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Pflugers Archiv : European Journal of... Dec 2022Atrial fibrillation (AF) from elevated adrenergic activity may involve increased atrial L-type Ca current (I) by noradrenaline (NA). However, the contribution of the...
Atrial fibrillation (AF) from elevated adrenergic activity may involve increased atrial L-type Ca current (I) by noradrenaline (NA). However, the contribution of the adrenoceptor (AR) sub-types to such I-increase is poorly understood, particularly in human. We therefore investigated effects of various broad-action and sub-type-specific α- and β-AR antagonists on NA-stimulated atrial I. I was recorded by whole-cell-patch clamp at 37 °C in myocytes isolated enzymatically from atrial tissues from consenting patients undergoing elective cardiac surgery and from rabbits. NA markedly increased human atrial I, maximally by ~ 2.5-fold, with EC 310 nM. Propranolol (β + β-AR antagonist, 0.2 microM) substantially decreased NA (310 nM)-stimulated I, in human and rabbit. Phentolamine (α + α-AR antagonist, 1 microM) also decreased NA-stimulated I. CGP20712A (β-AR antagonist, 0.3 microM) and prazosin (α-AR antagonist, 0.5 microM) each decreased NA-stimulated I in both species. ICI118551 (β-AR antagonist, 0.1 microM), in the presence of NA + CGP20712A, had no significant effect on I in human atrial myocytes, but increased it in rabbit. Yohimbine (α-AR antagonist, 10 microM), with NA + prazosin, had no significant effect on human or rabbit I. Stimulation of atrial I by NA is mediated, based on AR sub-type antagonist responses, mainly by activating β- and α-ARs in both human and rabbit, with a β-inhibitory contribution evident in rabbit, and negligible α involvement in either species. This improved understanding of AR sub-type contributions to noradrenergic activation of atrial I could help inform future potential optimisation of pharmacological AR-antagonism strategies for inhibiting adrenergic AF.
Topics: Animals; Humans; Rabbits; Atrial Fibrillation; Myocytes, Cardiac; Norepinephrine; Prazosin; Receptors, Adrenergic, alpha-2; Heart Atria; Receptors, Adrenergic, beta; Receptors, Adrenergic, alpha; Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Calcium Channels, L-Type
PubMed: 36131146
DOI: 10.1007/s00424-022-02746-z -
PloS One 2022The prevalence of chronic kidney disease (CKD) is increasing worldwide; black patients have an increased risk of developing CKD and end stage kidney disease (ESKD) at...
BACKGROUND
The prevalence of chronic kidney disease (CKD) is increasing worldwide; black patients have an increased risk of developing CKD and end stage kidney disease (ESKD) at significantly higher rates than other races.
METHODS
A cross sectional study was carried out on black patients with CKD attending the kidney outpatient clinic at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) in South Africa, between September 2019 to March 2020. Demographic and clinical data were extracted from the ongoing kidney outpatient clinic records and interviews, and were filled in a questionnaire. Patients provided blood and urine for laboratory investigations as standard of care, and data were descriptively and inferentially entered into REDcap and analysed using STATA version 17. Multivariable logistic regression analysis was used to identify demographic and clinical variables associated with advanced CKD.
RESULTS
A total of 312 black patients with CKD were enrolled in the study with a median age of 58 (IQR 46-67) years; 58% patients had advanced CKD, 31.5% of whom had grossly increased proteinuria, 96.7% had hypertension, 38.7% had diabetes mellitus and 38.1% had both hypertension and diabetes mellitus. In patients with advanced CKD, the median age was 61 (IQR 51-69) years, eGFR 33 (30-39) mL/min/1.73 m2, serum bicarbonate 22 (IQR 20-24), haemoglobin 12.9 (IQR 11.5-14.0) g/dl and serum uric acid 0.43 (IQR 0.37-0.53). The prevalence of metabolic acidosis was 62.4%, anemia 46.4% and gout 30.9% among those with advanced CKD, while the prevalence of metabolic acidosis and anaemia was 46.6% and 25.9% respectively in those with early CKD. Variables with higher odds for advanced CKD after multivariable logistic regression analysis were hypertension (OR 3.3, 95% CI 1.2-9.2, P = 0.020), diabetes mellitus (OR 1.8, 95% CI 1.1-3.3, P = 0.024), severe proteinuria (OR 3.5, 95% CI 1.9-6.5, P = 0.001), angina (OR 2.5, 95% CI 1.2-5.1, P = 0.008), anaemia (OR 2.9, 95% CI 1.7-4.9, P = 0.001), hyperuricemia (OR 2.4, 95% CI 1.4-4.1, P = 0.001), and metabolic acidosis (OR 2.0, 95% CI 1.2-3.1, P = 0.005). Other associations with advanced CKD were loss of spouse (widow/widower) (OR 3.2, 95% CI 1.4-7.4, P = 0.006), low transferrin (OR 2.4, 95% CI 1.1-5.1, P = 0.028), hyperkalemia (OR 5.4, 95% CI 1.2-24.1, P = 0.029), use of allopurinol (OR 2.4, 95% CI 1.4-4.3, P = 0.005) and doxazosin (OR 1.9, 95% CI 1.2-3.1, P = 0.006).
CONCLUSION
Hypertension and diabetes mellitus were strongly associated with advanced CKD, suggesting a need for primary and secondary population-based prevention measures. Metabolic acidosis, anemia with low transferrin levels, hyperuricemia and hyperkalemia were highly prevalent in our patients, including those with early CKD, and they were strongly associated with advanced CKD, requiring clinicians and dietitians to be proactive in supporting the needs of CKD patients in meeting their daily dietary requirements towards preventing and slowing the progression of CKD.
Topics: Acidosis; Aged; Allopurinol; Anemia; Bicarbonates; Cross-Sectional Studies; Diabetes Mellitus; Doxazosin; Hemoglobins; Humans; Hyperkalemia; Hypertension; Hyperuricemia; Middle Aged; Prevalence; Proteinuria; Renal Insufficiency, Chronic; South Africa; Tertiary Care Centers; Transferrins; Uric Acid
PubMed: 36121812
DOI: 10.1371/journal.pone.0266155 -
Toxicon : Official Journal of the... Oct 2022Rhinella marina toad is abundant in Brazil. Its poison contains cardiac glycosides called bufadienolides, which are extensively investigated for their bioactivity. Our...
Rhinella marina toad is abundant in Brazil. Its poison contains cardiac glycosides called bufadienolides, which are extensively investigated for their bioactivity. Our aim was to characterize the vasoactivity of Rhinella marina poison (RmP) on the aorta of male Wistar rats. For this, the RmP was first collected and processed to obtain an alcoholic extract. To determine cardiovascular effects of RmP, we performed in vivo tests by administering RmP intravenously in doses of 0.1-0.8 mg/kg. Vascular reactivity was also performed through concentration-response curves to RmP (10 ng/mL to 200 μg/mL) in aortic segments with and without endothelium. RmP induced a concentration-dependent contraction in rat aorta which was partly endothelium-mediated. Nitric oxide contributes with this response in view that incubation with L-NAME increased the contractile response. Additionally, treatment with indomethacin [cyclooxygenase, (COX) inhibitor], nifedipine (L-type voltage-gated calcium channels blocker), and BQ-123 (ET receptors antagonist) decreased maximum response, and ketanserin (5-HT receptors antagonist) decreased pEC, suggesting active participation of these pathways in the contractile response. On the other hand, apocynin (NADPH oxidase inhibitor) did not alter contractility. Incubation with prazosin (α-adrenergic receptor antagonist) abolished the contractile response, suggesting that the RmP-induced contraction is dependent on the adrenergic pathway. In the Na/K ATPase protocol, a higher Emax was observed in the RmP experimental group, suggesting that RmP potentiated Na/KATPase hyperpolarizing response. When this extract was injected (i.v.) in vivo, increase in blood pressure and decrease in heart rate were observed. The results were immediate and transitory, and occurred in a dose-dependent manner. Overall, these data suggest that the poison extract of R. marina toad has an important vasoconstrictor action and subsequent vasopressor effects, and its use can be investigated to some cardiovascular disorders.
Topics: Adenosine Triphosphatases; Adrenergic Agents; Adrenergic Antagonists; Animals; Bufanolides; Bufo marinus; Calcium Channels; Endothelium, Vascular; Hemodynamics; Indomethacin; Ketanserin; Male; Methanol; NADPH Oxidases; NG-Nitroarginine Methyl Ester; Nifedipine; Nitric Oxide; Poisons; Prazosin; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Serotonin; Vasoconstrictor Agents
PubMed: 36113683
DOI: 10.1016/j.toxicon.2022.08.018 -
IBRO Neuroscience Reports Dec 2022Mitragynine (MG) is an alkaloid found in (kratom) that is used as an herbal remedy for pain relief and opioid withdrawal. MG acts at μ-opioid and α-adrenergic...
Mitragynine (MG) is an alkaloid found in (kratom) that is used as an herbal remedy for pain relief and opioid withdrawal. MG acts at μ-opioid and α-adrenergic receptors in vitro but the physiological relevance of this activity in the context of neuropathic pain remains unknown. The purpose of the present study was to characterize the effects of MG in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN), and to investigate the potential impact of sex on MG's therapeutic efficacy. Inhibition of oxaliplatin-induced mechanical hypersensitivity was measured following intraperitoneal administration of MG. Both male and female C57BL/6J mice were used to characterize potential sex-differences in MG's therapeutic efficacy. Pharmacological mechanisms of MG were characterized through pretreatment with the opioid and adrenergic antagonists naltrexone, prazosin, yohimbine, and propranolol (1, 2.5, 5 mg/kg). Oxaliplatin produced significant mechanical allodynia of equal magnitude in both male and females, which was dose-dependently attenuated by repeated MG exposure. MG was more potent in males vs females, and the highest dose of MG (10 mg/kg) exhibited greater anti-allodynic efficacy in males. Mechanistically, activity at µ-opioid, α- and α-adrenergic receptors, but not β-adrenergic receptors contributed to the effects of MG against oxaliplatin-induced mechanical hypersensitivity. Repeated MG exposure significantly attenuated oxaliplatin-induced mechanical hypersensitivity with greater potency and efficacy in males, which has crucial implications in the context of individualized pain management. The opioid and adrenergic components of MG indicate that it shares pharmacological properties with clinical neuropathic pain treatments.
PubMed: 36093282
DOI: 10.1016/j.ibneur.2022.08.007 -
The Chinese Journal of Physiology 2022Bilateral nucleus tractus solitarii (NTS) lesions, possibly caused by enterovirus 71 infection, cause severe neurogenic hypertension, leading to acute heart failure...
Bilateral nucleus tractus solitarii (NTS) lesions, possibly caused by enterovirus 71 infection, cause severe neurogenic hypertension, leading to acute heart failure (HF), pulmonary edema, and death within hours. Alpha-adrenergic blockers attenuate blood pressure and ameliorate HF and pulmonary edema, thereby prolonging survival time. However, the molecular mechanisms of these blockers are not clear. In this study, we investigated these mechanisms in a rat model of 6-hydroxydopamine (6-OHDA)-induced HF. Sprague-Dawley rats were treated with prazosin 10 min after the microinjection of 6-OHDA into the NTS. Immunohistochemistry and dihydroethidium (DHE) staining were used for analysis. In the cardiac tissue of 6-OHDA-induced HF, in situ expression of tumor necrosis factor-alpha (TNF-α), fibroblast growth factor-23 (FGF23), and FGF receptor 1 (FGFR1) increased, but in situ expression of Vitamin D receptor (VDR) decreased. DHE staining revealed several heart cells with high reactive oxygen species production. Prazosin treatment decreased TNF-α, FGF23, and FGFR1 expression in the heart of rats with 6-OHDA-induced HF. It also prevented cardiomyopathy caused by 6-OHDA-induced bilateral NTS lesions by inhibiting the FGF23-FGFR1 pathway and downregulating TNF-α expression. In situ, FGF23, FGFR1, VDR, superoxide, and TNF-α in the heart were found to be involved in acute HF in our rat model of 6-OHDA-induced bilateral NTS lesions. These findings are potentially useful for treating fatal enterovirus 71 infection-induced NTS lesions and HF.
Topics: Animals; Down-Regulation; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Heart Failure; Oxidopamine; Prazosin; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha
PubMed: 36073566
DOI: 10.4103/cjp.cjp_9_22 -
The Mental Health Clinician Aug 2022Prazosin is an alpha-1 adrenergic receptor antagonist widely known by mental health providers for its off-label use for nightmares in patients with PTSD. Prazosin is...
Prazosin is an alpha-1 adrenergic receptor antagonist widely known by mental health providers for its off-label use for nightmares in patients with PTSD. Prazosin is lipophilic and crosses the blood-brain barrier to antagonize alpha-1 receptors in the central nervous system, potentially reducing autonomic arousal caused by PTSD. There have been numerous case reports describing the reduction of nightmares and daytime flashbacks due to PTSD with prazosin dosed at night and during the day, respectively. This case report illustrates the resolution of flashbacks related to chronic PTSD with prazosin dosed 3 times a day. As the half-life of prazosin is only 2 to 3 hours, even a twice daily dosing regimen may lead to breakthrough symptoms between doses. This case proposes a unique dosing strategy for prazosin and need for further research utilizing multiple daily doses of prazosin in the treatment of PTSD.
PubMed: 36071742
DOI: 10.9740/mhc.2022.08.267 -
Research and Reports in Urology 2022Recommendations for alpha-blockers have shifted in the conservative management of ureteral stones. It is unknown whether real-life practices regarding alpha-blocker...
PURPOSE
Recommendations for alpha-blockers have shifted in the conservative management of ureteral stones. It is unknown whether real-life practices regarding alpha-blocker prescriptions reflect updates in evidence. This study aimed to characterise alpha-blocker prescriptions for conservatively managed ureteral stones and relate this to recent literature.
METHODS
This was a retrospective audit, 01/01/2014 to 01/01/2019, of emergency acute renal colic presentations. Patients were included if they had a confirmed ureteral stone and were conservatively managed. The rates of alpha-blocker prescriptions were analysed using interrupted time-series analyses. May 2015 was selected as the cut-point to analyse before and after trend lines. Results were stratified by stone size and location. Tamsulosin and prazosin prescriptions were also compared.
RESULTS
This study included 2163 presentations: 70.4% were stones ≤5 mm and 61.4% were proximal stones. Altogether, 24.7% of presentations were prescribed alpha-blockers. There was a fall in alpha-blocker prescription rates from before to after May 2015, regardless of stone size or location (p < 0.001). Since May 2015, however, there was a monthly rate increase of 0.5% for patients with stones >5mm.
CONCLUSION
This study demonstrated a significant shift in rates of alpha-blocker prescriptions, possibly related to the influence of updates in available high-quality evidence.
PubMed: 36060307
DOI: 10.2147/RRU.S372208 -
Journal of Pharmacological Sciences Oct 2022We analyzed role of cardiac α-adrenoreceptors for the torsadogenic action of I blocker nifekalant in isoflurane-anesthetized atrioventricular block rabbits. Bradycardia...
We analyzed role of cardiac α-adrenoreceptors for the torsadogenic action of I blocker nifekalant in isoflurane-anesthetized atrioventricular block rabbits. Bradycardia was induced by atrioventricular node ablation, and the ventricle was electrically driven at a constant rate of 60 beats/min throughout the experiments to prevent rate-dependent modification by the I blocker in ventricular repolarization phase. Nifekalant (3 mg/kg per 10 min, n = 5) prolonged the duration of monophasic action potential (MAP) by +178 ± 43 ms, increased the short-term variability of repolarization (STV) to 4.2 ± 1.2 ms, and induced torsade de pointes (TdP) in 1 animal. In the presence of methoxamine (n = 5), nifekalant prolonged the MAP by +328 ± 32 ms, increased the STV to 8.0 ± 1.0 ms, and induced TdP in 2 animals. In the presence of prazosin and methoxamine (n = 5), nifekalant prolonged the MAP by +267 ± 22 ms, increased the STV to 9.2 ± 3.6 ms, and induced no TdP. These results suggest that cardiac α-adrenoreceptor activation by methoxamine essentially sensitizes the rabbit heart to nifekalant-induced QT interval prolongation, leading to the onset of TdP.
Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Atrioventricular Block; Electrocardiography; Long QT Syndrome; Methoxamine; Pyrimidinones; Rabbits; Torsades de Pointes
PubMed: 36055753
DOI: 10.1016/j.jphs.2022.07.003 -
Anatomical Record (Hoboken, N.J. : 2007) Feb 2023Ductus arteriosus is a muscular artery in fetal circulation, spanning from the bifurcation of the pulmonary trunk to the aortic arch, shunting blood directly from...
Ductus arteriosus is a muscular artery in fetal circulation, spanning from the bifurcation of the pulmonary trunk to the aortic arch, shunting blood directly from pulmonary circulation into systemic circulation thus by-passing the fluid-filled lungs. Postnatally, it changes name to the ligamentum arteriosum (LA), when a cascade of anatomical and physiological processes leads to its closure. Though the LA has generally been considered as a fibrosed remnant of the ductus arteriosus, anecdotal and contradictory reports still describe the LA as a small muscular artery. We hypothesized the likelihood of contractile muscular elements retainment in this so-called ligament. To investigate this, mediastinum of wild-type mouse, pig, and human LA were subjected to routine and special histological staining, single-immunolabeling, electron microscopy (mouse and pig only), and tension recording of explanted pig LA in organ bath experiments. Contrary to a canonical ligament, the LA was mainly made up of α-smooth muscle actin-positive cells in all three species, confirmed by routine and special histological staining as well as transmission electron microscopy. Myocytes within the LA contracted in response to exogenous noradrenalin (NA). NA-induced precontracted LA relaxed upon administration of the α1-adrenergic blockers (prazosin and tamsulosin). Though the LA does not function in its original capacity as fetal shunt, it is clearly not a passive structure, and may be described as muscular and contractile. The contractile abilities of LA myocytes may act on the two great vessels to which it is attached causing a change in their distensibility.
Topics: Animals; Mice; Humans; Swine; Aorta, Thoracic; Ductus Arteriosus, Patent; Ductus Arteriosus; Pulmonary Artery; Ligaments
PubMed: 36054486
DOI: 10.1002/ar.25058 -
Asian Journal of Urology Jul 2022Clinical practice guidelines recommend open adrenalectomy (OA) for large pheochromocytoma (LPCC) > 6 cm in size. Although laparoscopic adrenalectomy (LA) for the...
OBJECTIVE
Clinical practice guidelines recommend open adrenalectomy (OA) for large pheochromocytoma (LPCC) > 6 cm in size. Although laparoscopic adrenalectomy (LA) for the treatment of LPCC has been reported, its role remains unclear. This study aimed to compare the effectiveness of LA and OA, and summary the surgical treatment experience.
METHODS
Data concerning LPCC, from January 2010 to June 2019 of a single institution, were retrospectively reviewed. Altogether 82 patients with a tumor larger than 6 cm were included (52 patients in LA group and 30 patients in OA group). Groups were balanced by propensity score matching (PSM) into 15 pairs. Patients' demographics, preoperative characteristics, and prognosis were analyzed.
RESULTS
Before PSM, the OA group had larger tumor sizes (median [interquartile range, IQR]: 8.9 [7.3-10.3] 7.2 [6.7-8.0] cm; =0.000) and higher vanillylmandelic acid level (median [IQR]: 114.3 [67.8-326.4] 66.6 [37.8-145.8] μmol/24 h; =0.004) and needed a higher cumulative dose of prazosin (median [IQR]: 83.5 [37.0-154.0] 38.0 [21.0-81.0] mg; =0.028). After PSM, the baseline data showed no significant differences between both groups. The LA group had relatively more stable blood pressure in surgery, with a lower fluctuation of systolic blood pressure (mean±standard deviation [SD]: 70.9±25.1 107.4±46.2 mmHg, =0.012) and a lower percentage of hemodynamic instability (46.7% 86.7%, =0.020). The LA group had shorter postoperative hospital stays (mean±SD: 6.4±2.7 10.1±3.4 days; =0.003) than the OA group. Differences regarding metastasis rate (6.7% 0, =1.000) were not statistically significant between LA and OA groups. The median (IQR) follow-up time of 82 patients was 72.5 (47.0-103.5) months. Binary logistic regression showed that right-side tumors or those >8 cm in size were independent risk factors of OA.
CONCLUSION
LA is a safe, minimally invasive procedure for LPCC and has relatively better perioperative characteristics in large medical centers. Patients with tumors on the right side or larger than 8 cm are more likely to undergo OA initially.
PubMed: 36035344
DOI: 10.1016/j.ajur.2022.04.004