A fast-acting humoral factor mediates pressor hyperresponsiveness in deoxycorticosterone-salt rabbits

Six rabbits were sham operated and were given water to drink (sham-water group); six additional rabbits were sham operated and were given saline to drink (sham-salt group); another six rabbits received an implant of deoxycorticosterone (DOCA) and were given water to drink (DOCA-water group); a final group of six rabbits received implants of DOCA and were given saline to drink (DOCA-salt group). Two weeks later, all four groups of rabbits had approximately the same mean arterial pressures, and the sham-salt, DOCA-water, and DOCA-salt groups all had plasma renin activity values less than the sham-water group. The DOCA-salt group had greater pressor responses to norepinephrine (NE) at several doses than did the other three groups of rabbits. In another group of six sham-water and six DOCA-salt rabbits, measurements of cardiac output before and during infusions of NE at 800 ng/min/kg body wt revealed no changes in cardiac output before or during NE infusion, but the DOCA-salt group had significantly greater increases in mean arterial pressure and total peripheral resistance during NE than did the sham-water group. In another group of six DOCA-salt rabbits, the pressor response to several doses of NE were determined during infusion of the angiotensin II (AII) antagonist, [Sar1, Ile8] AII; this AII antagonist failed to alter the enhanced pressor responses to NE. A final experiment examined pressor responses to NE in six normal rabbits before and after cross circulation of blood with six DOCA-salt rabbits. After blood cross circulation the normal rabbits had exaggerated pressor responses to NE at 5, 15, and 30 min, but not at 60 min. Similar cross-circulation experiments between six pairs of normal rabbits did not show any transfer of pressor hyperresponsiveness. These studies indicated that pressor and vascular hyperresponsiveness in DOCA-salt rabbits is conveyed by a fast-acting hormonal factor and that AII probably is not involved in mediating this hyperresponsiveness.     

Pressor responsiveness in renal prehypertensive rabbits with a denervated kidney

Norepinephrine was infused iv at several doses into four groups of conscious rabbits (six per group), and the pressor responses were recorded. The groups were 3-day sham-operated rabbits; 3-day, two-kidney rabbits with unilateral renal artery stenosis (RAS); 3-day, two-kidney rabbits with unilateral renal denervation; and 3-day, two-kidney rabbits with unilateral renal denervation plus RAS of the denervated kidney. The rabbits with RAS of an innervated kidney and those with RAS of a denervated kidney had the same pressor responses to norepinephrine, which were greater than the pressor responses in the sham-operated rabbits or in the rabbits with a denervated kidney but without RAS. Four additional groups of similarly prepared rabbits were infused with norepinephrine at 800 ng/min/kg body wt, and mean arterial pressure and cardiac output were determined before and during norepinephrine infusion. The rabbits with RAS of an innervated or of a denervated kidney had greater increases in total peripheral resistance as well as in mean arterial pressure during norepinephrine infusion than did the two groups of rabbits without RAS. This indicated that the rabbits with RAS also had increased vascular responses to norepinephrine. The concentration of norepinephrine in six denervated kidneys was extremely low as compared to that of six innervated kidneys. Because renal denervation did not diminish pressor and vascular hyperresponsiveness in 3-day RAS rabbits, the signal that originates in the kidney following RAS and that results ultimately in pressor and vascular hyperresponsiveness is not mediated by renal nerves.     

Role of baroreflex in the pressor response of rats with hypertension developed by renal artery stenosis

We examined the interrelationships between the pressor response to the administration of norepinephrine and arginine vasopressin and baroreflex function in rats with hypertension of two days' duration induced by heminephrectomy and a clip placed on the right renal artery (2-day clipped rats). Mean arterial pressure was higher in the 2-day clipped rats than in heminephrectomized rats without clips (sham-operated rats). The pressor response in the 2-day clipped rats to both agents increased as compared to the sham-operated rats. This hyperresponsiveness was attenuated by administering an angiotensin II antagonist, [1-Sar, 8-Ile] angiotensin II. Baroreflex sensitivity was studied by measuring changes in arterial pressure and pulse interval in response to the injection of phenylephrine. Baroreflex sensitivity was not decreased but markedly increased in the 2-day clipped rats and unaffected by infusing the angiotensin II antagonist. These results provide evidence that 1) in the 2-day clipped rats there are exaggerated pressor responses to vasoconstrictors; 2) the hyperresponsiveness is not causally related to the change of baroreflex sensitivity; and 3) angiotensin II plays a significant role in the increased pressor responses; however, the baroreflex mechanism is not involved in attenuation of the hyperresponsiveness by the angiotensin II antagonist.     

Effect of angiotensin ii and norepinephrine on release of prostaglandins E2 and I2 by the perfused rat mesenteric artery

Prostaglandin E2 (PGE2) and 6 keto-PGF1 alpha, the stable metabolite of prostacyclin (PGI2), have been measured in the effluent of perfused rat mesenteric arteries by the use of a sensitive and specific radioimmunoassay (RIA) method. The PGE2 and 6 keto-PGF1 alpha were continuously released by the unstimulated mesenteric artery over a period of 145 min. After 100 min of perfusion the release of PGE2 and 6 keto-PGF1 alpha was 45.1 +/- 8.4 pg/min and 254 +/- 75 pg/min respectively, which is in accord with the general belief that PGI2 is the major PG synthesized by arterial tissue. Angiotensin II (AII) (5 ng/ml) induced an increase of PGE2 and 6 keto-PGF1 alpha release without changing the perfusion pressure. The effect of norepinephrine (NE) injections on release of PGs depended on the duration of the stabilization period. The changes of perfusion pressure induced by NE were not related to changes in release of PGs. Thus, it seems that the increase of PG release induced by AII and NE was due to a direct effect of the drugs on the vascular wall. This may represent an important modulating mechanism in the regulation of vascular tone.     

Efficacy of intravenous infusion of prostacyclin (PGI2) or prostaglandin E1 (PGE1) in augmentation of skin flap blood flow and viability in the pig

The dose-response effects of 6-h intravenous infusion of PGI2 (0, 5, 10, 25 or 75 ng/kg/min) or PGE1 (0, 25, 50, 100 or 300 ng/kg/min) on skin hemodynamics and viability were studied in 4 x 10 cm random pattern skin flaps (n = 24) raised on both flanks of the pig. Infusion of PGI2 or PGE1 was started immediately after intravenous injection of a loading dose 30 min before skin flap surgery. PGI2 infusion significantly (P less than 0.05) increased the total skin flap capillary blood flow at the dose of 10 ng/kg/min, compared with the control. However, the distance of blood flow along the skin flap from the pedicle to the distal end, i.e. perfusion distance, was not increased. Consequently, the length and area of skin flap viability was also not significantly increased. The effect of PGI2 infusion on skin blood flow was biphasic. Specifically, higher doses (greater than or equal to 25 ng/kg/min) of intravenous PGI2 infusion produced no beneficial effect on the skin flap capillary blood flow. PGI2 infusion at the dose of 10 or 75 ng/kg/min did not significantly increase plasma renin activities or plasma levels of norepinephrine compared with the control, therefore the biphasic effect of PGI2 on skin flap blood flow was not related to circulating levels of norepinephrine or angiotensin. Intravenous infusion of PGE1 did not produce any therapeutic effect on the skin capillary blood flow in the random pattern skin flaps at all doses tested. At the dose of 300 ng/kg/min, the mean arterial blood pressure was 17% lower (P less than 0.05) than the control, but the skin capillary flow still remained similar to the control. It was concluded that intravenous infusion of PGI2 or PGE1 was not effective in augmentation of distal perfusion or length of skin viability in the porcine random pattern skin flaps. Drug treatment modalities for prevention or treatment of skin flap ischemia is discussed.     

Release of prostaglandins by the mesenteric artery of the renovascular and spontaneously hypertensive rat

The release of prostaglandin E2 (PGE2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), the stable metabolite of prostacyclin (PGI2), by the perfused mesenteric arteries of renal and spontaneously hypertensive rats (SHR) have been measured. Unstimulated mesenteric arteries from two-kidney one-clip hypertensive rats (2K-1C) released 1.6 times as much PGE2 and 2.7 times as much 6-keto-PGF1 alpha as those of control rats. The release of PGE2 by mesenteric arteries from one-kidney one-clip hypertensive rats (1K-1C) was not significantly different from that of uninephrectomized normotensive rats, but the release of 6-keto-PGF1 alpha was 3.5 times higher in the former than in the latter. Norepinephrine (NE) induced a dose-related increase in perfusion pressure, in PGE2, and 6-keto-PGF1 alpha release in all four groups. However, its effect on the release of PGE2 was more pronounced in 2K-1C than in sham-operated rats. There was no difference between 1K-1C and the uninephrectomized group. The effect of NE on the release of 6-keto-PGF1 alpha was significantly higher for both renal hypertensive groups. These results indicate that the release of PGE2 is more dependent on the loss of renal mass than on hypertension, while the reverse applies to the release of 6-keto-PGF1 alpha. Unstimulated mesenteric arteries from SHR released less PGE2 and less 6-keto-PGF1 alpha than those of Wistar-Kyoto normotensive rats (WKY), but the release was not significantly different from Wistar rats. Under NE stimulation, WKY mesenteric arteries showed almost no increase in release of PGs. Compared with those of Wistar rats, SHR mesenteric arteries showed a greater pressor response to NE, a lower PGE2 release, and the same release of 6-keto-PGF1 alpha. These findings reveal the difficulty of selecting an appropriate control group in studies involving SHR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Corticosteroids inhibit prostaglandin release from perfused mesenteric blood vessels of rabbit and from perfused lungs of sensitized guinea pig.

Infusion of norephinephrine (NE) (1 - 3 mug/ml/min) into the isolated mesenteric vascular preparation of rabbit resulted in a rise in perfusion pressure, which was associated with the release of prostaglandin E-like substance (PGE) at a concentration of 2.81 +/- 0.65 ng/ml in terms of PGE2. Indomethacin (3 mug/ml) abolished the NE-induced release of PGE. Arachidonic acid (0.2 mug/ml) in the presence of indomethacin did not restore the NE-induced release of PGE. Hydrocortisone (10 - 30 mug/ml) and dexamethasone (2 - 5 mug/ml) also inhibited the NE-induced release of PGE. The inhibitory action of both corticosteroids was abolished by arachidonic acid (0.2 mug/ml). Antigen-induced release of a prostaglandin-like substance (PGs) (43.1 +/- 3.8 ng/ml in terms of PGE2 and a rabbit aorta contracting substance (RCS) from perfused lungs of sensitized guinea pigs was completely abolished by indomethacin (5 mug/ml) or by hydrocortisone (100 mug/ml). Indomethacin, however, increased histamine release up to 280% of the control level, which was 470 +/- 54 ng/ml, while hydrocortisone diminished histamine release down to 30% of the control level. A superimposed infusion of arachidonic acid (1 mug/ml) into the pulmonary artery reversed the hydrocortisone-induced blockade of the release of RCS and PGs. It may be concluded that corticosteroids neither inhibit prostaglandin synthetase nor influence prostaglandin transport through the membranes but they do impair the availability of the substrate for the enzyme.     

Effects of prostaglandins E2, I2 and F2α, arachidonic acid and indomethacin on pressor responses to norepinephrine in conscious rats

The effects of prostaglandins E₂ (PGE₂), I₂ (PGI₂) and F₂α (PGF₂α), arachidonic acid and indomethacin on pressor responses to norepinephrine were examined in conscious rats. Intravenously infused PGE₂ (0.3, 1.25 μg/kg/min), PGI₂ (50, 100 ng/kg/min), PGF₂α (1.8, 5.4 μg/kg/min) and arachidonic acid (0.7, 1.4 mg/kg/min) did not change the basal blood pressure. Both PGE₂ and PGI₂ significantly attenuated pressor responses to norepinephrine, whereas PGF₂α significantly potentiated them. Arachidonic acid, a precursor of the prostaglandins (PGs), significantly attenuated pressor responses to norepinephrine. Since the attenuating effect of arachidonic acid was completely abolished by the pretreatment with indomethacin (5 mg/kg), arachidonic acid is thought to exert an effect through its conversion to PGs. On the contrary, intravenously injected indomethacin (0.2–5.0 mg/kg) facilitated pressor responses to norepinephrine in a dose-related manner without any direct effect on the basal blood pressure. These results suggest that endogenous PGs may participate in the regulation of blood pressure by modulating pressor responses to norepinephrine in conscious rats.     

Effects of arginine vasopressin on blood pressure and renal prostaglandin E2 in rabbits.

The role of arginine vasopressin (AVP) in blood pressure regulation in humans and animals is still controversial. The present study was designed to investigate the effects of AVP on blood pressure and the excretion of sodium and prostaglandin (PG) E2 in rabbits. AVP dissolved in 0.01 M acetic acid was infused subcutaneously at a rate of 0.86 ng/kg/min with a miniosmotic pump into 12 New Zealand white rabbits (2.7-3.4 kg), while 10 controls were given vehicle alone. AVP infusion resulted in a 3.5-fold rise in the level of plasma AVP (21.8 +/- 4.4 (SEM) pg/ml) as compared with controls, associated with a significant decrease in the urine volume and urinary excretion of sodium. The PGE2 excretion was increased 1.8-fold after AVP infusion. In the chronic AVP-infused group, blood pressure was not significantly increased, but the acute vascular response to AVP was significantly attenuated without any changes in the vasopressor response to angiotensin II. Preadministration of V1-antagonist completely abolished the vasopressor action of AVP, but not that of angiotensin II, in either group. These results suggest that circulating AVP within physiological range of concentrations may stimulate renal PGE2 synthesis and attenuate the vascular response through vascular V1 receptors without affecting the baroreflex, which may be attenuated through V2 receptors.     

Predominance of prostaglandin D2 and I2 in the rat gastric mucosa--analysis by high-performance liquid chromatography

We have developed a method for measuring prostaglandins (PGs) in rat gastric mucosa by high-performance liquid chromatography (HPLC). The levels of PGD2 and 6-keto-PGF1 alpha, a degradation product of PGI2, were five times higher than those of PGE2 and PGF2 alpha. Oral administration of indomethacin (6 mg/kg body weight) completely abolished the synthesis of all detectable PGs uniformly. These results suggest that endogenous PGs, especially PGD2 and I2, play some roles in the function of the gastric mucosa.     

Factors regulating the production of prostaglandin E2 and prostacyclin (prostaglandin I2) in rat and human adipocytes.

The regulation of PGE2 (prostaglandin E2) and PGI2 (prostaglandin I2; prostacyclin) formation was investigated in isolated adipocytes. The formation of both PGs was stimulated by various lipolytic agents such as isoproterenol, adrenaline and dibutyryl cyclic AMP. During maximal stimulation the production of PGE2 and PGI2 (measured as 6-oxo-PGF1 alpha) was 0.51 +/- 0.04 and 1.21 +/- 0.09 ng/2 h per 10(6) cells respectively. Thus PGI2 was produced in excess of PGE2 in rat adipocytes. The production of the PGs was inhibited by indomethacin and acetylsalicylic acid in a concentration-dependent manner. The half-maximal effective concentration of indomethacin was 328 +/- 38 nM and that of acetylsalicylic acid was 38.5 +/- 5.3 microM. The PGs were maximally inhibited by 70-75% after incubation for 2 h. In contrast with their effect on PG production, the two agents had a small potentiating effect on the stimulated lipolysis (P less than 0.05). The phospholipase inhibitors mepacrine and chloroquine inhibited both PG production and triacylglycerol lipolysis and were therefore unable to indicate whether the PG precursor, arachidonic acid, originates from phospholipids or triacylglycerols in adipocytes. Angiotensin II significantly (P less than 0.05) stimulated both PGE2 and PGI2 production in rat adipocytes without affecting triacylglycerol lipolysis. Finally, it was shown that PGE2 and PGI2 were also produced in human adipocytes, although in smaller quantities than in rat adipocytes. It is concluded that the production of PGs in isolated adipocytes is regulated by various hormones. Moreover, at least two separate mechanisms for PG production may exist in adipocytes: (1) a mechanism that is activated concomitantly with triacylglycerol lipolysis (and cyclic AMP) and (2) an angiotensin II-sensitive, but lipolysis (and cyclic AMP)-independent mechanism.     

The lack of involvement of central nervous system in the antiarrhythmic effects of prostaglandins E2, F2 alpha, and I2 in cat

The role of the central nervous system (CNS) in the antiarrhythmic effects of prostaglandins (PGs) E2, F2 alpha, and I2 was studied by administering each agent into the left lateral cerebral ventricle (i.c.v. administration) of chloralose-anaesthetized cats. The cardiac arrhythmias were produced by intravenous (i.v.) infusion of ouabain (1 microgram/kg/min). The PGs E2, F2 alpha and I2 on i.c.v. administration in the dose range of 1 ng to 10 micrograms failed to inhibit ouabain-induced cardiac arrhythmias. However, when infused i.v., PGE2 (1 microgram/kg/min), PGF2 alpha (5 micrograms/kg/min), and PGI2 (2 micrograms/kg/min) effectively suppressed these arrhythmias. The standard antiarrhythmic drug propranolol (0.5-8.0 mg) on i.c.v. administration also significantly reduced the ouabain-induced cardiac arrhythmias. It is suggested that the CNS is not the site of action of PGs E2, F2 alpha, and I2 in antagonising the ouabain-induced cardiotoxicity in cats.     

Modulation of renal hemodynamics by renal eicosanoids during vasopressor infusions in man

Pressor doses of norepinephrine (NE) (n = 8) and angiotensin II (A II) (n = 5) were infused in normal volunteers to determine whether the systemic administration of vasopressor hormones influence renal eicosanoid production and whether, in turn, the eicosanoids produced could modulate renal hemodynamics and electrolyte excretion. At the doses administered, both pressor substances induced the expected rise in blood pressure, a significant decrease (P less than 0.05) in renal blood flow and a proportionally smaller fall in glomerular filtration rate, resulting in a consistent augmentation in filtration fraction. Fractional sodium excretion was concomitantly reduced. NE infusion produced only slight modifications in urinary prostaglandin (PG)E2, 2,3-dinor-6-keto-PGF1 alpha and thromboxane (TX)B2, while urinary 6-keto-PGF1 alpha and PGF2 alpha were increased by 38% and 176% respectively. The increase in urinary 6-keto-PGF1 alpha (the non-enzymatic degradation product of PGI2, predominantly of cortical origin) was proportional to the level of circulating NE (r = 0.78, P less than 0.05) and to the renal vascular resistance (r = 0.85, P less than 0.01), suggesting an immediate compensatory role for PGI2 in response to the NE-induced pressor stimulus. The renal production of PGE2 and PGF2 alpha (predominantly medullary) was inversely correlated with the filtration fraction: the greater the increase in PGE2 and PGF2 alpha the lower the elevation in filtration fraction or the decline in renal blood flow upon NE administration. All infusion variably stimulated the renal eicosanoid production: PGE2, 41%; PGF2 alpha, 102%; 6-keto-PGF1 alpha, 38%; 2,3-dinor-6-keto-PGF1 alpha, 38%; and TXB2, 25%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intraluteal infusions of prostaglandins of the E, D, I, and A series prevent PGF2 alpha-induced, but not spontaneous, luteal regression in rhesus monkeys

A luteotropic role for prostaglandins (PGs) during the luteal phase of the menstrual cycle of rhesus monkeys was suggested by the observation that intraluteal infusion of a PG synthesis inhibitor caused premature luteolysis. This study was designed to identify PGs that promote luteal function in primates. First, the effects of various PGs on progesterone (P) production by macaque luteal cells were examined in vitro. Collagenase-dispersed luteal cells from midluteal phase of the menstrual cycle (Day 6-7 after the estimated surge of LH, n = 3) were incubated with 0-5,000 ng/ml PGE2, PGD, 6 beta PGI1 (a stable analogue of PGI2), PGA2, or PGF2 alpha alone or with hCG (100 ng/ml). PGE2, PGD2, and 6 beta PGI1 alone stimulated (p less than 0.05) P production to a similar extent (2- to 3-fold over basal) as hCG alone, whereas PGA2 and PGF2 alpha alone had no effect on P production. Stimulation (p less than 0.05) of P synthesis by PGE2, PGD2, and 6 beta PGI1 in combination with hCG was similar to that of hCG alone. Whereas PGA2 inhibited gonadotropin-induced P production (p less than 0.05), that in the presence of PGF2 alpha plus hCG tended (p = 0.05) to remain elevated. Second, the effects of various PGs on P production during chronic infusion into the CL were studied in vivo. Saline with or without 0.1% BSA (n = 12), PGE2 (300 ng/h; n = 4), PGD2 (300 ng/h; n = 4), 6 beta PGI1 (500 ng/h; n = 3), PGA2 (300 ng/h; n = 4), or PGF2 alpha (10 ng/h; n = 8) was infused via osmotic minipump beginning at midluteal phase (Days 5-8 after the estimated LH surge) until menses. In addition, the same dose of PGE, PGD, PGI, or PGA was infused in combination with PGF2 alpha (n = 3-4/group) for 7 days. P levels over 5 days preceding treatment were not different among groups. In 5 of 8 monkeys receiving PGF2 alpha alone, P declined to less than 0.5 ng/ml within 72 h after initiation of infusion and was lower (p less than 0.05) than controls. The length of the luteal phase in PGF2 alpha-infused monkeys was shortened (12.3 +/- 0.9 days; mean +/- SEM, n = 8; p less than 0.05) compared to controls (15.8 +/- 0.5). Intraluteal infusion of PGE, PGD, PGI, or PGA alone did not affect patterns of circulating P or luteal phase length.(ABSTRACT TRUNCATED AT 400 WORDS)     

Antiabortifacient action of dibenzyloxyindanpropionic acid in mice

To evaluate the details of the adrenergic stimulation of urinary prostaglandins in man, ten normal volunteers were given various agonists and antagonists. The effect of 4 hour IV infusions of norepinephrine (NE), NE + phentolamine (PHT), NE + phenoxybenzamine (PHB), NE + prazosin (PZ), isoproterenol (ISO), and PHT alone on urinary PGE2 and PGI2 (6 keto PGF1 alpha) were determined. PGE2 and 6 keto PGF1 alpha were measured by radioimmunoassay from 4 hour urine samples. NE stimulated both PGE2 (196 +/- 40 to 370 +/- 84 ng/4 hrs/g creatinine and 6 keto PGF1 alpha (184 +/- 30 to 326 +/- 36), both p less than 0.01. In contrast, ISO had no effect on either PGE2 or 6 keto PGF1 alpha excretion. Alpha blockade with PHT. PHB, or PZ inhibited the NE induced systemic pressor effect. However, the effect of the alpha blockers on the NE induced stimulation of PGE2 and 6 keto PGF1 alpha varied. PHT did not alter the NE stimulated PGE2 or 6 keto PGF1 alpha release (370 +/- 84 vs. 381 +/- 80) PGE2 and (326 +/- 50 vs. 315 +/- 40) 6 keto PGF1 alpha both p greater than 0.2). PHT alone stimulated only 6 keto PGF1 alpha. PHB and the specific alpha 1 antagonist PZ similarly eliminated the NE induced prostaglandin release. These results suggest that adrenergically mediated urinary prostaglandin release in man is via an alpha receptor with alpha 1 characteristics.     

Bradykinin and not cholecystokinin stimulates exaggerated prostanoid release from the inflamed rabbit gallbladder.

The relationship of bradykinin and cholecystokinin (CCK) to inflamed gallbladder prostanoid synthesis and release was examined in rabbits treated with common bile duct ligation (BDL) for 24 or 72 h. Gallbladders removed from control and BDL groups were incubated in oxygenated Krebs buffer at 37 degrees C (pH 7.4) for 60 min. The slices were then placed every 20 min in vials containing increasing doses of bradykinin (30-3000 ng) or CCK (30-1000 ng). Incubation fluid was analyzed by RIA for 6-keto-prostaglandin (PG)F1 alpha (PGI2 metabolite), PGE2 and thromboxane (TX) B2. Bradykinin stimulated control gallbladder 6-keto-PGF1 alpha and PGE2 release was modest. Gallbladders from 24- and 72-h BDL groups released 3- to 10-fold higher levels of 6-keto-PGF1 alpha and PGE2 (not TXB2) following bradykinin stimulation when compared to controls, which was abolished with indomethacin pretreatment. CCK did not stimulate gallbladder prostanoid release in the control or BDL groups. These data show that bradykinin and not CCK stimulated PGI2 and PGE2 release from inflamed rabbit gallbladder. Increased BDL gallbladder PGI2 release may be prolonged or augmented by bradykinin as gallbladder distention and progressive acute inflammation stimulate local bradykinin formation.     

Effects of moderate short-term potassium depletion in normal humans the role of prostaglandins

The role of prostaglandins (PG) in the effects of potassium (K⁺)depletion was studied in six normal women. A mean K⁺-deficit of 220 mEq was induced with and without concomitant treatment with indomethacin (150 mg/day). Mean serum K⁺ concentration decreased from 4.2 ± (S.E.) 0.1 to 3.2 ± 0.1 mEq/L without indomethacin and from 4.1 ± 0.1 to 3.2 ± 0.1 mEq/L with indomethacin. “Supine” and “upright” plasma renin activity (PRA) and plasma norepinephrine concentration (NE) were unaltered by K⁺ -depletion alone but decreased with indomethacin. Plasma aldosterone (PA) was suppressed during K⁺-depletion (control: 7.2 ± 2.6 ng/dl supine, 19.3 ± 8.1 ng/dl upright; K⁺-depletion: 2.6 ± 0.3 ng/dl supine, 5.5 ± 1.3 ng/dl upright) and was paralleled by a decrease in urinary aldosterone. K⁺-depletion decreased urinary PGE₂ from 667 ± 133 to 343 ± 60 ng/day (P < 0.025) without a change in PGF₂. The dose of exogenous angiotensin II (A II) which increased diastolic blood pressure by 20 mm Hg (pressor dose) was 7.1 ± 1.4 ng/kg/min during control and increased to 11.0 ± 0.7 ng/kg/min during K⁺-depletion (P < 0.05). Indomethacin increased the sensitivity to A II both during control (pressor dose: 4.9 ± 0.6 ng/kg/min) and K⁺- depletion (pressor dose: 6.0 ± 1.0 ng/kg/min). These results indicate that in healthy subjects, moderate short-term K⁺-depletion does not affect PRA or NE but decreases production of aldosterone and PGE₂ by the kidney. The changes in vascular sensitivity to exogenous A II during K⁺-depletion and indomethacin and the decreases in plasma NE and PRA during indomethacin may be explained by changes in vascular vasodilator PG.     

Corticosteroids inhibit prostaglandin release from perfused mesenteric blood vessels of rabbit and from perfused lungs of sensitized guinea pig

Infusion of norephinephrine (NE) (1 – 3 μg/ml/min) into the isolated mesenteric vascular preparation of rabbit resulted in a rise in perfusion pressure, which was associated with the release of a prostaglandin E-like substance (PGE) at a concentration of 2.81 ± 0.65 ng/ml in terms of PGE₂. Indomethacin (3 μg/ml) abolished the NE-induced release of PGE. Arachidonic acid (0.2 μg/ml) in the presence of indomethacin did not restore the NE-induced release of PGE. Hydrocortisone (10 – 30 μg/ml) and dexamethasone (2 – 5 μg/ml) also inhibited the NE-induced release of PGE. The inhibitory action of both corticosteroids was abolished by arachidonic acid (0.2 μg/ml). Antigen-induced release of a prostaglandin-like substance(PGs) (43.1 ± 3.8 ng/ml in terms of PGE₂ and a rabbit aorta contracting substance (RCS) from perfused lungs of sensitized guinea pigs was completely abolished by indomethacin (5 μg/ml) or by hydrocortisone (100 μg/ml). Indomethacin, however, increased histamine release up to 280% of the control level, which was 470 ± 54 ng/ml, while hydrocortisone diminished histamine release down to 30% of the control level. A superimposed infusion of arachidonic acid (1 μg/ml) into the pulmonary artery reversed the hydrocortisone-induced blockade of the release of RCS and PGs. It may be concluded that corticosteroids neither inhibit prostaglandin synthetase nor influence prostaglandin transport through the membranes but they do impair the availability of the substrate for the enzyme.     

Corticosteroids inhibit prostaglandin release from perfused mesenteric blood vessels of rabbit and from perfused lungs of sensitized guinea pig

Infusion of norephinephrine (NE) (1 – 3 μg/ml/min) into the isolated mesenteric vascular preparation of rabbit resulted in a rise in perfusion pressure, which was associated with the release of a prostaglandin E-like substance (PGE) at a concentration of 2.81 ± 0.65 ng/ml in terms of PGE₂. Indomethacin (3 μg/ml) abolished the NE-induced release of PGE. Arachidonic acid (0.2 μg/ml) in the presence of indomethacin did not restore the NE-induced release of PGE. Hydrocortisone (10 – 30 μg/ml) and dexamethasone (2 – 5 μg/ml) also inhibited the NE-induced release of PGE. The inhibitory action of both corticosteroids was abolished by arachidonic acid (0.2 μg/ml). Antigen-induced release of a prostaglandin-like substance (PGs) (43.1 ± 3.8 ng/ml in terms of PGE₂ and a rabbit aorta contracting substance (RCS) from perfused lungs of sensitized guinea pigs was completely abolished by indomethacin (5 μg/ml) or by hydrocortisone (100 μg/ml). Indomethacin, however, increased histamine release up to 280% of the control level, which was 470 ± 54 ng/ml, while hydrocortisone diminished histamine release down to 30% of the control level. A superimposed infusion of arachidonic acid (1 μg/ml) into the pulmonary artery reversed the hydrocortisone-induced blockade of the release of RCS and PGs. It may be concluded that corticosteroids neither inhibit prostaglandin synthetase nor influence prostaglandin transport through the membranes but they do impair the availability of the substrate for the enzyme.     

Prostaglandin synthesis by the cochlea of the guinea pig. Influence of aspirin, gentamicin, and acoustic stimulation

This study describes the synthesis of prostaglandins (PGs) by the vascular structures of the inner ear (lateral wall = stria vascularis and spiral ligament) in vitro. The main PGs produced were PGI2, PGF2 alpha and PGE2. PGI2 and PGF2 alpha were also found in the perilymph. A 350 mg/kg ip injection of aspirin decreased PG synthesis by the lateral wall and PG levels in perilymph. This effect was reversed after 3 days. Gentamicin (10(-9) to 10(-5) M) decreased significantly and reversibly PG synthesis in vitro, as did 100 mg/kg ip injection. Acoustic stimulation increased ex vivo PGI2 and PGE2 synthesis without modifying PG levels in perilymph. Results suggest that PGs could be one humoral mediator of the cochlear microcirculation homeostasis, and, possibly, of the circulatory disturbances reported after acoustic stimulation. The decreased PG synthesis after gentamicin treatment could account for the angiotoxic component observed in aminoglycoside ototoxicity.