Systemic blood pressure is determined, in part, by arterial smooth muscle cells (myocytes). Several Transient Receptor Potential (TRP) channels are proposed to be expressed in arterial myocytes, but it is unclear if these proteins control physiological blood pressure and contribute to hypertension in vivo. We generated the first inducible, smooth muscle-specific knockout mice for a TRP channel, namely for PKD2 (TRPP1), to investigate arterial myocyte and blood pressure regulation by this protein. Using this model, we show that intravascular pressure and α1-adrenoceptors activate PKD2 channels in arterial myocytes of different systemic organs. PKD2 channel activation in arterial myocytes leads to an inward Na+ current, membrane depolarization and vasoconstriction. Inducible, smooth muscle cell-specific PKD2 knockout lowers both physiological blood pressure and hypertension and prevents pathological arterial remodeling during hypertension. Thus, arterial myocyte PKD2 controls systemic blood pressure and targeting this TRP channel reduces high blood pressure.

Rationale Smooth muscle cell (myocyte) large-conductance calcium (Ca2+)-activated potassium (BK) channels are functionally significant modulators of arterial contractility. Arterial myocytes express both pore-forming BKα and auxiliary β1 subunits, which increase channel Ca2+-sensitivity. Recently, several leucine-rich repeat containing (LRRC) proteins have been identified as auxiliary γ subunits that elevate the voltage-sensitivity of recombinant and prostate adenocarcinoma BK channels. LRRC expression and physiological functions in native cell types are unclear. Objective Investigate the expression and physiological functions of LRRC26 in arterial myocytes. Methods and Results RT-PCR and Western blotting detected LRRC26 mRNA and protein in cerebral artery myocytes. Biotinylation, immunofluorescence resonance energy transfer microscopy and co-immunoprecipitation indicated that LRRC26 was located in close spatial proximity to, and associated with, plasma membrane BKα subunits. LRRC26 knockdown (RNAi) reduced total and surface LRRC26, but did not alter BKα or β1, proteins in arteries. LRRC26 knockdown did not alter Ca2+ sparks, but reduced BK channel voltage-sensitivity, which reduced channel apparent Ca2+-sensitivity and transient BK current frequency and amplitude in myocytes. LRRC26 knockdown also increased myogenic tone over a range (40 – 100 mmHg) of intravascular pressures, and reduced vasoconstriction to iberiotoxin and vasodilation to NS1619, BK channel inhibitors and activators, respectively. In contrast, LRRC26 knockdown did not alter depolarization (60 mmol/L K+)-induced vasoconstriction. Conclusions LRRC26 is expressed, associates with BKα subunits, and elevates channel voltage- and apparent Ca2+-sensitivity in arterial myocytes to induce vasodilation. This study indicates that arterial myocytes express a functional BK channel γ subunit.

Background Coronavirus disease 2019 (COVID-19) continues to pose a significant threat to public health worldwide. The purpose of this study was to review current evidence obtained from randomized clinical trials on the efficacy of antivirals for COVID-19 treatment. Methods A systematic literature search was performed using PubMed to identify randomized controlled trials published up to September 4, 2021 that examined the efficacy of antivirals for COVID-19 treatment. Studies that were not randomized controlled trials or that did not include treatment of COVID-19 with approved antivirals were excluded. Risk of bias was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) method. Due to study heterogeneity, inferential statistics were not performed and data were expressed as descriptive statistics. Results Of the 2,284 articles retrieved, 31 (12,440 patients) articles were included. Overall, antivirals were more effective when administered early in the disease course. No antiviral treatment demonstrated efficacy at reducing COVID-19 mortality. Sofosbuvir/daclatasvir results suggested clinical improvement, although statistical power was low. Remdesivir exhibited efficacy in reducing time to recovery, but results were inconsistent across trials. Conclusions Although select antivirals have exhibited efficacy to improve clinical outcomes in COVID-19 patients, none demonstrated efficacy in reducing mortality. Larger RCTs are needed to conclusively establish efficacy.

Key points• Voltage-dependent L-type Ca 2+ (Ca V 1.2) channels are the major Ca 2+ influx pathway and are central to contractility regulation in arterial smooth muscle cells.• Ca V 1.2 exists as a full-length channel and undergoes cleavage to a short Ca V 1.2 and a C-terminus (CCt) fragment in rat and human arterial smooth muscle cells.• CCt decreases Ca V 1.2 transcription and shifts the voltage dependence of current activation and inactivation to more depolarized potentials in arterial smooth muscle cells.• CCt reduces pressure-and depolarization-induced vasoconstriction.• CCt is a bi-modal vasodilator.Abstract Voltage-dependent L-type Ca 2+ channels (Ca V 1.2) are the primary Ca 2+ entry pathway in vascular smooth muscle cells (myocytes). Ca V 1.2 channels control systemic blood pressure and organ blood flow and are pathologically altered in vascular diseases, which modifies vessel contractility. The Ca V 1.2 distal C-terminus is susceptible to proteolytic cleavage, which yields a truncated Ca V 1.2 subunit and a cleaved C-terminal fragment (CCt). Previous studies in cardiac myocytes and neurons have identified CCt as both a transcription factor and Ca V 1.2 channel inhibitor, with different signalling mechanisms proposed to underlie some of these effects. CCt existence and physiological functions in arterial myocytes are unclear, but important to study given the functional significance of Ca V 1.2 channels. Here, we show that CCt exists in myocytes of both rat and human resistance-size cerebral arteries, where it locates to both the nucleus and plasma membrane. Recombinant CCt expression in arterial myocytes inhibited Ca V 1.2 transcription and reduced Ca V 1.2 protein. CCt induced a depolarizing shift in the voltage dependence of both Ca V 1.2 current activation and inactivation, and reduced non-inactivating current in myocytes. Recombinant truncated CCt lacking a putative nuclear localization sequence ( 92CCt) did not locate to the nucleus and had no effect on arterial Ca V 1.2 transcription or protein. However, 92CCt shifted the voltage dependence of Ca V 1.2 activation and inactivation similarly to CCt. CCt and 92CCt both inhibited pressure-and depolarization-induced vasoconstriction, although CCt was a far more effective vasodilator. These data demonstrate that endogenous CCt exists and reduces both Ca V 1.2 channel expression and voltage sensitivity in arterial myocytes. Thus, CCt is a bi-modal vasodilator.

The purpose of this systematic review and meta‐analysis was to examine clinical outcomes associated with convalescent plasma therapy in COVID‐19 patients. We performed a literature search on PubMed, medRxiv, Web of Science, and Scopus to identify studies published up to December 10th, 2020 that examined the efficacy of convalescent plasma treatment for COVID‐19. The primary endpoints were mortality, clinical improvement, and hospital length of stay. We screened 859 studies that met the search criteria, performed full‐text reviews of 56 articles, and identified 15 articles that fulfilled inclusion criteria for meta‐analysis. The odds of mortality were significantly lower in the convalescent plasma group compared to the control group (OR = 0.59 [95% CI = 0.44; 0.78], P < .001), although results from two key randomized controlled trials did not support the mortality benefit. The odds of clinical improvement were significantly higher in the convalescent plasma group compared to the control group (OR = 2.02 [95% CI = 1.54; 2.65], P < .001). There was no difference in hospital length of stay between the convalescent plasma group and the control group (MD = −0.49 days [95% CI = −3.11; 2.12], P = .713). In all, these data indicate that a mortality benefit with convalescent plasma is unclear, although there remain benefits with convalescent plasma therapy for COVID‐19.