Search Results (6)

Background/Objectives: Raynaud’s phenomenon (RP) is characterized by an exaggerated vasoconstrictive response of small blood vessels in the fingers and toes to cold or stress. Oral therapy with tadalafil (TDL), a phosphodiesterase-5 inhibitor, is limited by systemic side effects and reduced patient compliance. This study aimed to develop and evaluate a TDL-loaded nanoemulgel for transdermal delivery as a non-invasive treatment alternative for cold-induced vasoconstriction. Methods: TDL-loaded nanoemulsions were prepared using the aqueous titration method with cinnamon oil as the oil phase and Cremophor RH40 and Transcutol as the surfactant–cosurfactant system. The optimized nanoemulsion was incorporated into a carbopol-based gel to form a nanoemulgel. The formulation was characterized for droplet size, morphology, thermodynamic stability, rheological properties, in vitro drug release, skin permeation, and pharmacokinetic behavior. Infrared thermography was employed to assess in vivo efficacy in cold-induced vasoconstriction models. Results: The optimized TDL nanoemulsion exhibited a spherical morphology, a nanoscale droplet size, and an enhanced transdermal flux. The resulting nanoemulgel displayed suitable physicochemical and rheological properties for topical application, a short lag time (0.7 h), and a high permeability coefficient (Kp = 3.59 × 10⁻² cm/h). Thermal imaging showed significant vasodilation comparable to standard 0.2% nitroglycerin ointment. Pharmacokinetic studies indicated improved transdermal absorption with a higher C_max (2.13 µg/mL), a prolonged half-life (t_1/2 = 16.12 h), and an increased AUC_0–24 compared to an oral nanosuspension (p < 0.001). Conclusions: The developed TDL nanoemulgel demonstrated effective transdermal delivery and significant potential as a patient-friendly therapeutic approach for Raynaud’s phenomenon, offering an alternative to conventional oral therapy. Full article

Background: Hydrogen sulfide (H₂S) is a gasotransmitter that modulates vascular tone, causing either vasodilation or vasoconstriction depending on the vascular bed, species, and experimental conditions. The cold-sensitive transient receptor potential ankyrin-1 (TRPA1) channel mediates H₂S-induced effects; however, its contribution to the vasomotor responses of different arteries at different temperatures has remained unclear. Here, we aimed to fill this gap by comparing the effects of sodium sulfide (Na₂S), which is a fast-releasing H₂S donor, on the isolated carotid and tail skin arteries of rats and mice at cold and normal body temperature with wire myography. Under the same circumstances, we also aimed to compare the effects of the canonical endothelium-dependent and -independent vasodilators, acetylcholine and sodium nitroprusside, respectively. Methods: We isolated the carotid and tail arteries from 32 adult Wistar rats and 64 TRPA1 knockout and wild-type mice, and then we studied their vasomotor responses to increasing doses (10⁻⁶–10⁻³ M) of Na₂S as well as to acetylcholine and sodium nitroprusside (10⁻⁵ M for both) at 37 °C and in cold (17 or 20 °C). Results: In rat vessels, Na₂S caused constriction of the carotids and relaxation of the tail arteries, which were not influenced by temperature. In mouse carotids, Na₂S caused vasorelaxation, which was more pronounced in the cold at a lower dose (10⁻⁴ M). At a higher dose (10⁻³ M), the dilation was markedly attenuated in the absence of the TRPA1 channel. In the mouse tail arteries, Na₂S caused vasorelaxation at 37 °C and vasocontraction in the cold. The genetic blockade of TRPA1 channels did not influence the vasomotor responses of the mouse tail arteries. Sodium nitroprusside-induced vasorelaxation was not influenced by any of the investigated factors, while acetylcholine-induced dilation decreased in the cold in all vessel types. Conclusions: Our results reveal the function of TRPA1 in the H₂S-induced dilation of carotid arteries in mice. We also highlight interspecies differences in the vasomotor responses between rats and mice, as well as the importance of the effect of temperature on vascular responses. The implementation of the identified variables in future research can advance our understanding of cardiovascular physiology, especially in conditions with hypothermia (either accidental or therapeutic). Full article

Hesperetin, a citrus flavonoid, exerts vasodilation and is expected to improve endothelial function and alleviate cold sensation by activating nervous system thermal transduction pathways. In this randomized, double-blind, crossover, and placebo-controlled study, the purpose was to assess the effect of an orally administered highly bioavailable soluble inclusion complex of hesperetine-7-O-glucoside with β-cyclodextrin (HEPT7G/βCD; SunActive^® HES/HCD) on cold sensation response during localized cold-stimulated stress in healthy humans. A significant (p ≤ 0.05) dose-dependent increase in skin cutaneous blood flow following relatively small doses of HEPT7G/βCD inclusion complex ingestion was confirmed, which led to a relatively effective recovery of peripheral skin temperature. The time delay of an increase in blood flow during rewarming varied significantly between low- and high-dose HEPT7G/βCD inclusion complex consumption (e.g., 150 mg and 300 mg contain 19.5 mg and 39 mg of HEPT7G, respectively). In conclusion, the substantial alteration in peripheral skin blood flow observed during local cooling stress compared to placebo suggested that deconjugated hesperetin metabolites may have a distinct capacity for thermoregulatory control of human skin blood flow to maintain a constant body temperature during cold stress exposure via cutaneous vasodilation and vasoconstriction systems. Full article

Background: Cold-induced vasodilation (CIVD) is a phenomenon that refers to a paradoxical increase in finger temperature that sometimes occurs during cold exposure. The aim of this study was to compare CIVD responses between women and men, during exposure to different environmental conditions. Methods: Seven men and seven women participated in a matched controlled study consisting of a familiarization protocol followed by three experimental sessions (cool (10.8 °C WBGT), thermoneutral (17.2 °C WBGT), and hot (27.2 °C WBGT)). In each session, participants were asked to immerse their left hand and foot in warm water (35 ± 1 °C) for five minutes. Thereafter, the left hand and foot were immersed in cold water (8 ± 1 °C) for 40 min. After that, the left hand and foot were removed from the water and participants remained seated for five minutes. Results: For a matched thermal stress, women experienced an elevated cardiovascular strain (heart rate and in some cases mean arterial pressure) and higher frequency of CIVD reactions (men: 31 vs. women: 60) in comparison to their male counterparts. Conclusions: The present study demonstrated that women experienced elevated cardiovascular strain and higher frequency of CIVD reactions, particularly in the toes, compared to their male counterparts during cold-water immersion. Full article

The total damage inflicted on the liver before transplantation is associated with several surgical manipulations, such as organ recovery, washout of the graft, cold conservation in organ preservation solutions (UW, Celsior, HTK, IGL-1), and rinsing of the organ before implantation. Polyethylene glycol 35 (PEG35) is the oncotic agent present in the IGL-1 solution, which is an alternative to UW and Celsior solutions in liver clinical transplantation. In a model of cold preservation in rats (4 °C; 24 h), we evaluated the effects induced by PEG35 on detoxifying enzymes and nitric oxide, comparing IGL-1 to IGL-0 (which is the same as IGL-1 without PEG). The benefits were also assessed in a new IGL-2 solution characterized by increased concentrations of PEG35 (from 1 g/L to 5 g/L) and glutathione (from 3 mmol/L to 9 mmol/L) compared to IGL-1. We demonstrated that PEG35 promoted the mitochondrial enzyme ALDH2, and in combination with glutathione, prevented the formation of toxic aldehyde adducts (measured as 4-hydroxynonenal) and oxidized proteins (AOPP). In addition, PEG35 promoted the vasodilator factor nitric oxide, which may improve the microcirculatory disturbances in steatotic grafts during preservation and revascularization. All of these results lead to a reduction in damage inflicted on the fatty liver graft during the cold storage preservation. In this communication, we report on the benefits of IGL-2 in hypothermic static preservation, which has already been proved to confer benefits in hypothermic oxygenated dynamic preservation. Hence, the data reported here reinforce the fact that IGL-2 is a suitable alternative to be used as a unique solution/perfusate when hypothermic static and preservation strategies are used, either separately or combined, easing the logistics and avoiding the mixture of different solutions/perfusates, especially when fatty liver grafts are used. Further research regarding new therapeutic and pharmacological insights is needed to explore the underlying mitochondrial mechanisms exerted by PEG35 in static and dynamic graft preservation strategies for clinical liver transplantation purposes. Full article

Biological systems, in general, represent a special type of control system. The physiological processes of homeostasis, which serve to maintain the organism’s internal equilibrium against external influences, are clear forms of biological control system. An example of the homeostasis is the control of the organism thermal state or the thermoregulation. The thermoregulatory control of human skin blood flow, via vasoconstriction and vasodilation, is vital to maintaining normal body temperatures during challenges to thermal homeostasis such as localised cooling. The main objective of this paper is to reverse engineer the localised thermoregulatory cold-induced vasoconstriction/vasodilation (CIVC/CIVD) reactions using a data-based mechanistic approach. Two types of localised cooling were applied to the fingers of 33 healthy participants, namely, continuous and intermittent cooling. Modelling of the thermoregulatory cold-induced vasoconstriction/vasodilation reactions suggested two underlying processes, with one process being 10 times faster. A new term is suggested in this paper, namely, the latent heat of CIVD, which represents the amount of dissipated heat required to trigger the CIVD. Moreover, a new model for the thermoregulatory localised CIVC/CIVD reactions is proposed. The suggested new model states that, with an initial vasodilation state, the initial localised CIVC is triggered based on a certain threshold in the rate of heat dissipation from the skin to the surrounding environment. Full article