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OBJECTIVE: This study tested the hypothesis that administration of the KCa channel activator SKA-31 restores endothelium-dependent vasodilation in vivo in Type 2 Diabetic (T2D) rats. BACKGROUND: Acute treatment of isolated resistance arteries from T2D rats and humans with SKA-31 significantly improved endothelium-dependent vasodilation. However, it is unknown whether these in situ actions translate to intact vascular beds in vivo. METHODS: Male Sprague Dawley (SD) and T2D Goto-Kakizaki (GK) rats (26-32 weeks of age) were injected intraperitoneally with either drug vehicle or 10 mg/kg SKA-31. Doppler ultrasound imaging was used to record reactive hyperemia/flow-mediated dilation (FMD) in the femoral artery following release of an occlusion cuff on the distal hind limb, along with diameter changes in the left main coronary artery in response to inhaled isoflurane (2 % â†’ 5 %). RESULTS: Vehicle treated SD rats exhibited a robust and reversible FMD response, the magnitude and time course of which did not differ in SD rats treated with SKA-31. In contrast, only a weak FMD response was observed in vehicle-treated T2D GK rats, whereas prior SKA-31 administration restored FMD to the level observed in control SD rats. Exposure of SD rats to 5 % isoflurane caused robust coronary artery dilation, which was not altered by prior treatment with SKA-31. In T2D GK rats, 5 % isoflurane inhalation alone did not increase coronary artery diameter, however, a strong vasodilatory response was observed following SKA-31 treatment. SKA-31 administration did not modify intrinsic heart rate responses in either protocol. CONCLUSIONS: Enhancement of KCa channel activity in vivo restores endothelium-dependent vasodilation in T2D rats that exhibit peripheral endothelial dysfunction.

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Rationale Evaluating approaches to reduce treatment burden is a research priority among people with CF (pwCF) on highly effective modulators including elexacaftor/tezacaftor/ivacaftor (ETI). Objective To evaluate the impact of discontinuing both hypertonic saline (HS) and dornase alfa (DA) versus continuing both therapies among a subgroup of participants in the SIMPLIFY study who sequentially participated in trials evaluating the independent clinical effects of discontinuing HS and DA. Methods SIMPLIFY participants ≥12 years old on ETI and comprising a subgroup using both HS and DA at study entry were randomized to the HS or DA trial, and then randomized 1:1 to continue or discontinue the applicable therapy for 6 weeks. After completion of the first trial, eligible participants could enroll in the second trial beginning with a 2-week run in. Study outcomes were compared across the duration of SIMPLIFY participation between a cohort remaining on both therapies during SIMPLIFY versus a cohort that sequentially discontinued both as a result of trial randomizations. Multivariable regression models were used to estimate treatment differences, adjusted for time between trials, trial order, baseline age, sex at birth and percent predicted forced expiratory volume in one second (ppFEV1) at study entry. Results There were 43 participants who discontinued both therapies by the end of SIMPLIFY and 63 who remained on both, with overall average ppFEV1 at study entry 96.7% and average duration of follow up from beginning of the first trial to completion of the second trial 3.9 months, including time between trials. No clinically meaningful difference in the change in ppFEV1 from baseline to completion of the second trial was observed between those who discontinued versus remained on both therapies (difference: 0.22% Off-On, 95% CI: -1.60,2.03). Changes in LCI2.5, patient reported, and safety outcomes were also comparable. Patient reported treatment burden, as measured by a CFQ-R subscale, significantly decreased in those discontinuing both therapies. Conclusions SIMPLIFY participants who sequentially discontinued both HS and DA experienced no meaningful changes in clinical outcomes and reported decreased treatment burden as compared to those who remained on both therapies. These data continue to inform a new era of post-modulator care of pwCF.

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Patients with severe cardiopulmonary morbidity present a unique challenge to peri- and intraoperative providers. Inducing general anesthesia in this patient population poses the risk of adverse events that could lead to poor surgical outcomes, prolonged debilitation, or death. Therefore, it is important that anesthesiologists become comfortable with preoperative evaluation as well as alternative strategies to providing surgical anesthesia. This case report details the clinical course of a patient with severe cardiopulmonary morbidity who underwent open inguinal hernia repair without oral or intravenous sedation after receiving multi-level paravertebral blocks in addition to isolated ilioinguinal and iliohypogastric nerve blocks. This medically challenging case provides educational value regarding preoperative evaluation, pertinent anatomy and innervation, and the importance of patient-centered care and communication.

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Patients with hypertrophic obstructive cardiomyopathy (HOCM) who are scheduled for elective, noncardiac surgery present a distinctive challenge for perioperative healthcare providers. The use of general anesthesia and neuraxial anesthesia carries the risk of unpredictable hemodynamic changes and potential complications. Regional anesthesia (RA) emerges as a prudent and effective option for HOCM patients. RA provides advantages such as minimizing hemodynamic fluctuations, avoiding intubation, reducing pharmacologic side effects, facilitating enhanced recovery after surgery, and contributing to greater patient satisfaction. We share the case of a 15-year-old individual diagnosed with HOCM and exercise intolerance, undergoing arthroscopic repair for right patellar instability. In this instance, the patient received preoperative peripheral nerve blocks for surgical anesthesia and underwent repair utilizing monitored anesthesia care (MAC) with a dexmedetomidine (DEX) infusion.

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Vitamin D sufficiency has been difficult to achieve consistently in patients with cystic fibrosis (CF), even with robust oral supplements. To assess vitamin D status and resistance to supplementation, we studied 80 adults using 25-hydroxyvitamin D (25OHD) determinations and whole genome sequencing to construct polygenic risk scores (PRS) that aggregate variants associated with vitamin D status. The results revealed that 30 % of patients were below the threshold of 30 ng/mL and thus should be regarded as insufficient despite normal vitamin E status, a reflection of adherence to fat soluble vitamin supplementation. The PRS values were significantly correlated with 25OHD concentrations, confirming our results in children with CF, and indicating that genetic factors play a role and have implications for therapy.

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Elevated levels of cholesterol in the blood can induce endothelial dysfunction, a condition characterized by impaired nitric oxide production and decreased vasodilatory capacity. Endothelial dysfunction can promote vascular disease, such as atherosclerosis, where macrophages accumulate in the vascular intima and fatty plaques form that impair normal blood flow in conduit arteries. Current pharmacological strategies to treat atherosclerosis mostly focus on lipid lowering to prevent high levels of plasma cholesterol that induce endothelial dysfunction and atherosclerosis. While this approach is effective for most patients with atherosclerosis, for some, lipid lowering is not enough to reduce their cardiovascular risk factors associated with atherosclerosis (e.g., hypertension, cardiac dysfunction, stroke, etc.). For such patients, additional strategies targeted at reducing endothelial dysfunction may be beneficial. One novel strategy to restore endothelial function and mitigate atherosclerosis risk is to enhance the activity of Ca2+-activated K+ (KCa) channels in the endothelium with positive gating modulator drugs. Here, we review the mechanism of action of these small molecules and discuss their ability to improve endothelial function. We then explore how this strategy could mitigate endothelial dysfunction in the context of atherosclerosis by examining how KCa modulators can improve cardiovascular function in other settings, such as aging and type 2 diabetes. Finally, we consider questions that will need to be addressed to determine whether KCa channel activation could be used as a long-term add-on to lipid lowering to augment atherosclerosis treatment, particularly in patients where lipid-lowering is not adequate to improve their cardiovascular health.

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BACKGROUND: Total hip arthroplasty (THA) is one of the most common operative procedures performed. Controlling postoperative pain following THA remains a challenge due to the complex innervation of the hip joint and the recent desire to preserve motor function following nerve blockade. Several nerve block techniques have been used for THA in the past, but the quadratus lumborum (QL) block and the blockade of the pericapsular nerve group (PENG) have emerged as opiate-sparing regional anesthesia techniques that preserve motor function. To date, little data comparing the two block techniques exists. The purpose of our study was to compare outcomes following these techniques in patients undergoing primary THA. MATERIALS AND METHODS: This retrospective analysis utilized data from three distinct groups who underwent primary THA at our institution: 45 patients who received PENG block, 38 patients who received QL block, and 77 control patients. Chart review analysis was performed by authorized personnel to obtain cumulative oral morphine equivalent (OME) data at 24 and 48 hours postoperatively (primary outcomes). In addition, visual analog pain scale (VAS) scores in the post-anesthesia care unit (PACU) and at 12, 24, and 48 hours, ambulation distance, and length of hospital stay data were obtained (secondary outcomes). Group comparisons were conducted using either analysis of variance (ANOVA) with Tukey's multiple comparison test for parametric data or Krustal-Wallis with Dunn's multiple comparison tests for nonparametric endpoints. RESULTS: This study found a statistically significant difference in cumulative OME usage across all groups at 24 and 48 hours. Significant difference in OMEs was found between QL and control and PENG and control; however, no difference was found in OMEs between PENG and QL groups at either time point. There was a statistically significant difference in VAS scores in the PACU across all groups; QL showed significantly lower VAS scores in the PACU compared to PENG and control, while PENG only showed significantly lower VAS scores compared to control. There was a statistically significant difference in VAS scores at 24 hours across all groups; however, only QL showed significantly lower VAS scores compared to control at 24 hours. QL was associated with a statistically significant increase in the length of hospital stay compared to PENG. CONCLUSION: This study showed no difference between OME usage in patients who received PENG or QL nerve blocks for primary THA. VAS scores were similar between groups with the exception of QL outperforming PENG in the PACU. Optimizing postoperative pain via multi-approach strategies should remain a priority for patients undergoing THA. Future research is warranted in order to provide guidance on best practice for these patients.

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Fibronectin (FN) enhances K+ channel activity by integrin-mediated mechanisms. As vascular smooth muscle (VSM) K+ channels mediate vasodilation, we hypothesized that modification of fibronectin, via advanced non-enzymatic glycation, would alter signaling of this extracellular matrix protein through these channels. Bovine FN (1 mg/ml) was glycated (gFN) for 5 days using methylglyoxal (50 mM), and albumin was similarly glycated as a non-matrix protein control. VSM cells were isolated from rat cerebral arteries for measurement of macroscopic K+ channel activity using whole cell patch clamp methodology. Pharmacological inhibitors, iberiotoxin (0.1 µM) and 4-aminopyridine (0.1 mM), were used to identify contributions of large-conductance, Ca2+-activated, K+ channels and voltage-gated K+ channels, respectively. Compared with baseline, native FN enhanced whole cell K+ current in a concentration-dependent manner, whereas gFN inhibited basal current. Furthermore, native albumin did not enhance basal K+ current, but the glycated form (gAlb) caused inhibition. gFN was shown to impair both the Kv and BKCa components of total macroscopic K+ current. Anti-integrin α5 and ß1 antibodies attenuated the effects of both FN and gFN on macroscopic K+ current at +70 mV. Consistent with an action on BKCa activity, FN increased, whereas gFN decreased the frequency of spontaneous transient outward current (STOCs). In contrast, gAlb inhibited whole cell K+ current predominantly through Kv, showing little effect on STOCs. A function-blocking, anti-RAGE antibody partially reversed the inhibitory effects of gFN, suggesting involvement of this receptor. Further, gFN caused production of reactive oxygen species (ROS) by isolated VSMCs as revealed by the fluorescent indicator, DHE. Evoked ROS production was attenuated by the RAGE blocking antibody. Collectively, these studies identify ion channel-related mechanisms (integrin and ROS-mediated) by which protein glycation may modify VSMC function.

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OBJECTIVE: Cystic fibrosis (CF) is a genetic disease that requires complex, lifelong treatment regimens to maintain health and reduce disease progression. The aims of this study were 1) to gain the perspectives of multiple health professions to understand medication and well-being challenges of people living with CF; and 2) to apply the Systems Engineering Initiative for Patient Safety (SEIPS) model to further identify opportunities for pharmacists to support people with CF. METHODS: Health care professionals were recruited from a Cystic Fibrosis Center in the Midwest, to participate in audio-recorded semistructured interviews. Topics examined during the interviews included medication education for patients as well as experiences with outpatient, specialty, and community pharmacists. The themes assessed during the pharmacist interviews included support for people living with CF, preferences in conducting medication education, and pharmacist-specific counseling. Interview transcripts were thematically analyzed into categories to determine major themes. Prevalent codes were categorized into 5 major themes guided by the SEIPS model. Interrater reliability was strong (kappa = 0.94). RESULTS: Five major themes were identified: 1) patient tasks; 2) external environment; 3) organizational conditions; 4) patient medication education; and 5) pharmacists' roles and tasks. Professionals identified the importance of the pharmacist on the multidisciplinary CF care team to enhance patient-centered care for people living with CF. CONCLUSIONS: This study highlights health care professionals' views on the unique skillset that pharmacists add to the care team, including a reduction in medication errors, improved adherence, and overall enhanced patient care.

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BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive genetic disease requiring complex, lifelong medication regimens. Given the importance of medication in CF treatment, pharmacists are vital CF care team members in the care of people living with CF (PwCF). OBJECTIVES: This study aimed to (1) define patients' CF medication experiences and educational needs and (2) investigate the CF outpatient clinic and community pharmacist's role in addressing patient challenges. METHODS: A work system approach informed by the Systems Engineering Initiative for Patient Safety (SEIPS) model was used to characterize knowledge and perception of CF medication regimens, educational modalities, and pharmacist interactions for PwCF. Semistructured interviews were conducted with adults living with CF at a CF center clinic. Data analyses identified relationships between the themes in the data and 4 SEIPS work system domains: tasks, tools and technology, person, and environment. RESULTS: Thirty PwCF interviews highlighted 4 themes regarding health care experiences: (1) medication use experience, (2) medication education needs, (3) disease experience, and (4) pharmacist and pharmacy interactions. Patients reported complex medication regimens leading to challenges with medication adherence, although the benefit of treatment was recognized. Although a high level of disease-state knowledge was identified among the participants, PwCF desired to learn about CF medication benefits and adverse effects through credible sources using multiple modalities. Many reported a benefit of pharmacist involvement in their care. CONCLUSION: Pharmacists are well-positioned to support PwCF in adherence, medication regimen management, and medication education. Opportunities exist for growth in these supportive roles of a pharmacist in both community and outpatient clinic settings.

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Reactive oxygen species (ROS), such as superoxide anions and hydrogen peroxide, are reported to contribute to the dynamic regulation of contractility in various arterial preparations, however, the situation in pressurized, myogenically active resistance arteries is much less clear. In the present study, we have utilized established pharmacological inhibitors of NADPH oxidase activity to examine the potential contribution of ROS to intrinsic myogenic contractility in adult Sprague-Dawley rat resistance arteries and responses to vasoactive agents acting via the endothelium (i.e., acetylcholine, SKA-31) or smooth muscle (i.e., sodium nitroprusside, phenylephrine). In cannulated and pressurized cremaster skeletal muscle and middle cerebral arteries, the NOX inhibitors 2-acetylphenothiazine (2-APT) and VAS2870, selective for NOX1 and NOX2, respectively, evoked concentration-dependent inhibition of basal myogenic tone in a reversible and irreversible manner, respectively, whereas the non-selective inhibitor apocynin augmented myogenic contractility. The vasodilatory actions of 2-APT and VAS2870 occurred primarily via the vascular endothelium and smooth muscle, respectively. Functional responses to established endothelium-dependent and -independent vasoactive agents were largely unaltered in the presence of either 2-APT or apocynin. In cremaster arteries from Type 2 Diabetic (T2D) Goto-Kakizaki rats with endothelial dysfunction, treatment with either 2-APT or apocynin did not modify stimulus-evoked vasoactive responses, but did affect basal myogenic tone. These same NOX inhibitors produced robust inhibition of total NADPH oxidase activity in aortic tissue homogenates from control and T2D rats, and NOX isozymes 1, 2 and 4, along with superoxide dismutase 1, were detected by qPCR in cremaster arteries and aorta from both species. Based on the diverse effects that we observed for established, chemically distinct NOX inhibitors, the functional contribution of vascular NADPH oxidase activity to stimulus-evoked vasoactive signaling in myogenically active, small resistance arteries remains unclear.

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BACKGROUND: In precapillary pulmonary hypertension (PH), nasal high flow therapy (NHF) may favorably alter sympathovagal balance (SVB) and sleep-related breathing through washout of anatomical dead space and alleviation of obstructive sleep apnea (OSA) due to generation of positive airway pressure. OBJECTIVES: To investigate the effects of NHF on SVB, sleep, and OSA in patients with PH, and compare them with those of positive airway pressure therapy (PAP). METHODS: Twelve patients with PH (Nice class I or IV) and confirmed OSA underwent full polysomnography, and noninvasive monitoring of SVB parameters (spectral analysis of heart rate, diastolic blood pressure variability). Study nights were randomly split into four 2-h segments with no treatment, PAP, NHF 20 L/min, or NHF 50 L/min. In-depth SVB analysis was conducted on 10-min epochs during daytime and stable N2 sleep at nighttime. RESULTS: At daytime and compared with no treatment, NHF20 and NHF50 were associated with a flow-dependent increase in peripheral oxygen saturation but a shift in SVB towards increased sympathetic drive. At nighttime, NHF20 was associated with increased parasympathetic drive and improvements in sleep efficiency, but did not alter OSA severity. NHF50 was poorly tolerated. PAP therapy improved OSA but had heterogenous effects on SVB and neutral effects on sleep outcomes. Hemodynamic effects were neutral for all interventions. CONCLUSIONS: In sleeping PH patients with OSA NHF20 but not NHF50 leads to decreased sympathetic drive likely due to washout of anatomical dead space. NHF was not effective in lowering the apnea-hypopnoea index and NHF50 was poorly tolerated.

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BACKGROUND: The Wisconsin Cystic Fibrosis Neonatal Screening Project was a randomized clinical trial (RCT) revealing that children receiving an early diagnosis of CF via newborn screening (NBS) had improved nutritional outcomes but similar lung disease severity compared to those who presented clinically. Because the evaluations of these subjects by protocol ended in 2012, our objective was to assess long-term pulmonary and mortality outcomes. METHODS: Retrospective analysis of the RCT cohort utilized longitudinal outcome measures obtained from the Cystic Fibrosis Foundation Patient Registry (CFFPR). Data included screening assignment, clinical characteristics, percent predicted forced expiratory volume in 1 s (ppFEV1) and mortality. A random intercept model was used to compare the ppFEV1 decline of subjects between the two groups up to age 26 years. Mortality was analyzed using the Kaplan-Meier method. RESULTS: Of the 145 subjects who consented to the original study, 104 subjects met inclusion criteria and had adequate data in the CFFPR. Of 57 subjects in the screened group and 47 in the control group, the rates of ppFEV1 decline were 1.76%/year (95% CI 1.62 to 1.91%) and 1.43%/year (95% CI 1.26 to 1.60%), respectively (p<0.0002). Pseudomonas aeruginosa acquired before 2 years was partially responsible. There was no difference in mortality between the two groups. CONCLUSIONS: NBS alone does not improve pulmonary outcomes in CF, particularly when other risk factors supervene. In an era prior to strict infection control and current therapies, NBS for CF may be associated with worse pulmonary outcomes.

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BACKGROUND: Endothelial dysfunction is an early pathogenic event in the progression of cardiovascular disease in patients with Type 2 Diabetes (T2D). Endothelial KCa2.3 and KCa3.1 K+ channels are important regulators of arterial diameter, and we thus hypothesized that SKA-31, a small molecule activator of KCa2.3 and KCa3.1, would positively influence agonist-evoked dilation in myogenically active resistance arteries in T2D. METHODOLOGY: Arterial pressure myography was utilized to investigate endothelium-dependent vasodilation in isolated cremaster skeletal muscle resistance arteries from 22 to 24 week old T2D Goto-Kakizaki rats, age-matched Wistar controls, and small human intra-thoracic resistance arteries from T2D subjects. Agonist stimulated changes in cytosolic free Ca2+ in acutely isolated, single endothelial cells from Wistar and T2D Goto-Kakizaki cremaster and cerebral arteries were examined using Fura-2 fluorescence imaging. MAIN FINDINGS: Endothelium-dependent vasodilation in response to acetylcholine (ACh) or bradykinin (BK) was significantly impaired in isolated cremaster arteries from T2D Goto-Kakizaki rats compared with Wistar controls, and similar results were observed in human intra-thoracic arteries. In contrast, inhibition of myogenic tone by sodium nitroprusside, a direct smooth muscle relaxant, was unaltered in both rat and human T2D arteries. Treatment with a threshold concentration of SKA-31 (0.3 µM) significantly enhanced vasodilatory responses to ACh and BK in arteries from T2D Goto-Kakizaki rats and human subjects, whereas only modest effects were observed in non-diabetic arteries of both species. Mechanistically, SKA-31 enhancement of evoked dilation was independent of vascular NO synthase and COX activities. Remarkably, SKA-31 treatment improved agonist-stimulated Ca2+ elevation in acutely isolated endothelial cells from T2D Goto-Kakizaki cremaster and cerebral arteries, but not from Wistar control vessels. In contrast, SKA-31 treatment did not affect intracellular Ca2+ release by the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor cyclopiazonic acid. CONCLUSIONS: Collectively, our data demonstrate that KCa channel modulation can acutely restore endothelium-dependent vasodilatory responses in T2D resistance arteries from rats and humans, which appears to involve improved endothelial Ca2+ mobilization.

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PURPOSE: In neuromuscular disorders (NMD), inspiratory muscle weakness may cause sleep-related hypoventilation requiring non-invasive ventilation (NIV). Alternatively, nasal high flow therapy (NHF) may ameliorate mild nocturnal hypercapnia (NH) through washout of anatomical dead space and generation of positive airway pressure. Ventilatory support by NIV or NHF might have favourable short-term effects on sympathovagal balance (SVB). This study comparatively investigated the effects of NHF and NIV on sleep-related breathing and SVB in NMD patients with evolving NH. METHODS: Transcutaneous CO2 (ptcCO2), peripheral oxygen saturation (SpO2), sleep outcomes and SVB (spectral analysis of heart rate, diastolic blood pressure variability) along with haemodynamic measures (cardiac index, total peripheral resistance index) were evaluated overnight in 17 patients. Polysomnographies (PSG) were randomly split into equal parts with no treatment, NIV and NHF at different flow rates (20 l/min vs. 50 l/min). In-depth analysis of SVB and haemodynamics was performed on 10-min segments of stable N2 sleep taken from each intervention. RESULTS: Compared with no treatment, NHF20 and NHF50 did not significantly change ptcCO2, SpO2 or the apnea hypopnea index (AHI). NHF50 was poorly tolerated. In contrast, NIV significantly improved both gas exchange and AHI without adversely affecting sleep. During daytime, NHF20 and NHF50 had neutral effects on ventilation and oxygenation whereas NIV improved ptcCO2 and SpO2. Effects of NIV and NHF on SVB and haemodynamics were neutral during both night and daytime. CONCLUSIONS: NHF does not correct sleep-disordered breathing in NMD patients with NH. Both NHF and NIV exert no immediate effects on SVB.

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BACKGROUND: Traumatic separation of the cervix from the uterine corpus is rare. We describe a case in which this injury was identified and surgically repaired at initial presentation to preserve fertility. CASE: An 18-year-old woman presented with a pelvic crush injury after a motor vehicle accident. Imaging revealed pelvic fractures and bladder rupture. Complete transection of the uterine corpus at the level of the internal os was identified at laparotomy. The gynecology service was consulted and circumferentially reattached the corpus to the cervix. CONCLUSION: Uterine integrity should be confirmed in female patients with pelvic crush injuries who undergo exploratory laparotomy given the unknown extent of intra-abdominal trauma. Immediate surgical correction of uterine transection at the time of injury with restoration of the genital outflow tract is feasible and may allow preservation of fertility.

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Variations in disease onset and/or severity have often been observed in siblings with cystic fibrosis (CF), despite the same CFTR genotype and environment. We postulated that genomic variation (modifier and/or pharmacogenomic variants) might explain these clinical discordances. From a cohort of patients included in the Wisconsin randomized clinical trial (RCT) of newborn screening (NBS) for CF, we identified two brothers who showed discordant lung disease courses as children, with one milder and the other more severe than average, and a third, eldest brother, who also has severe lung disease. Leukocytes were harvested as the source of DNA, and whole-genome sequencing (WGS) was performed. Variants were identified and analyzed using in-house-developed informatics tools. Lung disease onset and severity were quantitatively different between brothers during childhood. The youngest, less severely affected brother is homozygous for HFE p.H63D. He also has a very rare PLG p.D238N variant that may influence host-pathogen interaction during chronic lung infection. Other variants of interest were found differentially between the siblings. Pharmacogenomics findings were consistent with the middle, most severely affected brother having poor outcomes to common CF treatments. We conclude that genomic variation between siblings with CF is expected. Variable lung disease severity may be associated with differences acting as genetic modifiers and/or pharmacogenomic factors, but large cohort studies are needed to assess this hypothesis.

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Aging represents an independent risk factor for the development of cardiovascular disease, and is associated with complex structural and functional alterations in the vasculature, such as endothelial dysfunction. Small- and intermediate-conductance, Ca2+-activated K+ channels (KCa2.3 and KCa3.1, respectively) are prominently expressed in the vascular endothelium, and pharmacological activators of these channels induce robust vasodilation upon acute exposure in isolated arteries and intact animals. However, the effects of prolonged in vivo administration of such compounds are unknown. In our study, we hypothesized that such treatment would ameliorate aging-related cardiovascular deficits. Aged (∼18 months) male Sprague Dawley rats were treated daily with either vehicle or the KCa channel activator SKA-31 (10 mg/kg, intraperitoneal injection; n = 6/group) for 8 weeks, followed by echocardiography, arterial pressure myography, immune cell and plasma cytokine characterization, and tissue histology. Our results show that SKA-31 administration improved endothelium-dependent vasodilation, reduced agonist-induced vascular contractility, and prevented the aging-associated declines in cardiac ejection fraction, stroke volume and fractional shortening, and further improved the expression of endothelial KCa channels and associated cell signalling components to levels similar to those observed in young male rats (∼5 months at end of study). SKA-31 administration did not promote pro-inflammatory changes in either T cell populations or plasma cytokines/chemokines, and we observed no overt tissue histopathology in heart, kidney, aorta, brain, liver and spleen. SKA-31 treatment in young rats had little to no effect on vascular reactivity, select protein expression, tissue histology, plasma cytokines/chemokines or immune cell properties. Collectively, these data demonstrate that administration of the KCa channel activator SKA-31 improved aging-related cardiovascular function, without adversely affecting the immune system or promoting tissue toxicity.

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Pancreatic islets adapt to the increase in insulin demand during pregnancy by upregulating ß-cell number, insulin synthesis, and secretion. These changes require prolactin receptor (PrlR) signaling, as mice with PrlR deletion are glucose intolerant with a lower ß-cell mass. Prolactin also prevents ß-cell apoptosis. Many genes participate in these adaptive changes in the islet, and Lrrc55 is one of the most upregulated genes with unknown function in islets. Because Lrrc55 expression increases in parallel to the increase in ß-cell number and insulin production during pregnancy, we hypothesize that Lrrc55 might regulate ß-cell proliferation/apoptosis (thus ß-cell number) and insulin synthesis. Here, we found that Lrrc55 expression was upregulated by >60-fold during pregnancy in a PrlR-dependent manner, and this increase was restricted only to the islets. Overexpression of Lrrc55 in ß-cells had minimal effect on ß-cell proliferation and glucose-stimulated insulin secretion but protected ß-cells from glucolipotoxicity-induced reduction in insulin gene expression. Moreover, Lrrc55 protects ß-cells from glucolipotoxicity-induced apoptosis, with upregulation of prosurvival signals and downregulation of proapoptotic signals of the endoplasmic reticulum (ER) stress pathway. Furthermore, Lrrc55 attenuated calcium depletion induced by glucolipotoxicity, which may contribute to its antiapoptotic effect. Hence our findings suggest that Lrrc55 is a novel prosurvival factor that is upregulated specifically in islets during pregnancy, and it prevents conversion of adaptive unfolded protein response to unresolved ER stress and apoptosis in ß-cells. Lrrc55 could be a potential therapeutic target in diabetes by reducing ER stress and promoting ß-cell survival.

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