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Antioxidants (Basel, Switzerland) Oct 2023Endothelium-derived nitric oxide (NO)-induced vasodilation is impaired in pregnancy hypertension. However, the role of perivascular adipose tissue (PVAT)-derived...
Vasodilator Responses of Perivascular Adipose Tissue-Derived Hydrogen Sulfide Stimulated with L-Cysteine in Pregnancy Hypertension-Induced Endothelial Dysfunction in Rats.
Endothelium-derived nitric oxide (NO)-induced vasodilation is impaired in pregnancy hypertension. However, the role of perivascular adipose tissue (PVAT)-derived hydrogen sulfide (HS), as an alternative for counteracting vascular dysfunction, is incompletely clear in hypertensive disorders of pregnancy. Therefore, PVAT-derived HS-induced vasodilation was investigated in pregnancy hypertension-induced endothelial dysfunction. Non-pregnant (Non-Preg) and pregnant (Preg) rats were submitted (or not) to the deoxycorticosterone (DOCA)-salt protocol and assigned as follows ( = 10/group): Non-Preg, Non-Preg+DOCA, Preg, and Preg+DOCA groups. Systolic blood pressure (SBP), angiogenesis-related factors, determinant levels of HS (PbS), NO (NOx), and oxidative stress (MDA) were assessed. Vascular changes were recorded in thoracic aortas with PVAT and endothelium (intact and removed layers). Vasorelaxation responses to the substrate (L-cysteine) for the HS-producing enzyme cystathionine-γ-lyase (CSE) were examined in the absence and presence of CSE-inhibitor DL-propargylglycine (PAG) in thoracic aorta rings pre-incubated with cofactor for CSE (pyridoxal-5 phosphate: PLP) and pre-contracted with phenylephrine. Hypertension was only found in the Preg+DOCA group. Preg+DOCA rats showed angiogenic imbalances and increased levels of MDA. PbS, but not NOx, showed increased levels in the Preg+DOCA group. Pre-incubation with PLP and L-cysteine elevated determinants of HS in PVAT and placentas of Preg-DOCA rats, whereas no changes were found in the aortas without PVAT. Aortas of Preg-DOCA rats showed that PVAT-derived HS-dependent vasodilation was greater compared to endothelium-derived HS, whereas PAG blocked these responses. PVAT-derived HS endogenously stimulated with the amino acid L-cysteine may be an alternative to induce vasorelaxation in endothelial dysfunction related to pregnancy hypertension.
PubMed: 38001772
DOI: 10.3390/antiox12111919 -
Kardiochirurgia I Torakochirurgia... Sep 2023The rat vascular ischaemia and reperfusion model is used to evaluate the molecular and functional effects of potential agents against ischaemia and reperfusion injury...
INTRODUCTION
The rat vascular ischaemia and reperfusion model is used to evaluate the molecular and functional effects of potential agents against ischaemia and reperfusion injury of autologous graft veins. However, there is no consensus on whether hypoxia, rather than ischaemia, is sufficient to induce vascular dysfunction.
AIM
To compare the effects of hypoxia and ischaemia, with or without reperfusion, on the vascular functions of isolated thoracic aortic rings of rats.
MATERIAL AND METHODS
Thoracic aortas of 12 male Sprague-Dawley rats (350-500 g, 18-24 months old) were isolated and divided into rings that were randomly allocated to control, ischaemia, hypoxia, ischaemia-reperfusion, and hypoxia-reperfusion groups. Aortic rings other than those of the control group were stored at 4°C for 24 h in saline. For ischaemia, saline was gassed with nitrogen. After 24 h, aortic rings in the ischaemia-reperfusion and hypoxia-reperfusion groups were incubated with 200 μM sodium hypochlorite for 30 min. Vascular and endothelial functions were tested in an organ bath set-up.
RESULTS
Vascular response to potassium chloride (80 mM) decreased in all experimental groups compared to the control group ( = 0.007), but phenylephrine-induced contraction (10 M) increased only in the ischaemia-reperfusion group ( < 0.0001). Acetylcholine (10-10 M)-induced endothelium-dependent vasorelaxations were impaired in all groups - particularly in the ischaemia-reperfusion group ( = 0.0011). Sodium nitroprusside (10-10 M)-induced endothelium-independent vasorelaxations were similar across all groups ( = 0.1258).
CONCLUSIONS
Ischaemia followed by reperfusion should be implanted to achieve maximum endothelial and contractile dysfunction , and to replicate ischaemia and reperfusion injury of autologous graft veins.
PubMed: 37937174
DOI: 10.5114/kitp.2023.131952 -
BMC Anesthesiology Aug 2023Hypotension frequently occurs after spinal anesthesia during cesarean delivery, and fluid loading is recommended for its prevention. We evaluated the efficacy of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Hypotension frequently occurs after spinal anesthesia during cesarean delivery, and fluid loading is recommended for its prevention. We evaluated the efficacy of subclavian vein (SCV) ultrasound (US)-guided volume optimization in preventing hypotension after spinal anesthesia during cesarean delivery.
METHODS
This randomized controlled study included 80 consecutive full-term parturients scheduled for cesarean delivery under spinal anesthesia. The women were randomly divided into the SCVUS group, with SCVUS analysis before spinal anesthesia with SCVUS-guided volume management, and the control group without SCVUS assessment. The SCVUS group received 3 mL/kg crystalloid fluid challenges repeatedly within 3 min with a 1-min interval based on the SCV collapsibility index (SCVCI), while the control group received a fixed dose (10 mL/kg). Incidence of post-spinal anesthetic hypotension was the primary outcome. Total fluid volume, vasopressor dosage, changes in hemodynamic parameters, maternal adverse effects, and neonatal status were secondary outcomes.
RESULTS
The total fluid volume was significantly higher in the control group than in the SCVUS group (690 [650-757.5] vs. 160 [80-360] mL, p < 0.001), while the phenylephrine dose (0 [0-40] vs. 0 [0-30] µg, p = 0.276) and incidence of post-spinal anesthetic hypotension (65% vs. 60%, p = 0.950) were comparable between both the groups. The incidence of maternal adverse effects, including nausea/vomiting and bradycardia (12.5% vs. 17.5%, p = 0.531 and 7.5% vs. 5%, p = 1.00, respectively), and neonatal outcomes (Apgar scores) were comparable between the groups. SCVCI correlated with the amount of fluid administered (R = 0.885, p < 0.001).
CONCLUSIONS
SCVUS-guided volume management did not ameliorate post-spinal anesthetic hypotension but reduced the volume of the preload required before spinal anesthesia. Reducing preload volume did not increase the incidence of maternal and neonatal adverse effects nor did it increase the total vasopressor dose. Moreover, reducing preload volume could relieve the heart burden of parturients, which has high clinical significance.
CLINICAL TRIAL REGISTRATION
The trial was registered with the Chinese Clinical Trial Registry at chictr.org.cn (registration number, ChiCTR2100055050) on December 31, 2021.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Subclavian Vein; Anesthesia, Spinal; Hypotension; Ultrasonography, Interventional; Anesthetics
PubMed: 37620761
DOI: 10.1186/s12871-023-02242-6 -
Acta Pharmaceutica Sinica. B Feb 2024Stress and illness connection is complex and involves multiple physiological systems. Panax ginsengs, reputed for their broad-spectrum "cure-all" effect, are widely...
Stress and illness connection is complex and involves multiple physiological systems. Panax ginsengs, reputed for their broad-spectrum "cure-all" effect, are widely prescribed to treat stress and related illnesses. However, the identity of ginseng's "cure-all" medicinal compounds that relieve stress remains unresolved. Here, we identify ginsentides as the principal bioactives that coordinate multiple systems to restore homeostasis in response to stress. Ginsentides are disulfide-rich, cell-penetrating and proteolytic-stable microproteins. Using affinity-enrichment mass spectrometry target identification together with , and validations, we show that highly purified or synthetic ginsentides promote vasorelaxation by producing nitric oxide through endothelial cells intracellular PI3K/Akt signaling pathway, alleviate 1-adrenergic receptor overactivity by reversing phenylephrine-induced constriction of aorta, decrease monocyte adhesion to endothelial cells CD166/ESAM/CD40 and inhibit P2Y12 receptors to reduce platelet aggregation. Orally administered ginsentides were effective in animal models to reduce ADP-induced platelet aggregation, to prevent collagen and adrenaline-induced pulmonary thrombosis as well as anti-stress behavior of tail suspension and forced swimming tests in mice. Together, these results strongly suggest that ginsentides are the principal panacea compounds of ginsengs because of their ability to target multiple extra- and intra-cellular proteins to reverse stress-induced damages.
PubMed: 38322337
DOI: 10.1016/j.apsb.2023.10.022 -
BMC Pregnancy and Childbirth Dec 2023Prior studies have shown that, when administered as an intravenous bolus to prevent uterine atony, prophylactic phenylephrine infusion increased the dose requirement of... (Randomized Controlled Trial)
Randomized Controlled Trial
Oxytocin infusion for maintenance of uterine tone under prophylactic phenylephrine infusion for prevention of post-spinal hypotension in cesarean delivery: a prospective randomised double-blinded dose-finding study.
BACKGROUND
Prior studies have shown that, when administered as an intravenous bolus to prevent uterine atony, prophylactic phenylephrine infusion increased the dose requirement of oxytocin and second-line uterotonics. For the prevention of uterine atony, oxytocin should be delivered by continuous infusion. Here, we aimed to determine the ED50 and ED90 parameters (the effective doses for 50 and 90% patients without uterine atony) of oxytocin for co-infusion with prophylactic phenylephrine during cesarean delivery.
METHODS
In this prospective randomized double-blinded dose-finding study, one hundred patients were divided into four groups to receive 2.5, 5.0, 7.5, or 10 IU/h oxytocin infusion, after the umbilical cord was clamped during the study period. The uterine tone was evaluated and defined as either adequate or inadequate. Probit regression analysis was applied to calculate the ED50 and ED90 of oxytocin infusion. Uterine tone, the percentage of patients who needed additional oxytocin bolus, second-line uterotonics, side effects, estimated blood loss, and neonatal outcomes were monitored.
RESULTS
The estimated ED50 and ED90 values of the oxytocin infusion doses for the prevention of uterine atony were 1.9 IU/h (95% CI -4.6-3.8) IU/h and 9.3 IU/h (95% CI 7.3-16.2) IU/h, respectively. Across groups, there was a significant linear trend between the infusion dose and the percentage of patients who required additional oxytocin (p-value = 0.002). No differences were observed in the incidence of side effects and neonatal outcomes.
CONCLUSION
Under the conditions of this study, the ED90 of oxytocin infusion for the prevention of uterine atony was 9.3 IU/h, which is higher than the current recommendation. This finding is helpful for clinical practice, because of the routine use of phenylephrine in cesarean delivery. Further studies are needed to determine the appropriate initial bolus of oxytocin after neonatal delivery.
TRIAL REGISTRATION
The study was registered on the Chinese Clinical Trial Register (register no. ChiCTR2200059556 ).
Topics: Pregnancy; Female; Infant, Newborn; Humans; Oxytocin; Phenylephrine; Uterine Inertia; Prospective Studies; Hypotension; Double-Blind Method; Infusions, Intravenous; Oxytocics
PubMed: 38057742
DOI: 10.1186/s12884-023-06165-5 -
ACS Omega Jan 2024(Hausskn.) Pugsley (FIP), a member of the Papaveraceae family, has a documented history of use in traditional medicine to treat cardiovascular ailments, particularly...
(Hausskn.) Pugsley (FIP), a member of the Papaveraceae family, has a documented history of use in traditional medicine to treat cardiovascular ailments, particularly hypertension, and has shown substantial therapeutic efficacy among native cultures worldwide. However, the identification of bioactive compounds and the mechanism of hypotensive effect with the cardioprotective potential investigations are yet to be determined. The study aimed to identify bioactive compounds, explore the hypotensive mechanism and cardioprotective potential, and assess the safety of (Hausskn.) Pugsley hydromethanolic extract (Fip.Cr). LC ESI-MS/MS analysis was performed to identify the bioactive compounds. In vitro experiments were conducted on isolated rat aorta and atria, and an invasive BP measurement model was used. Acute and subacute toxicities were assessed for 14 and 28 days, respectively. Isoproterenol (ISO) was used to develop the rats' myocardial infarction damage model. The mRNA levels of NLRP3 inflammasome and the abundance level of Firmicutes and Lactobacillus were measured by qRT-PCR. The hypotensive effect of FIP bioactive compounds was also investigated using in silico methods. Fip. Cr LC ESI-MS/MS analysis discovered 33 bioactive compounds, including alkaloids and flavonoids. In isolated rat aorta, Fip.Cr reversed contractions induced by K (80 mM), demonstrating a calcium entry-blocking function, and had a vasorelaxant impact on phenylephrine (PE) (1 μM)-induced contractions unaffected by L-NAME, ruling out endothelial NO participation. Fip.Cr caused negative chronotropic and inotropic effects in isolated rat atria unaffected by atropine pretreatment, eliminating cardiac muscarinic receptor involvement. Safety evaluation showed no major adverse effects. In vivo, invasive BP measurement demonstrated a hypotensive effect comparable to verapamil. Fip.Cr protected the rats from ISO-induced MI interventions significantly in biometrical and cardiac serum biochemical indicators and histological examinations by reducing inflammation via inhibiting NLRP3 inflammasome and elevating Firmicutes and Lactobacillus levels. The network pharmacology study revealed that the FIP hypotensive mechanism might involve MMP9, JAK2, HMOX1, NOS2, NOS3, TEK, SERPINE1, CCL2, and VEGFA. The molecular docking study revealed that FIP bioactive compounds docked better with CAC1C_ HUMAN than verapamil. These findings demonstrated that Fip.Cr's hypotensive mechanism may include calcium channel blocker activity. Fip.Cr ameliorated ISO-induced myocardial infarction in rats by attenuating inflammation, which might be via inhibiting NLRP3 inflammasome and may prove beneficial for treating MI.
PubMed: 38284069
DOI: 10.1021/acsomega.3c07655 -
International Journal of Molecular... Nov 2023Both the endocannabinoid system (ECS) and estrogens have significant roles in cardiovascular control processes. Cannabinoid type 1 receptors (CBRs) mediate acute...
Both the endocannabinoid system (ECS) and estrogens have significant roles in cardiovascular control processes. Cannabinoid type 1 receptors (CBRs) mediate acute vasodilator and hypotensive effects, although their role in cardiovascular pathological conditions is still controversial. Estrogens exert cardiovascular protection in females. We aimed to study the impact of ECS on vascular functions. Experiments were performed on CBR knockout (CBR KO) and wild-type (WT) female mice. Plasma estrogen metabolite levels were determined. Abdominal aortas were isolated for myography and histology. Vascular effects of phenylephrine (Phe), angiotensin II, acetylcholine (Ach) and estradiol (E2) were obtained and repeated with inhibitors of nitric oxide synthase (NOS, Nω-nitro-L-arginine) and of cyclooxygenase (COX, indomethacin). Histological stainings (hematoxylin-eosin, resorcin-fuchsin) and immunostainings for endothelial NOS (eNOS), COX-2, estrogen receptors (ER-α, ER-β) were performed. Conjugated E2 levels were higher in CBR KO compared to WT mice. Vasorelaxation responses to Ach and E2 were increased in CBR KO mice, attenuated by NOS-inhibition. COX-inhibition decreased Phe-contractions, while it increased Ach-relaxation in the WT group but not in the CBR KO. Effects of indomethacin on E2-relaxation in CBR KO became opposite to that observed in WT. Histology revealed lower intima/media thickness and COX-2 density, higher eNOS and lower ER-β density in CBR KO than in WT mice. CBR KO female mice are characterized by increased vasorelaxation associated with increased utilization of endothelial NO and a decreased impact of constrictor prostanoids. Our results indicate that the absence or inhibition of CBRs may have beneficial vascular effects.
Topics: Animals; Female; Mice; Acetylcholine; Aorta, Abdominal; Cyclooxygenase 2; Estrogen Receptor beta; Estrogens; Indomethacin; Mice, Knockout; Nitric Oxide Synthase Type III; Receptors, Cannabinoid; Vascular Remodeling; Vasodilation
PubMed: 38003619
DOI: 10.3390/ijms242216429 -
International Journal of Molecular... Jul 2023This study aimed to investigate the mechanism underlying social stress (SS)-induced erectile dysfunction (ED) and evaluate the effects of a single subanesthetic dose of...
This study aimed to investigate the mechanism underlying social stress (SS)-induced erectile dysfunction (ED) and evaluate the effects of a single subanesthetic dose of ketamine on SS-related ED. Male FVB mice were exposed to retired male C57BL/6 mice for 60 min daily over a 4-week period. In the third week, these FVB mice received intraperitoneal injections of either saline (SSS group) or ketamine (SSK group). Erectile function was assessed by measuring the intracavernosal pressure (ICP) during electrical stimulation of the major pelvic ganglia. Corpus cavernosum (CC) strips were utilized for wire myography to assess their reactivity. Both SSS and SSK mice exhibited significantly lower ICP in response to electrical stimulation than control mice. SS mice showed increased contractility of the CC induced by phenylephrine. Acetylcholine-induced relaxation was significantly reduced in SSS and SSK mice. Sodium nitroprusside-induced relaxation was higher in SSS mice compared to control and SSK mice. Nicotine-induced neurogenic and nitric oxide-dependent relaxation was significantly impaired in both SSS and SSK mice. An immunohistochemical analysis revealed co-localization of tyrosine hydroxylase and neuronal nitric oxide synthase-immunoreactive fibers in the CC. These findings highlight the complex nature of SS-related ED and suggest the limited efficacy of ketamine as a therapeutic intervention.
Topics: Humans; Male; Mice; Animals; Erectile Dysfunction; Ketamine; Mice, Inbred C57BL; Penile Erection; Penis; Synaptic Transmission
PubMed: 37569356
DOI: 10.3390/ijms241511973 -
Brazilian Journal of Medical and... 2024Arthritis has important cardiovascular repercussions. Phenylephrine-induced vasoconstriction is impaired in rat aortas in the early phase of the adjuvant-induced...
Arthritis has important cardiovascular repercussions. Phenylephrine-induced vasoconstriction is impaired in rat aortas in the early phase of the adjuvant-induced arthritis (AIA), around the 15th day post-induction. Therefore, the present study aimed to verify the effects of AIA on hyporesponsiveness to phenylephrine in rat aortas. AIA was induced by intradermal injection of Mycobacterium tuberculosis (3.8 mg/dL) in the right hind paw of male Wistar rats (n=27). Functional experiments in isolated aortas were carried out 15 days after AIA induction. Morphometric and stereological analyses of the aortas were also performed 36 days after the induction of AIA. AIA did not promote structural modifications in the aortas at any of the time points studied. AIA reduced phenylephrine-induced contraction in endothelium-intact aortas, but not in endothelium-denuded aortas. However, AIA did not change KCl-induced contraction in either endothelium-intact or denuded aortas. L-NAME (non-selective NOS inhibitor), 1400W (selective iNOS inhibitor), and ODQ (guanylyl cyclase inhibitor) reversed AIA-induced hyporesponsiveness to phenylephrine in intact aortas. 7-NI (selective nNOS inhibitor) increased the contraction induced by phenylephrine in aortas from AIA rats. In summary, the hyporesponsiveness to phenylephrine induced by AIA was endothelium-dependent and mediated by iNOS-derived NO through activation of the NO-guanylyl cyclase pathway.
Topics: Animals; Male; Phenylephrine; Rats, Wistar; Arthritis, Experimental; Nitric Oxide; Vasoconstriction; Endothelium, Vascular; Vasoconstrictor Agents; Rats; Aorta
PubMed: 38775546
DOI: 10.1590/1414-431X2024e13304 -
Plants (Basel, Switzerland) Feb 20243-demethyl-2-geranyl-4-prenylbellidifoline (DGP), a natural xanthone isolated from , has previously demonstrated remarkable diuretic and renal protective actions. The...
3-demethyl-2-geranyl-4-prenylbellidifoline (DGP), a natural xanthone isolated from , has previously demonstrated remarkable diuretic and renal protective actions. The present study expands its actions on the cardiovascular system by evaluating its vasorelaxant and blood pressure-lowering effects in spontaneously hypertensive rats (SHRs). Aortic endothelium-intact (E+) preparations of SHRs pre-contracted by phenylephrine and exposed to cumulative concentrations of extract, fractions, and DGP exhibited a significant relaxation compared to vehicle-only exposed rings. The non-selective muscarinic receptor antagonist (atropine), the non-selective inhibitor of nitric oxide synthase (L-NAME), as well as the inhibitor of soluble guanylate cyclase (ODQ) altogether avoided DGP-induced relaxation. Tetraethylammonium (small conductance Ca-activated K channel blocker), 4-aminopyridine (a voltage-dependent K channel blocker), and barium chloride (an influx-rectifying K channel blocker) significantly reduced DGP capacity to induce relaxation without the interference of glibenclamide (an ATP-sensitive inward rectifier 6.1 and 6.2 K channel blocker). Additionally, administration of DGP, 1 mg/kg i.v., decreased the mean, systolic, and diastolic arterial pressures, and the heart rate of SHRs. The natural xanthone DGP showed promising potential as an endothelium-dependent vasorelaxant, operating through the nitric oxide pathway and potassium channels, ultimately significantly reducing blood pressure in hypertensive rats.
PubMed: 38498544
DOI: 10.3390/plants13040528