Cyclic AMP and gastric secretion in man. An in vivo study in healthy volunteers, duodenal ulcer patients, and pernicious anaemia patients.

The metabolism of cyclic AMP and HCl secretion has been studied in eight healthy volunteers, in eight duodenal ulcer (DU) patients, and in four pernicious anaemia patients. Pentagastrin showed a tendency to increase adenylate cyclase and cyclic nucleotide phosphodiesterase activities in the fundal mucosa and caused a significant increase in cyclic AMP output into the gastric juice in healthy volunteers and in DU patients. Cimetidine inhibited all these events but had no effect on basal cyclic AMP output. Vagotomy significantly inhibited basal cyclic AMP output. We conclude that cyclic AMP is involved both in basal and in pentagastrin-stimulated gastric secretion in man. Basal secretion is mainly controlled by vagal tone. The main pathway for this stimulus at the parietal cell may be via other than H2-receptors, probably through acetylcholinergic receptors. However, a significant part of the pentagastrin stimulation of the human parietal cell is via H2-receptors.

Comparison of the effects of adrenergic agonists and alpha-, beta 1-, beta 2-antagonists on the intraocular pressure and adenylate cyclase activity in the ciliary processes of the rabbit.

The hypotensive effect of different adrenergic agonists and antagonists were screened both in normo- and hypertensive rabbit eyes. The drugs were applicated topically and intraocular pressure (IOP) was monitored constantly with a manometric method. Subsequently the inhibitory effect of the antagonists on isoproterenol-stimulated adenylate cyclase activity in the ciliary processes was analyzed in vitro. In normotensive eyes agonist isoproterenol (beta) and antagonists labetalol (alpha beta), metoprolol (beta 1) and acebutolol (beta 1) decreased significantly IOP. In hypertensive eyes only isoproterenol and labetalol decrease IOP markedly. Timolol (beta) did not decrease IOP, although it inhibited adenylate cyclase activity as actively as labetalol. The other antagonists showed no inhibitory effect on in this respect. The results indicated that alpha-activity (labetalol, alpha beta) seems to potentiate the beta-activity (timolol, beta) in decreasing IOP. Whether this alpha-effect is a presynaptic effect (adrenergic denervation destroys it) is not yet clear. Similarly the beta 1-effect (metoprolol), without affecting adenylate cyclase activity, decreased IOP as well. This might be due to pre-synaptic release of endogenous transmitter(s) which in turn stimulate post-synaptic adenylate cyclase and induce the decreased IOP. Besides this, the possible role of blood vessels and CNS must also be kept in mind.

Urinary cyclic adenosine 3',5'-monophosphate excretion in children in short stature: effect of somatotropin.

Excretion of urinary cyclic adenosine 3',5'-monophosphate (cAMP) was determined in twenty-four children of short stature and in sixteen normal children. Of the patients, eight suffered from anterior panhypopituitarism, six from isolated deficiency or somatotropin, seven had a family history of short stature, and three had growth failure of pre-natal onset. In children suffering from anterior panhypopituitarism or from isolated somatotropin deficiency, excretion of cAMP was found to be depressed. Short-term administration of purified somatotropin in normal therapeutic dose (3.4 mg per 1.7 m2 i.m. daily for 5 days) had no effect on urinary cAMP, but reduced urine volume in all patient groups. During somatotropin treatment there was a positive correlation between changes in urine volume and nitrogen balance (r = 0.67).

Effects of corticotrophin and choriogonadotrophin on urinary cyclic adenosine 3',5'-monophosphate.

The actions of exogenous corticotrophin (ACTH) and human choriogonadotrophin (HCG) were assessed by measuring cyclic adenosine 3',5'-monophosphate (cAMP), 17-ketosteroids (17-KS), 17-ketogenic steroids (17-KGS), androsterone (A), etiocholanolone (E), dehydroepiandrosterone (DHEA) and pregnanetriol (P3) in 24 h urine. ACTH was infused intravenously into six healthy women. A dexamethasone (DXM) suppression test was also performed, and continued when HCG was injected intramuscularly. The effects of intramuscular injection of ACTH and administration of DXM on urinary cAMP, 17-KS and 17-KGS were also studied in an adrenalectomized and ovariectomized patient. ACTH, 250 microgram (25 i.u.), increased excretion of cAMP in the healthy women and also in the patient. In the six controls there was a simultaneous normal increase in 17-KS, 17-KGS, A, E, DHEA and P3 excretion. DXM did not cause the excretion of cAMP to fall below the basal level in any of the subjects examined but the excretion of all the steroids studied decreased significantly. The only effect of HCG was to increase P3 excretion. The results indicate that the increment in cAMP is probably related to an extra-adrenal effect regulated by ACTH.

Determination of cyclic adenosine 3',5'-monophosphate in urine.

A modification of Aurbach & Houston's enzymic method for measuring cAMP is presented. The procedure is relatively simple and in several respects new. Urinary cAMP is separated from other nucleotides and phosphate by ZnSO4-Ba(OH)2 precipitation and column chromatography. The eluate is concentrated by evaporation. Recovery at this stage is 60-82%. The cAMP from urine and the standards are dissolved in a reaction mixture and converted to 5-AMP with cyclic 3',5'-nucleotide phosphodiesterase (PDE) and further to ATP with adenylate kinase and pyruvate kinase. The ATP formed is labelled with 32P by an exchange reaction catalysed by glyceraldehyde phosphate dehydrogenase and phosphoglycerate kinase. The remaining 32P used to count the [32P]ATP in the aqueous phase. Daily human urinary cAMP excretion is 3380 +/- 836 nmol (S.D.). After an injection of 100 USP units of parathormone intravenously into a patient with idiopathic hypoparathyroidism, urinary cAMP excretion increased 40-fold above the basal concentration within 30 min. Drinking of coffee or water did not affect cAMP excretion. The limit of detection of the method is 170 pmol of cAMP, and the variation coefficient for urine ranges from 7 to 10%. When the enzymic cAMP method was compared with a radioimmunological procedure, the correlation coefficient was found to be 0.98.

Effect of salbutamol inhalations of plasma and urinary cyclic adenosine monophosphate levels in asthmatics and non-atopic controls.

Twenty asthmatics and 14 non-atopic controls were given long-acting theophylline tablets, 400 mg twice daily, and were then challenged, after a control period, with 0.5 mg salbutamol as an inhalant, divided in two doses. Urinary and plasma cyclic adenosine monophosphate (cAMP) levels were determined at the beginning of the study, during theophylline treatment and after the challenge with salbutamol inhalation. In neither the asthmatics nor the controls did theophylline alone raise the concentration of cAMP in plasma or its excretion in urine. Inhalation of salbutamol caused a significant rise in plasma cAMP levels in the controls but not in asthmatics. The inhaled sympathomimetic aerosol caused a slight simultaneous rise in urinary cAMP excretion in non-atopic controls, but in the asthmatics. Our results show that sympathomimetics administered directly to the bronchial mucosa do not elicit the same metabolic cAMP response in asthmatics as in controls.

Effect of the carboxyl-terminal tripeptide of vasopressin on plasma free fatty acids and cyclic adenosine monophosphate in man.

The carboxyl-terminal tripeptide of casopressin (Pro-Arg-Gly.NH2) and adrenocorticotrophic hormone (ACTH) were injected intravenously into six human subjects, and the effects of these peptides on plasma free fatty acids (FFA) and cAMP concentrations were compared with that of saline. Twenty mug of the tripetide and 100 mug of ACTH INCREASED THE PLASMA FFA CONCENTRATION TO THE SAME EXTENT, WHEREAS 200 MUG OF THE TRIPETIDE WAS WITHOUT THIS LIPOLYTIC EFFECT. ACTH and the smaller dose of the tripeptide elevated the plasma cAMP level only in the same two subjects.

Cyclic adenosine 3',5'-monophosphate in prostaglandin-induced abortion.

PIP: Cyclic AMP (cAMP) in blood samples was followed during abortions induced with an intraamniotic injection of prostaglandin F2a (PGF2a) and E2 (PGE2) in women in the second trimester. The effect of intraamniotic administration of PGE2 on tissue cAMP levels and adenyl cyclase (AC) and cyclic nucleotide phosphodiesterase (PDE) in myometrium, maternal abdominal rectus muscle, placenta, and fetal liver and leg muscle was studied in women undergoing abortion with hysterotomy. Saline was injected intraamniotically into controls. Plasma cAMP values showed inconsistent variation after injection of both types of PGs. On administration of PGE2 uterine contraction started after 3 minutes. Myometrial cAMP increased 4-fold within 10 minutes, and these values also showed inconsistent variation. Neither AC or PDE activities were affected in myometrium by PGE2.^ieng