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Key points: In arterial smooth muscle, Ca2+ sparks are elementary Ca2+‐release events generated by ryanodine receptors (RyRs) to cause vasodilatation by opening maxi Ca2+‐sensitive K+ (BKCa) channels.This study elucidated the contribution of T‐type Cav3.2 channels in caveolae and their functional interaction with L‐type Cav1.2 channels to trigger Ca2+ sparks in vascular smooth muscle cells (VSMCs).Our data demonstrate that L‐type Cav1.2 channels provide the predominant Ca2+ pathway for the generation of Ca2+ sparks in murine arterial VSMCs.T‐type Cav3.2 channels represent an additional source for generation of VSMC Ca2+ sparks. They are located in pit structures of caveolae to provide locally restricted, tight coupling between T‐type Cav3.2 channels and RyRs to ignite Ca2+ sparks. Recent data suggest that T‐type Cav3.2 channels in arterial vascular smooth muscle cells (VSMCs) and pits structure of caveolae could contribute to elementary Ca2+ signalling (Ca2+ sparks) via ryanodine receptors (RyRs) to cause vasodilatation. While plausible, their precise involvement in igniting Ca2+ sparks remains largely unexplored. The goal of this study was to elucidate the contribution of caveolar Cav3.2 channels and their functional interaction with Cav1.2 channels to trigger Ca2+ sparks in VSMCs from mesenteric, tibial and cerebral arteries. We used tamoxifen‐inducible smooth muscle‐specific Cav1.2−/− (SMAKO) mice and laser scanning confocal microscopy to assess Ca2+ spark generation in VSMCs. Ni2+, Cd2+ and methyl‐β‐cyclodextrin were used to inhibit Cav3.2 channels, Cav1.2 channels and caveolae, respectively. Ni2+ (50 μmol L−1) and methyl‐β‐cyclodextrin (10 mmol L−1) decreased Ca2+ spark frequency by ∼20–30% in mesenteric VSMCs in a non‐additive manner, but failed to inhibit Ca2+ sparks in tibial and cerebral artery VSMCs. Cd2+ (200 μmol L−1) suppressed Ca2+ sparks in mesenteric arteries by ∼70–80%. A similar suppression of Ca2+ sparks was seen in mesenteric artery VSMCs of SMAKO mice. The remaining Ca2+ sparks were fully abolished by Ni2+ or methyl‐β‐cyclodextrin. Our data demonstrate that Ca2+ influx through CaV1.2 channels is the primary means of triggering Ca2+ sparks in murine arterial VSMCs. CaV3.2 channels, localized to caveolae and tightly coupled to RyR, provide an additional Ca2+ source for Ca2+ spark generation in mesenteric, but not tibial and cerebral, arteries. Key points: In arterial smooth muscle, Ca2+ sparks are elementary Ca2+‐release events generated by ryanodine receptors (RyRs) to cause vasodilatation by opening maxi Ca2+‐sensitive K+ (BKCa) channels.This study elucidated the contribution of T‐type Cav3.2 channels in caveolae and their functional interaction with L‐type Cav1.2 channels to trigger Ca2+ sparks in vascular smooth muscle cells (VSMCs).Our data demonstrate that L‐type Cav1.2 channels provide the predominant Ca2+ pathway for the generation of Ca2+ sparks in murine arterial VSMCs.T‐type Cav3.2 channels represent an additional source for generation of VSMC Ca2+ sparks. They are located in pit structures of caveolae to provide locally restricted, tight coupling between T‐type Cav3.2 channels and RyRs to ignite Ca2+ sparks. [ABSTRACT FROM AUTHOR]

Background: Relaxins are small peptide hormones, which are novel candidate molecules that play important roles in cardiometablic syndrome. Relaxins are structurally related to the insulin hormone superfamily, which provide vasodilatory effects by activation of G-protein-coupled relaxin receptors (RXFPs) and stimulation of endogenous nitric oxide (NO) generation. Recently, relaxin could be demonstrated to activate Gi proteins and phosphoinositide 3-kinase (PI3K) pathways in cultured endothelial cells in vitro. However, the contribution of the Gi-PI3K pathway and their individual components in relaxin-dependent relaxation of intact arteries remains elusive. Methods: We used Gai2- (Gnai2-/-) and Gαi3-deficient (Gnai3-/-) mice, pharmacological tools and wire myography to study G-protein-coupled signaling pathways involved in relaxation of mouse isolated mesenteric arteries by relaxins. Human relaxin-1, relaxin-2, and relaxin-3 were tested. Results: Relaxin-2 (~50% relaxation at 10-11 M) was the most potent vasodilatory relaxin in mouse mesenteric arteries, compared to relaxin-1 and relaxin-3. The vasodilatory effects of relaxin-2 were inhibited by removal of the endothelium or treatment of the vessels with N (G)-nitro-L-arginine methyl ester (L-NAME, endothelial nitric oxide synthase (eNOS) inhibitor) or simazine (RXFP1 inhibitor). The vasodilatory effects of relaxin-2 were absent in arteries of mice treated with pertussis toxin (PTX). They were also absent in arteries isolated from Gnai2-/- mice, but not from Gnai3-/- mice. The effects were not affected by FR900359 (Gαq protein inhibitor) or PI-103 (PI3Ka inhibitor), but inhibited by TGX-221 (PI3Kβ inhibitor) or AS-252424 (PI3Kα inhibitor). Simazine did not influence the anti-contractile effect of perivascular adipose tissue. Conclusion: Our data indicate that relaxin-2 produces endothelium- and NO-dependent relaxation of mouse mesenteric arteries by activation of RXFP1 coupled to Gi2-PI3K-eNOS pathway. Targeting vasodilatory Gi-protein-coupled RXFP1 pathways may provide promising opportunities for drug discovery in endothelial dysfunction and cardiometabolic disease. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) and NO are important gasotransmitters, but how endogenous H2S affects the circulatory system has remained incompletely understood. Here, we show that CTH or CSE (cystathionine γ-lyase)-produced H2S scavenges vascular NO and controls its endogenous levels in peripheral arteries, which contribute to blood pressure regulation. Furthermore, eNOS (endothelial NO synthase) and phospho-eNOS protein levels were unaffected, but levels of nitroxyl were low in CTH-deficient arteries, demonstrating reduced direct chemical interaction between H2S and NO. Pretreatment of arterial rings from CTH-deficient mice with exogenous H2S donor rescued the endothelial vasorelaxant response and decreased tissue NO levels. Our discovery that CTH-produced H2S inhibits endogenous endothelial NO bioavailability and vascular tone is novel and fundamentally important for understanding how regulation of vascular tone is tailored for endogenous H2S to contribute to systemic blood pressure function. [ABSTRACT FROM AUTHOR]

Background: Perivascular adipose tissue (PVAT) exerts anti-contractile effects on visceral arteries by release of various perivascular relaxing factors (PVRFs) and opening voltage-gated K+ (Kv) channels in vascular smooth muscle cells (VSMCs). Palmitic acid methyl ester (PAME) has been proposed as transferable PVRF in rat aorta. Here, we studied PVAT regulation of arterial tone of human mesenteric arteries and clarified the contribution of Kv channels and PAME in the effects. Methods: Wire myography was used to measure vasocontractions of mesenteric artery rings from patients undergoing abdominal surgery. Isolated aortic rings from Sprague-Dawley rats were studied for comparison. PVAT was either left intact or removed from the arterial rings. Vasocontractions were induced by external high K+ (60mM), serotonin (5-HT) or phenylephrine. PAME (10 nM-3μM) was used as vasodilator. Kv channels were blocked by XE991, a Kv7 (KCNQ) channel inhibitor, or by 4-aminopyridine, a non-specific Kv channel inhibitor. PAME was measured in bathing solutions incubated with rat peri-aortic or human visceral adipose tissue. Results: We found that PVAT displayed anti-contractile effects in both human mesenteric arteries and rat aortas. The anti-contractile effects were inhibited by XE991 (30μM). PAME (EC50 ~1.4μM) was capable to produce relaxations of PVAT-removed rat aortas. These effects were abolished by XE991 (30μM), but not 4-aminopyridine (2mM) or NDGA (10μM), a lipoxygenases inhibitor. The cytochrome P450 epoxygenase inhibitor 17-octadecynoic acid (ODYA 10μM) and the soluble epoxide hydrolase inhibitor 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA 10μM) slightly decreased PAME relaxations. PAME up to 10μM failed to induce relaxations of PVAT-removed human mesenteric arteries. 5-HT induced endogenous PAME release from rat peri-aortic adipose tissue, but not from human visceral adipose tissue. Conclusions: Our data also suggest that Kv7 channels are involved in the anticontractile effects of PVAT on arterial tone in both rat aorta and human mesenteric arteries. PAME could contribute to PVAT relaxations by activating Kv7 channels in rat aorta, but not in human mesenteric arteries. [ABSTRACT FROM AUTHOR]

Background: Mild-to-moderate chronic kidney disease (CKD G3a) is prevalent in older adults. Substantial evidence suggests that individuals with advanced CKD face a high risk for common geriatric conditions, like functional impairment and cognitive decline, whereas the relationships between mild-to-moderate CKD and functional impairment and cognitive decline, but also poor nutritional status and mood disorders, are still unclear.Objective: The aim of this study was to explore associations between mild-to-moderate CKD and impairments in the core domains of geriatric assessment (GA) in a large cohort of community-dwelling older adults.Methods: This was a cross-sectional analysis of 1,476 participants of the Berlin Aging Study II. Study participants were stratified as to presence or absence of CKD G3a (estimated glomerular filtration rate [eGFR] 45-59 mL/min/1.73 m2 vs. eGFR ≥60 mL/min/1.73 m2). GA comprised the following instruments: the Activities of Daily Living Scale (ADL), the Timed up and Go (TUG), the Tinetti test (Tinetti), the Mini-Mental-State Examination (MMSE), the Geriatric Depression Scale (GDS), and the Mini Nutritional Assessment (MNA). We used logistic regression models to estimate multivariable-adjusted associations between CKD G3a and impairments in the respective domains.Results: A total of 282 subjects with mild-to-moderate CKD (CKD G3a) were identified (19.1%). Overall, the prevalence of impairments identified was higher among subjects with compared to without CKD G3a (21 vs. 15.9%, p = 0.043). In multivariable-adjusted models, CKD G3a was consistently associated with increased odds of an impaired gait performance as to the TUG (adjusted odds ratio 2.06, 95% CI 1.04-4.09). In contrast, on average, individuals with and without CKD G3a did not differ as to their results in the MMSE, the ADL, the MNA, and the GDS.Conclusion: GA identified impairments in 21 versus 15.9% of older adults with and without mild-to-moderate CKD, respectively. However, except for an increased likelihood of impaired gait performance (TUG) with mild-to-moderate CKD, we did not find independent associations between mild-to-moderate CKD and geriatric conditions. [ABSTRACT FROM AUTHOR]

Abstract: Resistant hypertension is defined as high blood pressure that remains uncontrolled despite treatment with at least three antihypertensive drugs at adequate doses. Resistant hypertension is an increasingly common clinical problem in older age, obesity, diabetes, sleep apnea, and chronic kidney disease. Although the direct vasodilator minoxidil was introduced in the early 1970s, only recently has this drug been shown to be particularly effective in a subgroup of patients with treatment‐resistant or uncontrolled hypertension. This pharmacological approach is interesting from a mechanistic perspective as minoxidil is the only clinically used K+ channel opener today, which targets a subclass of K+ channels, namely KATP channels in VSMCs. Beside KATP channels, two other classes of VSMC K+ channels could represent novel effective targets for treatment of resistant hypertension, namely Kv7 (KCNQ) and inward rectifier potassium (Kir2.1) channels. Interestingly, these channels are unique among VSMC potassium channels. First, both have been implicated in the control of microvascular tone by perivascular adipose tissue. Second, they exhibit biophysical properties strongly controlled and regulated by membrane voltage, but not intracellular calcium. This review focuses on Kv7 (Kv7.1‐5) and Kir (Kir2.1) channels in VSMCs as potential novel drug targets for treatment of resistant hypertension, particularly in comorbid conditions such as obesity and metabolic syndrome. [ABSTRACT FROM AUTHOR]

Background and Purpose: KV 7.1 voltage-gated potassium channels are expressed in vascular smooth muscle cells (VSMC) of diverse arteries, including mesenteric arteries. Based on pharmacological evidence using R-L3 (KV 7.1 channel opener), HMR1556, chromanol 293B (KV 7.1 channel blockers), stimulation of these channels has been suggested to evoke profound relaxation in various vascular beds of rats. However, the specificity of these drugs in vivo is uncertain.Experimental Approach: We used Kcnq1-/- mice and pharmacological tools to determine whether KV 7.1 channels play a role in the regulation of arterial tone.Key Results: R-L3 produced similar concentration-dependent relaxations (EC50  ~ 1.4 μM) of arteries from wild-type (Kcnq1+/+ ) and Kcnq1-/- mice, pre-contracted with either phenylephrine or 60 mM KCl. This relaxation was not affected by 10 μM chromanol 293B, 10 μM HMR1556 or 30 μM XE991 (pan-KV 7 channel blocker). The anti-contractile effects of the perivascular adipose tissue (PVAT) were normal in Kcnq1-/- arteries. Chromanol 293B and HMR1556 did not affect the anti-contractile effects of (PVAT). Isolated VSMCs from Kcnq1-/- mice exhibited normal peak KV currents. The KV 7.2-5 channel opener retigabine caused similar relaxations in Kcnq1-/- and wild-type vessels.Conclusion and Implications: We conclude that KV 7.1 channels were apparently not involved in the control of arterial tone by α1 -adrenoceptor agonists and PVAT. In addition, R-L3 is an inappropriate pharmacological tool for studying the function of native vascular KV 7.1 channels in mice. [ABSTRACT FROM AUTHOR]

The arterial myogenic response is an inherent property of resistance arteries. Myogenic tone is crucial for maintaining a relatively constant blood flow in response to changes in intraluminal pressure and protects delicate organs from excessive blood flow. Although this fundamental physiological phenomenon has been extensively studied, the underlying molecular mechanisms are largely unknown. Recent studies identified a crucial role of mechano-activated angiotensin II type 1 receptors (AT1R) in this process. The development of myogenic response is affected by aging. In this review, we summarize recent progress made to understand the role of AT1R and other mechanosensors in the control of arterial myogenic response. We discuss age-related alterations in myogenic response and possible underlying mechanisms and implications for healthy aging. • Arterial myogenic constriction requires Gq/11‐dependent mechanoactivated angiotensin II type 1 receptor signaling in VSMCs. • The strong link between mechanoactivation and canonical G q/11 signaling suggests a potential mechanism of vascular ageing. • These insights establish a strong foundation for further investigations on blood flow and pressure in the elderly. [ABSTRACT FROM AUTHOR]