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European Journal of Pharmacology Jun 2024We explored the vasorelaxant effects of ipragliflozin, a sodium-glucose cotransporter-2 inhibitor, on rabbit femoral arterial rings. Ipragliflozin relaxed...
We explored the vasorelaxant effects of ipragliflozin, a sodium-glucose cotransporter-2 inhibitor, on rabbit femoral arterial rings. Ipragliflozin relaxed phenylephrine-induced pre-contracted rings in a dose-dependent manner. Pre-treatment with the ATP-sensitive K channel inhibitor glibenclamide (10 μM), the inwardly rectifying K channel inhibitor Ba (50 μM), or the Ca-sensitive K channel inhibitor paxilline (10 μM) did not influence the vasorelaxant effect. However, the voltage-dependent K (Kv) channel inhibitor 4-aminopyridine (3 mM) reduced the vasorelaxant effect. Specifically, the vasorelaxant response to ipragliflozin was significantly attenuated by pretreatment with the Kv7.X channel inhibitors linopirdine (10 μM) and XE991 (10 μM), the sarcoplasmic/endoplasmic reticulum Ca-ATPase (SERCA) pump inhibitors thapsigargin (1 μM) and cyclopiazonic acid (10 μM), and the cAMP/protein kinase A (PKA)-associated signaling pathway inhibitors SQ22536 (50 μM) and KT5720 (1 μM). Neither the cGMP/protein kinase G (PKG)-associated signaling pathway nor the endothelium was involved in ipragliflozin-induced vasorelaxation. We conclude that ipragliflozin induced vasorelaxation of rabbit femoral arteries by activating Kv channels (principally the Kv7.X channel), the SERCA pump, and the cAMP/PKA-associated signaling pathway independent of other K (ATP-sensitive K, inwardly rectifying K, and Ca-sensitive K) channels, cGMP/PKG-associated signaling, and the endothelium.
Topics: Animals; Rabbits; Femoral Artery; Vasodilation; Signal Transduction; Cyclic AMP-Dependent Protein Kinases; Thiophenes; Male; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Vasodilator Agents; Potassium Channels, Voltage-Gated; Glucosides
PubMed: 38631503
DOI: 10.1016/j.ejphar.2024.176589 -
Internal Medicine (Tokyo, Japan) 2024Neuronal intranuclear inclusion disease (NIID) exhibits diverse clinical manifestations. Our patient was a 64-year-old woman with bilateral ptosis as the chief...
Neuronal intranuclear inclusion disease (NIID) exhibits diverse clinical manifestations. Our patient was a 64-year-old woman with bilateral ptosis as the chief complaint. She had bilateral miosis, and the pupil was only slightly dilated 60 min after 1% phenylephrine administration, suggesting autonomic dysfunction secondary to preganglionic sympathetic impairment. A head-up tilt test revealed asymptomatic orthostatic hypotension. She was diagnosed with NIID based on a skin biopsy and genetic testing. This study suggests that blepharoptosis is an early manifestation of NIID. Furthermore, patients with suspected NIID should be examined carefully for autonomic dysfunction.
Topics: Female; Humans; Middle Aged; Blepharoptosis; Autonomic Nervous System Diseases; Biopsy; Genetic Testing; Neurodegenerative Diseases; Intranuclear Inclusion Bodies
PubMed: 38616117
DOI: 10.2169/internalmedicine.2384-23 -
Scientific Reports Apr 2024Although the esophageal stethoscope is used for continuous auscultation during general anesthesia, few studies have investigated phonocardiographic data as a continuous...
Although the esophageal stethoscope is used for continuous auscultation during general anesthesia, few studies have investigated phonocardiographic data as a continuous hemodynamic index. In this study, we aimed to induce hemodynamic variations and clarify the relationship between the heart sounds and hemodynamic variables through an experimental animal study. Changes in the cardiac contractility and vascular resistance were induced in anesthetized pigs by administering dobutamine, esmolol, phenylephrine, and nicardipine. In addition, a decrease in cardiac output was induced by restricting the venous return by clamping the inferior vena cava (IVC). The relationship between the hemodynamic changes and changes in the heart sound indices was analyzed. Experimental data from eight pigs were analyzed. The mean values of the correlation coefficients of changes in S1 amplitude (ΔS1amp) with systolic blood pressure (ΔSBP), pulse pressure (ΔPP), and ΔdP/dt during dobutamine administration were 0.94, 0.96, and 0.96, respectively. The mean values of the correlation coefficients of ΔS1amp with ΔSBP, ΔPP, and ΔdP/dt during esmolol administration were 0.80, 0.82, and 0.86, respectively. The hemodynamic changes caused by the administration of phenylephrine and nicardipine did not correlate significantly with changes in the heart rate. The S1 amplitude of the heart sound was significantly correlated with the hemodynamic changes caused by the changes in cardiac contractility but not with the variations in the vascular resistance. Heart sounds can potentially provide a non-invasive monitoring method to differentiate the cause of hemodynamic variations.
Topics: Animals; Swine; Heart Sounds; Dobutamine; Nicardipine; Hemodynamics; Phenylephrine; Propanolamines
PubMed: 38615106
DOI: 10.1038/s41598-024-59362-3 -
ACS Biomaterials Science & Engineering May 2024Intratumoral injection of anticancer agents has limited efficacy and is not routinely used for most cancers. In this study, we aimed to improve the efficacy of...
Intratumoral injection of anticancer agents has limited efficacy and is not routinely used for most cancers. In this study, we aimed to improve the efficacy of intratumoral chemotherapy using a novel approach comprising peri-tumoral injection of sustained-release liposomal nanoparticles containing phenylephrine, which is a potent vasoconstrictor. Using a preclinical model of melanoma, we have previously shown that systemically administered (intravenous) phenylephrine could transiently shunt blood flow to the tumor at the time of drug delivery, which in turn improved antitumor responses. This approach was called dynamic control of tumor-associated vessels. Herein, we used liposomal phenylephrine nanoparticles as a "local" dynamic control strategy for the B16 melanoma. Local dynamic control was shown to increase the retention and exposure time of tumors to intratumorally injected chemotherapy (melphalan). C57BL/6 mice bearing B16 tumors were treated with intratumoral melphalan and peri-tumoral injection of sustained-release liposomal phenylephrine nanoparticles (i.e., the local dynamic control protocol). These mice had statistically significantly improved antitumor responses compared to melphalan alone ( = 0.0011), whereby 58.3% obtained long-term complete clinical response. Our novel approach of local dynamic control demonstrated significantly enhanced antitumor efficacy and is the subject of future clinical trials being designed by our group.
Topics: Animals; Phenylephrine; Liposomes; Nanoparticles; Mice, Inbred C57BL; Melanoma, Experimental; Mice; Antineoplastic Agents; Melphalan; Cell Line, Tumor; Melanoma
PubMed: 38613483
DOI: 10.1021/acsbiomaterials.4c00078 -
Indian Journal of Anaesthesia Apr 2024There is limited data on the effects of norepinephrine on neonatal outcomes and maternal complications relative to other vasopressors. The study aimed to compare...
Comparison of the effect of intravenous phenylephrine and norepinephrine boluses for post-spinal hypotension on neonatal outcome in elective caesarean section: A randomised controlled trial.
BACKGROUND AND AIMS
There is limited data on the effects of norepinephrine on neonatal outcomes and maternal complications relative to other vasopressors. The study aimed to compare neonatal outcomes and maternal complications after bolus intravenous doses of phenylephrine and norepinephrine for post-spinal hypotension in elective caesarean section women.
METHODS
This randomised study was done on 100 elective caesarean section women under spinal anaesthesia. Block randomisation divided women into two groups to receive intravenous phenylephrine 50 μg bolus (Group A) or norepinephrine 5 μg bolus (Group B) following post-spinal hypotension. Groups were evaluated and compared for umbilical arterial blood gas analysis, birth weight, APGAR (appearance, pulse, grimace, activity, and respiration) score, maternal haemodynamics, and complications. Kolmogorov-Smirnov and Shapiro-Wilk tests were used to verify data normality. Independent samples -test or Mann-Whitney U test was employed to compare continuous variables based on data normality, and the Chi-square test was used to determine categorical variable associations.
RESULTS
Demographic characteristics of women were found to be comparable between groups. Umbilical arterial potential of hydrogen, partial pressure of oxygen, partial pressure of carbon dioxide, base excess, bicarbonate, birth weight, and APGAR scores were comparable across groups, showing no significant differences ( > 0.05). Groups had similar maternal haemodynamic characteristics and episodes of nausea, vomiting, and chest pain across groups without statistical significance ( > 0.05).
CONCLUSION
No notable distinction was found between neonatal outcomes and maternal complications between phenylephrine and norepinephrine bolus regimens. Norepinephrine can be used as an alternative to phenylephrine post-spinal hypotension in women undergoing elective caesarean section.
PubMed: 38586272
DOI: 10.4103/ija.ija_920_23 -
Frontiers in Neurology 2024Stroke interventions that increase collateral flow have the potential to salvage penumbral tissue and increase the number of patients eligible for reperfusion therapy....
INTRODUCTION
Stroke interventions that increase collateral flow have the potential to salvage penumbral tissue and increase the number of patients eligible for reperfusion therapy. We compared the efficacy of two different collateral therapeutics during transient middle cerebral artery occlusion (tMCAO) in normotensive and hypertensive rats.
METHODS
The change in collateral and core perfusion was measured using dual laser Doppler in response to either a pressor agent (phenylephrine, 10 mg/kg iv or vehicle) or a collateral vasodilator (TM5441, 5 mg/kg iv or vehicle) given 30 min into tMCAO in male Wistar and spontaneously hypertensive rats (SHRs).
RESULTS
Pressor therapy increased collateral flow in the Wistar rats but was ineffective in the SHRs. The increase in collateral flow in the Wistar rats was associated with impaired cerebral blood flow autoregulation (CBFAR) that was intact in the SHRs. TM5441 caused a decrease in collateral perfusion in the Wistar rats and a modest increase in the SHRs. The pressor therapy reduced early infarction in both groups but increased edema in the SHRs, whereas TM5441 did not have any beneficial effects in either group.
CONCLUSIONS
Thus, the pressor therapy was superior to a collateral vasodilator in increasing collateral flow and improving outcomes in the Wistar rats, likely due to pial collaterals that were pressure passive; the lack of CBF response in the SHRs to pressor therapy was likely due to intact CBFAR that limited perfusion. While TM5441 modestly increased CBF in the SHRs but not in the Wistar rats, it did not have a beneficial effect on stroke outcomes. These results suggest that collateral therapies may need to be selected for certain comorbidities.
PubMed: 38585360
DOI: 10.3389/fneur.2024.1373445 -
Contact Dermatitis Apr 2024The prevalence of contact allergy to various ophthalmic medications appears to be rare; however, data on culprits, clinical relevance of sensitizations, and changes in...
BACKGROUND
The prevalence of contact allergy to various ophthalmic medications appears to be rare; however, data on culprits, clinical relevance of sensitizations, and changes in frequency within recent decades are limited.
OBJECTIVE
This study aimed to investigate the clinical relevance, risk factors, and prevalence of contact allergy to topical ophthalmic medications in patients suspected of allergic contact dermatitis to ophthalmic medication.
METHODS
We retrospectively analysed patch test results and clinical data for 754 patients patch-tested with an ophthalmic medication series at our tertiary referral centre between January 1992 and December 2022.
RESULTS
In total, 37.5% (283/754) of patch-tested patients had a contact allergy to at least one ophthalmic allergen, with 87.3% (247) being clinically relevant sensitization. Phenylephrine (31.8%, 192/604), povidone-iodine (29%, 27/93), and tobramycin (23%, 46/200) were the most important sensitizers. The incidence of contact allergies increased significantly in a linear manner (p = 0.008) from 20% to 44.1% within the study period. Male sex and age above 40 were risk factors for contact allergy to ophthalmic medication.
CONCLUSIONS
One third of patch tested patients had allergic contact dermatitis to ophthalmic medication, particularly phenylephrine. Male sex and age above 40 years were independent risk factors and drove the linear increase in contact allergy to ophthalmic medications within the past 31 years.
PubMed: 38581258
DOI: 10.1111/cod.14552 -
Hypertension (Dallas, Tex. : 1979) Jun 2024Abnormalities of resistance arteries may play essential roles in the pathophysiology of aging and hypertension. Deficiency of the vascular extracellular matrix protein...
BACKGROUND
Abnormalities of resistance arteries may play essential roles in the pathophysiology of aging and hypertension. Deficiency of the vascular extracellular matrix protein MFAP4 (microfibrillar-associated protein 4) has previously been observed as protective against aberrant arterial remodeling. We hypothesized that MFAP4-deficiency would reduce age- and hypertension-dependent arterial changes in extracellular matrix composition and stiffening.
METHODS
Mesenteric arteries were isolated from old (20-23 months) littermate and mice, and 2-photon excitation microscopy imaging was used to quantify elastin and collagen volumes and dimensions in the vascular wall. Ten-week-old littermate and mice were subjected to 20 days of continuous Ang II (angiotensin II) infusion and hypertension was monitored using invasive blood pressure measurements. Arterial stiffness, responses to vascular constrictors, and myogenic tone were monitored using wire- or pressure-myography. Collagen contents were assessed by Western blotting.
RESULTS
MFAP4-deficiency significantly increased collagen volume and elastin fragmentation in aged mesenteric arteries without affecting arterial stiffness. MFAP4-deficient mice exhibited reduced diastolic pressure in Ang II-induced hypertension. There was no significant effect of MFAP4-deficiency on mesenteric artery structural remodeling or myogenic tone, although collagen content in mesenteric arteries was tendentially increased in hypertensive mice relative to mice. Increased efficacy of vasoconstrictors (phenylephrine, thromboxane) and reduced stiffness were observed in Ang II-treated mouse mesenteric arteries in ex vivo myography recordings.
CONCLUSIONS
MFAP4-deficiency reduces the elastin/collagen ratio in the aging resistance artery without affecting arterial stiffness. In contrast, MFAP4-deficiency reduces the stiffness of resistance arteries and ameliorates Ang II-induced hypertension.
Topics: Animals; Hypertension; Mice; Mesenteric Arteries; Vascular Stiffness; Vascular Resistance; Aging; Angiotensin II; Elastin; Blood Pressure; Extracellular Matrix Proteins; Mice, Knockout; Disease Models, Animal; Male; Collagen
PubMed: 38563153
DOI: 10.1161/HYPERTENSIONAHA.123.22283 -
Physiological Genomics Jun 2024Short-chain fatty acids (SCFAs) produced by the gut bacteria have been associated with cardiovascular dysfunction in humans and rodents. However, studies exploring...
Short-chain fatty acids (SCFAs) produced by the gut bacteria have been associated with cardiovascular dysfunction in humans and rodents. However, studies exploring effects of SCFAs on cardiovascular parameters in the zebrafish, an increasingly popular model in cardiovascular research, remain limited. Here, we performed fecal bacterial 16S sequencing and gas chromatography/mass spectrometry (GC-MS) to determine the composition and abundance of gut microbiota and SCFAs in adult zebrafish. Following this, the acute effects of major SCFAs on heart rate and vascular tone were measured in anesthetized zebrafish larvae using fecal concentrations of butyrate, acetate, and propionate. Finally, we investigated if coincubation with butyrate may lessen the effects of angiotensin II (ANG II) and phenylephrine (PE) on vascular tone in anesthetized zebrafish larvae. We found that the abundance in , , and phyla in the adult zebrafish resembled those reported in rodents and humans. SCFA levels with highest concentration of acetate (27.43 µM), followed by butyrate (2.19 µM) and propionate (1.65 µM) were observed in the fecal samples of adult zebrafish. Immersion in butyrate and acetate produced a ∼20% decrease in heart rate (HR), respectively, with no observed effects of propionate. Butyrate alone also produced an ∼25% decrease in the cross-sectional width of the dorsal aorta (DA) at 60 min (* < 0.05), suggesting compensatory vasoconstriction, with no effects of either acetate or propionate. In addition, butyrate significantly alleviated the decrease in DA cross-sectional width produced by both ANG II and PE. We demonstrate the potential for zebrafish in investigation of host-microbiota interactions in cardiovascular health. We highlight the presence of a core gut microbiota and demonstrate in vivo short-chain fatty acid production in adult zebrafish. In addition, we show cardio-beneficial vasoactive and chronotropic properties of butyrate, and chronotropic properties of acetate in anesthetized zebrafish larvae.
Topics: Animals; Zebrafish; Gastrointestinal Microbiome; Fatty Acids, Volatile; Larva; Heart Rate; Feces; Butyrates; Angiotensin II; Bacteria; Phenylephrine; Acetates; RNA, Ribosomal, 16S
PubMed: 38557279
DOI: 10.1152/physiolgenomics.00013.2024 -
Cureus Feb 2024Systolic anterior motion of the mitral valve and left ventricular outflow tract obstruction are complications following transcatheter aortic valve implantation and can...
Systolic anterior motion of the mitral valve and left ventricular outflow tract obstruction are complications following transcatheter aortic valve implantation and can lead to hemodynamic collapse. Medical management for those complications is usually centered on a reduction in left ventricular contractility with negative inotropes. An 88-year-old woman underwent transcatheter aortic valve implantation for severe aortic stenosis. Hemodynamic collapse and exacerbation of mitral regurgitation occurred immediately after valve implantation. For suspected left ventricular outflow tract obstruction, medical management centered on negative inotropes was performed. Hemodynamics and left ventricular outflow tract obstruction improved over time; however, the oxygen supply-demand imbalance progressed. On postoperative day 5, the patient suddenly went into pulseless electrical activity. Cardiopulmonary resuscitation was performed for three minutes, resulting in the return of spontaneous circulation. Subsequent refractory hypotension and oxygen supply-demand imbalance improved with continuous infusion of adrenaline, dobutamine, and phenylephrine. Her hemodynamics remained stable after she was weaned off the pressor infusions, and negative inotropes were not required again. In summary, the cause of cardiac arrest was possibly due to excessive negative inotropic effects even though the effects contributed to improvement of left ventricular outflow tract obstruction. Anesthesiologists and intensivists should recognize the risk of cardiac arrest induced by negative inotropic effects and use negative inotropes with rigorous hemodynamic monitoring, even when left ventricular outflow tract obstruction is treated effectively.
PubMed: 38550487
DOI: 10.7759/cureus.55026