A role for histamine and histamine H2-receptors in non-opiate footshock-induced analgesia

Scrambled DC current applied to the hind paws of rats caused an analgesic response that was inhibited by the histamine H2-receptor antagonists cimetidine, ranitidine and oxmetidine, but not by high doses of naloxone (the opiate antagonist), or other transmitter receptor antagonists. In contrast, AC current applied to all paws produced analgesia that was blocked by naloxone, but not cimetidine, showing the independence of these systems. These findings indicate a specific role for histamine and H2-receptors as mediators of endogenous non-opiate analgesia. In addition, a combination of cimetidine and naloxone did not abolish either form of footshock analgesia, implying the existence of a non-opiate, non-H2, endogenous pain-relieving system. These results also suggest that drugs capable of penetrating the brain and stimulating H2-receptors might have analgesic properties.     

Role of brain histamine H1- and H2-receptors in neostigmine-induced hyperglycemia in rats.

We previously reported that when neostigmine, an inhibitor of acetylcholine esterase, was injected into the third cerebral ventricle, the concentration of hepatic venous plasma glucose was increased via central muscarinic receptors in anesthetized rats. To determine whether brain histamine receptors are involved in cholinergic system transmission with regard to central nervous system (CNS)-mediated glucoregulation, we examined the effects of the H1 receptor antagonist pyrilamine and the H2 receptor antagonist ranitidine on neostigmine-induced hyperglycemia in anesthetized rats. The injection of pyrilamine (5 x 10(-9)-5 x 10(-7) mol) into the third cerebral ventricle suppressed hyperglycemia induced by intraventricular injection of neostigmine (1 x 10(-9) mol) in a dose-dependent manner. Injection of ranitidine (5 x 10(-9)-5 x 10(-7) mol) into the third cerebral ventricle did not suppress the hyperglycemia induced by neostigmine, but enhanced it in a dose-dependent manner. These findings suggest that neostigmine-induced CNS-mediated hyperglycemia is transmitted by not only brain cholinergic muscarinic receptors but also in part by histamine H1 receptors.     

Identification of [3H] histamine binding sites on gastric mucosal cells unrelated to histamine H2-receptors

Acidic unfolding process of myoglobin was investigated in the presence of external ligands (azide, cyanide, fluoride and imidazole). With azide, cyanide and fluoride as ligand, myoglobin unfolds through a single exponential decay process, whereas it is not the case with imidazole. No faster decays were observed as in the case of myoglobin without external ligands. These results demonstrate the important role of iron-ligand interaction on the conformational stability of myoglobin.     

Presynaptic localization of histamine H3-receptors in rat brain.

The localization of histamine H3-receptors in subcellular fractions from the rat brain was examined in a [3H] (R) alpha-methylhistamine binding assay and compared with those of histamine H1- and adrenaline alpha 1- and alpha 2-receptors. Major [3H](R) alpha-methylhistamine binding sites with increased specific activities ([3H]ligand binding vs. protein amount) were recovered from the P2 fraction by differential centrifugation. Minor [3H](R)alpha-methylhistamine binding sites with increased specific activities were also detected in the P3 fraction. Further subfractionation of the P2 fraction by discontinuous sucrose density gradient centrifugation showed major recoveries of [3H](R)alpha-methylhistamine binding in myelin (MYE) and synaptic plasma membrane (SPM) fractions. A further increase in specific activity was observed in the MYE fraction, but the SPM fraction showed no significant increase in specific activity. Adrenaline alpha 2-receptors, the pre-synaptic autoreceptors, in a [3H] yohimbine binding assay showed distribution patterns similar to histamine H3-receptors. On the other hand, post-synaptic histamine H1- and adrenaline alpha 1-receptors were closely localized and distributed mainly in the SPM fraction with increased specific activity. Only a negligible amount was recovered in the MYE fraction, unlike the histamine H3- and adrenaline alpha 2-receptors.     

Late-phase bronchial vascular responses in allergic sheep

Sheep were classified on the basis of their airway response to Ascaris suum antigen aerosols as allergic or nonsensitive. Allergic sheep were classed as acute or dual responders. Acute responders had only an immediate increase in mean airflow resistance after antigen, whereas dual responders had an immediate and late-phase (6-8 h after antigen challenge) increase in mean airflow resistance; nonsensitive sheep had minimal airway responses to antigen (less than 30% increase from base line). The sheep were anesthetized 2 wk later and, after a left thoracotomy, were challenged with antigen to determine bronchial vascular responses; bronchial artery blood flow was measured with an electromagnetic flow probe. Airway responses to antigen aerosol challenge were similar in the anesthetized and conscious animals. The mean fall in bronchial vascular resistance (BVR) immediately after antigen challenge was similar in acute and dual responders (41 +/- 7 and 47 +/- 9% of base line, respectively). In dual responders, late-phase airway responses were preceded by a significant increase from base line in Qbr and a fall in bronchovascular resistance (BVR). The mean fall in BVR 6-8 h after antigen challenge in documented dual responders was significantly different from bronchial vascular responses in acute responders (59 +/- 3 vs. 89 +/- 10%, respectively). Sheep without airway responses to A. suum had no significant changes in bronchial hemodynamics or airways mechanics. Late-phase-associated changes in BVR are a specific response to antigen challenge and may be a sensitive index of mediators being released.(ABSTRACT TRUNCATED AT 250 WORDS)     

ICI 125,211: a new gastric antisecretory agent acting on histamine H2-receptors.

$\text{In}$$\text{vitro}$, ICI 125,211 competitively antagonized the action of dimaprit on guinea pig atrium with an apparent dissociation constant of 1.5 × 10^?8M (pA₂ = 7.8). $\text{In}$$\text{vivo}$, the histamine dose-response curve in conscious gastric fistula beagles was shifted rightward in parallel without change in the maximal response by intravenous infusions of ICI 125,211 at doses of 0.01 and 0.03 umol/kg/hr (estimated pA₂ = 7.3). Our data show that this new drug is at least 10x more potent than cimetidine as an inhibitor of gastric secretion in the dog. ICI 125,211, which is an orally effective antisecretory agent in man and devoid of antiandrogenic activity, is the most potent selective H₂-blocker described to date.     

Increased severity of reperfusion arrhythmias in mouse hearts lacking histamine H3-receptors

We had previously reported that activation of histamine H(3)-receptors (H(3)R) on cardiac adrenergic nerve terminals decreases norepinephrine (NE) overflow from ischemic hearts and alleviates reperfusion arrhythmias. Thus, we used transgenic mice lacking H(3)R (H(3)R(-/-)) to investigate whether ischemic arrhythmias might be more severe in H(3)R(-/-) hearts than in hearts with intact H(3)R (H(3)R(+/+)). We report a greater incidence and longer duration of ventricular fibrillation (VF) in H(3)R(-/-) hearts subjected to ischemia. VF duration was linearly correlated with NE overflow, suggesting a possible cause-effect relationship between magnitude of NE release and severity of reperfusion arrhythmias. Thus, our findings strengthen a protective antiarrhythmic role of H(3)R in myocardial ischemia. Since malignant tachyarrhythmias cause sudden death in ischemic heart disease, attenuation of NE release by selective H(3)R agonists may represent a new approach in the prevention and treatment of ischemic arrhythmias.     

Synaptic and extra-synaptic distribution of histamine H1-receptors in rat and guinea pig brains

Localization of histamine H1-receptors in subcellular fractions from rat and guinea pig brains was examined in a [3H]mepyramine binding study. Major [3H]mepyramine binding sites with increased specific activities [( 3H]mepyramine binding vs. protein amount) were recovered from P2 fractions from both rat and guinea pig brains by differential centrifugation. Further subfractionation of both rat and guinea pig P2 fractions by a discontinuous sucrose density gradient centrifugation showed the highest recovery of [3H]mepyramine binding with further increased specific activities found in synaptic plasma membrane (SPM) fractions. Minor [3H]mepyramine binding sites with increased specific activities were detected in both rat and guinea pig P3 fractions. [3H]Mepyramine binding sites in SPM and P3 fractions showed identical Kd values in each species. These results indicate that histamine H1-receptors are located not only in synaptic but also in extra-synaptic membranes of both rat and guinea pig brains.     

Electrically induced release of radiolabeled histamine from rat hippocampal slices: opposing roles for H1- and H2-receptors

Rat hippocampal slices were preloaded with 3H-histamine and superfused with physiological medium and electrically stimulated in the absence (S1) and in the presence (S2) of drugs. The electrically evoked 3H-overflow consisted mainly of histamine, was Ca++ dependent and completely blocked by tetrodotoxin, all pointing towards an impulse triggered neuronal release. Mepyramine, promethazine and diphenhydramine the H1-antagonists, inhibited the stimulation evoked histamine release in a dose dependent manner. Burimamide and cimetidine, the H2-antagonists, enhanced the stimulation induced release of histamine whereas dimaprit, the H2-antagonist, had the opposite effect. Histamine by itself did not influence its own release. The observations indicate an opposing role for H1- and H2-receptors in modulating spike induced histamine release and represents a functional consequence of the stimulation of the receptors.     

Modulation of acetylcholine-induced secretion of gastric bombesin-like immunoreactivity by cholinergic and histamine H2-receptors, somatostatin and intragastric pH

Recently we have shown the release of bombesin-like immunoreactivity (BLI) from the isolated perfused rat stomach. In these experiments we have shown that BLI secretion is stimulated by acetylcholine. Gastric inhibitory peptide (GIP) exerts an inhibitory effect which is dependent on the intraluminal pH. The present study was designed to examine further the exact cholinergic mechanisms and to study the interaction between cholinergic and histaminergic mechanisms as well as the effect of the intraluminal pH. Acetylcholine elicited a dose-dependent increase in BLI and gastrin secretion (10(-6) M and 2 X 10(-6)M), whereas somatostatin release was suppressed at luminal pH 7. Blockade of muscarinic cholinergic receptors by atropine (10(-5)M) and nicotinic cholinergic receptors by hexamethonium (10(-5) M) abolished the effect of acetylcholine on all three peptides. Reduction of the intraluminal pH to 2 also abolished acetylcholine-induced stimulation of BLI and gastrin secretion and the inhibition of somatostatin secretion. Changes of intraluminal pH per se had no effect on the secretion of either peptide. Somatostatin (10(-7) M) reduced both BLI and gastrin secretion during stimulation with acetylcholine. The addition of the H2-receptor antagonist cimetidine (10(-5) M) abolished the effect of both doses of acetylcholine on BLI and somatostatin secretion and also the effect of the lower dose of acetylcholine (10(-6) M) on gastrin secretion during luminal pH 7. At luminal pH 2 cimetidine did not alter BLI and somatostatin secretion in response to acetylcholine, however, gastrin release was augmented in the presence of cimetidine. These data demonstrate that the effect of acetylcholine on BLI, gastrin, and somatostatin secretion is mediated by muscarinic and nicotinic cholinergic receptors and also by histamine H2-receptors. Somatostatin inhibits cholinergically induced BLI secretion. The cholinergic effects on BLI, somatostatin and gastrin secretion are abolished during an acidic intragastric pH. In this isolated perfused rat stomach model the inhibitory effect of intraluminal acid on gastrin secretion is, at least in part, mediated by H2-receptors. This suggests that the secretion of bombesin, a potential peptidergic neurotransmitter is modulated by neural, endocrine and local tissue factors and also by alterations of intragastric pH.     

Effect of cardiogenic and noncardiogenic pulmonary edema on histamine responsiveness in sheep

We compared the effects of cardiogenic pulmonaryedema, brief pulmonary vascular congestion without frank edema, andnoncardiogenic pulmonary edema on responsiveness to inhaled histaminein chronically instrumented awake sheep. Histamine responsiveness wasmeasured before and after 1)cardiogenic pulmonary edema induced by raising left atrial pressure to35 cmH₂O(Pla) for 3.5 h by partial obstruction of flowacross the mitral valve, 2) briefcardiogenic congestion via Pla for 0.5 h,3) noncardiogenic pulmonary edemainduced by 25 mg/kg intravenous perilla ketone (PK), and4) 3.5 h of monitoring withoutPla or PK (controls). Treatment for 3.5 h with Pla(n = 9) and PK(n = 11) each significantly lessenedthe histamine dose required to cause a fall to 65% of baseline dynamiclung compliance (ED₆₅Cdyn), i.e.,increased responsiveness. Sheep treated for 0.5 h with Pla(n = 7) and controls(n = 5) showed no significant changein ED₆₅Cdyn. Intravenous atropine(0.1 mg/kg) before the second histamine challenge altered neither thereduction of ED₆₅Cdyn inPla (n = 8) and PK(n = 9) sheep nor theED₆₅Cdyn level of controls(n = 9). These data imply that thelocal effects of edema, rather than bronchial vascular hemodynamics,cholinergic reflexes, and permeability changes, are germane to lunghyperresponsiveness during pulmonary edema in sheep.

     

Short-term desensitization of phosphatidylinositol turnover via muscarinic acetylcholine receptors and histamine H1-receptors in smooth muscle

Smooth muscle of guinea-pig taenia caecum was desensitized by treatment with 10(-4)M carbachol or 10(-4)M histamine for 30 min in Ca-free solution containing 2mM EGTA. Phosphatidylinositol turnover stimulated by carbachol was not reduced by desensitization with either carbachol or histamine, while the turnover stimulated by histamine was reduced by desensitization with histamine, but not with carbachol. These results are consistent with our previous report (1) that heterologous desensitization induced by carbachol occurs at intracellular Ca stores and homologous desensitization by histamine occurs at H1 receptors.     

HeLa cells have histamine H1-receptors which mediate activation of the K+ conductance

HeLa cells responded to exogenous histamine with a transient hyperpolarization due to increased membrane conductance to K+. After successive applications of histamine, the cell membrane became virtually unresponsive (desensitized). The responses were blocked by pyrilamine but not by cimetidine. Thus, it appears that HeLa cells have H1-receptors which mediate an increase in the K+ conductance.     

Specific binding of [3H] mepyramine to histamine H1-receptors in the sarcolemma from porcine aorta and coronary artery

We studied the subcellular distribution and the properties of [3H] mepyramine binding in the porcine vascular smooth muscle. A close correlation was observed between the specific binding activity of [3H] mepyramine and the extent of the enrichment of sarcolemmal marker enzyme in 4 subfractions obtained by sucrose density gradient centrifugation of the aortic microsome. In the binding isotherm in the sarcolemmal fractions from the aorta and coronary artery, there was no difference in the Kd value, but the Bmax of the coronary artery was significantly lower than that of the aorta. Thus, there is a single type of high affinity mepyramine binding site in the porcine vascular smooth muscle sarcolemma and the number of H1-receptors of the coronary artery may be smaller than that of the aorta.