Histamine (H2) receptor-adenylate cyclase system in pig skin (epidermis).

Histamine activated adenylate cyclase in pig skin (epidermal) slices, resulting in the accumulation of cyclic AMP. This effect was highly potentiated by the addition of cyclic AMP-phosphodiesterase inhibitors (theophylline, papaverine). A specific H2 receptor inhibitor (metiamide) inhibited the effect of histamine completely, while other antihistamines (diphenhydramine, acetophenazine, perphenazine, fluphenazine, promethazine) inhibited the effect of histamine to various lesser degrees. It has been shown that both epinephrine and prostaglandin E stimulate epidermal adenylate cyclase. Our data using specific blocking agents indicate that histamine, epinephrine and prostaglandin E2 act independently on the epidermal adenylate cyclase system.     

Histamine (H2) receptor-adenylate cyclase system in pig skin (epidermis)

Histamine activated adenylate cyclase in pig skin (epidermal) slices, resulting in the accumulation of cyclic AMP. This effect was highly potentiated by the addition of cyclic AMP-phosphodiesterase inhibitors (theophylline, papaverine). A specific H₂ receptor inhibitor (metiamide) inhibited the effect of histamine completely, while other antihistamines (diphenhydramine, acetophenazine, perphenazine, fluphenazine, promethazine) inhibited the effect of histamine to various lesser degrees. It has been shown that both epinephrine and prostaglandin E stimulate epidermal adenylate cyclase. Our data using specific blocking agents indicate that histamine, epinephrine and prostaglandin E₂ act independently on the epidermal adenylate cyclase system.     

5'guanylyl-imidodiphosphate actions on adenylate cyclase in homogenates of rat cerebral cortex plus neuronal and capillary fractions

A variety of neurohumoral agents activate adenylate cyclase in homogenates of rat frontal cortex (norepinephrine, isoproterenol, dopamine, apomorphine, histamine, 4-Me-histamine and prostaglandins E₁, E₂ and A₂). The enzyme in homogenates of isolated cortical neurons is likewise sensitive to norepinephrine, isoproterenol, dopamine, apomorphine, histamine, 2-Me- and 4-Me-histamine, and prostaglandin F_2α. Capillary-enriched fractions from the cortex possess an enzyme that is activated by norepinephrine, isoproterenol and dopamine. Addition of 5′-guanylyl-imidodiphosphate (Gpp(NH)p) to the cortical homogenates and neuronal fractions resulted in enhanced enzyme responses to norepinephrine, isoproterenol, dopamine, 2-Me- and 4-Me-histamine and the prostaglandins E₁ and E₂. The actions of histamine and apomorphine were not increased by the GTP analog. The sensitivity of the catecholamine-induced adenylate cyclase activation in cortical capillaries was augmented by Gpp(NH)p. Thus various cellular types within the cerebral cortex may possess different receptor characteristics with respect to stimulation of adenylate cyclase by neurohormones.     

Regulation by monovalent cations of histamine H2 receptor-coupled adenylate cyclase from guinea pig fundic gastric mucosa

In thoroughly washed guinea pig fundic gastric mucosal membranes, NaCl markedly potentiates the maximal histamine-stimulated adenylate cyclase activity and increases the concentration of histamine required for half-maximal effect (EC₅₀). The apparent dissociation constants for the antagonists cimetidine and metiamide are only slightly increased in the presence of NaCl. Potassium chloride does not change the histamine EC₅₀ but does increase the maximal histamine-stimulated adenylate cyclase activity. These results suggest that Na and K ions may play an important role in the regulation of histamine-sensitive adenylate cyclase in gastric mucosa. The effect of the Na ion appears to be more specific for histamine H₂ receptor agonists than for antagonists.     

Studies on histamine H2 receptors coupled to cardiac adenylate cyclase. Effects of guanylnucleotides and structural requirements for agonist activity.

In particulate preparations from guinea-pig ventricle, histamine in the concentration range 10(-6)--10(-3) M caused a 3--5fold stimulation of adenylate cyclase activity which was dependent on the presence of GTP. The effects of fourteen analogs of histamine were examined on this cyclase preparation. Five of the compounds studied proved to be partial agonists relative to histamine while nine others had essentially the same intrinsic activity as histamine. The intrinsic activities of the partial agonists were increased by GppNHp to the extent that dimaprit, which was a partial agonist in the presence of GTP, became a full agonist in the presence of GppNHp. The relative potencies of the full agonists as activators of the cyclase were found to correlate with the relative potencies on physiologically defined H2 receptor systems. Activation of the cyclase by histamine, as well as by several of the agonist analogs, including dimaprit and tolazoline, was completely blocked by the H2 antagonist cimetidine, but was not affected by pharmacologically relevant concentrations of the H1 antagonist mepyramine, the beta-blocker alprenolol, or the alpha-blocker phentolamine. The results suggest that all the agonists studied probably interact with a common H2 receptor site on the cardiac muscle cell leading to activation of adenylate cyclase. The accompanying increase in cyclic AMP is presumably responsible for the chronotropic and inotropic effects of histamine and related compounds on cardiac muscle.     

Studies on the involvement of histamine in the hypothalamic-pituitary-adrenal axis activation induced by nerve growth factor

Nerve growth factor (NGF) has been shown to stimulate the hypothalamic-pituitary-adrenocortical (HPA) axis. Since NGF induces the release of histamine from mast cells and in consideration of the fact that histamine is an HPA axis activator, we investigated whether NGF adrenocortical stimulation is mediated by histamine. To accomplish with it, the H1 histamine antagonist promethazine and the H2 antagonists metiamide and zolantidine were used in freely-moving cannulated rats. The increase in plasma corticosterone concentration induced by histamine administration was prevented completely by promethazine pretreatment but was unaffected by the H2 antagonists. Neither H1 nor H2 antagonists affected the adrenocortical stimulation induced by NGF administration. Moreover, since mast cells are reportedly present in the rat adrenal gland and the locally released histamine mediates the release of adrenaline which, in turn, stimulates glucocorticoid synthesis and secretion, we studied the effect of NGF on basal and ACTH-stimulated corticosterone release from in vitro isolated quartered adrenal glands and collagenase-dispersed adrenal cells. The results from these in vitro experiments have indicated that NGF modified neither spontaneous nor stimulated corticosterone release. Altogether these observations suggest that endogenous histamine is unlikely to be involved in HPA axis stimulation by NGF and reinforce the previously proposed concept of an active participation of NGF in the control of adrenocortical activity.     

Effects of histamine and antihistamines on the kinetics of carbon dioxide in the rat

We have investigated the effects of chlorpheniramine (an H1 histamine inhibitor) and metiamide (an H2 inhibitor) on response to 14C pulse-labeling of carbon dioxide in the rat in the presence and absence of histamine. Neither chlorpheniramine nor metiamide alone had any effect upon the gastric venous/arterial ratio (VG/A) or the peripheral venous/arterial ratio (Vp/A). As in the case with no drug present, Vp/A rose with time following pulse-labeling to a value of 1.15-1.20. The presence of a preexisting steady-state infusion of histamine caused no changes in the ratios in the presence or absence of the inhibitors. The inhibitors did completely abolish the oscillations of both VG/A and Vp/A caused by initiation of histamine infusion coincident with the pulse-labeling. The results suggest that the histamine effects are largely mediated through H1 receptors.     

Evidence for delta opioid receptor subtypes regulating adenylyl cyclase activity in rat brain

Opioid agonists selective for mu- or delta opioid receptors inhibit adenyl yl cyclase in membranes from rat caudate-putamen and nucleus accumbens. The presence of subtypes of delta opioid receptors has been suggested. In both brain regions we have found that the inhibition of adenylyl cyclase by DPDPE was more readily antagonized by 7-benzylidenenaltrexone (BNTX), than by naltriben. In contrast, the inhibitory effects of deltorphin-II and DSLET were more readily antagonized by naltriben, than by BNTX. neither naltriben nor BNTX significantly antagonized the effect of a mu selective agonist. These results suggest that inhibition of adenylyl cyclase in caudate-putamen and nucleus accumbens is regulated by two forms of delta-opioid receptor with ligand selectivities similar to those two forms proposed to mediate analgesic effect.     

H2 Histamine Receptors on the Epithelial Cells of Choroid Plexus

A major site of cerebrospinal fluid production in vertebrates is the choroid plexus. The epithelial cells of the choroid plexus accumulate intracellular cyclic AMP in response to several effectors, including histamine. Since histamine is known to regulate fluid secretion in the stomach via H2 histamine receptors, we asked whether H2 receptors might also be present on epithelial cells of bovine choroid plexus. Using agonists and antagonists of histamine, we show that an agonist and antagonist pair specific for the H2 subtype were clearly more effective than an H1 agonist and antagonist pair in mimicking or inhibiting histamine stimulation of cellular cyclic AMP. Analysis by Schild plot allowed assignment of an apparent dissociation constant to the H2 antagonist metiamide which was 34-fold lower than that of its H1 counterpart, diphenhydramine. These results indicate that epithelial cells of the choroid plexus possess H2 histamine receptors.     

Effect of histamine receptor agonists and antagonists on the uterine vasculature

Histamine H1 and H2 receptors are known to exist in uterine smooth muscle; however, neither receptor has been clearly identified in the uterine vasculature. In the present study, 12 nonpregnant ewes were chronically instrumented with catheters in the carotid artery, jugular vein, uterine arteries, and electromagnetic flow probes on the uterine arteries for continuous measurement of uterine blood flow. Dose response curves were determined for bolus injections of Histamine (1-10 micrograms), the H1 receptor agonist 2PEA (10-100 micrograms), and the H2 receptor agonist Dimaprit (30-300 micrograms) before H1 receptor blockade with pyrilamine, following H1 receptor blockade, and following H2 receptor blockade with metiamide. Uterine vasodilator responses to histamine and 2PEA were essentially abolished by pyrilamine, while responses to dimaprit were not altered. Following addition of metiamide, responses to histamine were reduced further and responses to dimaprit were abolished. Baseline uterine blood flow was not altered by either H1 or H2 receptor blockade or their combination. Intraarterial bolus injections of the mast cell histamine-releasing compound 48/80 (100-1000 micrograms) had no effect on uterine blood flow. These experiments demonstrate that the uterine vasculature of the ovine contains almost exclusively H1 receptors, does not contain compound 48/80 sensitive mast cells and is not dependent upon endogenous histamine to maintain blood flow.     

Histamine H1- and H2-receptors in canine renal artery in vivo and in vitro

The present work investigates (a) the modification by pretreatment with selective H1- and H2-receptor antagonists on the dose-response curves (DRC) to histamine for heart rate, blood pressure, renal arterial blood flow and renal vascular resistance in anesthetized dogs, and (b) the characteristics of the DRC to histamine in canine isolated renal artery. In vivo, pretreatment with metiamide (10 mg/kg i.v.) did not modify the DRC to histamine. In contrast, significant rightward shift of the DRC to histamine for all the hemodynamic parameters was observed after diphenhydramine (5 mg/kg i.v.). Combined pretreatment with metiamide and diphenhydramine resulted in further rightward displacement of the DRC to histamine. Analysis of the DRC to the relaxant effect of histamine in depolarized (K+ 67 mM) isolated canine renal artery yielded an ED50 of 3.3 x 10(-4) M and a Hill coefficient of 1.74. The results demonstrate the existence of the two types of histamine receptors, H1 and H2, in the renal artery of the dog, both mediating dilator responses, although the H1-receptor appears to predominate.     

Characterization of the effects of serotonin on the release of [3H]dopamine from rat nucleus accumbens and striatal slices

The effect of serotonin agonists on the depolarization (K⁺)-induced, calcium-dependent, release of [³H]dopamine (DA) from rat nucleus accumbens and striatal slices was investigated. Serotonin enhanced basal³H overflow and reduced K⁺-induced release of [³H]DA from nucleus accumbens slices. The effect of serotonin on basal³H overflow was not altered by the serotonin antagonist, methysergide, or the serotonin re-uptake blocker, chlorimipramine, but was reversed by the DA re-uptake carrier inhibitors nomifensine and benztropine. With the effect on basal overflow blocked, serotonin did not modulate K⁺-induced release of [³H]DA in the nucleus accumbens or striatum. The serotonin agonists, quipazine (in the presence of nomifensine) and 5-methoxytryptamine, did not significantly affect K⁺-induced release of [³H]DA in the nucleus accumbens. This study does not support suggestions that serotonin receptors inhibit the depolarization-induced release of dopamine in the nucleus accumbens or striatum of the rat brain. The present results do not preclude the possibility that serotonin may affect the mesolimbic reward system at a site which is post-synaptic to dopaminergic terminals in the nucleus accumbens.     

Effects of H1 and H2 receptor antagonists on Tetrahymena.

In Tetrahymena pyriformis the phagocytotic rate increases in response to histamine, but neither the H1 antagonist phenindamine nor the H2 antagonist metiamide stimulate phagocytosis. The H1 antagonist counteracts the effect of histamine, whereas the H2 antagonist does not. The histamine receptor of Tetrahymena is of H1-type, since it cannot distinguish between histamine and antagonists which are closely related to it chemically. It does, however, distinguish between histamine and the chemically unrelated H1 antagonist, phenindamine. The H2 antagonist does not interact with the receptor.     

Studies on histamine H2 receptors coupled to cardiac adenylate cyclase Effects of guanylnucleotides and structural requirements for agonist activity

In particular preparations from guinea-pig ventricle, histamine in the concentration range 10^?6–10^?3 M caused a 3–5-fold stimulation of adenylate cyclase activity which was dependent on the presence of GTP. The effects of fourteen analogs of histamine were examined on this cyclase preparation. Five of the compounds studied proved to be partial agonists relative to histamine while nine others had essentially the same intrinsic activity as histamine. The intrinsic activities of the partial agonists were increased by GppNHP to the extent that dimaprit, which was a partial agonist in the presence of GTP, became a full agonist in the presence of GppNHp. The relative potencies of the full agonists as activators of the cyclase were found to correlate with the relative potencies on physiologically defined H₂ receptor systems. Activation of the cyclase by histamine, as well as by several of the agonist analogs, including dimaprit and tolazoline, was completely blocked by the H₂ antagonist cimetidine, but was not affected by pharmacologically relevant concentrations of the H₁ antagonist mepyramine, the β-blocker alprenolol, or the α-blocker phentolamine. The results suggest that all the agonists studied probably interact with a common H₂ receptor site on the cardiac muscle cell leading to activation of adenylate cyclase. The accompanying increase in cyclic AMP is presumably responsible for the chronotropic and inotropic effects of histamine and related compounds on cardiac muscle.     

Suppression of pulmonary and systemic vascular histamine H2-receptors in allergic sheep

We have previously demonstrated a depression of airway H2-receptor function in sheep allergic to Ascaris suum antigen. To investigate whether this is a generalized defect, we studied the H1- and H2- histamine receptor functions in the pulmonary and systemic circulations of allergic and nonallergic sheep. Pulmonary arterial pressure, and cardiac output were measured for calculation of pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) before and immediately after a rapid intrapulmonary infusion of histamine (10 micrograms/kg), with and without pretreatment with H1- (chlorpheniramine) and H2- (metiamide) antagonists. Histamine alone increased mean PVR to 435 and 401% of base line and decreased mean SVR by 51 and 54% in the nonallergic and allergic sheep, respectively (P less than 0.001). In the nonallergic sheep following pretreatment with chlorpheniramine (selective H2 stimulation) or metiamide (selective H1 stimulation), histamine decreased SVR by 18 and 36%, respectively, suggesting that approximately two-thirds of the vasodepressor response was mediated by H1-receptors and one-third by H2-receptors. Combined H1- and H2-antagonists completely blocked the histamine response. In allergic sheep the histamine-induced decrease in SVR was primarily mediated by H1-receptors, because the response was blocked by H1-antagonist, chlorpheniramine, and the H2-antagonist, metiamide, had no effect. In the pulmonary circulation selective H1-stimulation caused a similar increase in PVR in allergic (365%) and nonallergic sheep (424%), whereas selective H2-stimulation caused a significant decrease in PVR in the nonallergic group (14%) but not in the allergic group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanism of adenylate cyclase activation by the rat lung cytoplasmic factors

Epinephrine, histamine and prostaglandin E₁ stimulated adenylate cyclase activity in lung membranes and their stimulation of the enzyme activity was completely blocked by propranolol, metiamide and indomethacin, respectively. A partially-purified activator from the adult rat lung also enhanced adenylate cyclase activity in membranes. However, stimulation of adenylate cyclase by the rat lung activator was not abolished by the above receptor antagonists. Further, epinephrine, NaF and Gpp(NH)p stimulated adenylate cyclase activity rather readily, whereas stimulation of the enzyme activity by the lung activator was evident after an initial lag phase of 10 min. Also, the lung activator produced additive activation of adenylate cyclase with epinephrine, NaF and Gpp(NH)p. These results indicate that the lung activator potentiates adenylate cyclase activity in membranes by a mechanism independent from those known for epinephrine, NaF and Gpp(NH)p. Incubation of lung membranes for 30 min at 40°C resulted in a loss of adenylate cyclase activation by NaF and Gpp(NH)p. Addition of the released proteins to the heat-treated membranes did not restore the enzyme response to these agonists. However, heat treatment of lung membranes in the presence of 2-mercaptoethanol or dithiothreitol prevented the loss of adenylate cyclase response to NaF and Gpp (NH)p. N-ethylmaleimide abolished adenylate cyclase activation by epinephrine, NaF, Gpp(NH)p and the lung activator. These results indicate that the sulfhydryl groups are important for adenylate cyclase function in rat lung membranes.Abbreviations Gpp(NH)p 5-Guanylimidodiphosphate     

Effects of histamine on bronchial artery blood flow and bronchomotor tone

The effects of aerosolized 5% histamine (10 breaths) on bronchial artery blood flow (Qbr), airflow resistance (RL), and pulmonary and systemic hemodynamics were studied in mechanically ventilated sheep anesthetized with pentobarbital sodium. Histamine increased mean Qbr and RL to 252 +/- 45 and 337 +/- 53% of base line, respectively. This effect was significantly different from base line for 30 min after challenge. The histamine-induced increase in RL was blocked by pretreatment with the histamine H1 receptor antagonist, chlorpheniramine, whereas the histamine-induced elevation in Qbr was prevented by the H2 antagonist, metiamide. Both responses were blocked only when both antagonists were present. Changes in Qbr were not directly associated with alterations in systemic and pulmonary hemodynamics or arterial blood gas composition. In vitro histamine caused a dose-dependent contraction of ovine bronchial artery strips that was prevented by H1 antagonist. The H2 agonist, impromidine, caused relaxation of precontracted arterial strips and was more potent and efficacious than histamine, whereas H1 agonists failed to elicit a relaxant response. Thus these findings indicate that histamine aerosol induces a vasodilation in the bronchial vascular bed; histamine has a direct effect on Qbr that is independent of alterations in RL, systemic and pulmonary hemodynamics, or arterial blood gas composition; and, histamine-induced bronchoconstriction is mediated predominantly by H1-receptors, whereas increased Qbr is controlled predominantly by H2-receptors, probably located in resistance vessels. This local effect of histamine on Qbr may have important implications in the pathophysiology of bronchial asthma and pulmonary edema.     

Comparing binding of histamine and H2-antagonist with their effects on gastric acid secretion

A microsomal fraction from isolated frog gastric mucosa was used to study the binding of labeled histamine, labeled metiamide (a histamine H2-antagonist), and competition between labeled histamine and unlabeled metiamide. The separation of free from bound ligand was done by gel chromatography. The acid secretion was studied in frog gastric mucosa in vitro by a pH-stat method. The binding data could be interpreted in terms of two independent binding sites for both histamine and metiamide. However, the competition between histamine and metiamide does not support the independence of the sites. Moreover, the dissociation kinetics of labeled metiamide in the presence of unlabeled metiamide is non-monotone and, thus, indicates cooperativity. In the physiological studies, the dependence of the rate of acid secretion on histamine stimulation occurs within very narrow limits, which is the result of characteristics other than related to binding. However, the total amount of acid secreted caused by a pulse of histamine does indicate two sites, of which the high-affinity site is the more effective. Metiamide inhibition of acid secretion can be interpreted as an interaction between high-affinity sites of histamine and metiamide. Overall, studies involving physiological effects provide less precise data than the direct binding studies.     

Localization of (3H)histamine and (3H)prostaglandin E2 receptors in isolated cells of rat gastric mucosa

Isolated cells of rat gastric mucosa were obtained by treatment of rat stomach with pronase. Two fractions were isolated, one of which was rich (up to 90%) and the second one poor (to 25%) of parietal cells. Using specific antagonists and agonists of H1- and H2-receptors of histamine (diphenhydramine, metiamide, cimetidine, impromidine, dimaprit) the H2-receptors of histamine were shown to be localized in parietal cells. A preferential binding of (3H)prostaglandin E2 by the receptor proteins of plasma membranes of non-parietal (presumably mucoid) cells was found. The data obtained indicate that rat gastric mucosa contains receptors of histamine and PGE2 which differ in their intracellular localization and strictly selectively bind (3H)histamine and (3H)PGE2. It is assumed that the starting point in the mechanism of action of these intercellular regulators on gastric secretion is probably the process of their specific recognition by the protein receptors localized in functionally different cells.     

On the mechanism of stimulation of H+ transport in gastric mucosa by Ca++ ionophore A23187. II. Ca++-cyclic AMP interactions

The possibility of interactions between calcium and cyclic AMP (cAMP) in the mechanism of stimulation of H+ transport by A23187 was studied in the isolated gastric mucosa of the toad Bufo marinus. A23187 stimulated H+ secretion and histamine release. The amount of histamine released by A23187 did not explain the degree of stimulation. Metiamide partially inhibited the response to A23187. Ca++ ionophore produced an overstimulation of secretion after H+ transport had been induced by supramaximal effective concentrations of histamine (10-4 M). In the presence of metiamide, IMX potentiated the response to A23187. Also, in the same condition (metiamide treated) the effects of db-cAMP and A23187 were additive. The results are consistent with an interaction between Ca++ and ionophore-released histamine at the oxyntic cell in the stimulation by A23187. The stimulatory response may be the result of a potentiation between calcium and cAMP at the intracellular level.