Mitigation of dexamethasone-induced nephrotoxicity by modulating the activity of adrenergic receptors: Implication of Wnt/ß-arrestin2/ß-catenin pathway.

The present study aimed to investigate the role of α and ß-adrenergic receptors (ßARs) in mediation or modulation of the dexamethasone-induced nephrotoxicity by using different pharmacological interventions. Nephrotoxicity was induced by subcutaneous injection of dexamethasone (10 mg/kg) for 7 days in Wistar albino rats. Eight groups were used: control; dexamethasone; carvedilol; phenylephrine; carvedilol and phenylephrine; propranolol; doxazosin; propranolol and doxazosin. At the end of experiment, rats were euthanized and blood, urine and kidney samples were collected. Serum and urinary creatinine and urinary total protein levels were measured. Also, the renal tissue levels of diacylglycerol (DAG); Akt kinase activity, malondialdehyde (MDA), NADPH oxidase 2 (NOX2), transforming growth factor-ß (TGF-ß), Wnt3A and ß-catenin were recorded. Furthermore, histopathological and ß-arrestin2-immunohistochemical examinations of renal tissues were performed. Results: Dexamethasone induced glomerular damage, proteinuria, renal oxidative stress and upregulated the renal Wnt/ß-arrestin2/ß-catenin pathway and the profibrotic signals. Blocking the α1 and ßARs by carvedilol reduced the dexamethasone-induced nephrotoxicity. Pre-injection of phenylephrine did not reduce the reno-protective action of carvedilol. Blocking the ßARs only by propranolol reduced the dexamethasone-induced nephrotoxicity to the same extent of carvedilol group. Blocking the α1ARs only by doxazosin reduced dexamethasone-induced nephrotoxicity to a higher extent than other treatments. However, combined use of propranolol and doxazosin did not synergize the reno-protective effects of doxazosin. Conclusion: Dexamethasone induces nephrotoxicity, possibly, by upregulating the Wnt/ß-arrestin2/ß-catenin pathway. Blocking either α1ARs or ßARs can effectively protect against the dexamethasone-induced nephrotoxicity. However, combined blocking of α1ARs and ßARs does not synergize the reno-protective effects.

Combined inorganic nitrate/nitrite supplementation blunts α-mediated vasoconstriction during exercise in patients with type 2 diabetes.

AIMS: Patients with type 2 diabetes mellitus (T2DM) have reduced vasodilatory responses during exercise partially attributable to low nitric oxide (NO) levels. Low NO contributes to greater α-adrenergic mediated vasoconstriction in contracting skeletal muscle. We hypothesized boosting NO bioavailability via 8wks of active beetroot juice (BRA, 4.03 mmol nitrate, 0.29 mmol nitrite, n = 19) improves hyperemia, via reduced α-mediated vasoconstriction, during handgrip exercise relative to nitrate/nitrite-depleted beetroot juice (BRP, n = 18) in patients with T2DM. METHODS: Forearm blood flow (FBF) and vascular conductance (FVC) were calculated at rest and during handgrip exercise (20%max, 20contractions·min-1). Phenylephrine (α1-agonist) and dexmedetomidine (α2-agonist) were infused intra-arterially during independent trials to determine the influence of α-mediated vasoconstriction on exercise hyperemia. Vasoconstriction was quantified as the percent-reduction in FVC during α-agonist infusion, relative to pre-infusion, as well as the absolute change in %FVC during exercise relative to the respective rest trial (magnitude of sympatholysis). RESULTS: ΔFBF (156 ± 69 to 175 ± 73 ml min-1) and ΔFVC (130 ± 54 to 156 ± 63 ml min-1·100 mmHg-1, both P < 0.05) during exercise were augmented following BRA, but not BRP (P = 0.96 and 0.51). Phenylephrine-induced vasoconstriction during exercise was blunted following BRA (-17.1 ± 5.9 to -12.6 ± 3.1%, P < 0.01), but not BRP (P = 0.58) supplementation; the magnitude of sympatholysis was unchanged by either (beverage-by-time P = 0.15). BRA supplementation reduced dexmedetomidine-induced vasoconstriction during exercise (-23.3 ± 6.7 to -19.7 ± 5.2%) and improved the corresponding magnitude of sympatholysis (25.3 ± 11.4 to 34.4 ± 15.5%, both P < 0.05). CONCLUSIONS: BRA supplementation improves the hyperemic and vasodilatory responses to exercise in patients with T2DM which appears to be attributable to reduced α-adrenergic mediated vasoconstriction in contracting skeletal muscle.

Acute Ischemia of Lower Extremities Caused by Ergotamine Toxicity due to Pharmacologic Interaction With Cobicistat in an HIV-Positive Patient.

Ergotism is an uncommon condition that affects patients with exposure to ergot alkaloids causing ischemia of extremities. We report the case of lower extremities ischemia caused by ergot toxicity in a human immunodeficiency virus (HIV) positive individual due to the interaction between ergot alkaloid and Cobicistat. In addition, we present a brief review of medical, and pharmacological aspects of this condition. To our knowledge, this is the second reported case describing this interaction.

Effect of Topical Phenylephrine 2.5% on Episcleral Venous Pressure in Normal Human Eyes.

Purpose: Phenylephrine has been shown to affect intraocular pressure (IOP) but the mechanism of action is poorly understood. However, its action as a vasoconstrictor suggests possible effects on episcleral venous pressure (EVP). In this study, we evaluated the effect of phenylephrine on EVP and IOP in healthy subjects. Methods: Forty eyes of 20 subjects were included. Each subject received 3 drops of phenylephrine 2.5% in one eye at 1-minute intervals. The fellow eye served as control. Blood pressure, heart rate, and IOP and EVP of both eyes were measured at baseline, 15 minutes, and 60 minutes after instillation of phenylephrine. IOP was measured by pneumatonometry. EVP was assessed by using a computer-controlled episcleral venomanometer. Changes in IOP, EVP, blood pressure, and heart rate at 15 and 60 minutes were analyzed by paired t-tests. Results: IOP increased 15 minutes after instillation of phenylephrine in both treated (P = 0.001) and control eyes (P = 0.01) and returned to baseline at 60 minutes. The change in IOP at 15 minutes was not significantly different between the 2 groups. EVP in treated eyes was unchanged at 15 minutes (P = 0.8) but decreased significantly at 60 minutes (P < 0.001). In control eyes, there was no change in EVP at any time (P > 0.6). There were no significant changes from baseline in systolic and diastolic blood pressure and heart rate after instillation of phenylephrine. Conclusions: IOP elevation associated with topical phenylephrine is not caused by an increase in EVP in healthy subjects. Instead, EVP decreases with phenylephrine, but the mechanism remains to be determined.

Effect of ingesting a meal and orthostasis on the regulation of splanchnic and systemic hemodynamics and the responsiveness of cardiovascular α1-adrenoceptors.

Postprandial orthostasis activates mechanisms of cardiovascular homeostasis to maintain normal blood pressure (BP) and adequate blood flow to vital organs. The underlying mechanisms of cardiovascular homeostasis in postprandial orthostasis still require elucidation. Fourteen healthy volunteers were recruited to investigate the effect of an orthostatic challenge (60°-head-up-tilt for 20 min) on splanchnic and systemic hemodynamics before and after ingesting an 800-kcal composite meal. The splanchnic circulation was assessed by ultrasonography of the superior mesenteric and hepatic arteries and portal vein. Systemic hemodynamics were assessed noninvasively by continuous monitoring of BP, heart rate (HR), cardiac output (CO), and the pressor response to an intravenous infusion on increasing doses of phenylephrine, an α1-adrenoceptor agonist. Neurohumoral regulation was assessed by spectral analysis of HR and BP, plasma catecholamine and aldosterone levels and plasma renin activity. Postprandial mesenteric hyperemia was associated with an increase in CO, a decrease in SVR and cardiac vagal tone, and reduction in baroreflex sensitivity with no change in sympathetic tone. Arterial α1-adrenoceptor responsiveness was preserved and reduced in hepatic sinusoids. Postprandial orthostasis was associated with a shift of 500 mL of blood from mesenteric to systemic circulation with preserved sympathetic-mediated vasoconstriction. Meal ingestion provokes cardiovascular hyperdynamism, cardiac vagolysis, and resetting of the baroreflex without activation of the sympathetic nervous system. Meal ingestion also alters α1-adrenoceptor responsiveness in the hepatic sinusoids and participates in the redistribution of blood volume from the mesenteric to the systemic circulation to maintain a normal BP during orthostasis.NEW & NOTEWORTHY A unique integrated investigation on the effect of meal on neurohumoral mechanisms and blood flow redistribution of the mesenteric circulation during orthostasis was investigated. Food ingestion results in cardiovascular hyperdynamism, reduction in cardiac vagal tone, and baroreflex sensitivity and causes a decrease in α1-adrenoceptor responsiveness only in the venous intrahepatic sinusoids. About 500-mL blood shifts from the mesenteric to the systemic circulation during orthostasis. Accordingly, the orthostatic homeostatic mechanisms are better understood.

Phenylephrine increases tear cathepsin S secretion in healthy murine lacrimal gland acinar cells through an alternative secretory pathway.

Little is known about the relationship between stimulation of lacrimal gland (LG) tear protein secretion by parasympathetic versus sympathetic nerves, particularly whether the spectrum of tear proteins evoked through each innervation pathway varies. We have previously shown that activity and abundance of cathepsin S (CTSS), a cysteine protease, is greatly increased in tears of Sjögren's syndrome (SS) patients and in tears from the male NOD mouse of autoimmune dacryoadenitis that recapitulates SS-associated dry eye disease. Beyond the increased synthesis of CTSS detected in the diseased NOD mouse LG, increased tear CTSS secretion in NOD mouse tears was recently linked to increased exocytosis from a novel endolysosomal secretory pathway. Here, we have compared secretion and trafficking of CTSS in healthy mouse LG acinar cells stimulated with either the parasympathetic acetylcholine receptor agonist, carbachol (CCh), or the sympathetic α1-adrenergic agonist, phenylephrine (PE). In situ secretion studies show that PE significantly increases CTSS activity and protein in tears relative to CCh stimulation by 1.2-fold (***, p = 0.0009) and ∼5-fold (*, p-0.0319), respectively. A similar significant increase in CTSS activity with PE relative to CCh is observed when cultured LGAC are stimulated in vitro. CCh stimulation significantly elevates intracellular [Ca2+], an effect associated with increases in the size of Rab3D-enriched vesicles consistent with compound fusion, and subsequently decreases in their intensity of labeling consistent with their exocytosis. PE stimulation induces a lower [Ca2+] response and has minimal effects on Rab3D-enriched SV diameter or the intensity of Rab3D-enriched SV labeling. LG deficient in Rab3D exhibit a higher sensitivity to PE stimulation, and secrete more CTSS activity. Significant increases in the colocalization of endolysosomal vesicle markers (Lamp1, Lamp2, Rab7) with the subapical actin suggestive of fusion of endolysosomal vesicles at the apical membrane occur both with CCh and PE stimulation, but PE demonstrates increased colocalization. In conclusion, the α1-adrenergic agonist, PE, increases CTSS secretion into tears through a pathway independent of the exocytosis of Rab3D-enriched mature SV, possibly representing an alternative endolysosomal secretory pathway.

Altered stress hormone levels affect in vivo vascular function in the hAPP23+/- overexpressing mouse model of Alzheimer's disease.

Alzheimer's disease (AD) has long been considered a brain-specific dementia syndrome. However, in recent decades, the occurrence of cardiovascular (CV) disease in the progression of AD has been confirmed by increasing epidemiological evidence. In this study, we conducted an in-depth cardiovascular characterization of a humanized amyloid precursor protein (APP) overexpressing mouse model (hAPP23+/-), which overexpresses the Swedish mutation (KM670/671NL). At the age of 6 mo, hAPP23+/- mice had a lower survival, lower body weight, and increased corticosterone and VMA levels compared with C57BL/6 littermates. Systolic blood pressure was increased in hAPP23+/- animals compared with C57BL/6 littermates, but diastolic blood pressure was not statistically different. Pulse pressure remained unchanged but abdominal and carotid pulse-wave velocity (aPWV and cPWV) were increased in hAPP23+/- compared with C57BL/6 mice. Echocardiography showed no differences in systolic or diastolic cardiac function. Ex vivo evaluation of vascular function showed decreased adreno receptor dependent vasoconstriction of hAPP23+/- aortic segments, although the isobaric biomechanics of the aortic wall were similar to C57BL/6 aortic segments. In conclusion, hAPP23+/- mice exhibited high serum corticosterone levels, elevated systolic blood pressure, and increased arterial stiffness in vivo. However, ex vivo aortic stiffness of hAPP23+/- aortic segments was not changed and vascular reactivity to α1-adrenoceptor stimulation was attenuated. These findings highlight the need for more frequent assessment of circulating stress hormone levels and PWV measurements in daily clinical practice for people at risk of AD.NEW & NOTEWORTHY We showed that male amyloid precursor protein (APP) transgenic mice have higher circulating stress hormone levels. As a result, higher systolic blood pressure and pulse-wave velocity were measured in vivo in addition to a smaller α-adrenergic receptor-dependent contraction upon ex vivo stimulation with phenylephrine. Our findings highlight the need for more frequent assessment of circulating stress hormone levels and PWV measurements in daily clinical practice for people at risk of Alzheimer's disease.

The selectivity of α-adrenoceptor agonists for the human α1A, α1B, and α1D-adrenoceptors.

Highly selective drugs offer a way to minimize side-effects. For agonist ligands, this could be through highly selective affinity or highly selective efficacy, but this requires careful measurements of intrinsic efficacy. The α1-adrenoceptors are important clinical targets, and α1-agonists are used to manage hypotension, sedation, attention deficit hypersensitivity disorder (ADHD), and nasal decongestion. With 100 years of drug development, there are many structurally different compounds with which to study agonist selectivity. This study examined 62 α-agonists at the three human α1-adrenoceptor (α1A, α1B, and α1D) stably expressed in CHO cells. Affinity was measured using whole-cell 3 H-prazosin binding, while functional responses were measured for calcium mobilization, ERK1/2-phosphorylation, and cAMP accumulation. Efficacy ratios were used to rank compounds in order of intrinsic efficacy. Adrenaline, noradrenaline, and phenylephrine were highly efficacious α1-agonists at all three receptor subtypes. A61603 was the most selective agonist and its very high α1A-selectivity was due to selective α1A-affinity (>660-fold). There was no evidence of Gq-calcium versus ERK-phosphorylation biased signaling at the α1A, α1B, or α1D-adrenoceptors. There was little evidence for α1A calcium versus cAMP biased signaling, although there were suggestions of calcium versus cAMP bias the α1B-adrenoceptor. Comparisons of the rank order of ligand intrinsic efficacy suggest little evidence for selective intrinsic efficacy between the compounds, with perhaps the exception of dobutamine which may have some α1D-selective efficacy. There seems plenty of scope to develop affinity selective and intrinsic efficacy selective drugs for the α1-adrenoceptors in future.

Metformin suppresses phenylephrine-induced hypertrophic responses by inhibiting p300-HAT activity in cardiomyocytes.

INTRODUCTION: Heart failure is the final pathway for a wide spectrum of myocardial stress, including hypertension and myocardial infarction. However, the potential effects of metformin on cardiac hypertrophy are still unclear. PURPOSE: The purpose of this study was to investigate whether metformin leads to suppression of hypertrophic responses in cardiomyocytes. METHODS AND RESULTS: To investigate whether metformin inhibited p300-histone acetyltransferase (HAT), we performed an in vitro HAT assay. Metformin directly inhibited p300-mediated acetylation of histone-H3K9. To examine the effects of metformin on hypertrophic responses, cardiomyocytes prepared from neonatal rats were treated with metformin and stimulated with saline or phenylephrine (PE), a α1-adrenergic agonist for 48 h. PE stimulus showed an increase in cell size, myofibrillar organization, expression of the endogenous atrial natriuretic factor and brain natriuretic peptide genes, and acetylation of histone-H3K9 compared with saline-treated cells. These PE-induced changes were inhibited by metformin. Next, to examine the effect of metformin on p300-mediated hypertrophy, cardiomyocytes were transfected with expression vector of p300. Metformin significantly suppressed p300-induced hypertrophic responses and acetylation of histone-H3K9. CONCLUSIONS: The study demonstrates that metformin can suppress PE-induced and p300-mediated hypertrophic responses. Metformin may be useful for the treatment of patients with diabetes and heart failure.

Lateral hypothalamus-projecting noradrenergic locus coeruleus pathway modulates binge-like ethanol drinking in male and female TH-ires-cre mice.

A growing body of literature implicates noradrenergic (NE) signaling in the modulation of ethanol consumption. However, relatively few studies have detailed specific brain pathways that mediate NE-associated binge-like ethanol consumption. To begin to fill this gap in the literature, male and female C57BL6/J and TH-ires-cre mice underwent pharmacological and chemogenetic testing, respectively, in combination with "drinking in the dark" procedures to model binge-like consumption of ethanol or sucrose solutions. First, we showed that intraperitoneal administration of the NE reuptake inhibitor, reboxetine, blunted binge-like ethanol intake in C57BL6/J mice. Chemogenetic activation of locus coeruleus (LC) tyrosine hydroxylase (TH)-expressing neurons blunted binge-like ethanol intake regardless of sex. Chemogenetic activation of LC projections to the lateral hypothalamus (LH), a region implicated in ethanol consumption, blunted binge-like ethanol drinking without altering sucrose intake in ethanol-experienced or ethanol-naïve mice. In C57BL/6 J mice, LH-targeted microinfusion of an α1-adrenergic receptor (AR) agonist blunted binge-like ethanol intake across both sexes, while LH infusion of a ß-AR agonist blunted binge-like ethanol intake in females exclusively. Finally, in mice with high baseline ethanol intake both an α1- AR agonist and an α-2 AR antagonist blunted binge-like ethanol intake. The present results provide novel evidence that increased NE tone in a circuit arising from the LC and projecting to the LH reduces binge-like ethanol drinking in mice, and may represent a novel approach to treating binge or heavy drinking prior to the development of dependence. This article is part of the special Issue on "Neurocircuitry Modulating Drug and Alcohol Abuse".

Mitochondrial Disruption Is Involved in the Effect of Nuclear Factor of Activated T cells, Cytoplasmic 4 on Aggravating Cardiomyocyte Hypertrophy.

ABSTRACT: Nuclear factor of activated T cells, cytoplasmic 4 (NFATc4), a nuclear transcription factor, has been implicated in cardiac hypertrophy through the enhancement of hypertrophic gene expression. However, the role of NFATc4 in mitochondrial modulation is mostly unknown. The current study aimed to investigate the role of NFATc4 in regulating mitochondrial function during phenylephrine (PE)-induced cardiac hypertrophy. Our results showed that overexpression of NFATc4 aggravated the PE-induced decrease in mitochondrial genesis, membrane potential, and mitochondrial gene expression as well as impaired mitochondrial respiration. However, knockdown of NFATc4 relieved PE-induced perturbations in mitochondria and cardiomyocyte hypertrophy. Mechanistically, by activating phosphoinositide-dependent kinase 1 and promoting a combination of AKT and phosphoinositide-dependent kinase 1, phosphorylation and sequential acetylation of PGC-1α were aggravated by NFATc4 and suppressed the activity of PGC-1α. In conclusion, NFATc4-regulated factors were shown to be associated with mitochondrial function and exacerbated PE-induced mitochondrial dysfunction. These findings revealed new roles of NFATc4 in cardiac hypertrophy.

Midodrine, an Oral Alpha-1 Adrenoreceptor Agonist, Successfully Treated Refractory Congenital Chylous Pleural Effusion and Ascites in a Neonate.

A trisomy 21 neonate presented with congenital chylous pleural effusion and ascites that was refractory to conventional pharmacotherapy. Midodrine, an oral alpha-1-adrenoreceptor agonist, achieved remission of chylous effusion without any adverse effects. To the best of our knowledge, this is the first neonatal case of successful management of congenital chylous pleural effusion and ascites with midodrine.

GPR55 regulates the responsiveness to, but does not dimerise with, α1A-adrenoceptors.

Emerging evidence suggests that G protein coupled receptor 55 (GPR55) may influence adrenoceptor function/activity in the cardiovascular system. Whether this reflects direct interaction (dimerization) between receptors or signalling crosstalk has not been investigated. This study explored the interaction between GPR55 and the alpha 1A-adrenoceptor (α1A-AR) in the cardiovascular system and the potential to influence function/signalling activities. GPR55 and α1A-AR mediated changes in both cardiac and vascular function was assessed in male wild-type (WT) and GPR55 homozygous knockout (GPR55-/-) mice by pressure volume loop analysis and isolated vessel myography, respectively. Dimerization of GPR55 with the α1A-AR was examined in transfected Chinese hamster ovary-K1 (CHO-K1) cells via Bioluminescence Resonance Energy Transfer (BRET). GPR55 and α1A-AR mediated signalling (extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation) was investigated in neonatal rat ventricular cardiomyocytes using AlphaScreen proximity assays. GPR55-/- mice exhibited both enhanced pressor and inotropic responses to A61603 (α1A-AR agonist), while in isolated vessels, A61603 induced vasoconstriction was attenuated by a GPR55-dependent mechanism. Conversely, GPR55-mediated vasorelaxation was not altered by pharmacological blockade of α1A-ARs with tamsulosin. While cellular studies demonstrated that GPR55 and α1A-AR failed to dimerize, pharmacological blockade of GPR55 altered α1A-AR mediated signalling and reduced ERK1/2 phosphorylation. Taken together, this study provides evidence that GPR55 and α1A-AR do not dimerize to form heteromers, but do interact at the signalling level to modulate the function of α1A-AR in the cardiovascular system.

Inhibition of the norepinephrine transporter rescues vascular hyporeactivity to catecholamine in obstructive jaundice.

In patients with obstructive jaundice, the cardiovascular system exhibits hypotension and vascular hyporeactivity. Most norepinephrine is taken up through the neuronal norepinephrine transporter (NET), which is implicated in cardiovascular diseases. A previous study demonstrated that pharmacological NET inhibition could increase resting blood pressure. However, the role of NETs in vascular hyporeactivity induced by obstructive jaundice is poorly understood. This study used the NET inhibitor nisoxetine and a rat model of bile duct ligation (BDL) to investigate whether NET is associated with BDL-induced vascular hyporeactivity. Rats were injected with nisoxetine via the tail vein for 7 consecutive days after BDL. Samples of the superior cervical sympathetic ganglion (SCG) and thoracic aortic rings were processed for investigations. Our results showed that NET expression in the SCG was significantly increased after BDL. Nisoxetine prevented the augmentation of NET expression, increased α1-adrenoceptor activation, and enhanced the weakened contractile responses of thoracic aortic rings after BDL. Our study demonstrates that nisoxetine plays a protective role in BDL-induced vascular hyporeactivity through increased α1-adrenoceptor activation in rats.

Comparison of Outcomes with Midodrine and Fludrocortisone for Objective Recurrence in Treating Syncope (COMFORTS trial): Rationale and design for a multi-center randomized controlled trial.

BACKGROUND: The cornerstone of the treatment of vasovagal syncope (VVS) is lifestyle modifications; however, some patients incur life-disturbing attacks despite compliance with these treatments which underscores the importance of pharmacological interventions. METHODS: In this open-label multi-center randomized controlled trial, we are going to randomize 1375 patients with VVS who had ≥2 syncopal episodes in the last year into three parallel arms with a 2:2:1 ratio to receive midodrine, fludrocortisone, or no medication. All patients will be recommended to drink 2 to 3 liters of fluids per day, consume 10 grams of NaCl per day, and practice counter-pressure maneuvers. In medication arms, patients will start on 5 mg of midodrine TDS or 0.05 mg of fludrocortisone BD. After one week the dosage will be up-titrated to midodrine 30 mg/day and fludrocortisone 0.2 mg/day. Patient tolerance will be the principal guide to dosage adjustments. We will follow-up the patients on 3, 6, 9, and 12 months after randomization. The primary outcome is the time to first syncopal episode. Secondary outcomes include the recurrence rate of VVS, time interval between first and second episodes, changes in quality of life (QoL), and major and minor adverse drug reactions. QoL will be examined by the 36-Item Short Form Survey questionnaire at enrollment and 12 months after randomization. CONCLUSION: The COMFORTS trial is the first study that aims to make a head-to-head comparison between midodrine and fludrocortisone, against a background of lifestyle modifications for preventing recurrences of VVS and improving QoL in patients with VVS.

Long-term electronic cigarette exposure induces cardiovascular dysfunction similar to tobacco cigarettes: role of nicotine and exposure duration.

Electronic cigarette (e-cig) vaping (ECV) has been proposed as a safer alternative to tobacco cigarette smoking (TCS); however, this remains controversial due to a lack of long-term comparative studies. Therefore, we developed a chronic mouse exposure model that mimics human vaping and allows comparison with TCS. Longitudinal studies were performed to evaluate alterations in cardiovascular function with TCS and ECV exposure durations of up to 60 wk. For ECV, e-cig liquid with box-mod were used and for TCS, 3R4F-cigarettes. C57/BL6 male mice were exposed 2 h/day, 5 days/wk to TCS, ECV, or air control. The role of vape nicotine levels was evaluated using e-cig-liquids with 0, 6, or 24 mg/mL nicotine. Following 16-wk exposure, increased constriction to phenylephrine and impaired endothelium-dependent and endothelium-independent vasodilation were observed in aortic segents, paralleling the onset of systemic hypertension, with elevations in systemic vascular resistance. Following 32 wk, TCS and ECV induced cardiac hypertrophy. All of these abnormalities further increased out to 60 wk of exposure, with elevated heart weight and aortic thickness along with increased superoxide production in vessels and cardiac tissues of both ECV and TCS mice. While ECV-induced abnormalities were seen in the absence of nicotine, these occurred earlier and were more severe with higher nicotine exposure. Thus, long-term vaping of e-cig can induce cardiovascular disease similar to TCS, and the severity of this toxicity increases with exposure duration and vape nicotine content.NEW & NOTEWORTHY A chronic mouse exposure model that mimics human e-cigarette vaping and allows comparison with tobacco cigarette smoking was developed and utilized to perform longitudinal studies of alterations in cardiovascular function. E-cigarette exposure led to the onset of cardiovascular disease similar to that with tobacco cigarette smoking. Impaired endothelium-dependent and endothelium-independent vasodilation with increased adrenergic vasoconstriction were observed, paralleling the onset of systemic hypertension and subsequent cardiac hypertrophy. This cardiovascular toxicity was dependent on exposure duration and nicotine dose.

Medical treatment of recurrent ischaemic priapism: a review of current molecular therapeutics and a new clinical management paradigm.

OBJECTIVES: To examine the current molecular therapeutics in the medical treatment of recurrent ischemic priapism (RIP). To propose a stepwise clinical management paradigm for the treatment of RIP. METHODS: We performed a literature search using the PubMed database for the terms 'recurrent ischemic priapism' and 'stuttering priapism' up until December 2020. We assessed pre-clinical and clinical studies regarding medical management of RIP and molecular pathophysiology. Case series and randomized trials were evaluated by study quality and patient outcomes to determine a potential clinical management scheme. RESULTS: Recent research has fostered an improved understanding of the underlying molecular pathophysiology of RIP that has paved the way forward for developing new therapeutic agents. Medications targeting neurovascular, hormonal and haematological mechanisms associated with RIP show great promise towards remedying this condition. A host of therapeutic agents operating across different mechanistic directions may be implemented according to a clinical management scheme to potentially optimize RIP outcomes. CONCLUSION: RIP remains a medically neglected condition with current management focused on treating the acute condition rather than modulating the course of disease. Continued research into the molecular mechanisms of RIP and standardized clinical pathways can improve the quality of care for patients suffering from this condition.

Phenylephrine impairs host defence mechanisms to infection: a combined laboratory study in mice and translational human study.

BACKGROUND: Immunosuppression after surgery is associated with postoperative complications, mediated in part by catecholamines that exert anti-inflammatory effects via the ß-adrenergic receptor. Phenylephrine, generally regarded as a selective α-adrenergic agonist, is frequently used to treat perioperative hypotension. However, phenylephrine may impair host defence through ß-adrenergic affinity. METHODS: Human leukocytes were stimulated with lipopolysaccharide (LPS) in the presence or absence of phenylephrine and α- and ß-adrenergic antagonists. C57BL/6J male mice received continuous infusion of phenylephrine (30-50 µg kg-1 min-1 i.v.) or saline via micro-osmotic pumps, before LPS administration (5 mg kg-1 i.v.) or caecal ligation and puncture (CLP). Twenty healthy males were randomised to a 5 h infusion of phenylephrine (0.5 µg kg-1 min-1) or saline before receiving LPS (2 ng kg-1 i.v.). RESULTS: In vitro, phenylephrine enhanced LPS-induced production of the anti-inflammatory cytokine interleukin (IL)-10 (maximum augmentation of 93%) while attenuating the release of pro-inflammatory mediators. These effects were reversed by pre-incubation with ß-antagonists, but not α-antagonists. Plasma IL-10 levels were higher in LPS-challenged mice infused with phenylephrine, whereas pro-inflammatory mediators were reduced. Phenylephrine infusion increased bacterial counts after CLP in peritoneal fluid (+42%, P=0.0069), spleen (+59%, P=0.04), and liver (+35%, P=0.09). In healthy volunteers, phenylephrine enhanced the LPS-induced IL-10 response (+76%, P=0.0008) while attenuating plasma concentrations of pro-inflammatory mediators including IL-8 (-15%, P=0.03). CONCLUSIONS: Phenylephrine exerts potent anti-inflammatory effects, possibly involving the ß-adrenoreceptor. Phenylephrine promotes bacterial outgrowth after surgical peritonitis. Phenylephrine may therefore compromise host defence in surgical patients and increase susceptibility towards infection. CLINICAL TRIAL REGISTRATION: NCT02675868 (Clinicaltrials.gov).

Both α1B- and α1A-adrenoceptor subtypes are involved in contractions of rat spleen.

BACKGROUND: The spleen is a reservoir for circulating blood cells, and can contract to expel them. METHODS: We have investigated the adrenoceptors involved in isometric contractions of rat spleen produced by noradrenaline (NA) and the α1-adrenoceptor agonist phenylephrine (Phe). RESULTS: Contractions to NA were antagonized by both the α1-adrenoceptor antagonist prazosin (10-8 M) and the α2-adrenoceptor antagonist yohimbine (10-6M), and the combination produced further shifts in NA potency. Contractions to Phe were antagonized by prazosin (10-8 M) which caused a marked parallel shift in the concentration-response curve. High non-selective concentrations of the α1D-adrenoceptor antagonist BMY7378 (10-6 M), the α1A-adrenoceptor antagonist RS100329 ((3 × 10-8 M), and the putative α1B-adrenoceptor antagonist cyclazosin (10-8 M) also produced parallel shifts in the Phe concentration-response curve. BMY7378 at the selective concentration of 3 × 10-8 M had no effect on responses to Phe, but RS100329 in the selective concentration of 3 × 10-9 M produced a marked shift in the effects of high concentrations of Phe. Hence, antagonists in concentrations that block both α1A- and α1B-adrenoceptors produce approximately parallel shifts in Phe potency. CONCLUSIONS: Contractions of rat spleen to adrenergic agonists involve α2- and α1B-adrenoceptors, with a lesser role for α1A-adrenoceptors. This confirms the suggestion that smooth muscle contractions commonly involve multiple subtypes.

Alpha adrenergic receptor signaling in the hypothalamic paraventricular nucleus is diminished by the chronic intermittent hypoxia model of sleep apnea.

Chronic intermittent hypoxia (CIH) is a model for obstructive sleep apnea. The paraventricular nucleus (PVN) of the hypothalamus has been suggested to contribute to CIH-induced exaggerated cardiorespiratory reflexes, sympathoexcitation and hypertension. This may occur, in part, via activation of the dense catecholaminergic projections to the PVN that originate in the brainstem. However, the contribution of norepinephrine (NE) and activation of its alpha-adrenergic receptors (α-ARs) in the PVN after CIH exposure is unknown. We hypothesized CIH would increase the contribution of catecholaminergic input. To test this notion, we determined the expression of α-AR subtypes, catecholamine terminal density, and synaptic properties of PVN parvocellular neurons in response to α-AR activation in male Sprague-Dawley normoxic (Norm) and CIH exposed rats. CIH decreased mRNA for α1d and α2b AR. Dopamine-ß-hydroxylase (DßH) terminals in the PVN were similar between groups. NE and the α1-AR agonist phenylephrine (PE) increased sEPSC frequency after Norm but not CIH. Block of α1-ARs with prazosin alone did not alter sEPSCs after either Norm or CIH but did prevent agonist augmentation of sEPSC frequency following normoxia. These responses to NE were mimicked by PE during action potential block suggesting presynaptic terminal alterations in CIH. Altogether, these results demonstrate that α1-AR activation participates in neuronal responses in Norm, but are attenuated after CIH. These results may provide insight into the cardiovascular, respiratory and autonomic nervous systems alterations in obstructive sleep apnea.