The Role of Nitric Oxide Related Therapeutics in the Treatment of Cardiovascular Pathologies

Derici, Mehmet Kursat/0000-0002-8260-7492WOS: 000446931200001The heart is a bio pump responsible for the provision of oxygen and nutrients to all body cells. It plays a vital role in the survival of the organism. The essential function of the heart is performed through the close interaction of the cardiac myocytes with the endocardial and capillary endothelial cells. The endothelium releases nitric oxide (NO) and modulates several physiological and pathological processes. The cardiac myocyte is also capable of NO production. Although the effect of NO on cardiac responses has been examined, data regarding the effect of NO on the heart remain controversial. The discrepancies in studies can be explained by several factors, such as different animal species, preparation, redox status, and NO concentration. However, an increasing interest in the role of NO has generated significant progress in the investigation of NO-based therapies. In this review, first, the general properties of NO are described as well as the physiological functions and pathological role in the heart. Then, an evaluation is made of several important NO-related treatment options, such as NO donors, NO synthase inhibitors, phosphodiesterase inhibitors, and soluble guanylate cyclase stimulators/activators. A summary is also given of NO-based drug candidates planned for use in clinical trials in the near future

Age- and sex-dependent alteration of functions and epigenetic modifications of vessel and endothelium related biomarkers.

Aging is a main risk factor for development of cardiovascular diseases associated with the impairment of endothelial function in both sexes. In the present study, age-related changes in vascular responsiveness, epigenetic modifications of vessel wall, and blood biomarkers related to endothelial functions were examined in an age- and sex-dependent manner. Acetylcholine (ACh)-induced relaxations of the aorta were decreased in 3-, 6-, and 12-month-old rats compared to those in 1-month-old female rats. In males, maximum relaxations related to ACh were higher in 1- and 6-month-old rats than in 3- and 12-month-old rats. Plasma levels of nitric oxide (NO) and asymmetric dimethylarginine (ADMA) decreased with age in female rats, and total antioxidant capacity (TAC) and hydrogen sulfide (H 2S) levels displayed biphasic alterations. In male rats, plasma levels of NO, TAC, and ADMA decreased with age, and H2S levels increased. Aging also caused a sex-dependent alteration in epigenetic modification of vessels. Expressions of H3K27me2, H3K27me3, H3K36me2, and H3K36me3 were much higher in vessels of 12-month-old female rats compared to those in younger age groups. These results indicate that vascular functions, epigenetic modifications of vessels, and plasma levels of endothelium-related biomarkers are affected by age and sex. These findings could be important for the assessment of vascular status over the course of the life span

Diurnal Temporal Blood H2S Variations Correlate with the Circadian Rhythm of Vascular Contraction and Blood Pressure

Background: It is well known that blood pressure has a circadian rhythm in rat. However, the underlying mechanisms that modulate circadian rhythm of blood pressure have not been fully clarified. The aim of this study was to investigate the probable mechanisms that regulate time dependent variation of blood pressure. In present study, the correlations among the following s:alpha-1 adrenoceptor stimulated aortic contractions, thoracic aortic expression of Rho-kinase ll and myosin phosphatase target subunit-1 and blood biomarkers (nitric oxide, hydrogen sulfide {[}H2S] and total antioxidant capacity) that regulate blood pressure at six different times of the day and night were examined. Materials and Methods: Systolic blood pressure was measured every 4 h during a 24 h period in male albino Wistar rats by tail-cuff plethysmography. At each time point, contraction and relaxation responses of isolated thoracic aortas were recorded. The expression of protein from aortas was determined by western blot method. Nitric oxide, total antioxidant capacity and H2S levels were measured spectrophotometrically in plasma samples. One-way analysis of variance and student t-test was used to determine statistical differences. Results: Rat systolic blood pressure displayed a circadian rhythm, which reached the maximum at 05:00 am and minimum at 09;00 am. Diurnal variation of phenylephrine-induced contractions in the isolated thoracic aorta was also observed. Although, the Rho-kinase inhibitor Y-27632 reduced phenylephrine-induced contractions, the circadian pattern of the contractions did not change. Interestingly, Rho-kinase II and myosin phosphatase target subunit -1 protein expression in the thoracic aorta did not show significant changes throughout the day. Further, plasma levels of nitric oxide and total antioxidant capacity did not vary during the day. However, H2S levels in the systemic circulation showed circadian variation, which was the maximum at 01:00 am and minimum at 05;00 am. Conclusions: These results suggest that, in addition to alpha-1 adrenoceptor sensitivity of vessels, the circadian rhythm of plasma H2S could contribute to diurnal blood pressure variations. This highlights a potential novel experimental and therapeutic approach to blood pressure regulation

Age- and sex-dependent alteration of functions and epigenetic modifications of vessel and endothelium related biomarkers

Aging is a main risk factor for development of cardiovascular diseases associated with the impairment of endothelial function in both sexes. In the present study, age-related changes in vascular responsiveness, epigenetic modifications of vessel wall, and blood biomarkers related to endothelial functions were examined in an age- and sex-dependent manner. Acetylcholine (ACh)-induced relaxations of the aorta were decreased in 3-, 6-, and 12-month-old rats compared to those in 1-month-old female rats. In males, maximum relaxations related to ACh were higher in 1- and 6-month-old rats than in 3- and 12-month-old rats. Plasma levels of nitric oxide (NO) and asymmetric dimethylarginine (ADMA) decreased with age in female rats, and total antioxidant capacity (TAG) and hydrogen sulfide (H2S) levels displayed biphasic alterations. In male rats, plasma levels of NO, TAG, and ADMA decreased with age, and H2S levels increased. Aging also caused a sex-dependent alteration in epigenetic modification of vessels. Expressions of H3K27me2, H3K27me3, H3K36me2, and H3K36me3 were much higher in vessels of 12-month-old female rats compared to those in younger age groups. These results indicate that vascular functions, epigenetic modifications of vessels, and plasma levels of endothelium-related biomarkers are affected by age and sex. These findings could be important for the assessment of vascular status over the course of the life span

Effects of Ozone Treatment in Endotoxin Induced Shock Model in Rats

Objective: This study was focused on effects of ozone application on vital and biochemical parameters in rat model of endotoxin-induced shock. Materials and Methods: Lipopolysaccharide (LPS; 10 mg kg(-1), i.p.) induced shock model was used in male Wistar albino rats. Three different doses of ozone were used for this study (0.1, 0.3 and 1.0 mg kg(-1), i.p.). Tail-cuff method was preferred for measurements of systolic blood pressure and heart rate. Plasma nitric oxide (NO), total antioxidant capacity (TAC), asymmetric dimethylarginine (ADMA), aspartate transaminase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH) levels were detected as biochemical parameters. Results: Decline in systolic blood pressure and increment in heart rate of rats were observed an hour after injection of LPS. Ozone application did not possess any significant improvement on impaired systolic blood pressure and heart rate. Increased plasma levels of NO and decreased TAC levels with endotoxemic shock were reversed by ozone treatment. No significant effect on augmentated plasma levels of ALT by endotoxemia was observed with ozone application. On the other hand ADMA, AST and LDH levels were not changed with endotoxemia or ozone application. Conclusion: These results suggested that ozone treatment reversed the LPS-induced changes inplasma NO and TAC levels, but not other vital and biochemical parameters in rat model of endotoxin induced shock