Besides, during prolonged single-agent therapy curantyl reduced renin plasma activity, increased circulating blood volume, insignificantly reduced BP, and possessed an antiproteinuric and antihematuric effect. It is concluded that curantyl can stimulate PG renal biosynthesis improving RHD in hypertensive nephritis that can have a beneficial effect on a course of this disease.     

Sulindac is not renal sparing in man

We investigated the claimed renal-sparing effect of the cyclooxygenase inhibitor sulindac. Fifteen normal women following a diet of 50 mEq salt a day were randomly assigned to 5 days of either placebo, sulindac, 200 mg b.i.d., or indomethacin, 25 mg q.i.d., after first serving as their own controls. Renal effects were assessed by the excretion rate of prostaglandin (PG) E2 (an index of renal PG synthesis), sodium balance, plasma renin activity (PRA), and the response to furosemide. Systemic effects were assessed by collagen-induced platelet aggregation and thromboxane B2 formation and by the urinary excretion of a systemically formed metabolite of PGF2 alpha (PGF-M). Both sulindac and indomethacin resulted in a positive sodium balance and a reduction in 24-hour urinary PGE2 excretion (range -49% to -86%). Basal PRA was decreased by indomethacin only, but the increases in PRA and in urinary PGE2 excretion in response to furosemide were inhibited by both sulindac and indomethacin. Sulindac reduced the natriuresis induced by furosemide, and indomethacin reduced the rise in inulin clearance after furosemide. Thus the two nonsteroidal anti-inflammatory drugs had similar effects on the kidney. Indomethacin had a greater effect than sulindac on the inhibition of collagen-induced platelet aggregation and thromboxane synthesis and the two drugs had equivalent effects on the reduction of PGF-M excretion. Peak plasma drug concentration of indomethacin (1.9 +/- 0.4 microgram/ml) and sulindac sulfide (7.7 +/- 1.9 microgram/ml) were those associated with clinical efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of short-term beta blockade on blood pressure, plasma thromboxane B2, and plasma and urinary prostaglandins E2 and F2 alpha in normal subjects

The effect of short-term beta blockade with the nonselective antagonist propranolol and with the cardioselective antagonist metoprolol on arterial blood pressure, heart rate, serum renin activity, plasma thromboxane (Tx) B2 (the stable metabolite of TxA2). and plasma and urinary prostaglandin (PG) E2 and F2 alpha levels were examined in 11 normal subjects. After propranolol (160 mg by mouth), supine and standing mean arterial pressure (MAP) fell from 82 +/- 2 and 88 +/- 4 mm Hg to 71 +/- 3 (P less than 0.001) and 78 +/- 3 mm Hg (P less than 0.01) within 13 hr. MAP fell from 78 +/- 2 and 88 +/- 3 mm Hg to 72 +/- 2 (P less than 0.025) and 80 +/- 2 mm Hg (P less than 0.01) after metoprolol (200 mg by mouth). These blood pressure effects were associated with beta blockade; both drugs induced reduction in heart rate and serum renin activity and the reductions were of the same order. Propranolol and metoprolol also reduced plasma TxB2 levels by 33% (P less than 0.005) and 46% (P less than 0.05), but plasma and urinary PGE2 and PGF2 alpha levels were not changed by either drug. These findings suggest that changes in PGE2 or PGF2 alpha levels are unlikely to contribute to the short-term hypotensive effects of propranolol or metoprolol in normal subjects. Alterations in the synthesis or metabolism of the potent vasoconstrictor and proaggregatory drug TxA2, however, may be involved in the hypotensive, cardioprotective, and antiplatelet effects of beta-adrenergic antagonists.     

Effect of thrombin on proliferation, contraction and prostaglandin production of rat glomerular mesangial cells in culture.

The effect of thrombin on mesangial cell function was investigated. Thrombin caused a dose-dependent increase in [3H] thymidine incorporation (EC50 = 0.36 +/- 0.09 U/ml), intracellular calcium [(Ca++)i] mobilization (EC50 = 1.9 +/- 0.5 U/ml) and prostaglandin E2 (PGE2) production (EC50 = 0.25 +/- 0.02 U/ml) in rat glomerular mesangial cells. These effects were blocked by the thrombin inhibitor, hirudin (KB = 10.4 +/- 0.2 nM). The role of (Ca++)i mobilization and arachidonate metabolism in thrombin-stimulated proliferation was tested by the addition of the calcium channel blocker, nifedipine, and the cyclooxygenase inhibitor, indomethacin, to mesangial cell cultures. Indomethacin, at doses that completely inhibited the thrombin-mediated production of PGE2, had no significant effect on proliferation. The Ca++ channel blocker, nifedipine, inhibited both PGE2 production and [3H] thymidine incorporation in a dose-dependent fashion, but only at concentrations considered nonspecific. In addition to its effects on PGE2, thymidine incorporation and Ca++ mobilization, thrombin caused mesangial cell contraction as determined by a substrate distortion technique. This effect was not inhibited by indomethacin. These results indicate that thrombin can alter mesangial cell function in vitro.     

Importance of renal prostaglandins in control of renal function after chronic ligation of the common bile duct in dogs

To explore the possible vasoregulatory role of renal prostaglandins during liver disease, excretory rates of PGE2, PGF2 alpha, and a metabolite of PGI2, 6k-PGF1 alpha, were determined before and after chronic ligation of the common bile duct in 23 dogs. Bile duct ligation for 50 +/- 3.7 days (mean +/- SEM) significantly increased serum bilirubin and alkaline phosphatase. PGE2, PGF2 alpha, and 6k-PGF1 alpha excretion rates were significantly (p less than 0.01) increased following chronic bile duct ligation, by approximately 100%, 80%, and 500%, respectively, with similar increments in both ascitic and nonascitic animals. In 10 sham-ligated animals, PGE2, PGF2 alpha, and 6k-PGF1 alpha excretion rates were unchanged. In 6 dogs sequential measurements of urine prostaglandins indicated that PGE2 and 6k-PGF1 alpha excretion were significantly increased at 2, 4, and 6 weeks after ligation, whereas the increase in PGF2 alpha excretion was not significant until 6 weeks. Indomethacin (2 mg/kg) reduced prostaglandin excretion by 65% to 90% and significantly increased arterial pressure, decreased glomerular filtration rate and renal blood flow, and increased renal vascular resistance from 0.53 +/- 0.09 to 0.90 +/- 0.13 mm Hg/ml/min. Fractional renal blood flow, assessed by microspheres, was disproportionately reduced in the inner cortex after prostaglandin inhibition in the chronic bile duct ligation group. Indomethacin did not significantly alter renal function in sham animals, despite comparable reductions in prostaglandin excretion. These data demonstrate that, in dogs with experimental liver disease produced by chronic bile duct ligation, renal prostaglandin synthesis is increased, and the enhanced synthesis of vasodilatory prostaglandins serves to maintain renal blood flow and glomerular filtration rate.     

Renal and femoral vascular responses to endothelin-1 in dogs: role of prostaglandins

Vascular responses to endothelin were examined with special reference to prostaglandins (PGs). Intrarenal infusion of endothelin (ET)-1 (1-5 ng/kg/min) to dogs caused a transient increase followed by a sustained decrease in renal blood flow, with no change in blood pressure or heart rate. Renal secretion rates of PGE2 and I2 (determined as 6-keto PGF1 alpha) were increased with ET, dose-dependently, and the intrarenal infusion of ET (5 ng/kg/min) elevated the systemic arterial concentration of 6-keto PGF1 alpha from 26 +/- 5 to 83 +/- 14 pg/ml. Because this increase in PG secretion was not affected by the platelet activating factor antagonist, CV 6209, it is unlikely that ET-induced renal PG production was platelet activating factor-mediated. Pretreatment with aspirin abolished completely the increased PG secretion elicited by ET and potentiated the ET-induced reduction renal blood flow. Intrafemoral infusion of ET (5 ng/kg/min) also induced an initial increase followed by a gradual decrease in femoral blood flow, without any increase in PG secretion from the hindlimb. Aspirin had no effects on the femoral hemodynamic action of ET. In addition, initial transient increases in either renal or femoral blood flow by endothelin were not affected by aspirin. Thus, the ET-induced production of renal PGs counteracts the renal vasoconstrictor action of ET, an event in marked contrast to the lack of any apparent involvement of PGs in the femoral hemodynamic action of ET. The ET-induced transient vasodilation shows no apparent relation to the cyclooxygenase products.     

Conditions for humoral alpha-adrenoceptor stimulation of renin release in anaesthetized dogs

To examine whether an alpha-adrenergic agonist, methoxamine, influences renin release solely by its haemodynamic effect, experiments were performed in anaesthetized dogs with denervated kidneys. Methoxamine was infused intrarenally at rates which reduced renal blood flow (RBF) by 30-40%. At control blood pressure, renin release rose during infusion of methoxamine from 1.4 +/- 0.7 to 31 +/- 11 microgram/min. A beta-adrenergic stimulator, isoproterenol, did not increase renin release significantly when administered alone into the renal artery, but doubled the effect of methoxamine infusion: at control blood pressure renin release rose from 0.5 +/- 0.3 to 71 +/- 17 microgram/min during combined infusion of isoproterenol and methoxamine. Mechanical constriction of the renal artery left RBF unaltered down to a renal perfusion pressure of 90 +/- 4 mmHg during methoxamine infusion, whereas the lowest autoregulating pressure in control experiments averaged 60 +/- 5 mmHg. At renal infusion pressure below the range of autoregulation, renin release was not further increased by intrarenal infusion of methoxamine. Isoproterenol infusion at low renal perfusion pressure doubled renin release, which was not significantly altered by additional infusion of methoxamine. The stimulatory effect of methoxamine on renin release at control blood pressure could be diminished but not prevented by infusing 2.9% NaCl intravenously in large amounts. These data indicate that methoxamine induces autoregulated dilation of afferent arterioles by disproportionate vasoconstriction on pre-afferent arteries. Thereby afferent arterioles are conditioned for stimulation of renin release by isoproterenol.     

Failure of chronic aspirin treatment to inhibit urinary prostaglandin excretion in spontaneously hypertensive rats: comparison with indomethacin and flurbiprofen

The inability of chronic treatment with aspirin to cause sustained inhibition of urinary prostaglandin (PG) excretion observed previously prompted us to compare the effects of 9-day treatment of spontaneously hypertensive rats with aspirin, 200 mg/kg/day s.c., flurbiprofen, 2.5 mg/kg/b.i.d. s.c. and indomethacin, 2.5 mg/kg/b.i.d. s.c. on the excretion rate of radioimmunoassayable PGE2 and PGF2 alpha. Conversion of 1-[14C]arachidonic acid and the release of PGs from endogenous substrate by the renal papilla were also examined. In vehicle-treated control rats, PGF2 alpha excretion ranged from 32.2 +/- 6.2 (mean +/- S.E.M.) to 41.6 +/- 7.3 ng/6 h, and was 2- to 4-fold higher than that of PGE2. Within 6 h of administration all three drugs reduced excretion of PGF2 alpha and PGE2 to less than 20% and 35% of control rats, respectively. Thereafter, PGF2 alpha and PGE2 excretion in aspirin-treated rats returned to values similar to the vehicle-treated group, whereas inhibition of PG excretion in indomethacin and flurbiprofen groups was sustained. Urine volume was doubled by aspirin throughout the study. In contrast, urine volume in flurbiprofen- and indomethacin-treated rats was unaffected. Paradoxically, metabolism of 1-[14C]arachidonic acid to PGs by renal papilla dissected on day 10, 2 to 4 h after the last drug dose, was reduced markedly by aspirin as was the release of immunoreactive PGs but was unaffected by flurbiprofen or indomethacin. The failure of long-term aspirin treatment to inhibit urinary PG excretion and the disparity between in vivo and ex vivo indices of PG release emphasize the need to verify their intended action by measuring PGs in biological fluids.     

Longitudinal study of renal prostaglandin excretion in cirrhotic rats: relationship with the renin-aldosterone system

1. A cross-sectional study (protocol A) was performed in 19 rats with cirrhosis, induced by carbon tetrachloride (CCl4), and ascites and in 10 control animals to assess renal prostaglandin (PG) excretion in experimental cirrhosis. In an additional group of animals, including nine rats chronically exposed to CCl4 (CCl4 rats) and six control rats, a longitudinal study (protocol B) was performed to investigate the temporal relationship between changes in renal PG excretion, the renin--aldosterone system and renal function. 2. Urinary PG excretion was assessed by specific radioimmunoassay of PGE2, PGF2 alpha, 6-keto-PGF1 alpha and thromboxane (TX) B2 after extraction with octadecyl silica cartridges and h.p.l.c. purification. Recoveries for each prostanoid (61 +/- 8% for PGE2, 64 +/- 12% for PGF2 alpha, 65 +/- 11% for 6-keto-PGF1 alpha and 66 +/- 17% for TXB2) were determined in every sample by adding tritiated standards, and the final values were corrected according to the individual recoveries. 3. Cirrhotic rats with ascites in protocol A showed a significantly higher plasma renin and aldosterone concentrations and urinary excretion of 6-keto-PGF1 alpha and TXB2 than did control animals. Urinary excretion of PGE2 and PGF2 alpha, however, was significantly reduced in cirrhotic animals as compared with controls. 4. In CCl4 rats included in protocol B, there was a close chronological relationship between the activation of the renin-aldosterone system, as estimated by urinary aldosterone excretion, the onset of sodium retention and the increase in urinary excretion of 6-keto-PGF1 alpha and TXB2. The urinary excretion of PGE2 and PGF2 alpha in CCl4 rats was reduced throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)     

Conditions for augmentation of renin release by theophylline

Isoproterenol, dopamine, glucagon and dibutyryl cyclic AMP (DB-cAMP) increase renin release at low but not at control blood pressure. These findings suggest that autoregulated afferent arteriolar dilation is a prerequisite of renin release mediated by intracellular generation of cyclic AMP. To examine this hypothesis further the effects on renin release of theophylline, which would maintain high intracellular concentration of cAMP by inhibiting phosphodiesterase, were studied in anesthetized dogs. After inhibiting beta-adrenergic stimulation with propranolol, theophylline increased renin release significantly from 0.7 +/- 0.2 to 1.8 +/- 0.7 micrograms/min at control blood pressure and from 23 +/- 4 to 41 +/- 5 micrograms/min at a renal perfusion pressure of about 50 mmHg. The greater effect at low blood pressure occurred despite adjustment of the infusion rate of theophylline to keep arterial plasma concentration of theophylline unaltered. Isoproterenol infusion at low blood pressure raised renin release from 41 +/- 11 to 76 +/- 19 micrograms/min before and 54 +/- 13 to 108 +/- 31 micrograms/min during continuous infusion of theophylline. The renin release response to infusion of theophylline at low blood pressure was not enhanced by DB-cAMP infusion. We conclude that arteriolar dilation provides a condition for stimulation of renin release during the theophylline infusion. Theophylline infusion may augment the effect of isoproterenol on renin release by delaying the intracellular degradation of cAMP.     

Enhancement of prostaglandin output during activation of beta-1 adrenoceptors in the isolated rabbit heart

The purpose of this study was to elucidate the type of adrenoceptor that mediates the effect of adrenergic stimuli on prostaglandin (PG) synthesis in the isolated rabbit heart and to determine the relationship of the released PGs to the mechanical changes elicited by catecholamines and stimulation of the cardiac sympathetic nerves. The output of 6-keto PGF1 alpha, PGE2 and PGF2 alpha was increased by electrical stimulation of the sympathetic nerves, norepinephrine, isoproterenol, dobutamine and angiotensin II, but not by phenylephrine or isoetharine. Propranolol or atenolol, but not phentolamine or butoxamine, blocked the output of PGs elicited by adrenergic stimuli. Indomethacin prevented the increase in PG formation caused by all stimuli. Moreover, the adrenergically induced release of PGs was not related to changes in heart rate, systolic tension or vascular tone elicited by the adrenergic stimuli. These data indicate that the adrenergically induced release of PGs in the isolated rabbit heart is due to the activation of beta-1 adrenoceptors and is independent of the mechanical effects produced by the adrenergic stimuli.     

Differential effects of 20-hydroxyeicosatetraenoic acid on intrarenal blood flow in the rat

We recently demonstrated that endothelin-1-induced medullary vasodilation despite a potent cortical vasoconstriction in the rat kidney may be accounted for by 20-hydroxyeicosatetraenoic acid (20-HETE) production. This study characterized the effects of 20-HETE and its metabolites, 20-hydroxy prostaglandin E(2) (20-OH PGE(2)) and 20-hydroxy prostaglandin F(2alpha) (20-OH PGF(2alpha)), and the contribution of nitric oxide (NO) and prostanoids to the changes evoked in cortical blood flow (CBF) and medullary blood flow (MBF). We tested the hypothesis that 20-HETE produces qualitatively different regional hemodynamic effects in the kidney with 20-OH PGF(2alpha) or 20-OH PGE(2), accounting for the vasoconstriction or vasodilation, respectively, in the cortex and medulla. Renal intra-arterial infusion of 1, 2.5, 5, and 10 ng/min 20-HETE decreased CBF by 10 +/- 3, 24 +/- 4, 40 +/- 7, and 58 +/- 9 perfusion units (PU), respectively, but increased MBF by 4 +/- 2, 16 +/- 4, 27 +/- 3, and 41 +/- 10 PU, respectively. 20-OH PGF(2alpha) mimics the effects of 20-HETE, as did PGF(2alpha). However, 20-OH PGE(2) increased both CBF and MBF, as did PGE(2). Indomethacin (5 mg/kg) blunted the effects of 20-HETE but not that of 20-OH PGE(2) and 20-OH PGF(2alpha). However, SQ29548 ([1S-[1alpha,2alpha(Z),3alpha,4alpha]]-7-[3[[2-[(phenylamino)carbonyl[hydrazino]methyl]-7-oxabicyclo]2.2.1]hept-2-yl]-5-heptenoic acid) (0.1 mg/kg), a prostaglandin H(2)/thromboxane A(2) receptor antagonist, blunted the cortical and medullary hemodynamic effects elicited by 20-HETE, 20-OH PGE(2), 20-OH PGF(2alpha), and PGF(2alpha) but not PGE(2). N(omega)-L-nitro arginine methyl ester (5 mg/kg), the inhibitor of NO synthase, exacerbated the cortical constrictor effects of 20-HETE and 20-OH PGF(2alpha) without affecting the medullary perfusion produced by 20-HETE or its metabolites. These findings suggest that 20-HETE, through its hydroxyl metabolites, produced differential effects in the kidney. The medullary perfusion appears to be independent of NO.     

Histamine contraction of isolated human airway muscle preparations: role of prostaglandins

Histamine concentration-effect curves were obtained using either an individual or cumulative dosing method. The maximal response to histamine in bronchial preparations using the individual dosing protocol was 0.25 +/- 0.03 g/mm2 and similar results were obtained using the cumulative method (0.24 +/- 0.03 g/mm2). The sensitivity (pD2 value) of isolated human bronchial muscle preparations was comparable for both the individual and cumulative methods (5.71 and 5.16, respectively). Prostaglandin (PG) E2 and PGF2 alpha contracted isolated human bronchial muscle preparations and the pD2 values were 5.64 and 5.59, respectively. PGE2 did not relax bronchial muscle preparations contracted with histamine (50 microM). At high concentrations prostacyclin (3 microM) relaxed histamine-contracted bronchial tissues but this effect was quite variable. Indomethacin (1.7 microM) did not affect basal tone in bronchial tissues. Isolated human bronchial preparations which were contracted maximally with histamine always released measurable quantities of PGs. In some experiments the rat stomach strip was used to detect the presence of these substances before and subsequent to the indomethacin (1.7 microM) treatment. The use of radioimmunoassay for PGE2 and PGF2 alpha confirmed these bioassay results. In a large number of experiments (18 preparations from 9 individual lung samples) the baseline production of PGs was PGE2, 22.9 +/- 2.8 pg/mg of tissue and PGF2 alpha, 11.9 +/- 2.5 pg/mg of tissue. Subsequent to histamine stimulation the quantities of PGs released were PGE2, 72.4 +/- 7.6 pg/mg of tissue and PGF2 alpha, 40.9 +/- 7.3 pg/mg of tissue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Positive inotropic effect and phosphoinositide breakdown mediated by arachidonic acid and prostaglandin F2 alpha

We investigated the mechanism of arachidonate- and prostaglandin-induced alteration of cardiac contractile activity in isolated rat left ventricular papillary muscles. Superfusion with 10(-6) to 10(-4) M arachidonic acid resulted in a slow developing positive inotropic effect (PIE) in a concentration-dependent manner. The PIE was abolished by pretreatment with 10(-5) M indomethacin. Prostaglandin (PG) F2 alpha also produced a significant PIE in a concentration-dependent manner, but the EC50 value was approximately 2 orders of magnitude lower and the maximum contractile response was 2-fold higher than those of arachidonate. PGE2 and PGI2 were without an effect on contractile force at concentrations ranging from 10(-9) to 10(-6) M. Both arachidonate and PGF2 alpha provoked slow responses in the partially depolarized muscles in a time course similar to that of development in the PIE. Neither arachidonate nor PGF2 alpha affected tissue levels of cyclic AMP and cyclic GMP, but these molecules increased accumulations of [3H]inositol phosphates (IPs) in a concentration-dependent manner similar to that observed for their PIE. The enhanced accumulation of [3H]IPs induced by arachidonate was abolished by pretreatment with 10(-5) M indomethacin. Although an increase in [3H]IP level was relatively rapid in PGF2 alpha-treated tissues, maximum accumulations of [3H]IPs were identical between arachidonate- and PGF2 alpha-treated tissues. Thus, for comparable increases in [3H]IPs, there was a greater PIE with PGF2 alpha than with arachidonate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of prostaglandin E in the biphasic fever response to endotoxin

Biphasic fevers were induced in sheep with intravascular infusions or injections of 4-10 μg (80-200 ng/kg) of endotoxin, whereas monophasic fevers were obtained with doses of 1-2/μg (20-40 ng/kg). A marked increase in arterial blood pressure invariably accompanied the onset of fever; the latency of responses to the higher and lower doses of endotoxins averaged 26 min and 42 min, respectively. Prostaglandin (PG) assays of plasma from the carotid artery and jugular vein during fever episodes revealed a surge of PGE and PGF coincident with the pressor response and the first phase of fever, but PG were not detected in plasma samples taken throughout the second phase of fever. PG measurements of arterial and venous plasma collected at a distal site (hind limb) showed a similar surge of PGE and PGF in association with the early fever response, indicating that intravascular PG synthesis and release represents a generalized systemic response to circulating endotoxin. Carotid arterial infusions of PGE(2) produced immediate monophasic fevers and pressor responses, whereas PGD(2) infusions produced an immediate pressor effect but no fever. Infusions of PGF(2α) or prostacyclin, however, evoked neither fever nor pressor effects. Intracarotid infusions of leukocyte pyrogen (LP) caused monophasic fevers with latent periods of 15-20 min but pressor responses were not seen and neither PGE nor PGF were detected in plasma samples from the carotid artery or jugular vein before or during fever. Indomethacin, a potent inhibitor of arachidonic acid metabolism, blocked fever responses to endotoxin and to LP. These findings implicate PGE as the mediator of the early phase of endotoxin fever and imply a role for another pyrogenic metabolite ofarachidonic acid in the mediation of the second phase of fever, i.e., the phase associated with circulating LP. It is possible that both pyrogenic metabolites are generated within the vascular compartment, reaching thermoregulatory centers of the brain by transfer across the blood-brain interface.