The Role of Histamine and Serotonin in the Control of Vascular Motricity of the Anterior Ocular Segment-Review of the Literature from 1997 to 2018

1 Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, „Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 2 Department of Physiology, Faculty of Pharmacy, „Carol Davila” University of Medicine and Pharmacy Bucharest, Romania 3 Department of Ophthalmology, „Dr. Carol Davila” Central Military Emergency University Hospital, Bucharest, Romania Corresponding author: Horia Paunescu, Faculty of Medicine, 8th Eroilor Sanitari Boulevard, 5th District, Bucharest, Romania. E-mail: phpaunescu@yahoo.com Abstract


INTRODUCTION
Histamine and serotonin (5-hydroxytryptamine) are two amino acid derivatives with important biological functions 1 .
Histamine, an endogenous monoamine, is synthesized from the histidine and is stored in most tissues and degraded in liver by histaminase.Th e most important roles of histamine are: mediation of type I allergic reactions, stimulation of stomach secretion of hydrochloric acid and pepsin (as autacoid), and functioning as a neurotransmitter (especially in the central nervous system) 2 .Regarding the vascular eff ects of histamine in non-ocular territories, there have not been many published literature reviews, for example, there are data reviewed for pulmonary artery 3 , brain territory 4 , but these data are not recent.
Serotonin (5-HT), synthesized from the tryptophan, exhibits vascular eff ects, which began to be studied a few years after its discovery (the "vasoconstrictionproducing serum substance" described and identifi ed as 5-hydroxytryptamine by Rapport in 1948) 5 .Several reviews about the cardiovascular eff ects of serotonin 6 have been published.

AIM
Th is paper aims to evaluate the infl uence of histamine, serotonin and related substances acting on histamine and serotonin receptors upon anterior ocular vascularisation by studying the literature from 1997-2018.
For the purpose of explaining the working method of the reviewed scientifi c articles, it is necessary to present a brief introduction to the vascular anatomy of the anterior ocular segment.

Anatomical data on anterior eye segment vascularization
Choroid vascularization includes ophthalmic artery branches: two long posterior ciliary arteries (LPCA) and a variable number of two to four short ciliary arteries originated either in the ophthalmic artery or LPCA.Th e iris and the ciliary body are considered to be a unitary one because they have the same embryological origin and the same arterial vasculature, mainly provided by the LPCA.Anterior ciliary arteries are described in humans, but are absent in some mammalian species (e.g., in the rat).At the level of the ocular equator, the two LPCAs pass from the supra-corodial space into the choroid, from where it continues to the ciliary body, at which level each vessel divides dichotomically -a dorso-anterior and a ventro-anterior branch to form the great arterial artery of the iris 7 .

MATERIALS AND METHODS
We used the pubmed.comelectronic platform of the National Library of Medicine using a non-restrictive tag: "(histamine OR serotonine OR 5-HT OR 5-hydroxytryptamine) AND (eye OR eye) AND (vessels OR arteries OR veins)".Th e "Date publication" fi lter was chosen between 1997/01/01 and 2018/12/31.A total of 65 articles resulted at the search performed on 2018/02/01.It is noted that the interest in this fi eld is slightly decreasing compared to the period 1984-2012 (see Figure 1).Of these, 20 articles of interest were selected by reading the abstracts (no articles referring strictly on retinal circulation were selected).Table 1.
The Role of Histamine and Serotonin in the Control of Vascular Motricity of the Anterior Ocular Segment sal mucosa [34][35][36] .H 4 receptors are expressed on mast cells and immune system cells, play a role in chemotaxis and together with H 2 receptors, control IL-16 release 37,33 .
In the following, according to IUPHAR, we will present histamine receptor-associated intracellular signaling systems.
H 1 receptors are coupled with the G q /G 11 protein family, having as primary mechanism of action the stimulation of adenylate cyclase through G subunit of Gq protein, and as secondary transduction mechanism, the activation of phospholipase C (PLC) 38 .
H 2 receptors use the G q /G 11 family of proteins as the primary mechanism of transduction, with sequential activation of PLC, and as a secondary mechanism, the G s protein family which stimulates adenylate cyclase 38 .
H 3 receptors are coupled to the G i /G o protein family, with the subsequent adenylate cyclase inhibition.By the year 2017, H 3 receptors have not been described in mammalian ocular structures 38 .
H 4 receptors are coupled to the G i /G o protein family with consequent activation of PLC 38 .

RESULTS
Of the 20 selected articles, 14 refer only to the histamine domain, 5 refers to the serotonin domain and one article refers to both domains.In addition, we have considered in Discussion section three literature reviews (Buckley, Hadoke, & O'Brien, 1997, Sharif, 2010, Zugravu et al., 2016) 8,9,10 .
Th e results are presented in Table 1.

The histamine system
According to IUPHAR 31 , the histamine receptors described so far are of four types: H 1 , H 2 , H 3 , H 4 .H 1 receptors are widely distributed in the body, including the eye and the eye surface 32,33 , under basal or pathological conditions, such as chronic ocular allergies.H 2 receptors are described mainly in the gastric mucosa, but also in vessels, including ocular blood vessels, causing VD 32,34 .H 3 receptors are found in the brain and the na-  Observations: L-NMMA and L-NNA are NO synthase inhibitors, for the specifi c pharmacological effects for the other substances, see Table 2.
Table 1.continuare ced VD of the conjunctival territory in Guinea pig eyes and at the level of choroidal vessels in humans 23,12 .In human eyes, histamine induced VD in the choroidal territory is NO dependent (VD is signifi cantly attenuated by concomitant administration of L-NMMA).In the porcine ciliary arteries, in vitro, blocking H 1 produces VD 20 .H 1 blockers have no eff ect on vascular size in rat iris 21 .
H 2 blockers have a VC eff ect in the rat in vivo 21 , but not in humans, in the choroidal territory 17 .

The serotonin system
Th ere are 7 types of serotonin receptors, of which 5-HT 3 are ion channels, and 5-HT 1-2 and 5-HT 4-7 are coupled to G proteins 45 .Reviews of types and receptor subtypes have recently been published 46,47 .

ROLES:
Serotonin receptors and their intracellular signal transduction mechanisms are very complex.Th e impor tance of each mechanism is diffi cult to assess without the Th e localization of specifi c H 1 , H 2 , H 3 and H 4 receptors in human and mammalian ocular structures is still elusive 39 .
According to some clinical observations, intraocular pressure (IOP) could be increased by H 2 blockers (cimetidine and ranitidine) 40,41 , data that was not found in the summary of each medicine product characteristics 42,43 .It is very diffi cult to demonstrate the involvement of H 1 receptors in the setting of IOP in clinical trials, as most H 1 inverse agonists or antagonists also exhibit anticholinergic actions 44 .
Regarding earlier research conducted before 1997, in the data reviewed by Buckley et al.,1997, histamine was not studied in the PC arteries 8 .In one of the studies, histamine produced VD in the retinal arteries with intact endothelial artery, in vitro.In bovine eyes, VD is probably dependent on NO and cyclooxygenase (COX).In human eyes, the VD component of the ophthalmic artery is H 2 -mediated and independent of vascular endothelium.In canide, VD is partially dependent of H 2 receptors on vascular smooth muscle fibers, but is not (probably) dependent on endothelium.In bovine eyes and cat eyes, the histamine response is VC 8,12 .
In rat eyes, in vivo, histamine produced a statistically insignifi cant VD of the irian arteries and antagonized VC induced by ranitidine 21 .In vivo, histamine produ- 5-HT 7 receptors were highlighted in the ciliary body, iris and conjunctiva 48 .
Earlier research from 1997 have shown that in vitro, 5-HT produces a vasoconstrictor eff ect of the ciliary and/or ophthalmic arteries of various species: canines, felines, bovines, monkeys and humans 8 .Our in vivo research on rats showed that the 2.5 mM concentration of 5-HT topically applied to the eye surface, has an important VD eff ect in the iris arteries (our unpublished results).
Buckley et al. 26 studied endothelial denuded bovine vessels, in which 5-HT produced vasoconstriction.In vitro, vasoconstrictive eff ects of 5-HT have been highlighted in the literature since 1997.In ciliary arteries obtained from bovine and pigs eyes, various researchers have demonstrated that 5-HT administration, as well as specifi c or selective 5-HT 2 receptor subtypes agonists, produced vasoconstriction.A recent article, published by Njie-Mbye et al., 2018, showed that 5-HT 2 agonists (5-HT 2A , 5-HT 2B , 5-HT 2C ) produced VC that can be antagonized by 5-HT 2 receptor blockers.5-HT 1 receptor agonists did not produce vasoconstrictor eff ect in vitro 30 .
A list of eff ects obtained by in vitro or in vivo administration of the substances from the histamine and serotonin systems are presented in Table 2.

CONCLUSIONS
It is noted that administration of histamine or serotonin in diff erent ways (topical -on the ocular surface, intravenously or in organ bath), may have opposite eff ects and is highly dependent on species and experimental conditions.Specifi c 5-HT 2 receptor agonists are probably vasoconstrictor substances, and 5-HT 2 blockade produces VD that could be a new way of lowering IOP.Regarding the histamine domain, it is diffi cult to fi nd substances that cause VD or even decrease IOP.use of agonists or antagonists with specifi c action on these receptor types or subtypes.Th e review published by Sharif et al., 2010 presents the intraocular pressure lowering eff ect of at least 20 substances in Cynomolgus monkeys.5-HT 6 antagonists have shown intraocular pressure lowering eff ect, which may lead us to the conclusion that there are off -target eff ects of these very specifi c agonists or antagonists.Th e most obvious data on ocular hypotensive eff ect were obtained for 5-HT 2A agonists or 5-HT 2A /5-HT 2C mixt agonists 9 .
Very old research on feline and equine animal model showed that 5-HT produces contraction of the iris sphincter muscle and relaxation of the iris radius muscle 49 .
EFFECTS AND LOCATION: 5-HT 1A receptors are mainly coupled to the G i /G o protein family 50 and are involved in the antioxidant protection of the retinal pigment epithelium 51 and the function of the iris sphincter muscle 52,49 .
5-HT 2A receptors are mainly coupled with the G q / G 11 protein family 53 .Th e same type of intracellular coupling exists for 5-HT 2B and 5HT 2C receptors.Th ere are some studies in animals and humans (Phase II studies) with 5-HT 2A agonists for the treatment of glaucoma 9,48 .Th ey are found mostly at the trabecular meshwork.5-HT 2B and 5-HT 2C receptors are also involved in lowering IOP, with the remark that the 5-HT 2C receptors are not constantly expressed in the ciliary body.Th ey are especially found in the central nervous system.
5-HT 3 receptors are ligand-dependent ion channels with the following ionic conductivity: Na + = K + >Ca 2+ 54 .5-HT 3 receptors are expressed inconstantly in the human ciliary body and probably play a minor role in regulating intraocular pressure 9 .
5-HT 4 receptors are found in the ciliary body, choroida, conjunctiva and inconstantly in iris.
5-HT 5 receptors are found in the ciliary body and iris.