Inhibition of gastric secretion in man by rioprostil, a new synthetic methyl prostaglandin E1

The effect of rioprostil, a new synthetic prostaglandin (PG) E1 (2-decarboxy-2-hydroxymethyl-15-deoxy-16RS-hydroxy-16-methyl PGE1), on basal and pentagastrin stimulated gastric secretion was investigated in a placebo controlled double-blind crossover study in 6 healthy male volunteers. Rioprostil reduced both basal and stimulated gastric secretory volume, as well as acid and pepsin secretion. At doses of 300 and 600 micrograms rioprostil reduced basal acid secretion by 54 and 88% and basal pepsin secretion by 86 and 68%, respectively. The two doses of rioprostil reduced stimulated acid secretion by 44 and 59% and stimulated pepsin secretion by 40 and 67%, respectively. Loose stools were observed in three subjects, other side-effects were minor and not different as compared to placebo. It is concluded that rioprostil is a potent inhibitor of both acid and pepsin secretion in man.     

Influence of parenteral prostaglandin E1 on lung mechanics in normal man

The effects of an infusion of prostaglandin E1 0.02 microgram/kg/min on lung mechanisms were studied in 10 healthy subjects. No change occurred in total lung volume and its subdivisions, airway resistance or maximal expiratory flow-volume curves. During the infusion, a slight but significant shift to the left of the static pressure-volume curve of the lung was observed, without any significant change in the upstream resistance (RUS), calculated at 70, 60 and 50% of total lung capacity. The loss of elastic recoil pressure without any variation in airway resistance or RUS, suggests that intravenous PGE1 selectively relaxes the contractile elements of the lung parenchyma, perhaps more by its action on the vascular wall than on the tone of the peripheral bronchiolar smooth muscle.     

Stimulation of insulin secretion after prostaglandin PGE 1 in the anesthetized dog

Overnight fasted anesthetized dogs were treated with prostaglandin PGE₁ infused at a rate of 0.5 or 1 μg/kg/min for 40 min and compared with saline-infused dogs. PGE₁ infusion caused a significant transient drop in arterial blood pressure (25–30 per cent) and in pancreaticoduodenal vein (PDV) blood flow (40–50 per cent). Total insulin output was unchanged during infusion. The cessation of PGE₁ infusion (1 μg/ kg/min) was accompanied by a slight tendency toward recovery of PDV blood flow and a highly significant (P < 0.01) increase in insulin output. No significant change in blood glucose was observed during PGE₁ infusion; however a moderate hypoglycemia was recorded at the time of maximal insulin output. These results (1), confirm that insulin output is relatively independant of gross changes in pancreaticoduodenal blood flow; and (2), demonstrate that insulin release is significantly increased in response to PGE₁ infusion. The relationship between the PGE₁-induced insulin increase and the adenylate cyclase system of the β-cell remains to be elucidated.     

Impairment of insulin secretion in man by nifedipine

Summary The effect of nifedipine, a calcium antagonist, on carbohydrate metabolism and insulin secretion was evaluated in patients who required treatment with this drug. 20 subjects underwent two oral glucose tolerance tests (100 g), one under basal conditions, and the other after ten days of treatment with nifedipine 30 mg/day by mouth, in three divided doses. 10 subjects had normal glucose tolerance; in them nifedipine administration reduced the insulin response to oral glucose in the first 60 min, but improved glucose tolerance. The other 10 subjects had impaired glucose tolerance and nifedipine treatment resulted in a further reduction both of insulin secretion and glucose tolerance. No such effects were seen in the placebo (weight- and disease-matched) group. The mechanism by which nifedipine influences carbohydrate metabolism and insulin secretion is discussed.     

Cardiac and microcirculatory effects of different doses of prostaglandin E1 in man

Summary A cumulative dose response to intravenous PGE₁ was established in 12 healthy volunteers. Systolic time intervals, including pre-ejection period (PEP), the ventricular ejection time (VET) and the RR-interval, were continuously determined, and transcutaneous oxygen pressure (tcpO₂) was recorded.RR-intervals fell in a dose dependent manner, reaching a significantly lower level at 128 ng·kg^–1·min^–1 of PGE₁ (basal value 842 ms falling to 756 ms). PEP decreased from 89 ms to 74 ms and the ratio PEP/VET decreased from 35% to 30%, indicating increased myocardial contractility. The maximal increase in tcpO₂ was 125% on the calf and 60% on the foot. The peak tcpO₂ was observed at an infusion rate of 16 ng·kg^–1·min^–1 PGE₁. A decline in tcpO₂ was seen at infusion rates >64 ng·kg^–1·min^–1 PGE₁, indicating a decrease in skin perfusion.The results indicate that the effects of intravenous PGE₁ on skin perfusion occur at a lower threshold than the increase in myocardial contractility. A maximal increase in skin perfusion can be achieved with doses of PGE₁ devoid of systemic haemodynamic effects.     

Inhibition of food stimulated acid secretion by misoprostol, an orally active synthetic E1 analogue prostaglandin

The effect of 200 micrograms misoprostol (a synthetic prostaglandin E1 analogue) on food stimulated intragastric acidity has been monitored over a 9 h period in 16 normal volunteers. Misoprostol caused a significant inhibition of intragastric acidity for 2 h post-dosing, but no significant effect was seen thereafter on either basal or food stimulated acidity.     

Effect of propranolol on the airway response to prostaglandin E2 in normal man.

1 The airway response to inhaled prostaglandin E2 (PGE2) and the effect of oral propranolol on this response was studied in eight normal subjects in a double-blind randomised trial. The airway response was measured as specific airway conductance (sGaw). 2 Inhalation of PGE2 caused retrosternal soreness, coughing and an awareness of mucus production. Despite this, PGE2 caused bronchodilatation and reproducible dose-response curves were obtained, with a maximum increase in sGaw of 53%. 3 Inhalation of the diluent of PGE2, an ethanol/saline mixture, did not cause irritation nor did it alter sGaw. 4 Prior administration of propranolol 80 mg did not alter baseline sGAW, nor the response to PGE2, indicating that the action of PGE2 in vivo is unaffected by bronchial beta-adrenoceptor blockade. 5 This technique should be of value in studying bronchodilator prostaglandins and their interaction with other drugs.     

Human jejunal secretion induced by prostaglandin E1: a dose-response study

1. Intraluminally infused prostaglandins induce jejunal secretion of water and electrolytes in man, and a receptor-mediated process in the intestinal epithelial cells has been suggested to explain this secretion. In an attempt to obtain data under basal conditions for pharmacological studies, we tested the dose-response effect of PGE1 on jejunal hydroelectrolytic movements in 10 healthy volunteers. 2. Accordingly, a solution with or without PGE1 was infused via a four-lumen tube with a proximal occluding balloon and jejunal water and electrolyte transport were determined. The segment tested was 40 cm long. Seven randomized doses of PGE1 ranging from 0.01 to 1.3 micrograms kg-1 min-1 (2.83 to 364 pmol kg-1 min-1) were infused in an isotonic control saline solution. The secretion induced by PGE1 was evaluated in each subject as the difference between fluxes in response to the control saline solution and to PGE1. 3. Whatever the dose, PGE1 induced secretion of water, Na+, K+ and Cl- which was dose-dependent and saturable, with a mean Km of congruent to 6-8 pmol kg-1 min-1, suggesting that at the pharmacological doses used, enterocytes have a saturable membrane site similar to a single class of receptor for PGE1. 4. These findings may be of great importance if prostaglandins are administered as drugs or used as jejunal secretory agents in vivo when the antisecretory effect of another drug is studied.     

Binding of prostaglandin E2, to blood in man

1 A new dialysis technique has been used to investigate the binding of prostaglandin E₂ (PGE₂) to circulating blood in five subjects.

2 The results indicate that added PGE₂ binds to blood, that the binding is to plasma albumin, and that binding is complete within 40 s of adding PGE₂.

     

Effect of loperamide on jejunal electrolyte and water transport,prostaglandin E 2-induced secretion and intestinal transit time in man

Summary Jejunal perfusion was performed in 12 healthy volunteers to evaluate the dose dependent effects of loperamide on intestinal absorption, stimulated secretion and transit.In 6 volunteers intestinal perfusion of the jejunal segment with isotonic NaCl solution was followed by addition of loperamide in increasing doses (2–8 mg·l^–1). The volunteers were pretreated with 1 mg·l^–1 prostaglandin E2 (PgE2) in the perfusate before addition of 4 mg·l^–1 loperamide. Phenolsulphonphtalein (PSP) boluses (2 ml) were given to measure mean transit time (MTT).Loperamide 2 mg·l^–1 converted the minor secretion after perfusion with the standard solution (water –1.45 ml·min^–1, Na –0.09 and Cl –0.04 mmol·min^–1) to absorption (water 0.93 ml·min^–1, Na 0.23, Cl 0.25 mmol·min^–1) within 15 min. Higher doses of loperamide did not increase absorption.The addition of PgE2 induced net secretion of water (–4.48 ml·min^–1) and electrolytes (Na –0.57, Cl –0.51 mmol·min^–1). Loperamide 4 mg·l^–1 significantly diminished the PgE2-induced net secretion by approximately 50%.Loperamide dose dependently increased the MTT from 6 (2 mg·l^–1) to 13.3 min (8 mg·l^–1). MTT was still delayed 60 min after a wash out period (10.5 min).It is concluded that loperamide had a dual effect or intestinal activities stimulating absorption and prolonging intestinal transit time with rising doses.     

The effect of liver microsomal enzyme inducing and inhibiting drugs on insulin mediated glucose metabolism in man.

The effects of hepatic microsomal enzyme inducing (phenobarbitone and flumecinol), and inhibiting (cimetidine) drugs, and placebo treatment on insulin mediated glucose metabolism (M) were investigated in 29 healthy volunteers. Phenobarbitone (50 mg for 10 days) increased M (30%), metabolic clearance rate of glucose (MCRg), and antipyrine clearance rate (33%). Fasting immunoreactive insulin (IRI) decreased while fasting blood glucose (BG) remained unaltered. Flumecinol, another inducer, tested in two doses (200 mg and 600 mg for 6 days), did not alter glucose or antipyrine metabolism. Fasting IRI reduced on treatment with 600 mg of flumecinol, but not with the smaller dose. Cimetidine (600 mg for 6 days) decreased M (19.5%), MCRg (26%), and antipyrine clearance rate (20%). The placebo did not alter glucose or antipyrine metabolism. The results indicate that the insulin mediated glucose disposal rate can be altered by drugs influencing hepatic microsomal enzyme activity.     

Effect of prostaglandin E1 on neuromuscular transmission in the rat.

1 The effect of prostaglandin E1 on neuromuscular transmission in the phrenic nerve-diaphragm muscle preparation of the rat was studied with intra- and extracellular recording techniques. 2 Prostaglandin E1, in concentrations from 10 nM, induced intermittent failures in the generation of the end-plate potential in response to repeated indirect stimulation. 3 Failures appeared abruptly, the end-plate potential behaving in an all-or-nothing fashion. The effect occurred only at 36-38 degrees C when the nerve was stimulated at 30-80 Hz and was reversible upon washing with drug-free solution. 4 Since miniature end-plate potentials were not affected, such failures must be attributed to a presynaptic action of prostaglandin E1. 5 Extracellular recording suggested that prostaglandin E1 prevented the action potential from reaching the nerve terminal.     

Effects of indomethacin and prostaglandin E2 on amylase secretion by rat parotid tissue.

Indomethacin increased the secretion by low concentrations of isoproterenol (IPR, 30-100 nM) and decreased the secretion by a high concentration of IPR (1 microM). Indomethacin also had opposite effects on the secretions induced by low and high concentrations of norepinephrine (NE). PGE2 did not affect the secretions induced by IPR and NE, but it reversed the stimulatory and inhibitory effects of indomethacin. These findings suggest that PG has a role in modulating the amylase secretory response of the rat parotid gland.     

Central inhibitory action of prostaglandin E2 on gastric secretion in the rat

The central nervous system action of prostaglandin E2 (PGE2) on gastric secretion was studied in conscious pylorus-ligated rats. It was found that 1-10 micrograms of PGE2 given i.c.v. reduced the gastric output of acid, pepsin and fluid in a dose-dependent manner whereas 30-300 micrograms was required for inhibition when given subcutaneously. Given i.c.v. 400 micrograms of indomethacin, a potent inhibitor of prostaglandin biosynthesis, enhanced gastric secretion but not when given intramuscularly. It is concluded that PGE2 has a central inhibitory action on gastric secretion in conscious rats. In addition, the possibility that PGE2 may be involved as inhibitory modulator in the central control of gastric secretion warrants further attention.     

Calcium mobilization, prostaglandin E2 and alpha 2-adrenoceptor modulation of glucose utilization and insulin secretion in pancreatic islets

alpha 2-Adrenoceptor agonists inhibit glucose-stimulated insulin release and glucose utilization in pancreatic islets. In isolated pancreatic islets of the rat, the Ca2+ channel agonists CGP-28392 and BAY-K-8644 increased insulin release in the presence of clonidine. Neither CGP-28392 nor BAY-K-8644 antagonized the effect of clonidine on glucose utilization. The Ca2+ ionophore, ionomycin, also did not affect glucose utilization in the presence or absence of clonidine. Glucagon partly reversed the effects of clonidine on insulin release, and it potentiated glucose-stimulated insulin release in the absence of clonidine. Glucagon reversed the effects of clonidine on glucose utilization. Amiloride antagonized the effects of clonidine on insulin secretion but did not enhance markedly glucose utilization in the presence or absence of clonidine. Carbamylcholine and arecoline reversed the effects of clonidine on glucose utilization and partly reversed the effects on insulin release in the absence of extracellular Ca2+. Prostaglandin (PG) E2, but not PGF2 alpha, inhibited glucose utilization in a time- and concentration-dependent manner. PGE2 also inhibited glucose-stimulated insulin release. Pertussis toxin blocked both actions of PGE2. The cyclooxygenase inhibitor indomethacin did not affect insulin release or glucose utilization in the presence of clonidine. Thus, elevated intracellular Ca2+ levels antagonize the effects of clonidine on insulin release, whereas other mediators appear to be required to alter glucose utilization.