The sodium-glucose co-transporter (SGLT)-2 inhibitor dapagliflozin was recently reported to reduce renal tyrosine hydroxylase (TH) and norepinephrine levels, lowering blood pressure and preventing endothelial dysfunction, in a murine model of neurogenic hypertension. This suggested that dapagliflozin may combat sympathetic nervous system (SNS) hyperactivity, which is known to accompany and aggravate chronic heart failure (CHF). Adrenal G protein-coupled receptor kinase (GRK)-2 upregulation is a major driver of circulating catecholamine (CA) elevation and SNS hyperactivity, especially in CHF. GRK2 severely dysregulates adrenal sympatho-inhibitory α 2-adrenergic receptors (ARs), leading to unchecked, chronically elevated CA secretion. Therefore, we hypothesized herein that SGLT2 inhibition with dapagliflozin may lower SNS hyperactivity in the adrenal gland by antagonizing GRK2 actions on α 2ARs in adrenal chromaffin cells. We used the rat pheochromocytoma PC12 cell line expressing human α 2AAR, as well as freshly isolated adrenal glands from adult male Sprague-Dawley rats treated with dapagliflozin in vivo. We measured circulating norepinephrine (NE) in vivo via RIA, GRK2 & TH expression levels via real-time PCR and immunoblotting, adrenal α 2AR density (Bmax) via saturation radioligand binding with [methyl-3H]-rauwolscine, and G protein activation via the GTPγS assay. Dapagliflozin treatment for 7 consecutive days (20 mg/kg/d in drinking water) led to a significant reduction in blood circulating NE levels (217+67 pg/ml, n=6), compared to control, vehicle-treated rats (363+77 pg/ml, n=6, p<.05), suggesting reduced SNS activity. This was accompanied by reduced GRK2 and TH mRNA and protein levels in dapagliflozin-treated rat adrenals vs. vehicle-treated animal-derived glands, indicating reduced adrenal CA synthesis and secretion. Finally, adrenal α 2AR density was higher in dapagliflozin- vs. vehicle-treated rats (51.3+7.3 vs. 26.1+8.1 fmol/mg of protein, respectively; n=12 glands from 6 animals per group, p<.05). These results (i.e. GRK2 and TH downregulation) were completely recapitulated in PC12 α 2AAR-expressing cells in culture, treated with 5 μM dapagliflozin (or vehicle) for 24 hours. Importantly, α 2AR-dependent G protein-mediated signaling towards inhibition of CA secretion was markedly enhanced at 24 hrs post-dapagliflozin application in PC12 cells. This was the result of reduced GRK2-dependent receptor desensitization, since dapagliflozin lacked this effect in cells co-transfected with a GRK2-encoding adenovirus to acutely overexpress GRK2. In conclusion, dapagliflozin exerts a sympatholytic action in the adrenal medulla via downregulation of both TH, which reduces CA biosynthesis, and GRK2, which reduces α 2AR desensitization in favor of enhanced inhibition of CA secretion.

Gout is a chronic disease characterized by recurrent attacks on joints from monosodium urate crystal deposition causing inflammation and severe pain. Patients at increased risk of developing gout include those with obesity, high consumption of alcohol or high-purine foods, genetic causes, and medication side effects. Typically, there are three stages of disease progression: acute, inter-critical, and chronic. Monoarticular joint disease is common however polyarticular gouty arthritis can result after years of acute flares. The chronic nature of the disease forms tophi, which are generally painless solid urate crystal collections. We present an unusual case of a 33-year-old male whose initial presentation was severe tophaceous gout affecting multiple joints, including bilateral elbows, knees, as well as hand and foot joints. His presentation was unique in that the tophi were not firm as expected, but were erythematous, tender, and fluctuant resembling an abscess. Laboratory and imaging studies confirmed the diagnosis of tophaceous gout and the patient's symptoms improved after starting systemic steroid therapy and colchicine. A multidisciplinary effort involving the medicine team and infectious disease, podiatry, and rheumatology consultants was essential in reaching the diagnosis. This case highlights the importance of keeping a broad differential diagnosis in a patient with polyarticular lesions and considering gout even with an atypical presentation such as in our patient.

Vertebral discitis is an infection of the vertebrae most commonly caused by Staphylococcus aureus (S. aureus) and usually presents in patients with preexisting medical conditions such as diabetes mellitus. This disease process involves the invasion of bacteria into the vertebral disc through one of three basic routes: hematogenous spread from a distant site, direct trauma due to iatrogenic causes, or due to a contiguous spread from adjacent soft tissue infection. Here, we present a 24-year-old Asian male with no past medical history or history of trauma who presented with nonspecific symptoms of fever and nasopharyngitis. The patient subsequently developed persistent thoracic back pain that failed multiple lines of treatment. Magnetic resonance imaging (MRI) of the spine showed vertebral discitis, and cultures confirmed Salmonella being the etiologic agent for his symptoms. Salmonella discitis is extremely rare, with only about 0.45% of these cases being reported in the literature. Even more uncommon is the isolation of Salmonella enterica serovar Agbeni in a young patient without comorbidities. This case report highlights the importance of including Salmonella as a possible causative agent in patients who present with signs and symptoms of vertebral discitis.

Background: In the heart, aldosterone (Aldo) binds the mineralocorticoid receptor (MR) to exert damaging, adverse remodeling-promoting effects. We recently showed that G protein-coupled receptor (GPCR)-kinase (GRK)-5 blocks the cardiac MR by directly phosphorylating it, thereby repressing its transcriptional activity. MR antagonist (MRA) drugs block the cardiac MR reducing morbidity and mortality of advanced human heart failure. Non-steroidal MRAs, such as finerenone, may provide better cardio-protection against Aldo than classic, steroidal MRAs, like spironolactone and eplerenone. Herein, we sought to investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent blockade. Methods: We used the cardiomyocyte cell line H9c2 and neonatal rat ventricular myocytes (NRVMs). Results: GRK5 phosphorylates the MR in H9c2 cardiomyocytes in response to finerenone but not to eplerenone. Unlike eplerenone, finerenone alone potently and efficiently suppresses cardiac MR transcriptional activity, thus displaying inverse agonism. GRK5 is necessary for finerenone`s inverse agonism, since GRK5 genetic deletion renders finerenone incapable of blocking cardiac MR transcriptional activity. Eplerenone alone does not fully suppress cardiac MR basal activity regardless of GRK5 expression levels. Finally in NRVMs, GRK5 is necessary for the anti-apoptotic and anti-fibrotic effects of both finerenone and eplerenone against Aldo, as well as for the higher efficacy and potency of finerenone at blocking Aldo-induced apoptosis and fibrosis. Conclusions: Finerenone, but not eplerenone, induces GRK5-dependent cardiac MR inhibition, which underlies, at least in part, its higher potency and efficacy, compared to eplerenone, as an MRA in the heart. GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium.

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