-
The Medical Letter on Drugs and... Jun 2024
Topics: Humans; Mydriasis; Phentolamine; Ophthalmic Solutions; Mydriatics; Administration, Ophthalmic
PubMed: 38905525
DOI: 10.58347/tml.2024.1705c -
Microvascular Research Jun 2024Patients with Takotsubo syndrome displayed endothelial dysfunction, but underlying mechanisms have not been fully clarified. This study aimed to explore molecular...
Patients with Takotsubo syndrome displayed endothelial dysfunction, but underlying mechanisms have not been fully clarified. This study aimed to explore molecular signalling responsible for catecholamine excess induced endothelial dysfunction. Human cardiac microvascular endothelial cells were challenged by epinephrine to mimic catecholamine excess. Patch clamp, FACS, ELISA, PCR, and immunostaining were employed for the study. Epinephrine (Epi) enhanced small conductance calcium-activated potassium channel current (I) through activating α1 adrenoceptor. Phenylephrine enhanced edothelin-1 (ET-1) and reactive oxygen species (ROS) production, and the effects involved contribution of I. HO enhanced I and ET-1 production. Enhancing I caused a hyperpolarization, which increases ROS and ET-1 production. BAPTA partially reduced phenylephrine-induced enhancement of ET-1 and ROS, suggesting that α1 receptor activation can enhance ROS/ET-1 generation in both calcium-dependent and calcium-independent ways. The study demonstrates that high concentration catecholamine can activate SK1-3 channels through α1 receptor-ROS signalling and increase ET-1 production, facilitating vasoconstriction.
PubMed: 38901735
DOI: 10.1016/j.mvr.2024.104699 -
Aesthetic Surgery Journal. Open Forum 2024The posterior Müller muscle-conjunctival resection (MMCR) procedure is a straightforward procedure for the correction of eyelid ptosis with a relatively short operating...
BACKGROUND
The posterior Müller muscle-conjunctival resection (MMCR) procedure is a straightforward procedure for the correction of eyelid ptosis with a relatively short operating time and fast recovery. Traditionally, its use was limited to patients with mild involutional ptosis and good levator function and a positive phenylephrine test result.
OBJECTIVES
To evaluate the efficacy of the MMCR procedure as a primary step to treat eyelid ptosis with varying etiology and severity, including patients with more severe ptosis and moderate levator function, and to produce a treatment algorithm.
METHODS
A retrospective analysis of the results of 34 patients, comprising 56 operated eyelids, treated with the MMCR procedure for eyelid ptotis between 2016 and 2018, was performed. Preoperative and postoperative pictures were analyzed for determining the margin-to-reflex distance (MRD1), symmetry, and complications.
RESULTS
We found a mean preoperative MRD1 of 1.3 mm (SD 1.1) and postoperative MRD1 of 3.2 mm (SD 1.0). The mean postoperative MRD1 for unilateral and bilateral cases was 3.4 (SD 0.8) and 3.2 (SD 1.1), respectively. Only 2 patients (5.9%) had an asymmetrical postoperative result (>1.0 mm MRD1 difference), and both were unilateral cases. Complications were scarce: only 1 patient (2.9%) developed dry eyes and 2 patients experienced temporary discomfort from the conjunctival sutures.
CONCLUSIONS
The MMCR procedure appears to be an excellent procedure as a primary step to correct eyelid ptosis with varying etiologies and severity, due to its low risk of asymmetry, short learning curve, and high success rate. A flow chart as treatment algorithm is provided for clinical decision making.
PubMed: 38887214
DOI: 10.1093/asjof/ojad111 -
Journal of Clinical Anesthesia Jun 2024Spinal anesthesia often causes hypotension, with consequent risk to the fetus. The use of vasopressor agents has been highly recommended for the prevention of spinal...
Norepinephrine or phenylephrine for the prevention of post-spinal hypotension after caesarean section: A double-blinded, randomized, controlled study of fetal heart rate and fetal cardiac output.
STUDY OBJECTIVE
Spinal anesthesia often causes hypotension, with consequent risk to the fetus. The use of vasopressor agents has been highly recommended for the prevention of spinal anesthesia-induced hypotension during caesarean delivery. Many studies have shown that norepinephrine can provide more stable maternal hemodynamics than phenylephrine. We therefore tested the hypothesis that norepinephrine preserves fetal circulation better than phenylephrine when used to treat maternal hypotension consequent to spinal anesthesia.
DESIGN
Prospective, randomized, double-blinded study.
SETTING
Operating room.
PATIENTS
We recruited 223 parturients with uncomplicated singleton pregnancies who were scheduled for elective caesarean section under combined spinal-epidural anesthesia.
INTERVENTIONS
The patients received prophylactic intravenous infusion of either 0.08 μg/kg/min norepinephrine or 0.5 μg/kg/min phenylephrine for prevention of spinal anesthesia-induced hypotension.
MEASUREMENTS
Changes in fetal heart rate and fetal cardiac output before and after spinal anesthesia were measured using noninvasive Doppler ultrasound.
MAIN RESULTS
90 subjects who received norepinephrine infusion and 93 subjects who received phenylephrine infusion were ultimately analyzed in the present study. The effects of norepinephrine and phenylephrine on the change of fetal heart rate and fetal cardiac output at 3 and 6 min after spinal block were similar. Although there was a statistically significant decrease in fetal cardiac output at 6 min after subarachnoid block initiation in both the norepinephrine group (mean difference 0.02 L/min; 95% CI, 0-0.04 L/min; P = 0.03) and the phenylephrine group (mean difference 0.02 L/min; 95% CI, 0-0.04 L/min; P = 0.02), it remained within the normal range.
CONCLUSIONS
Prophylactic infusion of comparable doses of phenylephrine or norepinephrine has similar effects on fetal heart rate and cardiac output changes after spinal anesthesia. Neither phenylephrine nor norepinephrine has meaningful detrimental effects on fetal circulation or neonatal outcomes.
PubMed: 38880002
DOI: 10.1016/j.jclinane.2024.111533 -
Atherosclerosis May 2024Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular events independently of glycemic control. However, the...
BACKGROUND AND AIMS
Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular events independently of glycemic control. However, the possibility that SGLT2 inhibitors improve vascular restenosis is unknown. The aim of this study was to examine whether dapagliflozin could prevent neointima thickening following balloon injury and, if so, to determine the underlying mechanisms.
METHODS
Saline, dapagliflozin (1.5 mg/kg/day), or losartan (30 mg/kg/day) was administered orally for five weeks to male Wistar rats. Balloon injury of the left carotid artery was performed a week after starting the treatment and rats were sacrificed 4 weeks later. The extent of neointima was assessed by histomorphometric and immunofluorescence staining analyses. Vascular reactivity was assessed on injured and non-injured carotid artery rings, changes of target factors by immunofluorescence, RT-qPCR, and histochemistry.
RESULTS
Dapagliflozin and losartan treatments reduced neointima thickening by 32 % and 27 %, respectively. Blunted contractile responses to phenylephrine and relaxations to acetylcholine and down-regulation of eNOS were observed in the injured arteries. RT-qPCR investigations indicated an increased in gene expression of inflammatory (IL-1beta, VCAM-1), oxidative (p47phox, p22phox) and fibrotic (TGF-beta1) markers in the injured carotid. While these changes were not affected by dapagliflozin, increased levels of AT1R and NTPDase1 (CD39) and decreased levels of ENPP1 were observed in the restenotic carotid artery of the dapagliflozin group.
CONCLUSIONS
Dapagliflozin effectively reduced neointimal thickening. The present data suggest that dapagliflozin prevents restenosis through interfering with angiotensin and/or extracellular nucleotides signaling. SGLT2 represents potential new target for limiting vascular restenosis.
PubMed: 38879387
DOI: 10.1016/j.atherosclerosis.2024.117595 -
Pharmacological Research Jul 2024Pressure overload-induced pathological cardiac hypertrophy eventually leads to heart failure (HF). Unfortunately, lack of effective targeted therapies for HF remains a...
Pressure overload-induced pathological cardiac hypertrophy eventually leads to heart failure (HF). Unfortunately, lack of effective targeted therapies for HF remains a challenge in clinical management. Mixed-lineage leukemia 4 (MLL4) is a member of the SET family of histone methyltransferase enzymes, which possesses histone H3 lysine 4 (H3K4)-specific methyltransferase activity. However, whether and how MLL4 regulates cardiac function is not reported in adult HF. Here we report that MLL4 is required for endoplasmic reticulum (ER) stress homeostasis of cardiomyocytes and protective against pressure overload-induced cardiac hypertrophy and HF. We observed that MLL4 is increased in the heart tissue of HF mouse model and HF patients. The cardiomyocyte-specific deletion of Mll4 (Mll4-cKO) in mice leads to aggravated ER stress and cardiac dysfunction following pressure overloading. MLL4 knockdown neonatal rat cardiomyocytes (NRCMs) also display accelerated decompensated ER stress and hypertrophy induced by phenylephrine (PE). The combined analysis of Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and RNA sequencing (RNA-seq) data reveals that, silencing of Mll4 alters the chromatin landscape for H3K4me1 modification and gene expression patterns in NRCMs. Interestingly, the deficiency of MLL4 results in a marked reduction of H3K4me1 and H3K27ac occupations on Thrombospondin-4 (Thbs4) gene loci, as well as Thbs4 gene expression. Mechanistically, MLL4 acts as a transcriptional activator of Thbs4 through mono-methylation of H3K4 and further regulates THBS4-dependent ER stress response, ultimately plays a role in HF. Our study indicates that pharmacologically targeting MLL4 and ER stress might be a valid therapeutic approach to protect against cardiac hypertrophy and HF.
Topics: Animals; Heart Failure; Histone-Lysine N-Methyltransferase; Myocytes, Cardiac; Endoplasmic Reticulum Stress; Male; Mice, Inbred C57BL; Humans; Mice, Knockout; Rats; Mice; Cells, Cultured; Cardiomegaly; Rats, Sprague-Dawley; Thrombospondins
PubMed: 38876442
DOI: 10.1016/j.phrs.2024.107263 -
Journal of AAPOS : the Official... Jun 2024Hyphema is rarely seen in neonates. Although most cases are secondary to instrument-assisted delivery, neonatal hyphema can occur spontaneously or result from an...
Hyphema is rarely seen in neonates. Although most cases are secondary to instrument-assisted delivery, neonatal hyphema can occur spontaneously or result from an underlying coagulopathy. We report the case of an infant who was born with unilateral hyphema and was subsequently found to have gestational alloimmune liver disease-a condition where maternal antibodies attack the infant's liver, leading to a hypocoagulable state. Our patient was treated with topical prednisolone and cyclopentolate/phenylephrine, with subsequent resolution of the hyphema.
PubMed: 38876158
DOI: 10.1016/j.jaapos.2024.103957 -
Pharmacological Reports : PR Jun 2024Apart from antagonizing ß-adrenoceptors, carvedilol antagonizes vascular α-adrenoceptors and activates G protein-independent signaling. Even though it is a commonly...
BACKGROUND
Apart from antagonizing ß-adrenoceptors, carvedilol antagonizes vascular α-adrenoceptors and activates G protein-independent signaling. Even though it is a commonly used antihypertensive and α-adrenoceptors are essential for the treatment of voiding symptoms in benign prostatic hyperplasia, its actions in the human prostate are still unknown. Here, we examined carvedilol effects on contractions of human prostate tissues, and on stromal cell growth.
METHODS
Contractions of prostate tissues from radical prostatectomy were induced by electric field stimulation (EFS) or α-agonists. Growth-related functions were examined in cultured stromal cells.
RESULTS
Concentration-response curves for phenylephrine, methoxamine and noradrenaline were right shifted by carvedilol (0.1-10 µM), around half a magnitude with 100 nM, half to one magnitude with 1 µM, and two magnitudes with 10 µM. Right shifts were reflected by increased EC values for agonists, with unchanged E values. EFS-induced contractions were reduced by 21-54% with 0.01-1 µM carvedilol, and by 94% by 10 µM. Colony numbers of stromal cells were increased by 500 nM, but reduced by 1-10 µM carvedilol, while all concentrations reduced colony size. Decreases in viability were time-dependent with 0.1-0.3 µM, but complete with 10 µM. Proliferation was slightly increased by 0.1-0.5 µM, but reduced with 1-10 µM.
CONCLUSIONS
Carvedilol antagonizes α-adrenoceptors in the human prostate, starting with concentrations in ranges of known plasma levels. In vitro, effect sizes resemble those of α-blockers used for the treatment of voiding symptoms, which requires concentrations beyond plasma levels. Bidirectional and dynamic effects on the growth of stromal cells may be attributed to "biased agonism".
PubMed: 38858312
DOI: 10.1007/s43440-024-00605-5 -
The Journal of Pharmacology and... Jun 2024Streptolysin O (SLO), a bacterial toxin produced by common hemolytic streptococci, including and resident microbiota, may be associated with inflammation in the...
Streptolysin O (SLO), a bacterial toxin produced by common hemolytic streptococci, including and resident microbiota, may be associated with inflammation in the cardiovascular system. We previously reported that short-term treatment with SLO at relatively high concentrations (10-1000 ng/mL) diminished acetylcholine-induced, endothelial-dependent relaxation in a concentration-dependent manner. However, the vascular function effects of long-term exposure to SLO at lower concentrations are poorly understood. In this study, treatment of rat aorta with endothelium with SLO (0.1-10 ng/mL) for 72 h inhibited contractions in response to norepinephrine and phenylephrine in a concentration-dependent manner, and this effect was abolished by endothelium denudation. We also observed decreased endothelium-dependent relaxation in aorta treated with a lower concentration of SLO (10 ng/mL) for 72 h. Long-term treatment with SLO (10 ng/mL) increased the expression of iNOS in aorta with endothelium but not aorta without endothelium, and the SLO-induced decrease in contraction was restored by treatment with NOS inhibitors. Pharmacologic and gene-mutant analyses further indicated that SLO-induced vascular dysfunction and iNOS upregulation are mediated through the TLR4/NOX2/ROS/p38 MAPK pathways. SLO treatment (46.8 pg/kg/min) for 7 days also diminished vascular contraction and relaxation activity in aorta with endothelium. We concluded that long-term treatment with SLO inhibits vascular contractile responses, primarily due to increased iNOS expression in the endothelium through TLR4-mediated pathways. Our present results, together with those of our previous study, suggest that endothelial cells play a key role in the pathophysiologic changes in cardiovascular function associated with long-term exposure to SLO. In the present study, we showed that long-term exposure to streptococcal exotoxin SLO inhibits agonist-induced contraction in rat aorta with endothelium, driven primarily by elevated iNOS production via NOX2-mediated ROS production through TLR4 activation on endothelial cells. treatment with SLO for 7 days also diminished vascular contraction and relaxation, providing evidence of possible pathophysiologic roles of SLO in endothelium-dependent vascular homeostasis.
PubMed: 38858090
DOI: 10.1124/jpet.124.002121 -
The Journal of Physiology Jun 2024Heart failure with preserved ejection fraction (HFpEF) has been characterized by lower blood flow to exercising limbs and lower peak oxygen utilization ( ), possibly...
Heart failure with preserved ejection fraction (HFpEF) has been characterized by lower blood flow to exercising limbs and lower peak oxygen utilization ( ), possibly associated with disease-related changes in sympathetic (α-adrenergic) signaling. Thus, in seven patients with HFpEF (70 ± 6 years, 3 female/4 male) and seven controls (CON) (66 ± 3 years, 3 female/4 male), we examined changes (%Δ) in leg blood flow (LBF, Doppler ultrasound) and leg to intra-arterial infusion of phentolamine (PHEN, α-adrenergic antagonist) or phenylephrine (PE, α-adrenergic agonist) at rest and during single-leg knee-extension exercise (0, 5 and 10 W). At rest, the PHEN-induced increase in LBF was not different between groups, but PE-induced reductions in LBF were lower in HFpEF (-16% ± 4% vs. -26% ± 5%, HFpEF vs. CON; P < 0.05). During exercise, the PHEN-induced increase in LBF was greater in HFpEF at 10 W (16% ± 8% vs. 8% ± 5%; P < 0.05). PHEN increased leg in HFpEF (10% ± 3%, 11% ± 6%, 15% ± 7% at 0, 5 and 10 W; P < 0.05) but not in controls (-1% ± 9%, -4% ± 2%, -1% ± 5%; P = 0.24). The 'magnitude of sympatholysis' (PE-induced %Δ LBF at rest - PE-induced %Δ LBF during exercise) was lower in patients with HFpEF (-6% ± 4%, -6% ± 6%, -7% ± 5% vs. -13% ± 6%, -17% ± 5%, -20% ± 5% at 0, 5 and 10 W; P < 0.05) and was positively related to LBF, leg oxygen delivery, leg , and the PHEN-induced increase in LBF (P < 0.05). Together, these data indicate that excessive α-adrenergic vasoconstriction restrains blood flow and limits of the exercising leg in patients with HFpEF, and is related to impaired functional sympatholysis in this patient group. KEY POINTS: Sympathetic (α-adrenergic)-mediated vasoconstriction is exaggerated during exercise in patients with heart failure with preserved ejection fraction (HFpEF), which may contribute to limitations of blood flow, oxygen delivery and oxygen utilization in the exercising muscle. The ability to adequately attenuate α-adrenergic vasoconstriction (i.e. functional sympatholysis) within the vasculature of the exercising muscle is impaired in patients with HFpEF. These observations extend our current understanding of HFpEF pathophysiology by implicating excessive α-adrenergic restraint and impaired functional sympatholysis as important contributors to disease-related impairments in exercising muscle blood flow and oxygen utilization in these patients.
PubMed: 38843407
DOI: 10.1113/JP285526