INTRODUCTION:

Serotonin or 5-hydroxytryptamine (5-HT) is a biogenic monoamine, which is widely spread in the body and manifests its various actions by binding to membrane receptors^1-4.

Serotonin has important physiological effects on the cardiovascular system. The subtypes of the 5-HT_1A, 5-HT₂ and 5-HT₃ receptors play a key role in the central mechanisms of regulation of cardiovascular activity.

The 5-HT₄ and 5-HT_2B receptors have been found in cardiomyocytes, which are involved in the regulation of myocardial contractility and affect the force of contraction. The 5-HT₃ receptors represent ion channels, while all others are G-protein coupled receptors⁵.

Serotonin is a key signaling molecule in heart progenitor cells involved in the development and differentiation of myocardial cells as well as the separation of the heart chambers⁶. It has been shown that the 5-HT_2B serotonin receptor is crucially important during embryogenesis since knockout of this gene in mice causes heart defects and embryonic lethality⁷.

Excitation of sympathetic cardiac nerves increases the frequency, strength of contractions, accelerates the speed of impulses through the atrioventricular node, and also has an adaptive trophic effect. Important pathways of cardiac control include membrane adrenergic receptors (AR)⁸.

It is known that β1-adrenergic receptors, β2-AR, β3-AR, and β4-AR, or atypical β1-AR, as well as alpha1-AR and alpha2-AR are present in the heart of humans and animals. In the heart, the two adrenergic receptors (ARs) are β-ARs, which account for approximately 90% of all cardiac ARs, and alpha1-ARs, which account for approximately 10%. β1 -adrenergic receptors are most abundant in the mammalian heart compared to β2 (75%: 25%)^9,10.

The peripheral 5-HT is mainly found in platelets. Once 5-HT is released into the circulation, it is taken up into the platelets by the serotonin transporter (SERT)¹¹.

The most commonly used pharmacological treatment for depression is currently based on selective serotonin reuptake inhibitors, which act by binding to SERT and preventing serotonin uptake, thereby increasing serotonin concentration^12-17. Administering serotonin reuptake inhibitors during pregnancy is associated with impaired cardiac morphogenesis and an increased risk of developing heart defects^18-20. In embryos grown at the high concentrations of 5-HT or specific 5-HT reuptake inhibitors, cardiac proliferation disorders have been observed ²¹. Thus, some cardiovascular pathologies such as heart valve abnormalities and primary pulmonary hypertension are related with increased peripheral serotonin levels^22,23.

Parachlorophenylalanine (pCPA) is widely used as an agent to lower serotonin levels. It has been found that pCPA is able to significantly reduce the level of serotonin in mice, rats and dogs ²⁴. Due to its inability to cross the BBB, it reduces peripheral 5-HT levels in mice after oral ingestion by approximately 50% without affecting central serotonin²⁵. Studies have provided evidence that in the absence of peripheral serotonin, serotonin synthesis in the blood is markedly reduced, and such a drop leads to heart failure²⁶.

It can be assumed that a change in the concentration of 5-HT or the blockade of its receptors during pregnancy adversely affects a number of cellular processes required for the normal formation of the heart in the fetus.

The objective is to analyze the effect of adrenaline on the inotropic function of the right ventricular myocardium in newborn rat pups with the blockade of serotonin and membrane transporter synthesis in the embryonic period of ontogenesis.

The aims of the given research are as follows:

1. To examine the effect of the blockade of the serotonin synthesis and membrane serotonin transporter in the embryonic period of ontogenesis on the force of myocardial contraction in rat pups of 7 and 14 days of age.

2. To examine the effect of different concentrations of serotonin on the right ventricular myocardium in 7- and 14-day old rat pups with the blockade of the membrane serotonin transporter and serotonin synthesis in the embryonic period of ontogenesis.

MATERIALS AND METHODS:

The research has been carried out in the scientific laboratory of the Department of Normal Physiology at Kazan State Medical University.

The object of the research is pregnant female Wistar rats and their offspring at the age of 7 and 14 days. Starting from the 11th day of pregnancy and for 10 days straight, the pregnant females have been intraperitoneally injected with the following: Group 1 (control group) – saline; Group 2 – selective serotonin reuptake inhibitor – antidepressant fluoxetine (Fluoxetine hydrochloride, Sigma, USA) at a dosage of 50 μg/kg; Group 3 – a blocker of serotonin synthesis pCPA (4-Chloro-DL-phenylalanine, Sigma, USA) at a dosage of 100 μg/kg. As a result, there have been 2 experimental groups: 1) a group of animals with the blockade of the serotonin transporter and 2) a group of animals with the blockade of serotonin synthesis.

Research method to study myocardial contractility in rats:

Myocardial contractility in an in vitro experiment has been studied on strips of the right ventricular myocardium. The responses of contraction force of the right ventricular myocardial strips to adrenaline (Adrenaline, Sigma, USA) have been evaluated at successive concentrations of 0.1 mM, 1.0 mM, and 10.0 mM.

The heart is removed from rats, which are pre-anesthetized with urethane (800 mg/kg). The heart is then placed in a Petri dish with an oxygenated working solution. The strips, 2-3mm long and 0.8-1mm in diameter, have been prepared from the myocardium of the right ventricle. The preparations are placed vertically in 25ml tanks with the supply of working solution into them. The response of the temporal parameters of contraction in response to adrenaline is calculated as a percentage of the initial value. The contractions are registered using the AcqKnowledge 4.1 program. The signals are processed using the Elf program (designed by A.V. Zakharov).

Statistical analysis. The statistical processing with the definition of M, m and δ on has been carried out using a PC as well as Microsoft Office Excel 2016 and Statistica V.6.0 software. The significance of differences is calculated using the Student's t-test. Differences are considered significant at p <0.05.

RESULTS AND DISCUSSION:

The effect of adrenaline on the contraction force of the right ventricular myocardium in 7- and 14-day-old rat pups with the blockade of the membrane serotonin transporter and the blockade of serotonin synthesis in the embryonic period of ontogenesis:

In the rat pups of 7 days of age, adrenaline in the experimental groups of animals at concentrations of 0.1mM and 1.0mM causes a significant increase in the contraction force of the right ventricular myocardium as compared with the control group. Thus, in the group of the rat pups with the blockade of the serotonin transporter, the contraction force is lower by 24.9% and 16.5%. In the group of the rat pups with the blockade of serotonin synthesis, the contraction force is lower by 27.4% and 29.6%. At the adrenaline concentration of 10.0mM in the second experimental group of the rat pups as compared to the control group, the contraction force is 28.7% lower (p<0.05). In the experimental groups of animals at the maximum concentration of adrenaline, there is a significant increase in the contraction force in the group with the blockade of the serotonin transporter in comparison with the group with the blockade of serotonin synthesis by 27.1%. A positive dosage-dependent inotropic effect of adrenaline on the right ventricular myocardium has been observed in the experimental group with the blockade of the serotonin transporter. The initial data of the contraction force is reliably higher in the control group of animals in comparison with the first experimental group of the rat pups – by 33.3%; and if compared with the second experimental group of rat pups – by 36%.

At 14-day-old rat pups, adrenaline at the concentrations of 1.0mM and 10.0 mM causes a significant increase in the contraction force of the right ventricle myocardium in the first experimental group by 10.8% and 12.6%, as compared with the initial level, and in the second experimental group by 13% and 12.8%, respectively. The initial values of the contraction force are higher in the control group of animals in comparison with the experimental group with an excess of serotonin by 31.2% (p<0.05), and with the experimental group with a deficiency of serotonin by 5.7% (p>0.05) (Fig. 1.).

Fig.1. The effect of adrenaline on the myocardial contraction force in the rat pups of 7 (A) and 14 (B) days of age with the blockade of the membrane serotonin transporter and the blockade of serotonin synthesis in the embryonic period of ontogenesis.

NaCl – saline; FL – fluoxetine hydrochloride; pСРА – 4-Chloro-DL-phenylalanine.

Note: * – statistically significant differences compared to the control group (*p<0.05).

The effect of adrenaline on the temporary characteristics of right ventricular myocardial contraction in 7- and 14-day-old rat pups with the blockade of the membrane serotonin transporter and the blockade of serotonin synthesis in the embryonic period of ontogenesis.

At 7 days of age, adrenaline at the concentrations of 0.1 mM, 1.0mM and 10.0mM shortens the time of myocardial contraction in the experimental group with an excess of serotonin by 0.008s (9.2%), 0.007s (9%) and 0.06s (7.8%) compared with the experimental group with serotonin deficiency (p<0.05). In the experimental group with serotonin deficiency, the contractions in the first and second concentrations increased by 0.004s and by 0.005s compared with the control group (p<0.05). Initial values are 0.005s higher compared to the control group.

At 14 days of age, serotonin at the concentrations of 0.1 mM, 1.0mM, and 10.0mM significantly reduces the duration of right ventricular myocardial contraction in the rat pups with the blockade of serotonin synthesis by 0.005s, 0.007s, and 0.006s compared to the control group, which is 6.7%, 9.2% and 8.2%, respectively. Between the first and second experimental groups, there are also significant differences in the time of reduction in the concentration of adrenaline. In the experimental group with the blockade of serotonin synthesis at the first concentration, the contraction time is 0.004s lower (5.4%); at the second concentration it is 0.008s lower (10.1%), and at the third concentration, it is 0.007s lower (9.3%) when compared with the experimental group with the blockade of the serotonin transporter (Fig. 2).

Fig. 2. The effect of adrenaline on the time of myocardial contraction in the rat pups of 7 (A) and 14 (B) days of age with the blockade of the membrane serotonin transporter and the blockade of serotonin synthesis in the embryonic period of ontogenesis.

NaCl – saline; FL – fluoxetine hydrochloride; pСРА – 4-Chloro-DL-phenylalanine.

Note: * – statistically significant differences compared to the control group (*p<0.05).

In 7-day-old rat pups, all three concentrations of adrenaline cause a significant decrease in the duration of ventricular relaxation by 0.01s (11.4%), 0.03s (18.9%) and 0.02s (15.1%) with the blockade of the serotonin transporter in comparison with the control group of the rat pups. In the experimental group with some serotonin deficiency at the concentration of 0.1, 1.0 and 10.0, the relaxation time has been increased by 0.01s (6.3%), 0.02s (11.5%) and 0.008s (5.9%) compared to the experimental group with an excess of serotonin.

In 14-day-old rat pups, when the concentrations of adrenaline are increased, the relaxation time significantly decreases in the group with serotonin deficiency by 0.02s (12.5%), 0.03s (18.7%) and 0.02s (16.4%) compared with the control group and by 0.03s (14.2%), 0.04s (24.6%) and 0.05s (27.8%) when compared with the group of the rat pups with an excess of serotonin (Fig. 3).

Fig. 3. The effect of adrenaline on the relaxation time of the myocardium in the rat pups of 7 (A) and 14 (B) days of age with the blockade of the membrane serotonin transporter and the blockade of serotonin synthesis in the embryonic period of ontogenesis.

NaCl – saline; FL – fluoxetine hydrochloride; pСРА – 4-Chloro-DL-phenylalanine.

Note: * – statistically significant differences compared to the control group (*p<0.05).

Thus, adrenaline has a positive inotropic effect on the ventricular myocardium of the rat pups in the two analyzed age groups. The inotropic reaction of the myocardium to adrenaline has been more expressed in the rat pups of the control group than in those of the experimental groups, both in 7-day-old and 14-day-old rats (Table 1).

Table 1. Inotropic reaction of the right ventricular myocardium to adrenaline in postnatal ontogenesis in 7- and 14-day-old rat pups with the blockade of the membrane serotonin transporter and serotonin synthesis in the embryonic period of ontogenesis.

Age, days	Concentration of adrenaline, mM	Measurements	NaCl	FL	pСРА
7	0.1	F, g	2.63±0.16	1.98±0.12§	1.91±0.48§
		time (myocardial contraction), s	0.085±0.001	0.082±0.003§	0.090±0.001§
		time (myocardial relaxation), s	0.167±0.006	0.148±0.006§	0.158±0.007
	1.0	F, g	2.97±0.10‡	2.48±0.17‡§	2.09±0.40§
		time (myocardial contraction), s	0.083±0.001‡	0.080±0.003	0.088±0.001‡§
		time (myocardial relaxation), s	0.168±0.006	0.136±0.007‡§	0.154±0.009§
	10	F, g	3.07±0.10‡	3.00±0.19‡	2.19±0.30§
		time (myocardial contraction), s	0.082±0.001‡	0.079±0.002§	0.085±0.003‡§
		time (myocardial relaxation), s	0.159±0.006‡	0.132±0.007‡§	0.140±0.010‡§
14	0.1	F, g	2.25±0.22*	1.93±0.21§	2.08±0.20
		time (myocardial contraction), s	0.088±0.002*	0.087±0.002*	0.082±0.001**§
		time (myocardial relaxation), s	0.169±0.014	0.172±0.006*	0.148±0.005*§
	1.0	F, g	3.18±0.17*‡	2.84±0.26*‡§	2.78±0.28*‡§
		time (myocardial contraction), s	0.085±0.002‡	0.085±0.002*	0.077±0.001**‡§
		time (myocardial relaxation), s	0.158±0.010	0.171±0.007*§	0.129±0.005*‡§
	10	F, g	3.50±0.10*‡‡	3.04±0.26‡§	3.04±0.30*‡§
		time (myocardial contraction), s	0.080±0.002‡	0.081±0.001‡	0.073±0.001*‡§
		time (myocardial relaxation), s	0.138±0.010*‡	0.160±0.006*‡§	0.115±0.004*‡§

NaCl (saline) – control group; FL (fluoxetine hydrochloride) – experimental group with blockade of the serotonin transporter; pСРА (4-Chloro-DL-phenylalanine) – experimental group with blockade of serotonin synthesis; * p<0.05, ** р<0.01 – in comparison with the previous age group; ‡ p<0.05, ‡‡ р<0.01 – change in response compared to concentration 0.1 mM; § p<0.05 – in comparison with the control group.

In 7-day-old rat pups, the reaction of the duration of contraction and relaxation of the right ventricular myocardium to the adrenaline concentration has been less expressed in the first experimental group of the rat pups with the blockade of the serotonin transporter as compared to the other groups. At 14 days of age, there is a more significant decrease in the time of contraction and relaxation in the second experimental group of animals with the blockade of serotonin synthesis compared to the other groups.

Compared with the control group, such a decrease in the response of the contraction function to adrenaline in the experimental groups of animals is potentially associated with the blockade of the synthesis and transporter of serotonin in ontogenesis in these rat pups.

The change in the contractility of the myocardium at the concentration of adrenaline in the experimental groups of the rat pups compared with the control group has occurred in the absence of sympathetic innervation, which possibly indicates some autonomic defects of cardiomyocytes.

The G-protein receptors (GPCRs) are closely associated with cardiac development and defects¹⁶. The regulation of cardiomyocyte activity through Gq-related pathways has still been poorly studied. Nevertheless, it is evident that the Gq-coupled 5-HT_2B receptors regulate cardiomyocytes²⁷.

It is known that the 5-HT_2B receptors regulate embryonic morphogenesis, possibly modulating the differentiation of myocardial progenitor cells. Blocking serotonergic signaling by the 5-HT₂ receptor antagonist, ritanserin, results in the premature differentiation of sarcomeres^7,28.

Myofibrillar structure and disturbed structures of intercellular junctions in the absence of 5-HT_2B receptors suggest that its activation plays a decisive and specific role in forming and expressing cytoskeletal structures in cardiomyocytes. One of the mechanisms leading to impaired contractility may be a change in the structure of the intercalary disc, which has been observed in the myocardium of 5HT_2B receptor knocked-out mice²⁹.

The 5-HT₄ receptor plays an important role in early cardiac development and is also markedly increased in case of ventricular dysfunction³⁰.

It is of interest to note that the distribution and functional role of serotonergic receptors in the heart mimics the role of adrenergic receptors. Similar to the alpha1-adrenergic subtype, the 5-HT₂ receptors are traditionally associated with Gq/diacylglycerol/inositol trisphosphate, while beta-adrenergic receptors and 5-HT₄ receptors are associated with the Gs/adenylate cyclase system³¹.

Adrenergic receptors are mediated by secondary effectors (messengers), namely, by protein kinase A and protein kinase C, as well as the family of kinases called GPCR kinase (GRK)³². The b1-adrenergic receptors of cardiomyocytes activate adrenaline, which, in turn, also activate the G-protein. The dissociation of G-protein results in activating adenylate cyclase, which converts adenosine triphosphate to cyclic adenosine monophosphate. This cyclic adenosine monophosphate activates protein kinase A, which phosphorylates L-type calcium channels and induces calcium influx into a cell. The phosphodiesterase inactivates cyclic adenosine monophosphate, converting it to 5-AMP. Calcium activates the ryanodine receptors of the sarcoplasmic reticulum, which releases calcium. In fact, the inotropic state of the myocardium is essentially determined by the ability of cardiomyocytes to effectively release Ca²⁺ from the contractile apparatus^32,33.

An important mechanism that regulates GPCR signaling is the phosphorylation of ligand-coupled receptors via GPCR kinases (GRKs). Overexpression of GRK2 in the heart may lead to a decrease in βAR density, thereby to a loss of inotropic reserve and a tendency to HF³⁴.

Whether there is a change in contractility in the experimental groups compared with the control group as a result of cross-transmission of signals formed between the 5-HT/5-HT_2B pathways and adrenergic receptors remains to be determined.

CONCLUSION:

The heart begins to function early in development. and thus most of the growth takes place in the womb.

The given research shows that the blockade of the carrier and serotonin synthesis in prenatal ontogenesis leads to a shift in the inotropic function of cardiomyocytes in early postnatal ontogenesis. This is due to a decrease in the response of the contraction force to increasing concentrations of adrenaline in the experimental groups compared to the control group. It is possible that changes in the serotonergic system during ontogenesis affect the intracellular signaling pathways of adrenaline in the heart. It is known that changes in the density and activity of adrenergic receptors cause different dynamics of the heart rate³⁵.

Thus. serotonin is critical for the cardiovascular system’s maintenance. development and normal embryogenesis of the heart. although the mechanisms and signaling pathways through which serotonin acts remain unclear and unestablished. Therefore, the serotonin signaling system attracts the attention of researchers in various fields of biology and medicine. These findings offer new perspectives to use serotonin in the treatment of cardiovascular diseases.

CONFIRMATION:

The research is funded by the MES RK (Grant No. AP05136034).

CONFLICT OF INTEREST:

The authors declare that there is no conflict of interest.

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Received on 31.07.2021 Modified on 04.09.2021

Research J. Pharm. and Tech. 2022; 15(5):2010-2016.

DOI: 10.52711/0974-360X.2022.00333