Influence of prostaglandins and adrenoceptor agonists on contractile activity in the human cervix at term.

The influence of prostaglandins as well as adrenoceptor agonists and antagonists on contractile activity of isolated cervical smooth muscle from term pregnant women was studied. Prostaglandin E2 had an inhibitory effect at extremely low concentrations. Inhibition also was induced by prostaglandin F2 alpha, prostaglandin I2, and 6-keto-prostaglandin F1 alpha, but at considerably higher concentrations. Contractions evoked by noradrenaline or phenylephrine were blocked by the alpha-adrenoceptor antagonist phenoxybenzamine. The beta-adrenoceptor agonist terbutaline acted as an inhibitor, whereas isoprenaline in most cases stimulated contractile activity. The inhibitory action of prostaglandins and especially the high sensitivity to prostaglandin E2 point to a physiologic role of these compounds for cervical dilatation and retraction. A predominance of alpha-adrenoceptors might be of importance for the maintenance of cervical competence during pregnancy.

The role of alpha and beta adrenoceptors in airway hyperresponsiveness to histamine.

The effect of a specific alpha 1-adrenoceptor antagonist, prazosin, on histamine-induced bronchoconstriction was compared to a beta 2-adrenoceptor agonist, salbutamol, in 16 subjects with nonspecific bronchial hyperresponsiveness whose PC20H ranged from 0.10 to 5.12 mg/ml. PC20H was calculated from a histamine inhalation test performed before and after 0.5 mg of prazosin by dry powder inhalation and 200 mcg of salbutamol by pressurized aerosol. PC20H was also measured in six subjects before and after placebo (20 mg lactose) by dry powder inhalation in a randomized double-blind study with prazosin. Mean (+/- SE) PC20H before and after placebo was 1.77 (0.32) and 1.57 (0.38) mg/ml, respectively, an 0.89-fold change. Mean (+/- SE) PC20H before and after prazosin for the 16 subjects was 1.92 (0.34) and 3.10 (0.72) mg/ml, a 1.51-fold change (p less than 0.001), and PC20H before and after salbutamol was 2.08 (0.33) and 9.54 (2.51) mg/ml, a 4.08-fold change (p less than 0.001). There was a positive correlation between the prazosin and salbutamol responses (r = 0.55, p less than 0.05). A dose response for salbutamol was performed in eight subjects, and PC20H was determined by use of increasing doses of salbutamol until PC20H was more than 16 mg/ml. The dose of salbutamol required varied widely between subjects and did not relate to baseline PC20H. The results suggest a role for alpha-adrenoceptors in addition to beta-adrenoceptors in histamine-induced bronchoconstriction.

Beta-adrenergic regulation of the blood lymphocyte phenotype distribution in normal subjects and splenectomized patients.

The beta-adrenergic effect on the release of immunoregulatory cells from the spleen was investigated by physical stress testing (bicycle ergometry up to submaximal work capacity) in 19 normal subjects (15 males, median 21 years) and in 10 male patients splenectomized for trauma (median 29 years). It was repeated in 6 subjects of each group during beta-blockade with 80 mg oxprenolol. Blood samples for leucocyte analysis were taken before and at the end of the test. Leucocyte subpopulations were analyzed in a cytofluorograph after staining of buffy coat cells by direct (B cells) or indirect immunofluorescence with monoclonal antibodies directed against the phenotypes of T- (Leu-1), T helper- (Leu-3a), T suppressor/cytotoxic (Leu-2a) cells and natural killer (OKM1+ lymphocytes) cells. In the controls all leucocyte subsets increased at ergometry, but B-, Leu-2a- and OKM1-cells increased more than Leu-3a cells. During beta-blockade the leucocyte changes reached only 50% of the value without treatment; the B- and Leu-2a cell mobilization was reduced more than the Leu-3a-, OKM1 cell- and monocyte changes. In splenectomized patients the proportional cellular changes were only half of those found in normal subjects, except for the Leu-3a cells which were not released. Beta-blockade during ergometry had no effect on Leu-3a cells, a similar effect on B- and Leu-2a cells as in normal subjects and a stronger effect on granulocytes, monocytes and OKM1 cells than in controls. In conclusion, the B- and Leu-2a cell mobilization from the spleen (50%) was beta-adrenoceptor dependent, while the one from other lymphoid organs was beta-adrenoceptor independent. The strongly spleen dependent Leu-3a cell changes were not beta-adrenoceptor mediated. Granulocyte-, monocyte- and OKM1 cell changes were only partly spleen dependent. The spleen independent changes however were strongly beta-adrenoceptor dependent.

Modulation of the response of a photosensitive muscle by beta-adrenergic regulation of cyclic AMP levels.

The light-induced constriction of the irises of some vertebrates is mediated by photosensitive pupillary sphincter cells, which have rhodopsin molecules in their sarcolemmas. Light-induced isomerization of these rhodopsin molecules leads to the release of Ca2+ from an internal pool, which in turn activate the contractile proteins. A central nervous reflex is therefore not essential for the light responsiveness of these irises, but they do appear to be innervated. The photosensitive iris of the toad receives sympathetic (adrenergic) innervation. Stimulation of sympathetic nerves to the eye or application of adrenergic agonists to the iris cause pupillary dilation due to relaxation of the sphincter muscle. We show here that beta-adrenergic stimulation of toad sphincter cells modulates their photoresponses by elevating the intracellular levels of cyclic AMP. However, cyclic AMP does not appear to be involved in the transduction event but rather alters the availability of Ca2+ for contraction.

Beta-adrenoceptor agonist responses in the skin and lungs of asthmatic subjects.

Concomitant intradermal injection of salbutamol inhibits histamine-induced weal volume in the skin of atopic asthmatic subjects and the degree of this inhibition (index of beta-adrenergic effect in the skin) correlates with the bronchodilator effect of inhaled salbutamol in the same subjects (index of beta-adrenergic effect in the lung).

Mechanism of regulation of amylase release by alpha- and beta-adrenergic agonists in rat parotid tissue.

The effect of forskolin and isobutyl-methylxanthine on amylase release and cyclic AMP accumulation by alpha- and beta-adrenergic agonists was studied in rat parotid slices. A small increase in cyclic AMP by beta-adrenergic agonists was sufficient for maximum stimulation of amylase release (Yoshimura et al., 1982a), but a similar increase in cyclic AMP by forskolin did not stimulate the maximum amount of amylase release. The amount of amylase release and cyclic AMP changed in parallel when lower doses of isobutyl-methylxanthine were used, but higher doses of isobutyl-methylxanthine further increased cyclic AMP without causing a significant increase in amylase release. Amylase release stimulated to its maximum by isobutyl-methylxanthine was much lower than that by isoproterenol. These results suggest that cyclic AMP is not the only chemical correlate for the activation of amylase release by beta-adrenergic agonists. The effect of phenylephrine and methoxamine on amylase release was augmented by either forskolin or isobutyl-methylxanthine, but the effect of methacholine was not. Phenylephrine increased the cyclic AMP concentration under the same conditions, but methoxamine did not. The inhibition of the effect of phenylephrine plus forskolin on cyclic AMP accumulation by propranolol was almost complete and stereospecific, but the inhibition of their effects on amylase release was incomplete and not stereospecific. Synergism of amylase release was observed in the effect between methoxamine and dibutyryl-cyclic AMP. These results suggest that the augmentation of the effect of alpha-adrenergic agonists on amylase release by forskolin or isobutyl-methylxanthine cannot be explained only on changes in cyclic AMP and that some other factor in collaboration with cyclic AMP may participate in the regulation of amylase release by alpha-adrenergic agonists.

Effect of beta-adrenergic stimulation on experimental canine anaphylaxis in vivo.

We studied beta-adrenergic modulation of antigen-induced release of histamine and changes in lung function in natively allergic, anesthetized dogs. After thoracotomy and bilateral cervical vagotomy, samples of peripheral lung frozen in situ were obtained for measurement of adenosine cyclic 3',5'-monophosphate (cAMP) and histamine. In 11 dogs with beta-adrenergic blockade (propranolol), subsequent Ascaris suum antigen (intravenous) decreased lung tissue histamine 21.5% +/- 5.3% (mean +/- SE), with marked physiologic changes of anaphylaxis. In six other dogs, with no pharmacologic treatment before antigen, A. suum decreased lung tissue histamine only 11.5% +/- 1.9%. In six other dogs, terbutaline (1 mg/kg, i.v.) increased concentration of cAMP in peripheral lung, indicating stimulation of beta-adrenergic receptors, and inhibited response to A. suum. When a beta-adrenergic agonist was given 15 sec prior to A. suum, cAMP doubled and inhibition was incomplete. When a beta-agonist was given 150 sec prior to A. suum, cAMP increased fivefold and inhibition was complete.

[The adenylate cyclase system of human platelets]. / Le système adénylate cyclasique des plaquettes humaines.

This review summarizes current knowledge on the adenylate cyclase system of human platelets. In the first part, the main molecular entities of this system are described, emphasis being layed on coupling proteins (Ns, Ni) which transduce the hormonal message from receptors to the catalytic unit. The mechanisms by which regulation of adenylate cyclase occurs is discussed and a comprehensive model is proposed. In the second part, are reviewed the hormonal and non hormonal regulators of the adenylate cyclase system. The role of the platelet adenylate cyclase system is discussed in relation to pathology and the action of certain drugs on platelet activity.

Autonomic transmitter actions on cardiac pacemaker tissue: a brief review.

Application of the voltage clamp technique to cardiac primary pacemaker tissue has yielded sufficiently detailed information that a qualitative model of the pacemaker response can now be formulated. One important difference between the generation of spontaneous activity in sinus tissue, and in the Purkinje fiber, appears to be the involvement of the slow inward current, Isi, in the sinus pacemaker depolarization. The voltage clamp results also demonstrate the importance of the Isi in the chronotropic responses of pacemaker tissue. Epinephrine has been shown to increase Isi in rabbit sinoatrial node, and there is indirect evidence that acetylcholine may reduce Isi in reptilian sinus venosus. Additional, more quantitative data are essential, however, before cardiac primary pacemaker activity and its modulation by the autonomic transmitters can be fully understood.

Clinical usefulness of the beta-adrenergic antagonists.

The pharmacology of the beta-adrenergic antagonists, particularly their role as competitive antagonists at the receptor site, is discussed. The clinical use of these agents is listed and a detailed outline of their use in angina pectoris, hypertension and conditions associated with increased sympathetic activity is provided. The relative contraindications to the use of beta-adrenergic antagonists are summarized and the pharmacology of those drug interactions involving these agents is discussed. A thorough understanding of the pharmacology and therapeutics of these agents, which interfere with physiological function, is mandatory prior to their clinical use.

Cyclic AMP and psoriasis.

Evidence that an adenyl cyclase system is present in all mammalian epidermis is reviewed. This adenyl cyclase is stimulated by at least two separate types of chemicals: catecholamines, which act at a beta-adrenergic receptor site, and prostaglandins of the E series, which act at a separate site. In the psoriatic lesion, the response to these stimulators, especially to the catecholamines, is reduced. Despite this lack of response to external agents which elevate cyclic AMP, the concentration of cyclic AMP within the epidermis of the psoriatic lesion is no lower than in noninvolved skin. How cyclic nucleotides act to control cell proliferation and cell differentiation remains unclear.

In vitro analysis of the control of keratinocyte proliferation in human epidermis by physiologic and pharmacologic agents.

Human keratinocytes grown in vitro as epithelial outgrowths or as organ cultures maintain many of their normal functions such as proliferation and keratinization. These in vitro systems have been used to analyze the effect of various agents on proliferation. All adenine nucleotides, including dibutyryl cyclic AMP, blocked mitosis in the G2 part of the cell cycle at concentrations of 1 times 10(-4) M. Some nonadenine nucleotides also showed this effect, but only at higher concentrations, an indication that the effect was specific for adenine nucleotides. Dibutyryl cyclic AMP and theophylline both depressed the incorporation of [3H]thymidine into DNA. Catecholamines such as isoproterenol, epinephrine, and norepinephrine were also potent inhibitors of mitosis (G2 block) at concentrations of 1 times 10(-8) to 1 times 10(-10) M. The fact that the effect could be blocked by the beta-blocking agent, propranolol, suggests the existence of specific membrane receptor sites. However, dichloroisoproterenol, another beta blocker, had distinct inhibitory properties in itself and thus indicated that the mechanism of action of catecholamines in human keratinocytes is complex and may involve more than binding to specific receptor sites. Histamine at a concentration of 2 times 10(-6) M was also a strong mitotic inhibitor. This finding is directly opposed to that in rat skin where mitosis is stimulated. Imidazole acetate, a histamine breakdown product, was found to be a striking mitotic stimulator in organ culture. A water-extractable protein (chalone) from human skin also caused a block in G2. Most of the substances tested occur naturally in the cell or organism and their ability to stimulate or depress proliferation in vitro suggests that they play a regulatory role in vivo.