CC BY
110
Section 2. Medical science
Ashurmetov Azizbek Mirsagatovich, Candidate of Medical Sciences, Central Clinical Hospital No. 1 Main Medical Department at the Presidential Administration of the Republic of Uzbekistan E-mail: ashur.az@mail.ru
PARADOXIAL VASOCONSTRICTION OF CAVERNOUS ARTERIES AS A MANIFESTATION OF SYSTEMIC OXIDATIVE STRESS
Abstract
Objective: To assess endothelial dysfunction and the degree of oxidative stress of cavernous arteries in men with cardiovascular diseases (CVD) and cardiovascular risk factors (CVRF).
Material and methods: 102 men with CVD and CFRF were examined. All men underwent a comprehensive examination, and besides, sexual constitution vector was estimated for all the examined individuals. Endothelial function of cavernous arteries was determined using ultrasonic Doppler examination after exposure to an infrared emitter.
Results: Erectile dysfunction (ED) was detected in 98 (96.1%) men. Endothelial dysfunction (EnD) of cavernous arteries was detected in 93.1% of the examined men. Moreover, in 74.7% of cases, paradoxical vasoconstriction was determined. The sexual constitution vector was within average and weakened average variants in 80.3% of men with ED. Paradoxical vasoconstriction of the cavernous arteries was noted in 57 (69.5%) men with such variants of sexual constitution.
Conclusion: Application of narrow-spectrum IR radiation in diagnosing endothelial dysfunction of cavernous arteries will take a particular place in comprehensive examination of patients with CVD and CVRF. Paradoxical vasoconstriction of cavernous arteries is a local manifestation of systemic oxidative stress. The weakened variant of average and the average variants of sexual constitution in men are a predictor of endothelial dysfunction and weakness of antioxidant protection of blood, organs and tissues.
Keywords: oxidative stress, endothelial dysfunction, terahertz infrared radiation, erectile dysfunction.
It is known that oxidizing (oxidative) stress is in- imbalance in the condition of pro- and antioxidant volved in pathogenesis of many diseases in humans systems of blood, organs and tissues. This indicates and animals [1; 2]. a need for its immediate pathogenetic correction,
Oxidative stress is one of the most common which can be carried out by means of both specific pathological processes, the essence of which is the and non-specific antioxidant therapy.
A large number of studies show that oxidative stress significantly stimulates progression of endothelial dysfunction [3-6].
Numerous studies have confirmed the fact that oxidative stress changes many endothelium functions, affecting vascular tone. Inactivation of nitric oxide (NO) and accumulation of superoxide anion and other reactive oxygen species (ROS) are noted in the presence of arterial hypertension, hypercholesteremia, diabetes, metabolic syndrome, etc.
In a number of laboratory studies on vascular cells researching various enzyme systems, in particular, xanthine oxidase, NADPH/NADPHN oxidase and eNOS, which are capable ofproducing ROS [7]. ROS are a family of molecules that are formed in all aerobic cells and have a high reactive ability with other biological molecules. Under normal physiological conditions, the production of ROS is balanced by an effective antioxidant system, the molecules ofwhich are able to neutralize them and thereby prevent oxi-dative damage. Enzymatic antioxidants (superoxide dismutase, glutathione peroxidase, catalase), which are present in tissues, play an important role in conversion of ROS into oxygen and water.
Non-enzymatic antioxidants (fat-soluble vitamins E and carotene, water-soluble vitamin C), which in particular protect plasma lipids from peroxidation and inactivate superoxide anion [8; 9].
In a number of pathological conditions, excessive formation of ROS occurs, suppressing endogenous mechanisms of antioxidant protection, this shift leads to oxidation of biological macromolecules (DNA, proteins, carbohydrates and lipids), having a detrimental effect on functions of cells and tissues.
The presence of risk factors for cardiovascular diseases contributes to progression of oxidative stress [8]. Oxidative stress, in its turn, is involved in pathogenesis of a number of cardiovascular diseases, including arterial hypertension, hypercholesterolemia, atherosclerosis, diabetes mellitus and heart failure [10; 11].
With excessive formation of ROS, endogenous antioxidant defense mechanisms are suppressed,
which contributes to oxidation of biological mac-romolecules (DNA, proteins, carbohydrates and lipids), having a detrimental effect on functions of cells and tissues.
For example, intracellular accumulation of free radicals contributes to lipid peroxidation, resulting in formation of new lipid radicals. Lipid radicals produced in this chain accumulate in cell membranes and can have a large number of undesirable effects, including disruption of plasmolemma integrity and dysfunction of membrane-binding proteins.
Under conditions of oxidative stress, low-density lipoprotein molecules (LDL) are easily oxidized. Oxidized LDL have a damaging effect on vascular intima, leading to production of foam cells involved in formation of atherosclerotic plaques [12; 13].
The first methods of assessing endothelial function were invasive. NO release inducing drugs (acetylcholine, methacholine, papaverine, etc.) were administered intracoronary, and then the degree of vasodilation was measured. In their experiments, P. L. Ludmer et al. found that administration of acetylcholine, when performing coronary angiogra-phy, causes endothelium-dependent vasodilation in healthy individuals, while paradoxical vasospasm was detected in the presence of atherosclerotic lesions, indicating endothelial dysfunction [14]. However, due to high cost and complexity of its implementation, the invasive method of research is not currently widely used. To date, the "gold standard" for assessing the functional state of endothelium is non-invasive determination of flow-mediated vasodilation (FMD). The technique described by D. S. Celerma-jer et al. in 1992, consists in the study of the brachial or radial artery with ultrasound scanning. Due to its availability, simplicity of execution, reliability, high sensitivity and specificity, it has become widespread and is currently used in fundamental scientific research [8]. Essentially, the method relies on the fact that after cessation of pressure in the cuff blood flow rate increases. With an increase in blood flow velocity in the brachial artery, shear stress increases,
affecting the endothelium, resulting in increased synthesis of NO by endotheliocytes, which leads to local vasodilatation. As a result, a flow-dependent vasodilation of the artery is recorded by ultrasound. The degree of vasodilation is directly proportional to the amount of NO produced, which characterizes the function of endothelium [8, 15]. Another way to assess the state of endothelium in a non-invasive way is to examine pulse wave velocity when performing photoplethysmography. There is a method of peripheral arterial tonometry or finger plethysmography, which is actually a modified Celermajer test. Laser Doppler-flowmetry also refers to non-invasive methods for diagnosing endothelial function, the essence of which consists in optical sensing of tissues and analyzing the signal reflected from red blood cells, which quantifies blood flow in microvessels [8]. Assessment of endothelial function is also possible using positron-emission tomography, which gives the opportunity to assess the coronary perfusion reserve, but this method is expensive, so conducting such a study is not possible in every clinic.
There is a well-grounded data on the use of a narrow spectrum of the far-range (from 8 to 50 ^m) infrared (IR) radiation in medicine and biology [16-18]. Living organisms for communication and control use the considered range of electromagnetic waves, while living organisms themselves emit millimeter-wave oscillations. Waves excited in the body, when exposed to infrared radiation of terahertz range, imitate, to a certain extent, the signals of internal communication and control (information communication) of biological objects.
The terahertz frequency range of electromagnetic waves is located between extremely high frequencies and optical infrared (IR) ranges (Fig. 1) on the scale of electromagnetic waves and is interesting, first of all, because molecular emission and absorption spectra ofvarious cellular metabolites (NO, CO, reactive oxygen species, etc.) belong to this range.
Purpose of the study. To assess endothelial dysfunction and the degree of oxidative stress of the cav-
ernous arteries in men with cardiovascular diseases (CVD) and cardiovascular risk factors (CVRF).
Material and methods
We examined 102 men, aged between 32 and 74, with CVD and CVRF. All men underwent a comprehensive examination, which included collection of general medical and sexological history, general examination, body mass index (BMI) was determination, waist circumference, blood pressure were measurement, and performing biochemical blood tests. In addition, the level of total testosterone and prostate-specific antigen, the lipid spectrum and blood glucose were determined. All patients were surveyed using IIEF-5 (International Index of Erectile Function) and examined for determining their sexual constitution vector (SCV).
Alongside this, all men were examined for en-dothelial function of cavernous arteries, using ultrasound study of diameter changes (ultrasound) after exposure to narrow-spectrum (long-range) IR emitters (Fugure 1).
The study of endothelial function of penis cavernous arteries was performed according to the original method. In the position of the patient lying on his back, linear sensor LA 523 10-5 was placed longitudinally along the ventral surface of the penis at a distance of 2-3 cm from the root. The diameter of cavernous arteries was assessed at least twice, by measuring the distance between the opposites walls of each vessel, and mean values were used for calculations. In addition, the following indicators were determined - peak systolic velocity (PSV), peak diastolic velocity (PDV), reactivity index (RI), pulse index (PI). Then, an infrared emitter was applied to the ventral surface of the penis at a distance of 10-12 cm from the root with 5 minutes of exposure (Fugure 2). After the exposure, a re-ultrasound was performed for measurement of the cavernous arteries diameter in the same place. We used the largest diameter values obtained with the repeated study for calculations.
10a 1 nanometer
10"6
1000 nanometer
10'3 10° 1 millimeter 1 meter
Cosmic rays
X-rays
Microwaves
Gamma rays
Ultraviolet <UV)
Infrared (IR)
Broadcast band
Short Wavelenghts
Visible Light
Ultraviolet
(UV)
Long Wavelengths
Infrared (IR)
400 nanometers
500 nanometers
600 nanometers
700 nanometers
Figure 1. Spectrum of electromagnetic radiation
Figure 2. Far-range infrared emitters
The Percentage of Cavernous Arteries Diameter Increase (PCADI) was calculated by the formula:
PCADI = 100% x (D2 - D1)D1 where D1 is the mean diameter of both cavernous arteries before irradiation with an infrared emitter;
D2 is the mea diameter of both cavernous arteries after irradiation.
All studies were conducted in the morning and by the same ultrasound diagnostics specialist. Before the study, patients were asked to refrain from smoking
and taking any medications that affect cardiovascular system. The threshold PCADI value for distinguishing endothelial dysfunction from the norm was 30%.
Results
Manifestations of erectile dysfunction (ED) were detected in 98 (96.1%) patients. According to IIEF-5: mild erectile disorders were detected in 31 (31.6%) men; moderate degree of impairment in 58 (59.2%) men; severe - in 9 (9.2%); signs of ED were absent in 4 (3.9%).
Figure 3. The technique of IR emitter application on cavernous arteries
During the study of endothelial function of cavernous arteries, endothelial dysfunction was detected in 95 (93.1%) patients. Paradoxical vasoconstriction was diagnosed in 71 (74.7%) patients (PCADI < 0%). In 24 (25.3%) patients, PCADI was detected at a level of less than 30% and made up, on average, 16.5%, indicating a dysfunction of cavernous arteries endothelium. In 7 (6.9%) men, endothelial function of cavernous arteries was within the normal range (PCADI > 30%).
Analysis of patients with a paradoxical reaction of the cavernous arteries to narrow-spectrum infrared radiation showed that in 49.3% of cases PCADI = 0%, and in 50.7% of cases PCADI < 0%. Absence of endothelium reaction and manifestations of cavernous arteries spasm were regarded by us as paradoxical vasoconstriction.
The scale for determining the sexual constitution vector revealed the following: 52 (50.9%) men had a weakened variant of the average constitution; the average variant was identified in 27 (26.5%); the stronger average variant - in 12 (11.8%); weak sexual constitution was found in 7 men (6.9%) and a very weak variant of sexual constitution was found in 1 (0.98%) men. In 3 (2.9%) men, a strong variant of sexual constitution was identified.
In 80.3% (n = 82) of men with ED, the sexual constitution vector was within average and weakened average variants. In 57 (69.5%) men with such variants of sexual constitution, paradoxical vasoconstriction of cavernous arteries was noted.
Discussion
It is known that free radical processes and the activity of antioxidant systems in all living organisms form a single whole - oxidative metabolism, which is one of the basic components of metabolism and is supported by appropriate homeostatic mechanisms [1; 2; 19]. Under normal state of body, functioning the rate of free-radical reactions of cell membrane lipids peroxidation and lipoprotein peroxidation is relatively low due to low levels of initiator-radicals formation and action of a balanced antioxidant defense system. However, in the process of inflammatory diseases emergence and development this balance is disturbed, the production of initiator-radicals increases sharply and inactivation of the antioxidant defense system is observed, thus, develops the so-called oxidative stress.
Oxidative stress is one of the links in the chain of pathogenetic changes formation in the body [20]. An increase in oxidative stress and a decrease in an-tioxidant protection lead to mitochondrial DNA damage and depletion of adenosine triphosphate
(ATP) [21]. Nowadays, the role of oxidative stress in the development of endothelial dysfunction has already been proven [22].
The antioxidant system of each individual, as well as the type of sexual constitution, is formed under the influence of hereditary factors and conditions of development in prenatal period as well as by early ontogenesis.
The paradoxical vasoconstriction of cavernous arteries, which was revealed by us in 74.7% of patients, indicates inactivation of the antioxidant system of endotheliocytes and smooth muscle cells. This requires use of corrective measures for improvement and restoration of endothelial function.
We assume a possible mechanism of paradoxical vasoconstriction in case of endothelial dysfunction of cavernous arteries under the influence of narrowspectrum (far-range) IR radiation.
The action of infrared radiation, with a frequency corresponding to the molecular emission and absorption spectra of NO and ROS, activates blood phagocytes (monocytes) and endothelial cells. This leads to release of NO and ROS, which increases oxidative stress of the endothelium. In addition, excessive NO can bind with superoxide radicals with formation of one of the strongest oxidizing agents -
peroxynitrite. This leads to endothelial dysfunction, depletion ofATP and increased production of endo-thelin-1 vasoconstrictor.
Unlike infrared radiation, mechanical vibrations, after elimination of compression (according to Celermajer), are converted into electromagnetic oscillations with a frequency that does not correspond to molecular emission and absorption spectra of NO and ROS. Consequently, there is no release of ROS and no increase in the level of NO in phagocytes (monocytes) of blood and endothelial cells.
Conclusion
Therefore, the paradoxical vasoconstriction of the cavernous arteries is a local manifestation of systemic oxidative stress.
The use of narrow-spectrum infrared radiation in the diagnosis of endothelial dysfunction of the cavernous arteries is able to determine the severity of oxidative stress. This suggests the need for immediate pathogenetic correction and inclusion of specific and nonspecific antioxidant therapy into the complex of ED treatment.
Weak, weakened variant of average and average variants of sexual constitution in men are predictors of endothelial dysfunction and weakness of antioxidant protection of blood, organs and tissues.
References:
1. Зенков Н. К., Ланкин В. З., Меньщикова Е. Б. Окислительный стресс. Биохимические и патофизиологические аспекты.- М.: Наука, 2001.- 340 с.
2. Меньщикова Е. Б., Ланкин В. З., Зенков Н. К., Бондарь И. А. с соавт. Окислительный стресс. Про-оксиданты и антиоксиданты.- М., 2006.- 556 с.
3. Keaney J. F., Vita J. A. Atherosclerosis, oxidative stress, and antioxidant protection in endotheliumderived relaxing factor action. Prog. Cardiovasc. Dis. 1995; 38: 129-54.
4. Heitzer Th., Schlinzig T., Krohn IK. et al. Endothelial dysfunction, oxidative stress, and risk ofcardiovascular events in patients with coronary artery disease. Circulation. 2001; 104: 2673-8.
5. Taddei S., Ghiadoni L., Virdis A., Versari D., Salvetti A. Mechanisms of endothelial dysfunction: clinical significance and pre ventive non-pharmacological therapeutic strategies. Curr. Pharm. Des. 2003; 9: 2385-402.
6. Ross R. Atherosclerosis: an inflammatory disease. N. Engl. J. Med. 1999; 340: 115-26.
7. Forstermann U., Sessa W. C. Nitric oxide synthases: regulation and function. Eur. Heart J. 2012; 33: 829-37.
8. Esper R.J., Nordaby R. A., Vilarino J. O., Paragano A. Endothelial dysfunction: a comprehensive appraisal. Cardiovasc. Diabetol. 2006; 54: 1475-2840.
9. Givertz M. M., Sawyer D. B., Colucci W. S. Antioxidants and myocardial contractility. Illuminating the "dark side" of ^-adrenergic receptor activation. Circulation. 2001; 103: 782-3.
10. Cai H., Harrison D. G. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ. Res. 2000; 87: 840-4.
11. Sharma А., Bernatchez P. N., Haan J. B. Targeting endothelial dysfunction in vascular complications associated with diabetes. Int. J. Vasc. Med. 2012; ID750126. 12.
12. Janeway C. A., Jr., MedzhitovR. Innate immune recognition. Ann. Rev. Immunol. 2002; 20: 197-216.
13. Peiser L., Mukhopadhyay S., Gordon S. Scavenger receptors in innate immunity. Curr. Opin. Immunol. 2002; 14: 123-8.
14. Ludmer P. L., Selwyn A. P., Shook T. L., Wayne R. R. et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerosis coronary arteries. N. Engl. J. Med. 1986; 315: 1046-51.
15. Уразовская И. Л. Взаимосвязь функционального состояния эндотелия и течения острого инфаркта миокарда с подъемом сегмента ST: дис. ... канд. мед. наук.- М.; 2010: 118.
16. Бецкий О. В., Девятков Н. Д., Кислов В. В. Миллиметровые волны низкой интенсивности в медицине и биологии // Биомедицинская радиоэлектроника. 1998.- № 4.- С13-29.
17. Баграев Н. Т., Клячкин Л. Е., Маляренко А. М., Новиков Б. А. Терагерцевая кремниевая наноэлек-троника в медицине. Инновации., № 10 (156), 2011; 105-119.
18. Гареев Г. З., Лучинин В. В. Применение терагерцевого излучения в биологии и медицине. Наноин-дустрия. № 6 (52), 2014; 34-45.
19. Казимирко В. К., Мальцев В. И., Бутылин В. Ю., Горобец Н. И. Свободнорадикальное окисление и антиоксидантная терапия.- К.: Морион, 2004.- 160 с.
20. Xu X. J., Gauthier M-S., Hess D. T., et al. Insulin sensitive and resistant obesity in humans: AMPK activity, oxidative stress, and depot-specific changes in gene expression in adipose tissue. J Lipid Res. 2012; 53(4): 792-801. doi: 10.1194/jlr.P022905.
21. Goossens G. H. The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol Behav. 2008; 94(2): 206-218. doi: 10.1016/j. physbeh.2007.10.010.
22. Wenceslau C. F., McCarthy C. G., Szasz T., et al. Mitochondrial damage-associated molecular patterns and vascular function. Eur Heart J. 2014; 35(18): 1172-1177. doi: 10.1093/eurheartj/ehu047
