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Histaminski sustav je uključen u regulaciju različitih fizioloških funkcija, kao što su izlučivanje želučane kiseline, neurotransmisija i imunomodulacija. Histaminski sustav u užem smislu obuhvaća četiri podtipa histaminskih receptora i njihove izoforme putem kojih histamin, endogeni biogeni amin ostvaruje svoje biološke učinke. Cilj ovog diplomskog rada bio je opisati ulogu histaminskog sustava u zdravlju i bolesti kroz prikaz najznačajnijih znanstvenih rezultata koja su dovela do sinteze lijekova koji svoje terapijske učinke ostvaruju modulirajući funkciju tog sustava. Tijekom nekoliko desetljeća postignut je značajan napredak u razumijevanju uloge histaminskog sustava u različitim patofiziološkim procesima, od ulkusa i alergija, do bolesti središnjeg živčanog sustava. Lijekovi koji blokiraju histaminske H1- i H2-receptora već se dugi niz godina uspješno koriste u liječenju čestih medicinskih stanja, kao što su alergijske reakcije i ulkusna bolest. Dodatno je identifikacija histaminskih H3- i H4-receptora otvorila nova područja za istraživanje fiziološke uloge histaminskog sustava te razvoj novih generacija lijekova. Potencijalne nove skupine lijekova, H3- i H4-antagonisti predmet su brojnih pretkliničkih istraživanja, s ciljem utvrđivanja njihove djelotvornosti i sigurnosnog profila te optimiranja fizikalno-kemijskih i farmakoloških svojstava. Za neke od najperspektivnijh spojeva u kliničkim se studijama ispituje potencijalna terapijska vrijednost, i to u stanjima kao što su narkolepsija, kognitivni poremećaji, pretilost, shizofrenija, bol, ovisnost. The histamine system regulates a variety of physiological functions, such as secretion of hydrochloric acid, neurotransmission and immunomodulation. In its core, the histamine system includes four subtypes of histamine receptors and its isoforms by which histamine, an endogenous biogenic amine, carries out its biological effects. The aim of this master’s thesis was to describe the role of histamine system in health and illnesses while reviewing most prominent scientific results that led to development of medications which achieve their effects by modulating the function of the system. During the last few decades great progress has been made in understanding the role of histamine system in many pathophysiological processes, from ulcer and allergies, to diseases of central nervous system. For many years drugs that block histamine H1- and H2-receptors are successfully used in treatment of common medical conditions, such as allergic reactions and peptic ulcer disease. Additionally, the identification of H3- and H4–receptors opened new areas for research about physiological role of the histamine system and development of new drugs. The potential new generations of H3- and H4-antagonists drugs are the subject of many preclinical researches with aim to establish their effectiveness and security profile as well as the optimization of the physical-chemical and pharmacological performance. In clinical studies, most promising compounds are examined for their therapeutic validity for wide variety of conditions such as narcolepsy, cognitive disorders, obesity, schizophrenia, pain and addiction.

Using knockout (KO) mice lacking the histamine (HA)-synthesizing enzyme (histidine decarboxylase, HDC), we have previously shown the importance of histaminergic neurons in maintaining wakefulness (W) under behavioral challenges. Since the central actions of HA are mediated by several receptor subtypes, it remains to be determined which one(s) could be responsible for such a role. We have therefore compared the cortical-EEG, sleep and W under baseline conditions or behavioral/pharmacological stimuli in littermate wild-type (WT) and H1-receptor KO (H1-/-) mice. We found that H1-/- mice shared several characteristics with HDC KO mice, i.e. 1) a decrease in W after lights-off despite its normal baseline daily amount; 2) a decreased EEG slow wave sleep (SWS)/W power ratio; 3) inability to maintain W in response to behavioral challenges demonstrated by a decreased sleep latency when facing various stimuli. These effects were mediated by central H1-receptors. Indeed, in WT mice, injection of triprolidine, a brain-penetrating H1-receptor antagonist increased SWS, whereas ciproxifan (H3-receptor antagonist/inverse agonist) elicited W; all these injections had no effect in H1-/- mice. Finally, H1-/- mice showed markedly greater changes in EEG power (notably in the 0.8-5 Hz band) and sleep-wake cycle than in WT mice after application of a cholinergic antagonist or an indirect agonist, i.e., scopolamine or physostigmine. Hence, the role of HA in wake-promotion is largely ensured by H1-receptors. An upregulated cholinergic system may account for a quasi-normal daily amount of W in HDC or H1-receptor KO mice and likely constitutes a major compensatory mechanism when the brain is facing deficiency of an activating system. This article is part of the Special Issue entitled 'Histamine Receptors'. Copyright (C) 2015 Elsevier Ltd. All rights reserved.

To evaluate whether histamine exerts a direct effect on coronary hemodynamics in humans, and to investigate the role played by H1and H2receptors in this response, intracoronary saline solution or histamine (4 μg) was administered in 10 patients with normal coronary arteries during diagnostic cardiac catheterization. Histamine injection was repeated after intravenous Cimetidine (400 mg) and diphenhydramine (10 mg). The electrocardiogram, arterial pressure and thermodilution coronary blood flow were continuously monitored during and for 40 seconds after each injection.Immediately after histamine injection there was a significant increase in coronary blood flow (65 ± 6%) and a decrease in coronary vascular resistance ( − 40 ± 3%) (both p < 0.001), with minor changes in the RR interval and the mean arterial pressure. H2receptor blockade with Cimetidine did not affect these changes, while H1receptor blockade with diphenhydramine sig- nificantly reduced the histamine-induced increase in coronary blood flow and the decrease in coronary vascular resistance (26 ± 6%, p < 0.005 and −18 ± 5%, p < 0.001, respectively). Twenty to 30 seconds after histamine injection, a significant decrease in mean arterial pressure (−17 ± 2%, p < 0.001) and in the RR interval (−4 ± 1%, p < 0.01) was observed. These changes persisted after H2receptor blockade with Cimetidine, but were completely abolished after H1receptor blockade with diphenhydramine. In each case coronary and systemic hemodynamics returned to normal within 40 seconds of the injection.Therefore, in patients with normal coronary arteries, histamine induces a direct dilation of the small resistance coronary arteries, regardless of myocardial metabolic requirement, that is predominantly, but not completely, mediated by H1receptors.

We evaluated the effects of selective activation of H1 receptors on coronary hemodynamics in 16 patients divided into two groups: group A, 11 patients with atypical angina or valvular heart disease and normal coronary arteries, and group B, five patients with spontaneous angina, four of whom had significant (greater than 70% stenosis) coronary artery disease and one with normal coronaries. Selective H1 receptor stimulation was achieved by infusing 0.5 microgram/kg/min of histamine intravenously for 5 min after pretreatment with cimetidine (25 mg/kg). Heart rate was maintained constant (100 beats/min) by coronary sinus pacing and coronary blood flow (CBF) was measured by thermodilution. In group A, during histamine infusion mean aortic pressure fell from 99 +/- 5 to 77 +/- 4 mm Hg (mean +/- SEM, p less than .001), coronary vascular resistance (CVR) decreased from 1.07 +/- 0.17 to 0.82 +/- 0.14 mm Hg/ml/min (p less than .02), and CBF and myocardial oxygen consumption remained unchanged. None of the patients in this subgroup developed angina during histamine infusion. In group B, while no significant average changes in mean arterial pressure, CVR, or CBF were observed, two of the five patients (40%) developed angina during histamine infusion, accompanied by ST-T elevation, a decrease in CBF, and an increase in CVR. In one of these two patients circumflex coronary arterial spasm was angiographically demonstrated during histamine-induced angina. Our results suggest that stimulation of the H1 receptor induces a reduction of CVR, probably resulting from vasodilation of small coronary resistance vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Exogenous histamine in man induces significant cardiovascular effects mediated by activation of H1 and H2-receptors present on human heart and on coronary arteries. We studied the effects of selective H1-receptor stimulation on human coronary hemodynamics in 10 patients undergoing cardiac catheterization. All patients were pretreated with cimetidine before the histamine infusion (0.5 micrograms/kg/min i.v. for 5 min). Six of these patients had normal coronary arteries and four had single vessel coronary artery disease (CAD) and vasospastic angina. During the study heart rate was held constant (100 beats/min) by coronary sinus pacing. We measured mean aortic pressure (MAP), coronary sinus blood flow (CSBF), coronary vascular resistance (CVR) and myocardial oxygen consumption (MVO2) at rest, during histamine infusion, and 10 min after the end of the infusion. During infusion, MAP decreased from 103 +/- 5 to 85 +/- 6 mmHg (p less than 0.02) and CVR from 1.00 +/- 0.16 to 0.81 +/- 0.14 mmHg/ml/min (p less than 0.05); CSBF and MVO2 did not significantly change. All parameters returned to baseline at the end of the infusion. The response was similar in patients with normal coronary arteries and in 3 patients with CAD. Only one patient with CAD developed angina with ST segment elevation in D3, reduction in CSBF and an increase in CVR. These results indicate that H1-receptor stimulation in man induces significant coronary dilatation and that histamine infusion after cimetidine pretreatment is unlikely to provoke coronary spasm in patients with vasospastic angina.