Evaluation of presynaptic histamine receptors in the canine renal vascular bed

Histamine has been shown to increase renal blood flow via H1- and H2-receptors. Furthermore, H2-receptors have been demonstrated to attenuate stimulation-induced release of norepinephrine. The present studies examined whether histamine has a presynaptic effect on sympathetic nerves in the canine renal vascular bed. Renal blood flow was measured in anesthetized dogs, and vasoconstrictor responses to renal nerve stimulation and i.a. injections of norepinephrine were compared before and during i.a. infusions of histamine. Histamine increased renal blood flow and decreased stimulation-induced vasoconstriction to a greater degree than norepinephrine responses. 2-(2-pyridyl)ethylamine, an H1-agonist, did not produce consistent effects. Dimaprit, an H2-agonist, produced responses similar to histamine but to a lesser extent. The H1-antagonist tripelennamine and the H2-antagonist cimetidine each minimally antagonized the effect of histamine on nerve stimulation. When both blocking agents were infused together, maximum antagonism of histamine occurred. Thus, it appears that histamine will produce a neuroinhibitory effect in the canine renal vascular bed and this effect appears to be mediated by both H1- and H2-receptors because both receptor antagonists are necessary to block this effect.     

Adenosine selectively attenuates H2- and beta-mediated cardiac responses to histamine and norepinephrine: an unmasking of H1- and alpha-mediated responses

Adenosine is known to attenuate the positive inotropic and chronotropic effects of norepinephrine and histamine by reducing cyclic AMP accumulation. We assessed whether adenosine, while inhibiting the cardiac responses mediated by beta and H2 receptors, leaves unmodified the responses mediated by alpha and H1 receptors. In isolated cardiac preparations from the guinea pig, adenosine antagonized the positive inotropic effect of histamine more than that of norepinephrine. This most likely occurred because, by attenuating H2 and beta responses, adenosine unmasked the H1-negative and alpha-1-positive components of the inotropic effects of histamine and norepinephrine. Consistent with this hypothesis, the pure H2 agonist impromidine appeared to be antagonized by adenosine less than histamine, and norepinephrine less than isoproterenol. In addition, adenosine antagonized the positive inotropic effect of norepinephrine in the presence of the alpha-1 blocker prazosin, whereas it did not affect the inotropic effect of phenylephrine. In the papillary muscle depolarized by 22 mM K+, adenosine antagonized the restoration of contractile responses induced by histamine or norepinephrine. This action of adenosine was reversed by the phosphodiesterase inhibitor papaverine and by the adenylate cyclase activator forskolin, suggesting that adenosine attenuates beta and H2 responses by suppressing the cyclic AMP-dependent facilitation of Ca++ influx promoted by the two amines. Our data indicate that adenosine selectively attenuates H2 and beta but not alpha and H1 responses. Thus, when catecholamines, histamine and adenosine are released together, as in myocardial ischemia, in addition to their individual effects, negative inotropism, decreased impulse conduction velocity and coronary constriction (i.e., H1- and alpha-mediated responses) may result from the adenosine-histamine-norepinephrine interaction.     

Positive inotropic effect of histamine on guinea pig left atrium: H1-receptor-induced stimulation of phosphoinositide turnover

The purpose of this study was to investigate the mechanism of histamine's H1-receptor-mediated positive inotropic effect, a response which is not associated with an increase in cyclic AMP levels. We found that the concentration-response curve for the positive inotropic effect of histamine on cavian left atrium was similar to that of the alpha-1 agonist phenylephrine, in terms of slope and maximum response. Additionally, both agents slightly prolonged time-to-peak tension and relaxation times. In contrast, the concentration-response relationship for the beta-agonist isoproterenol, whose positive inotropic effect is mediated by an increase in cyclic AMP, had a steeper slope and a much greater maximum. Furthermore, isoproterenol abbreviated time-to-peak tension and relaxation times. As reported previously for alpha-1 agonists, the development of the contractile response to a submaximal histamine concentration (10 microM) coincided with a rapid increase in left atrial tissue levels of inositol triphosphate. The concentration-response curves for histamine effects on contractility and phosphoinositide (PI) turnover were both unaffected by the H2-antagonist tiotidine, but were shifted markedly to the right by the H1-antagonist pyrilamine. High-performance liquid chromatography techniques were applied to resolve the various inositol mono-, di- and tri-phosphate isomers and to assess the possible production of higher phosphates (IP4, IP5 and IP6) in control and histamine-treated (10 microM) atria. Under both conditions IP products were qualitatively similar, but quantitatively greater after treatment with histamine; these products included inositol(1)phosphate, inositol(4)phosphate,inositol(1,4)diphosphate and inositol(1,4,5)triphosphate. No evidence of higher phosphate production was obtained.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of histamine receptors in isolated rabbit veins

Veins were isolated from 16 sites of the rabbit venous tree and responses to histamine and histamine receptor agonists were studied to characterize the histamine receptors. Isometric contraction and relaxation of ring segment preparations were recorded. Histamine produced concentration-dependent contractions in all veins in the resting state. Both the maximum response and pD2 value varied remarkably from vein to vein and regional differences in sensitivities to histamine varied considerably from previous findings in dog veins. Also in the precontracted state with a vasoconstricting agent, histamine predominantly contracted the veins. The contractile responses to histamine, in both resting and precontracted states, were antagonized competitively by the histamine H1-receptor antagonist, mepyramine. On the other hand, histamine relaxed the precontracted veins, in the presence of mepyramine. Selective H2-receptor agonists, dimaprit and impromidine, relaxed the precontracted veins even in the absence of mepyramine. These responses to histamine were antagonized competitively by the H2-receptor antagonist, cimetidine or ranitidine. The present study provides quantitative and systematic data regarding histamine receptors in rabbit veins. We propose that: 1) there are both vasoconstrictor H1-receptors and vasodilator H2-receptors, 2) histamine generally contracts rabbit veins through predominant H1-receptors and that 3) the H2-receptor-mediated relaxation does not depend on the presence of the endothelium.     

Effects of histamine, H1- and H2-receptor antagonists on the activity of serotonergic neurons in the dorsal raphe nucleus

We investigated the effects of histamine applied by microiontophoresis onto serotonin-containing (serotonergic) cells recorded extracellularly in the dorsal raphe nucleus of the rat. Application of histamine at low iontophoretic currents (1-5 nA) produced a rapid depression of the firing of all serotonergic neurons tested. The H1-receptor antagonists mepyramine and diphenhydramine were unable to attenuate the histamine-induced response. Antagonism of the effect of histamine by the iontophoretic application of the H2-receptor antagonists cimetidine and metiamide was not possible to evaluate since both were found to exert potent inhibitory effects by themselves. In contrast, the nonimidazole-derived H2-receptor antagonist ranitidine, which had no effect by itself, selectively antagonized the histamine-induced depression of neuronal activity. Histidine, 3-methylhistamine and a variety of histamine agonists selective for H1- or H2-receptors were unable to mimic the effect of histamine in dorsal raphe. Histamine's effects may, in part, be mediated at a gamma-aminobutyric acid receptor complex as the gamma-aminobutyric acid antagonists bicuculline and picrotoxin rapidly and reversibly antagonized both the histamine- and the cimetidine-induced depression of serotonin cell firing; the glycine antagonist strychnine selectively blocked the inhibitory effect of glycine without altering the histamine-induced response. These data show an inhibitory effect of histamine on serotonin-containing neurons in the dorsal raphe; this effect may be partially mediated at a subtype of H2-receptor. These data further indicate that the inhibitory effects of histamine and cimetidine observed in the dorsal raphe nucleus may result, in part, from an action directly or indirectly at a gamma-aminobutyric acid receptor complex.     

Decreased H2 Histamine Response of Granulocytes of Asthmatic Patients

Increased bronchial sensitivity to inhaled histamine in asthma is well known. The mechanism of this increased bronchial sensitivity is not known nor has it been demonstrated that isolated cells respond abnormally to histamine. Polymorpho-nuclear leukocytes (PMNs) provide a homogeneous cell population to study agonist response. Release of granulocyte lysosomal enzymes is inhibited by agonists increasing the PMN cyclic AMP concentration. The release of the lysosomal enzyme beta glucuronidase by serum-activated particles of zymosan was similar in PMNs isolated from normal and asthma subjects. Histamine (100-0.01 muM) inhibited enzyme release. Except at the maximal concentration of histamine (100 muM), the response to histamine was decreased in asthma. The inhibition of enzyme release paralleled an increase in intracellular PMN cyclic AMP. In asthma, the cyclic AMP response to histamine was reduced. The H2 antihistamine metiamide blocked histamine inhibition of lysosomal enzyme release and the increase in cyclic AMP. The effect was maximal at concentrations equimolar to those of histamine. The H1 antihistamine chlorpheniramine had no effect on histamine inhibition of granulocyte lysosomal enzyme release. A decrease in the inhibition of the release of the inflammatory lysosomal enzymes from granulocytes in asthma may contribute to an enhanced bronchial inflammatory reaction.     

Histamine and histamine receptor antagonists in splanchnic compartments in schistosomal portal hypertension

The type and distribution of histamine receptors in the portal circulation were studied in patients with schistosomal hypertension. At laparotomy, the umbilical, left gastric, splenic, and superior mesenteric veins were cannulated. Blood samples were drawn from the systemic circulation and from each vein for histamine assay. Portal pressures were then estimated in each vein. One group of patients received local injections of pheniramine p-aminosalicylate (H1-antagonist) in the four cannulated veins simultaneously. A second group received cimetidine (H2-antagonist), and a third group received a mixture of both drugs. Reestimation of portal pressures indicated that all treatments produced a significant drop in pressure in the four compartments. The highest drop was in the splenic vein after the H1-antagonist and in the gastric vein after the H2-antagonist. The histamine level was somewhat higher in the splenic compartment. These results suggest that both H1- and H2-receptors are present in the four portal compartments, but their distribution may not be uniform.     

Histamine modulates calcium current in guinea pig ventricular myocytes

In the present work we have examined the effects of histamine on electrophysiological parameters of isolated cardiocytes acutely dissociated from adult guinea pigs. The whole cell patch clamp technique was used to examine action potential and currents. Stable recordings of calcium current (average peak amplitude of 563 +/- 256 pA per cell, n = 83) were obtained. Application of histamine (5 nM-10 microM) resulted in marked modification of action potentials and calcium current. Calcium current was enhanced by histamine in a concentration-dependent manner (half-maximal dose, 10 nM) up to 315% of the control level. Action potentials were prolonged by small doses of histamine whereas larger doses caused voltage instabilities and spontaneous arrhythmic bursts. Histamine effects were reduced by cimetidine and ranitidine (1 microM), two H2-receptor antagonists. After the calcium current was increased by intracellular perfusion of micromolar cyclic AMP saturating doses of histamine had no effect. Micromolar concentrations of acetylcholine rapidly antagonized the histamine effect. The latter results indicate that the response to histamine is based on H2-receptor-mediated activation of adenylate cyclase and cyclic AMP regulation of phosphorylation of calcium channel.     

Identification and specific blockade of two receptors for histamine in the cardiovascular system.

Histamine caused a fall in blood pressure in anesthetized dogs and cats which was only partially attenuated by mepyramine (pyrilamine), a histamine type H1-receptor antagonist. Further treatment with burimide or metiamide, type H2-receptor antagonists, caused nearly complete attenuation of the response to histamine. Burimamide alone had no effect on vasodilatation produced by histamine in the dog gracilis muscle whereas mepyramine alone caused a partial attenuation. An H2-receptor agonist, 4-methylhistamine and an H1-receptor agonist, 2-(2-pyridyl)ethylamine, both produced vasodilatation which was blocked by metiamide and mepyramine, respectively. Constriction of the saphenous vein produced by histamine was found to involve interaction with H1-receptors only. In the intact dog, histamine increased heart rate and decreased left ventricular dp/dt through direct effects. Mepyramine prevented the increase in heart rate but did not affect the chronotropic actions of isoproterenol and glyceryl trinitrate. H1-receptor blockade did not alter inotropic effects whereas subsequent H2-receptor blockade prevented the negative inotropic effect of histamine. It is concluded that both peripheral vascular and cardiac responses to histamine are mediated through activation of H1- and H2-histamine receptors.     

Discriminative stimulus properties of histamine H1-antagonists in animals trained to discriminate d-amphetamine or pentobarbital

Pigeons were trained to discriminate i.m. administered d-amphetamine (AMPH) or pentobarbital (PB) from saline with responding maintained under a fixed-ratio 30 schedule of food delivery. Rhesus monkeys were trained to discriminate intragastrically administered AMPH or PB from saline using a signaled shock-avoidance trial procedure. In AMPH-trained pigeons the histamine H1-antagonists tripelennamine, diphenhydramine and chlorpheniramine consistently produced greater than 80% AMPH-appropriate responding. Pyrilamine substituted for AMPH in two of three pigeons. In contrast, chlorcyclizine, hydroxyzine, promethazine and the histamine H2-antagonist cimetidine all failed to produce AMPH-appropriate responding. None of the histamine H1-antagonists tested substituted for PB in PB-trained pigeons. In AMPH-trained monkeys, only tripelennamine completely substituted for AMPH. Whereas chlorpheniramine, diphenhydramine and pyrilamine did not produce AMPH-appropriate responding in monkeys, these compounds did produce observable excitation and convulsions. As with the PB-trained pigeons, none of the histamine H1-antagonists tested substituted for PB in monkeys. The results of the present study demonstrate that histamine H1-antagonists have differential discriminative stimulus properties in both pigeons and monkeys. Specifically, histamine H1-antagonists known to produce more central nervous system stimulation in humans share discriminative stimulus properties with AMPH and/or produce observable signs of stimulation in monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stimulation of cardiac slow Ca++ current by high concentration of cimetidine

Electrophysiological studies on the cardiac effects of a H2-antagonist, cimetidine, were examined in three kinds of preparations: guinea-pig papillary muscles, rat left atria and perfused chick hearts. Cimetidine (10(-5) to 10(-4) M) depressed or abolished the slow action potentials (APs) induced by histamine (10(-5) to 10(-4) M) in hearts whose fast Na+ channels had been inactivated by 25 mM K+. Higher concentrations of cimetidine (10(-3) to 5 X 10(-3) M) increased myocardial cyclic AMP level and allowed the generation of slow APs in such inexcitable tissues. These cimetidine-induced slow APs were not prevented by propranolol (10(-6) to 10(-5) M) or pretreatment with 6-hydroxydopamine (50 mg/kg). These results suggest that cimetidine, in doses higher than that required to block cardiac H2-receptors, may have a cardio-stimulating action mediated through increase of inward Ca++ current.     

Effect of Histamine and Its Methyl Derivatives on Cyclic AMP Metabolism in Gastric Mucosa and Its Blockade by an H2 Receptor Antagonist

In a cell-free system prepared from guinea pig gastric mucosa, histamine and Nalpha-methyl-histamine produced dose-dependent stimulation of cyclic AMP formation and 1,4-methylhistamine had a minimal stimulatory effect. N-methyl-N'-(2-[5-methylimidazole-4-yl-methylthio]-ethyl) -thiourea (metiamide), a new H2 receptor inhibitor, selectively blocked the stimulation of adenylate cyclase by histamine and its active methyl derivative but had no substantial effect on the basal adenylate cyclase activity or adenylate cyclase stimulated by sodium fluoride. Metiamide inhibited the histamine stimulation of adenylate cyclase at 1/100 the concentration of the histamine. Histamine, its methyl derivatives, and metiamide did not influence the activity of cyclic AMP phosphodiesterase from gastric mucosa. Therefore, histamine stimulates gastric mucosal adenylate cyclase via interaction with the H2 receptor without influencing cyclic AMP breakdown, and N-methylation of histamine on the side chain preserves or even increases its stimulating ability. On the other hand, N-methylation in the ring nearly abolishes the ability of histamine to interact with the H2 receptor.     

The Effects of the Immunologic Release of Histamine upon Human Lung Cyclic Nucleotide Levels and Prostaglandin Generation

The effect of the antigen-induced, immunoglobulin (Ig)E-dependent release of mediators from human lung tissue was analyzed for coincident changes in the tissue levels of cyclic nucleotides. Simultaneously with the appearance of mediators, lung cyclic guanosine 3',5'-monophosphate (GMP) increased from 0.9+/-0.2 to 12.63+/-4.5 pmol/mg protein and cyclic AMP increased threefold from the initial levels of 5.1+/-1.4 pmol/mg protein. The release of histamine and prostaglandin (PG)F(2alpha), as well as the associated increases in cyclic nucleotides, peaked within 10 min of anaphylaxis. Antagonists of histamine's H-1 receptor prevented anaphylaxis-associated increases in cyclic GMP, whereas H-2 antagonists prevented the cyclic AMP response. Neither of these antagonists influenced the pattern or quantity of histamine or slow-reacting substance of anaphylaxis release. Prevention of PGF(2alpha) synthesis with acetylsalicylic acid failed to influence histamine or slow-reacting substance of anaphylaxis release or the concomitant increases in cyclic nucleotides. Histamine, added exogenously, produced a prompt increase in the cyclic AMP and cyclic GMP levels of human lung. As was seen after anaphylaxis, H-1 anatagonists prevented the cyclic GMP response to histamine, whereas H-2 antagonists prevented the cyclic AMP response.H-1 antagonists prevented 50% of the PGF(2alpha) synthesis accompanying anaphylaxis; H-2 antagonists had no effect. Exogenous histamine induced PGF(2alpha) synthesis; this synthesis was prevented by H-1 but not H-2 antagonists, and was reproduced by 2-methylhistamine (H-1 agonist) but not by dimaprit (H-2 agonist). Arachidonic acid generation of PGF(2alpha) was not influenced by antihistamines. Therefore, histamine interactions with human lung result in the synthesis of both PGF(2alpha) and cyclic GMP in response to H-1 stimulation, and of cyclic AMP through H-2 stimulation.     

Regulation by histamine of cyclic nucleotide levels in sympathetic ganglia.

An investigation has been carried out of the role of histamine H1- and H2-receptors in the control of cyclic guanosine 3':5'-monophosphate (cGMP) and cyclic adenosine 3':5'-monophosphate (cAMP) levels in blocks of bovine superior cervical ganglion. The data suggest that activation of H1-receptors is associated with cGMP accumulation and that activation of H2-receptors is associated with cGMP accumulation. Histamine increased both cGMP and cGMP levels with similar time course and concentration-response relationships. Low concentrations of the H1-receptor agonist 2-(2-aminoethyl)thiazole increased cGMP but not cAMP levels. Conversely low concentrations of the H2-receptor agonist 4-methylhistamine increased cAMP but not cGMP levels. H1-receptor antagonists blocked the histamine-induced increase in cGMP at low concentrations but blocked the cAMP increase only at substantially higher concentrations. Conversely, H2-receptor antagonists blocked the histamine-induced increased in cAMP but not cGMP. The effects of histamine on cyclic nucleotide levels did not appear to be mediated via the release of an endogenous neurotransmitter. The histamine-induced increase in cGMP appeared to be mediated through calcium: the increase in cGMP required the presence of calcium in the extracellular medium, and the calcium ionophore A23187 caused a calcium-dependent increase in cGMP. When considered with previous electrophysiological and biochemical findings in sympathetic ganglia, a correspondence can be seen: both histamine (at H1-receptors) and acetylcholine (at muscarinic receptors) raise cGMP levels and are associated with excitatory actions; both histamine (at H2- receptors) and dopamine raise cAMP levels and are associated with inhibitory actions.     

Effect of histamine H2-receptor stimulation on postprandial pancreatic and gastric endocrine function in dogs

The effect of histamine H2-receptor stimulation via the infusion of impromidine was assessed with regard to postprandial plasma insulin, pancreatic polypeptide (PP), somatostatin, and gastrin levels. The effect of impromidine was assessed in the postprandial state during a liver extract/sucrose test meal which had a buffer capacity to maintain the intragastric pH at a constant level for the time impromidine was infused. Postprandial plasma insulin and gastrin levels were not changed by impromidine (10 micrograms/kg X h-1). Plasma somatostatin levels rose significantly, whereas the postprandial increase of plasma PP levels was attenuated. The effects on somatostatin and PP were antagonized by the infusion of cimetidine, a specific histamine H2-receptor blocker. In conclusion the present data demonstrate that in the postprandial state activation of H2-receptors stimulates somatostatin and inhibits PP release while insulin and gastrin release are not affected.     

Effects of antihistamines and local anesthetics on excess tachycardia in conscious dogs

Atropine produces cardioacceleration in conscious dogs partly by reversing the pre-existing parasympathetic cardioinhibition and partly by inducing "excess tachycardia" (ET). Because ET occurs independently of adrenergic mechanisms, the present study sought to determine whether ET is generated by a positive chronotropic action of endogenous histamine on pacemaker cell H1 receptors. ET was antagonized in conscious dogs by the H1-receptor antagonists pyrilamine, diphenhydramine, chlorpheniramine and promethazine (1-5 mg/kg i.v.), but not the H2-receptor antagonist cimetidine (2-10 mg/kg i.v.). Pyrilamine (0.1 mg/kg i.v.), but not cimetidine (4 mg/kg i.v.), also eliminated a histamine tachycardia (31 +/- 4.1 beats/min) produced by injecting histamine (22 +/- 14.2 micrograms) into the sinus node artery after pharmacological autonomic blockade. The 30-fold greater dose of pyrilamine required to antagonize ET than histamine tachycardia suggests a nonantihistaminic, and possibly a local anesthetic mechanism of action on ET. Indeed, lidocaine, procaine, propranolol and pyrilamine antagonized ET in doses corresponding to the known relative local anesthetic potencies of these agents. The same doses of pyrilamine, lidocaine and procaine had significantly less effects on a comparable beta adrenergic tachycardia produced by intravenous isoproterenol infusion (0.1-0.5 micrograms/kg/min i.v.) after hexamethonium (10 mg/kg i.v.). The results indicate that H1-receptor blockers antagonize ET because of their local anesthetic effects and not their antihistaminic properties. The results also suggest that the ionic pacemaker mechanisms generating ET and beta adrenergic tachycardia are different.     

Studies on the cardiovascular actions of central histamine H1 and H2 receptors

Histamine administered i.c.v. to conscious freely moving rats results in dose-related pressor responses and bradycardia. The selective H1 agonist pyridylethylamine (PEA) and the H2 agonist impromidine (IMP) were utilized to characterize the central receptor subtypes involved in the central cardiovascular actions of histamine. Blood pressure and heart rate were monitored directly via indwelling carotid catheters, and drugs were administered i.c.v. through permanently implanted cannulas. Central administration of PEA or IMP produced dose-dependent pressor responses and bradycardia. The H1 antagonist chlorpheniramine blocked the pressor response, but not the bradycardia produced by PEA. In contrast, the H2 antagonist BMY-25405 blocked both the increase in blood pressure and the bradycardia induced by IMP. Crossover experiments were carried out to examine the specificity of the antagonists' actions. Chlorpheniramine failed to block the actions of IMP and BMY-25405 likewise was ineffective in blocking the actions of PEA. These results suggest that both central H1 and H2 receptors mediate the central pressor effects of histamine, and that PEA and IMP are selectively acting at their respective receptors in the brain. The heart rate effects appear to be mediated directly by central H2 actions, as BMY-25405 was capable of blocking the heart rate changes. The finding that IMP is less potent in the central nervous system, compared to its known greater potency in the periphery, suggests that peripheral and central H2 receptors may be pharmacologically distinct.     

The effects of the H1 and H2 antihistamines on "allergic" histamine release and its inhibition by histamine.

Antigen-induced, IgE-mediated release of histamine from human basophiles is an in vitro model of allergic reacttions; it is blocked by extracellular histamine, presumably as a result of its ability to increase adenosine 3',5'-monophosphate (cyclic AMP) levels. The H1 antihistamines do not antagonize these effects of histamine but at approximately equal to 1 mM cause histamine release and at approximately equal to 0.1mM inhibit antigen-induced histamine release. The phenothiazine antihistamines are 10-30 fold more potent inhibitors than the rest; other tricyclic antidepressant drugs share this activity. The mechanism of this inhibition, which occurs in both the 1 degree and 2 degree stages of histamine release, is not known but it is not due to partial agonist activity since the anti-H1 drugs cause a significant fall in cyclic AMP levels. The anti-anaphylactic effects of the H1 antagonists probably play no therapeutic role but we suggest that drugs structurally similar to the phenothiazine antihistamines should be developed for clinical testing. The H2 antihistamines block histamine-induced inhibition of histamine release and the increase in cyclic AMP levels, but neither cause nor inhibit histamine release. The K-B values for the anti-H2 drugs (burimamide approximately equal to 5 muM); metiamide approximately equal to 0.5muM); are similar to those described for other H2 receptors.     

Inhibition of sympathetic nervous system by histamine:studies with H1- and H2-receptor antagonists.

A study was designed to investigate the effect of histamine on sympathetic transmission to the myocardium in pentobarbital-anesthetized dogs. Intravenous infusion of histamine (1.0 and 2.0 microgram/kg/min) produced dose-related decreases in blood pressure and caused significant impairment of cardioacceleration observed during stimulation of the right postganglionic cardiac sympathetic nerve fibers. Positive chronotropic effects of intravenously administered norepinephrine as well as tyramine were not altered during histamine infusion. Blockade of neuronal reuptake with desipramine did not modify the inhibitory action of histamine on sympathetic nerve function. Prior administration of mepyramine (pyrilamine), a histamine type H1-receptor antagonist caused partial attenuation of the depressor action of histamine, but did not prevent histamine-induced inhibition of neurogenic function. Further treatment with metiamide, a histamine type H2-receptor antagonist caused nearly complete attenuation of the depressor response to histamine and also significantly antagonized the inhibitory action of histamine on sympathetic transmission to the myocardium. It is concluded that while the depressor action of histamine is due to the activation of both H1- as well as H2-receptors, histamine causes impairment of sympathetic nerve function to the myocardium by acting on H2-receptors which may be located on sympathetic nerve terminals.     

Evidence for involvement of cyclic nucleotides in intrinsic factor secretion by isolated rabbit gastric mucosa.

Secretion of intrinsic factor (IF) has previously been demonstrated in isolated rabbit fundic mucosa maintained in organ culture. We have now investigated the possibility that cyclic nucleotides may play a role in IF secretion. A phosphodiesterase inhibitor, 3-isobutyl methylxanthine (IBMX), stimulated IF secretion nearly fourfold while increasing tissue levels of both cyclic AMP (cAMP) and cyclic GMP (cGMP). Peak IF secretion in response to IBMX was not reached until after tissue cAMP levels were maximal. Dibutyryl cAMP and 8-Br-cAMP increased secretion by the same order of magnitude as did IBMX, whereas corresponding analogues of cGMP had no such effect. Histamine increased secretion of IF. In the presence of 40 microM IBMX, histamine elevated tissue levels of cAMP, but not of cGMP, and the stimulating effect of 10 microM histamine on IF secretion was potentiated. An H2 receptor antagonist, cimetidine, blocked the increases in IF secretion and tissue cAMP levels due to histamine, and the increase in IF secretion due to IBMX. These observations are consistent with a role for cAMP in the secretion of IF by isolated gastric mucosa.