Angiotensin II-independent abnormal renal vascular reactivity during puromycin nephropathy.

Experimental glomerulonephritis results in hypertension that is sensitive to salt. Nevertheless, salt retention alone cannot explain the increase in blood pressure. Angiotensin antagonistic therapy reduces hypertension caused by puromycin amino nucleosides (PAN). We investigated the hypothesis that PAN modifies renal vascular reactivity through processes dependent on angiotensin. Long-Evans rats were given an intraperitoneal injection of either puromycin (150 mg/kg) or saline (controls). Group 1 was fed a normal sodium diet (NSD, n = 9). Group 2 was given 30 mg/L of quinapril (Q) in addition to NSD (NSD + Q; n = 6). Group 3 received a high sodium diet (HSD, n = 7), and Group 4 received HSD + Q (n = 7). Systolic blood pressure (SBP), plasma creatinine, proteinuria, and sodium balance were monitored for 12 days. On day 15, renal vascular reactivity was assessed by administering increasing doses of angiotensin II, acetylcholine (ACh), and sodium nitroprusside (SNP) directly into the renal artery. SBP progressively increased in all PAN groups. This increase in SBP was greater in the HSD groups and was not significantly altered by Q treatment. SBP increased by 22 ± 4% (NSD), 51 ± 5% (NSD + Q), 81 ± 10% (HSD), and 65 ± 8% (HSD + Q). The renal blood flow of PAN rats did not return to baseline despite their normal renal vasoconstrictor responses to angiotensin II. Additionally, they showed reduced renal vasodilator responses to SNP and Ach. The vasodilator responses to both vasodilators were surprisingly unaffected by the inhibition of the angiotensin-converting enzyme (ACE). Renal vasodilator responses to both endothelium-dependent and independent variables were reduced in early PAN-induced hypertension. We found that the angiotensin-mediated mechanism is not responsible for this altered renal vasoreactivity.

Fast fabrication of "all-in-one" injectable hydrogels as antibiotic alternatives for enhanced bacterial inhibition and accelerating wound healing.

Skin wound infection has become a notable medical threat. Herein, the polysaccharide-based injectable hydrogels with multifunctionality were developed by a simple and fast gelation process not only to inactivate bacteria but also to accelerate bacteria-infected wound healing. Sodium nitroprusside (SNP) loaded PCN-224 nanoparticles were introduced into the polymer matrix formed by the dynamic and reversible coordinate bonds between Ag+ with carboxyl and amino or hydroxyl groups on carboxymethyl chitosan (CMCS), hydrogen bonds and electrostatic interactions in the polymer to fabricate SNP@PCN@Gel hydrogels. SNP@PCN@Gel displayed interconnected porous structure, excellent self-healing capacity, low cytotoxicity, good blood compatibility, and robust antibacterial activity. SNP@PCN@Gel could produce reactive oxygen species (ROS) and NO along with Fe2+, and showed long-term sustained release of Ag+, thereby effectively killing bacteria by synergistic photothermal (hyperthermia), photodynamic (ROS), chemodynamic (Fenton reaction), gas (NO) and ion (Ag+ and -NH3+ in CMCS) therapy. Remarkably, the hydrogels significantly promoted granulation tissue formation, reepithelization, collagen deposition and angiogenesis as well as wound contraction in bacteria-infected wound healing. Taken together, the strategy represented a general method to engineer the unprecedented photoactivatable "all-in-one" hydrogels with enhanced antibacterial activity and paved a new way for development of antibiotic alternatives and wound dressing.

Individual or successiveseed priming with nitric oxide and calcium toward enhancing salt tolerance of wheat crop through early ROS detoxification and activation of antioxidant defense.

Despite the considerable efforts reported so far to enhance seed priming, novel ideas are still needed to be suggested to this sustainable sector of agri-seed industry. This could be the first study addressing the effect of nitric oxide (NO) under open field conditions. The impacts of seed redox-priming using sodium nitroprusside (SNP) and osmo-priming with calcium chloride (CaCl2), both applied individually or successively, were investigated under salinity stress conditions on wheat plants (Triticum aestivum L.). Various parameters, including water relations, growth, yield, photosynthetic pigments, and antioxidant activities (enzymatic and non-enzymatic), were recorded to assess the outcomes of these priming agents on mitigating the negative impacts of salinity stress on wheat plants. Water consumptive use (ETa) and irrigation water applied (IWA) decreased with seeds priming. Successive priming with SNP + CaCl2 induced the greatest values of crop water productivity (CWP), irrigation water productivity (IWP), seed index, grain yield and grain nitrogen content.Under salinity stress, the dry weight of plants was decreased. However, hydro-priming and successive chemical priming agents using combinations of calcium chloride and sodium nitroprusside (CaCl2 + SNP & SNP + CaCl2) preserved growth under salinity stress.Individual priming with sodium nitroprusside (SNP) and calcium chloride (CaCl2) resulted in the lowest recorded content of sodium in the shoot, with a value of 2 ppm. On the other hand, successive priming using CaCl2 + SNP or SNP + CaCl2 induced the contents of potassium in the shoot, with values of 40 ppm and 39 ppm, respectively. Malondialdehyde decreased in shoot significantly withapplicationof priming agents. Successive priming with CaCl2 + SNP induced the highest proline contents in shoot (6 µg/ g FW). The highest value of phenolics and total antioxidants contents in shoot were recorded under successive priming using CaCl2 + SNP and SNP + CaCl2.Priming agents improved the activities of ascorbate peroxidase and catalase enzymes. The successive priming improved water relations (ETa, IWA, CWP and IWP) and wheat growth and productivity under salinity stress more than individual priming treatments.

Deciphering the alleviation potential of nitric oxide, for low temperature and chromium stress via maintaining photosynthetic capacity, antioxidant defence, and redox homeostasis in rice (Oryza sativa).

Sodium nitroprusside (SNP) is a potent nitric oxide (NO) donor that enhances plant tolerance to various abiotic stresses. This research aims to assess the effect of SNP application on rice seedlings subjected to individual and combined exposure to two abiotic stresses viz., low-temperature (LT) and chromium (Cr). Exposure to LT, Cr, and LT+Cr caused severe oxidative damage by stimulating greater production and accumulation of reactive oxygen species (ROS) leading to lipid peroxidation and cell membrane instability. The combined LT+CR stress more intensly increased the cellular oxidative stress and excessive Cr uptake that in turn deteriorated the chlorophyll pigments and photosynthesis, as well as effected the level of tetrapyrrole biosynthesis in rice plants. The reduction in rice seedling growth was more obvious under LT+Cr treatment than their individual effects. The exogenous application of SNP diminished the toxic impact of LT and Cr stress. This was attributed to the positive role of SNP in regulating the endogenous NO levels, free amino acids (FAAs) contents, tetrapyrrole biosynthesis and antioxidants. Consequently, SNP-induced NO decreased photorespiration, ROS generation, lipid peroxidation, and electrolyte leakage. Moreover, exogenous SNP diminished the Cr uptake and accumulation by modulating the ionic homeostasis and strengthening the heavy metals detoxification mechanism, thus improving plant height, biomass and photosynthetic indexes. Essentially, SNP boosts plant tolerance to LT and Cr stress by regulating antioxidants, detoxification mechanism, and the plant's physio-biochemical. Hence, applying SNP is an effective method for boosting rice plant resilience and productivity in the face of escalating environmental stresses and pollutants.

Copper nitroprusside analogue nanoparticles against melanoma: detailed in vitro and in vivo investigation.

Melanoma is the most invasive and lethal form of skin cancer that arises from the malignant transformation of specialized pigment-producing cell melanocytes. Nanomedicine represents an important prospect to mitigate the difficulties and provide significant benefits to cure melanoma. In the present study, we investigated in vitro and in vivo therapeutic efficacies of copper nitroprusside analogue nanoparticles (abbreviated as CuNPANP) towards melanoma. Initially, in vitro anti-cancer activities of CuNPANP towards melanoma cells (B16F10) were evaluated by several experiments such as [methyl-3H]-thymidine incorporation assay, cell cycle and apoptosis assays using FACS analysis, ROS generation using DCFDA, DHE and DAF2A reagents, internalization of nanoparticles through ICP-OES analysis, co-localization of the nanoparticles using confocal microscopy, JC-1 staining to investigate the mitochondrial membrane potential (MMP) and immunofluorescence studies to analyze the expressions of cytochrome-c, Ki-67, E-cadherin as well as phalloidin staining to analyze the cytoskeletal integrity. Further, the in vivo therapeutic effectiveness of the nanoparticles was established towards malignant melanoma by inoculating B16F10 cells in the dorsal right abdomen of C57BL/6J mice. The intraperitoneal administration of CuNPANP inhibited tumor growth and increased the survivability of melanoma mice. The in vivo immunofluorescence studies (Ki-67, CD-31, and E-cadherin) and TUNEL assay further support the anti-cancer and apoptosis-inducing potential of CuNPANP, respectively. Finally, various signaling pathways and molecular mechanisms involved in anti-cancer activities were further evaluated by Western blot analysis. The results altogether indicated the potential use of copper-based nanomedicines for the treatment of malignant melanoma.

The effect of pre- and post-harvest sodium nitroprusside treatments on the physiological changes of cut Alstroemeria aurea 'Orange Queen' during vase life.

Cut flowers deteriorate rapidly after harvest, lasting mere days. To extend their vase life, various postharvest techniques are employed. Due to limited knowledge about the postharvest physiology of Alstroemeria cut flowers and the specific role of secondary compounds and antioxidant systems in their protection, this study investigated the optimal dosage of sodium nitroprusside (SNP) as a nitric oxide (NO) donor to enhance quality and antioxidant defenses. Preharvest foliar application of SNP at 0, 50, 100, and 200 µM followed by short-term pulsing treatments upon harvest at the same concentrations were applied in a factorial design. Results revealed that a preharvest 100 µM SNP treatment combined with a 50 µM postharvest pulse significantly increased the total amount of phenols (over 20%), antioxidant capacity (more than doubled), and the activity of two antioxidant enzymes (ascorbate peroxidase by over 35% and guaiacol peroxidase by about 20%). Notably, this combination also diminished ion leakage (by about 20%), ultimately extending the vase life by more than 40% compared to untreated plants. Therefore, SNP application at these specific dosages proves effective in bolstering Alstroemeria cut flower quality and vase life through enhanced total phenols and a strengthened antioxidant system.

Low-dose doxorubicin loaded extracellular vesicles combined Fas/FasL pathway-mediated chemo-sensitization and immunotherapy against tumor.

The clinical application of doxorubicin (DOX) is mainly restricted by its serious side effects, poor drug delivery efficiency, and limited immunogenic death (ICD) effect. To improve DOX-based chemotherapy and ameliorate its adverse effects, we utilized 3LL cell-derived extracellular vesicles to encapsulate DOX and sodium nitroprusside (SNP) to obtain DOX/SNP@CM, which could effectively target the tumor site by harnessing the inherent homologous targeting property of tumor cell membranes. DOX performed its role on chemotherapy, and SNP successfully respond to the intracellular GSH to continuously generate nitric oxide (NO). The in situ-produced NO upregulated the Fas expression on the tumor cell surface, thereby sensitizing the Fas/FasL pathway-mediated tumor cell apoptosis of DOX. Furthermore, NO also boosted the intratumoral infiltration of cytotoxic T cells by promoted ICD effect towards tumor cells. Importantly, the anti-tumor immunity tightly cooperated with Fas/FasL mediated tumor cell apoptosis by NO-mediated manipulation on Fas/FasL interaction, collectively making DOX/SNP@CM exert significant tumor growth inhibition with low-dose DOX. Remarkably, DOX and SNP both are widely used clinical medicines, ensuring DOX/SNP@CM a potential opportunity for future practical applications.

Effects of Sodium Nitroprusside on Lipopolysaccharide-Induced Inflammation and Disruption of Blood-Brain Barrier.

In various neurodegenerative conditions, inflammation plays a significant role in disrupting the blood-brain barrier (BBB), contributing to disease progression. Nitric oxide (NO) emerges as a central regulator of vascular function, with a dual role in inflammation, acting as both a pro- and anti-inflammatory molecule. This study investigates the effects of the NO donor sodium nitroprusside (SNP) in protecting the BBB from lipopolysaccharide (LPS)-induced inflammation, using bEnd.3 endothelial cells as a model system. Additionally, Raw 264.7 macrophages were employed to assess the effects of LPS and SNP on their adhesion to a bEnd.3 cell monolayer. Our results show that LPS treatment induces oxidative stress, activates the JAK2/STAT3 pathway, and increases pro-inflammatory markers. SNP administration effectively mitigates ROS production and IL-6 expression, suggesting a potential anti-inflammatory role. However, SNP did not significantly alter the adhesion of Raw 264.7 cells to bEnd.3 cells induced by LPS, probably because it did not have any effect on ICAM-1 expression, although it reduced VCAM expression. Moreover, SNP did not prevent BBB disruption. This research provides new insights into the role of NO in BBB disruption induced by inflammation.

Sodium nitroprusside modulates oxidative and nitrosative processes in Lycopersicum esculentum L. under drought stress.

KEY MESSAGE: Sodium nitroprusside mediates drought stress responses in tomatoes by modulating nitrosative and oxidative pathways, highlighting the interplay between nitric oxide, hydrogen sulfide, and antioxidant systems for enhanced drought tolerance. While nitric oxide (NO), a signalling molecule, enhances plant tolerance to abiotic stresses, its precise contribution to improving tomato tolerance to drought stress (DS) through modulating oxide-nitrosative processes is not yet fully understood. We aimed to examine the interaction of NO and nitrosative signaling, revealing how sodium nitroprusside (SNP) could mitigate the effects of DS on tomatoes. DS-seedlings endured 12% polyethylene glycol (PEG) in a 10% nutrient solution (NS) for 2 days, then transitioned to half-strength NS for 10 days alongside control plants. DS reduced total plant dry weight, chlorophyll a and b, Fv/Fm, leaf water potential (ΨI), and relative water content, but improved hydrogen peroxide (H2O2), proline, and NO content. The SNP reduced the DS-induced H2O2 generation by reducing thiol (-SH) and the carbonyl (-CO) groups. SNP increased not only NO but also the activity of L-cysteine desulfhydrase (L-DES), leading to the generation of H2S. Decreases in S-nitrosoglutathione reductase (GSNOR) and NADPH oxidase (NOX) suggest a potential regulatory mechanism in which S-nitrosylation [formation of S-nitrosothiol (SNO)] may influence protein function and signaling pathways during DS. Moreover, SNP improved ascorbate (AsA) and glutathione (GSH) and reduced oxidized glutathione (GSSG) levels in tomato plants under drought. Furthermore, the interaction of NO and H2S, mediated by L-DES activity, may serve as a vital cross-talk mechanism impacting plant responses to DS. Understanding these signaling interactions is crucial for developing innovative drought-tolerance strategies in crops.

Chemically induced cone degeneration in the 13-lined ground squirrel.

Animal models of retinal degeneration are critical for understanding disease and testing potential therapies. Inducing degeneration commonly involves the administration of chemicals that kill photoreceptors by disrupting metabolic pathways, signaling pathways, or protein synthesis. While chemically induced degeneration has been demonstrated in a variety of animals (mice, rats, rabbits, felines, 13-lined ground squirrels (13-LGS), pigs, chicks), few studies have used noninvasive high-resolution retinal imaging to monitor the in vivo cellular effects. Here, we used longitudinal scanning light ophthalmoscopy (SLO), optical coherence tomography, and adaptive optics SLO imaging in the euthermic, cone-dominant 13-LGS (46 animals, 52 eyes) to examine retinal structure following intravitreal injections of chemicals, which were previously shown to induce photoreceptor degeneration, throughout the active season of 2019 and 2020. We found that iodoacetic acid induced severe pan-retinal damage in all but one eye, which received the lowest concentration. While sodium nitroprusside successfully induced degeneration of the outer retinal layers, the results were variable, and damage was also observed in 50% of contralateral control eyes. Adenosine triphosphate and tunicamycin induced outer retinal specific damage with varying results, while eyes injected with thapsigargin did not show signs of degeneration. Given the variability of damage we observed, follow-up studies examining the possible physiological origins of this variability are critical. These additional studies should further advance the utility of chemically induced photoreceptor degeneration models in the cone-dominant 13-LGS.

Sodium nitroprusside restored lipopolysaccharide-induced learning and memory impairment in male rats via attenuating inflammation and oxidative stress.

Inflammation and oxidative stress upset memory. We explored influence of sodium nitroprusside (SNP) on memory deficits resulted from lipopolysaccharide (LPS).Groups include control, LPS, LPS + SNP 1 mg/kg, LPS + SNP 2 mg/kg, and LPS + SNP 3 mg/kg. Morris water maze and passive avoidance tests and biochemical measurements were carried out.In Morris water maze, LPS prolonged time and distance for finding the platform. In probe trial, it diminished time spent and traveled distance in the target zone. Injection of 2 and 3 mg/kg of SNP overturned the effect of LPS. In passive avoidance task, LPS postponed entrance into darkroom and reduced time spent in light room and incremented time spent in darkroom in 3, 24, and 72 h after electrical shock. All three doses of SNP restored the effects of LPS. Biochemical experiments confirmed that LPS elevated interleukin-6 and malondialdehyde concentration and declined total thiol content and superoxide dismutase and catalase activity in the hippocampus and cortex tissues. SNP particularly at a 3 mg/kg dose ameliorated LPS effects on these parameters.SNP attenuated memory disabilities resulting from LPS through modifying inflammation and boosting antioxidant defense.

A novel multifunctional microneedle patch for synergistic photothermal- gas therapy against maxillofacial malignant melanoma and associated skin defects.

Considering the high recrudescence and the long-lasting unhealed large-sized wound that affect the aesthetics and cause dysfunction after resection of maxillofacial malignant skin tumors, a groundbreaking strategy is urgently needed. Photothermal therapy (PTT), which has become a complementary treatment of tumors, however, is powerless in tissue defect regeneration. Therefore, a novel multifunctional sodium nitroprusside and Fe2+ ions loaded microneedles (SNP-Fe@MNs) platform was fabricated by accomplishing desirable NIR-responsive photothermal effect while burst releasing nitric oxide (NO) after the ultraviolet radiation for the ablation of melanoma. Moreover, the steady releasing of NO in the long term by the platform can exert its angiogenic effects via upregulating multiple related pathways to promote tissue regeneration. Thus, the therapeutic dilemma caused by postoperative maxillofacial skin malignancies could be conquered through promoting tumor cell apoptosis via synergistic PTT-gas therapy and subsequent regeneration process in one step. The bio-application of SNP-Fe@MNs could be further popularized based on its ideal bioactivity and appealing features as a strategy for synergistic therapy of other tumors occurred in skin.

Rapid formed temperature-sensitive hydrogel for the multi-effective wound healing of deep second-degree burn with shikonin based scar prevention.

Burns are a significant public health issue worldwide, resulting in prolonged hospitalization, disfigurement, disability and, in severe cases, death. Among them, deep second-degree burns are often accompanied by bacterial infections, insufficient blood flow, excessive skin fibroblasts proliferation and collagen deposition, all of which contribute to poor wound healing and scarring following recovery. In this study, SNP/MCNs-SKN-chitosan-ß-glycerophosphate hydrogel (MSSH), a hydrogel composed of a temperature-sensitive chitosan-ß-glycerophosphate hydrogel matrix (CGH), mesoporous carbon nanospheres (MCNs), nitric oxide (NO) donor sodium nitroprusside (SNP) and anti-scarring substance shikonin (SKN), is intended for use as a biomedical material. In vitro tests have revealed that MSSH has broad-spectrum antibacterial abilities and releases NO in response to near-infrared (NIR) laser to promote angiogenesis. Notably, MSSH can inhibit excessive proliferation of fibroblasts and effectively reduce scarring caused by deep second-degree burns, as demonstrated by in vitro and in vivo tests.

Synergistic regulation of hydrogen sulfide and nitric oxide on biochemical components, exopolysaccharides, and nitrogen metabolism in nickel stressed rice field cyanobacteria.

The present study examined the regulatory mechanism of hydrogen sulfide (H2S) and nitric oxide (NO) in nickel (Ni) stressed cyanobacteria viz., Nostoc muscorum and Anabaena sp. by analyzing growth, photosynthetic pigments, biochemical components (protein and carbohydrate), exopolysaccharides (EPS), inorganic nitrogen content, and activity of enzymes comprised in nitrogen metabolism and Ni accumulation. The 1 µM Ni substantially diminished growth by 18% and 22% in N. muscorum and Anabaena sp. respectively, along with declining the pigment contents (Chl a/Car ratio and phycobiliproteins), and biochemical components. It also exerted negative impacts on inorganic uptake of nitrate and nitrite contents; nitrate reductase and nitrite reductase; and ammonium assimilating enzymes (glutamine synthetase, glutamate synthase, and glutamate dehydrogenase exhibited a reverse trend) activities. Nonetheless, the adverse impact of Ni can be mitigated through the exogenous supplementation of NaHS [sodium hydrosulfide (8 µM); H2S donor] and SNP [sodium nitroprusside (10 µM); NO donor] which showed substantial improvement on growth, pigments, nitrogen metabolism, and EPS layer and noticeably occurred as a consequence of a substantial reduction in Ni accumulation content which minimized the toxicity effects. The accumulation of Ni on both the cyanobacterial cell surface (EPS layer) are confirmed by the SEM-EDX analysis. Further, the addition of NO scavenger (PTIO; 20 µM) and inhibitor of NO (L-NAME; 100 µM); and H2S scavenger (HT; 20 µM) and H2S inhibitor (PAG; 50 µM) reversed the positive responses of H2S and NO and damages were more prominent under Ni stress thereby, suggesting the downstream signaling of H2S on NO-mediated alleviation. Thus, this study concludes the crosstalk mechanism of H2S and NO in the mitigation of Ni-induced toxicity in rice field cyanobacteria.

Hyperaemia during dynamic handgrip exercise is preserved in healthy young subjects after recovery from COVID-19.

We sought to investigate possible impaired hyperaemia during dynamic handgrip exercise (HGE) in young healthy individuals who had recovered from COVID-19. We tested the vascular function in individuals recovered from COVID-19 using a nitric oxide donor (i.e., sodium nitroprusside; SNP), which could revert a possible impaired endothelial function during HGE. Further, we tested whether individuals who recovered from COVID-19 would present exaggerated brachial vascular resistance under an adrenergic agonist (i.e., phenylephrine; PHE) stimuli during HGE. Participants were distributed into two groups: healthy controls (Control; men: n = 6, 30 ± 3 years, 26 ± 1 kg/m2; and women: n = 5, 25 ± 1 years, 25 ± 1 kg/m2) and subjects recovered from COVID-19 (post-COVID; men: n = 6, 29 ± 3 years, 25 ± 1 kg/m2; and women: n = 10, 32 ± 4 years, 22 ± 1 kg/m2). Participants in the post-COVID group tested positive (RT-PCR) 12-14 weeks before the protocol. Heart rate (HR), brachial blood pressure (BP), brachial blood flow (BBF) and vascular conductance (BVC) at rest were not different between groups. The HGE increased HR (Control: Δ9 ± 0.4 bpm; and post-COVID: Δ11 ± 0.4 bpm) and BP (Control: Δ6 ± 1 mmHg; and post-COVID: Δ12 ± 0.6 mmHg) in both groups. Likewise, BBF (Control: Δ632 ± 38 ml/min; and post-COVID: Δ620 ± 27 ml/min) and BVC (Control: Δ6.6 ± 0.4 ml/min/mmHg; and post-COVID: Δ6.1 ± 0.3 ml/min/mmHg) increased during HGE. SNP did not change HGE-induced hyperaemia but did decrease BP, which induced a reflex-related increase in HR. PHE infusion also did not change the HGE-induced hyperaemia but raised BP and reduced HR. In conclusion, exercise-induced hyperaemia is preserved in healthy young subjects 12-14 weeks after recovery from COVID-19 infection.

The role of T-type calcium channels in elderly human vascular function: A pilot randomized controlled trial.

Endothelial dysfunction develops with age and may precede cardiovascular disease. Animal data suggest that T-type calcium channels play an important role in endothelial function, but data from humans are lacking. This study included 15 healthy, sedentary, elderly males for a double blinded, randomized controlled trial. For 8 weeks, they were given 40 mg/day of either efonidipine (L- and T-type calcium channel blocker (CCB)) or nifedipine (L-type CCB). Vascular function was evaluated by graded femoral arterial infusions of acetylcholine (ACh; endothelium-dependent vasodilator) and sodium nitroprusside (endothelium-independent vasodilator) both with and without co-infusion of N-acetylcysteine (NAC; antioxidant). We measured leg blood flow and mean arterial pressure and calculated leg vascular conductance to evaluate the leg vascular responses. Despite no significant change in blood pressure in either group, we observed higher leg blood flow responses (Δ 0.43 ± 0.45 l/min, P = 0.006) and leg vascular conductance (Δ 5.38 ± 5.67 ml/min/mmHg, P = 0.005) to intra-arterial ACh after efonidipine, whereas there was no change in the nifedipine group, and no differences between groups. We found no upregulation of endothelial nitric oxide synthase in vastus lateralis muscle biopsies within or between groups. Smooth muscle cell responsiveness was unaltered by efonidipine or nifedipine. Intravenous co-infusion of NAC did not affect endothelium-dependent vasodilatation in either of the CCB groups. These results suggest that 8 weeks' inhibition of T- and L-type calcium channels augments endothelium-dependent vasodilatory function in healthy elderly males. Further studies are required to elucidate if T-type calcium channel inhibition can counteract endothelial dysfunction.

Utilizing venous occlusion plethysmography to assess vascular effects: A study with buloxibutid, an angiotensin II type 2 receptor agonist.

Buloxibutid (also known as C21) is a potent and selective angiotensin II type 2 receptor (AT2R) agonist, in development for oral treatment of fibrotic lung disease. This phase I, open-label, pharmacodynamic study investigated vascular effects of buloxibutid in five healthy male volunteers. Subjects were administered intra-arterial infusions of buloxibutid for 5 min in ascending doses of 3, 10, 30, 100, and 200 µg/min, infused sequentially in the forearm. Infusions of sodium nitroprusside (SNP) solution in doses of 0.8-3.2 µg/min were administered as a positive control. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Safety and tolerability of intra-arterial administrations of buloxibutid were evaluated. Following infusion of buloxibutid in doses of 3-200 µg/min, the range of increase in FBF was 27.8%, 17.2%, 37.0%, 28.5%, and 60.5%, compared to the respective baseline. The largest increase was observed in the highest dose group. Infusions of SNP as a positive control, increased FBF 230-320% compared to baseline. Three adverse events (AEs) of mild intensity, not related to buloxibutid or SNP, were reported for two subjects. Two of these AEs were related to study procedures. There were no clinically relevant changes in arterial blood pressure during the study period. Intra-arterial infusion of buloxibutid in low, ascending doses increased FBF, indicating that buloxibutid may be effective in conditions associated with endothelial dysfunction. Venous occlusion plethysmography was found to be a useful method to explore pharmacodynamic vascular effects of novel AT2R agonists, while avoiding systemic adverse effects.