Contraction Of Arteries Research Articles

Correlation of Coronary Artery Disease with Risk Factors on Computed Tomography Angiography

Background: Coronary Artery Disease (CAD) was the contraction of coronary arteries that was frequently began through the atherosclerosis which primes to restraint of blood flowing to cardiac muscles. Atherosclerosis was an accumulation of plaque or fats deposition upon the internal walls of arteries. Aim: To correlate coronary artery disease with risk factors on Computed Tomography Angiography. Duration and place of study: This study was conduct from 17-July-2019 to 13-Oct-2020 at Punjab Institute of Cardiology Lahore. Methods: A cross sectional analytical study was conducted at Punjab Institute of Cardiology, Lahore. Data were collected according to the age, gender and risk factors such as diabetes mellitus, hypertension, hyperlipidemia; high cholesterol level, contrast with volume, vessels involved and extent of vessels involvement.132 participants including 103 males (78%) and 29 females (22%) were selected through convenient sampling technique. Results: Data examination exhibited that out of 132 patients, 101 patients (76.5%) had CAD and 31 patients (23.5%) had no CAD. Out of 29 females, 21 female patients (20.8%) had CAD whereas out of 103 males, 80 male patients (79.2%) had coronary artery disease. According to our study, as correlated the coronary artery disease with various risk factors on computed tomography angiography. The patient had one or more than one risk factors; out of 132 patients, 72 patients (54.5%) had diabetes mellitus, 102 patients (77.3%) had hypertension, 55 patients (41.7%) had hyperlipidemia, 56 patients (42.4%) familial hypercholesterolemia, and 30(22.7%) were smokers. Conclusions: We concluded from our study that patients with Diabetes Mellitus (DM) were more prone to develope coronary artery disease CAD. Males were more at risk (79.2%) than females (20.8%) for CAD. Diabetes mellitus and hypertension were stronger predictors of CAD than smoking, hyperlipidemia and familial hypercholesterolemia. Keywords: Coronary Artery disease, Computed Tomography Angiogrpahy, Diabetes Mellitus, Hypertension

O‑GlcNAcylation contributes to intermittent hypoxia‑associated vascular dysfunction via modulation of MAPKs but not CaMKII pathways.

Intermittent hypoxia (IH) leads to vascular dysfunction, and O-linked-β-N-acetylglucosamine (O-GlcNAc)ylation may regulate vascular reactivity through the modulation of intracellular signaling. The present study hypothesized that O-GlcNAc modifications contributed to the vascular effects of acute IH (AIH) and chronic IH (CIH) through the MAPK and Ca2+/calmodulin-dependent kinase II (CaMKII) pathways. Rat aortic and mesenteric segments were incubated with DMSO, O-GlcNAcase (OGA) or O-GlcNAc transferase (OGT) inhibitor under either normoxic or AIH conditions for 3 h, and arterial function was then assessed. Meanwhile, arteries isolated from control and CIH rats were exposed to 3 h of incubation under normoxic conditions using DMSO, OGA or OGT as an inhibitor, before assessing arterial reactivity. CIH was found to increase the expression of vascular O-GlcNAc protein and OGT, phosphorylate p38 MAPK and ERK1/2, and decrease OGA levels, but it had no effects on phosphorylated CaMKII levels. OGA inhibition increased global O-GlcNAcylation and the phosphorylation of p38 MAPK, ERK1/2 and CaMKII, whereas OGT blockade had the opposite effects. OGA inhibition preserved acetylcholine-induced relaxation in AIH arteries, whereas OGT blockade attenuated the relaxation responses of arteries under normoxic conditions or undergoing AIH treatments. However, the impairment of acetylcholine dilation in CIH mesenteric arteries was improved. CIH artery contraction was increased following angiotensin II (Ang II) exposure. Blockade of p38 MAPK and ERK1/2, but not CaMKII, attenuated Ang II-induced contractile responses in CIH arteries isolated from the non-OGT inhibitor-treated groups. OGT inhibition significantly blocked contractile responses to Ang II and abolished the inhibitory effects of MAPK inhibitors. These findings indicated that O-GlcNAcylation regulates IH-induced vascular dysfunction, at least partly by modulating MAPK, but not CaMKII, signaling pathways.

The promoting role of Cx43 on the proliferation and migration of arterial smooth muscle cells for angiotensin II-dependent hypertension

BackgroundRecent studies have shown that endothelin-1 and angiotensin II (AngII) can increase gap junctional intercellular communication (GJIC) by activating Mitogen-activated protein kinases (MAPKs) pathway. However, not only the precise interaction of AngII with Connexin43(Cx43) and the associated functions remain unclear, but also the regulatory role of Cx43 on the AngII-mediated promotion proliferation and migration of VSMCs is poorly understood. Material and methodsOur research applicated pressure myography measurements, immunofluorescence and Western blot analyses to investigate the changes in physiological indicators in spontaneously hypertensive rats (SHRs) and AngII-stimulated proliferation and migration of A7r5 SMCs(Rat vascular smooth muscle cells). The aim was to elucidate the role of CX43 in hypertension induced by AngII. ResultsChronic ramipril (angiotensin converting enzyme inhibitor) management for SHRs significantly attenuated blood pressure and blood vessel wall thickness, also reduced contraction rate in the cerebral artery. The cerebral artery contraction rates, mRNA and protein expression of Cx43, osteopontin (OPN) and proliferating cell nuclear antigen (PCNA) protein expression in the SHR + ramipril and SHR + ramipril + carbenoxolone (CBX, Cx43 specific blocker) groups were significantly lower than those in the SHR group. Cx43 protein expression and Ser368 phosphorylated Cx43 protein levels increased significantly in AngII-stimulated A7r5 cells. However, the levels of phosphorylated Cx43 decreased after pre-treatment with candesartan (AT1 receptor blocker), GF109203X (protein kinase C (PKC) blocker) and U0126 (mitogen-activated protein kinases/extracellular signal-regulated kinase1/2(MEK/ERK1/2)-specific blocker) in AngII-stimulated A7r5 cells. Cx43 was widely distributed in the cell membrane, nucleus, and cytoplasm of the SMCs. Furthermore, pre-treatment of the AngII- stimulated A7r5 cells with Gap26 (Cx43 blocker) significantly inhibited cell migration and decreased the expression levels of MEK1/2, ERK1/2, P-MEK1/2, and P-ERK1/2. ConclusionOur research confirms that Cx43 plays an important role in the regulation of proliferation and migration of VSMCs via MEK/ERK and PKC signal pathway in AngII-dependent hypertension.

Secondhand Smoke Exposure Impairs Ion Channel Function and Contractility of Mesenteric Arteries.

Cigarette smoke, including secondhand smoke (SHS), has significant detrimental vascular effects, but its effects on myogenic tone of small resistance arteries and the underlying mechanisms are understudied. Although it is apparent that SHS contributes to endothelial dysfunction, much less is known about how this toxicant alters arterial myocyte contraction, leading to alterations in myogenic tone. The study's goal is to determine the effects of SHS on mesenteric arterial myocyte contractility and excitability. C57BL/6J male mice were randomly assigned to either filtered air (FA) or SHS (6 h/d, 5 d/wk) exposed groups for a 4, 8, or 12-weeks period. Third and fourth-order mesenteric arteries and arterial myocytes were acutely isolated and evaluated with pressure myography and patch clamp electrophysiology, respectively. Myogenic tone was found to be elevated in mesenteric arteries from mice exposed to SHS for 12 wk but not for 4 or 8 wk. These results were correlated with an increase in L-type Ca2+ channel activity in mesenteric arterial myocytes after 12 wk of SHS exposure. Moreover, 12 wk SHS exposed arterial myocytes have reduced total potassium channel current density, which correlates with a depolarized membrane potential (Vm). These results suggest that SHS exposure induces alterations in key ionic conductances that modulate arterial myocyte contractility and myogenic tone. Thus, chronic exposure to an environmentally relevant concentration of SHS impairs mesenteric arterial myocyte electrophysiology and myogenic tone, which may contribute to increased blood pressure and risks of developing vascular complications due to passive exposure to cigarette smoke.

Docosahexaenoic acid inhibits U46619- and prostaglandin F2α-induced pig coronary and basilar artery contractions by inhibiting prostanoid TP receptors

Docosahexaenoic acid (DHA, an n-3 polyunsaturated fatty acid) inhibits U46619 (a TP receptor agonist)- and prostaglandin F2α-induced contractions in rat aorta and mesenteric arteries. However, whether these effects could be replicated in vasospasm-prone vessels, such as coronary and cerebral arteries, remains unknown. Here, we evaluated the changes in pig coronary and basilar artery tensions and intracellular Ca2+ concentrations in human prostanoid TP or FP receptor-expressing cells. We aimed to clarify whether DHA inhibits U46619- and prostaglandin F2α-induced contractions in spasm-prone blood vessels and determine if the TP receptor is the primary target for DHA. In both pig coronary and basilar arteries, DHA suppressed U46619- and prostaglandin F2α-induced sustained contractions in a concentration-dependent manner, but did not affect contractions induced by 80 mM KCl. SQ 29,548 (a TP receptor antagonist) suppressed U46619- and prostaglandin F2α-induced contractions by approximately 100% and 60%, respectively. DHA suppressed both U46619- and prostaglandin F2α-induced increases in intracellular Ca2+ concentrations in human TP receptor-expressing cells. However, DHA did not affect prostaglandin F2α-induced increases in intracellular Ca2+ concentrations in human FP receptor-expressing cells. These findings suggest that DHA potently inhibits TP receptor-mediated contractions in pig coronary and basilar arteries, and the primary mechanism underlying its inhibitory effects on arterial contractions involves inhibiting TP receptors.

ASUHAN KEPERAWATAN DENGAN PENATALAKSANAAN TEKNIK RELAKSASI GENGGAM JARI DAN NAFAS DALAM TERHADAP PENURUNAN TEKANAN DARAH PADA PENDERITA HIPERTENSI

Background : Hypertension is a medical condition characterized by increased contraction of arteries which causes resistance to blood flow which increases blood pressure against the walls of blood through narrow blood vessels. Objective : To determine the effect of finger grip relaxation techniques and deep breathing on reducing blood pressure in hypertensive patients. Methods : Research design with descriptive method with case study approach. The implementation of Hypertension nursing care was carried out in the internal medicine room starting from June 15 to June 21, 2021. The subjects in this study were 2 patients suffering from hypertension morning and afternoon. Results : After being treated for 3 days, the results showed that the blood pressure of both patients decreased in patient 1 Mr “I” from 180/100 mmHg to 160/90 mmHg, in patients 2 Mrs “S” from 160/100 mmHg to 140/90 mmHg the pain scale of the two patients from 6 (moderate) to 3 (mild) the body is not weak, has started to be energetic and can sleep at night. cooperation between the health team and patients and families is very necessary for the success of nursing care for patients. Conclusion : With the management of finger grip relaxation techniques and deep breathing to reduce blood pressure in hypertensive patients with the results of the nursing evaluation the problem was partially resolved.

Effects of different vasopressors on the contraction of the superior mesenteric artery and uterine artery in rats during late pregnancy

BackgroundHypotension after neuraxial anaesthesia is one of the most common complications during caesarean section. Vasopressors are the most effective method to improve hypotension, but which of these drugs is best for caesarean section is not clear. We assessed the effects of vasopressors on the contractile response of uterine arteries and superior mesenteric arteries in pregnant rats to identify a drug that increases the blood pressure of the systemic circulation while minimally affecting the uterine and placental circulation.MethodsIsolated ring segments from the uterine and superior mesenteric arteries of pregnant rats were mounted in organ baths, and the contractile responses to several vasopressor agents were studied. Concentration-response curves for norepinephrine, phenylephrine, metaraminol and vasopressin were constructed.ResultsThe contractile response of the mesenteric artery to norepinephrine, as measured by the pEC50 of the drug, was stronger than the uterine artery (5.617 ± 0.11 vs. 4.493 ± 1.35, p = 0.009), and the contractile response of the uterine artery to metaraminol was stronger than the mesenteric artery (pEC50: 5.084 ± 0.17 vs. 4.92 ± 0.10, p = 0.007). There was no statistically significant difference in the pEC50 of phenylephrine or vasopressin between the two blood vessels.ConclusionsIn vitro experiments showed that norepinephrine contracts peripheral blood vessels more strongly and had the least effect on uterine artery contraction. These findings support the use of norepinephrine in mothers between the time of neuraxial anaesthesia and the delivery of the foetus.

MAPKs Are Highly Abundant but Do Not Contribute to α1-Adrenergic Contraction of Rat Saphenous Arteries in the Early Postnatal Period.

Previously, the abundance of p42/44 and p38 MAPK proteins had been shown to be higher in arteries of 1- to 2-week-old compared to 2- to 3-month-old rats. However, the role of MAPKs in vascular tone regulation in early ontogenesis remains largely unexplored. We tested the hypothesis that the contribution of p42/44 and p38 MAPKs to the contraction of peripheral arteries is higher in the early postnatal period compared to adulthood. Saphenous arteries of 1- to 2-week-old and 2- to 3-month-old rats were studied using wire myography and western blotting. The α1-adrenoceptor agonist methoxamine did not increase the phosphorylation level of p38 MAPK in either 1- to 2-week-old or 2- to 3-month-old rats. Accordingly, inhibition of p38 MAPK did not affect arterial contraction to methoxamine in either age group. Methoxamine increased the phosphorylation level of p42/44 MAPKs in arteries of 2- to 3-month-old and of p44 MAPK in 1- to 2-week-old rats. Inhibition of p42/44 MAPKs reduced methoxamine-induced contractions in arteries of 2- to 3-month-old, but not 1- to 2-week-old rats. Thus, despite a high abundance in arterial tissue, p38 and p42/44 MAPKs do not regulate contraction of the saphenous artery in the early postnatal period. However, p42/44 MAPK activity contributes to arterial contractions in adult rats.

Vascular Effects of Ginkgo Biloba Extract (EGb-761) on Isolated Human Umbilical Artery Contraction Responses

Amac: Ginkgo biloba, geleneksel Cin tibbinda astim, oksuruk ve enurezis gibi cesitli hastaliklarin tedavisinde kullanilmaktadir. Standardize Ginkgo biloba ekstresi, EGb-761, hayvan calismalarinda vazodilatasyona neden olan flavonoidler ve terpenoidler icerir. EGb-761'in insandaki umbilikal dolasim uzerindeki etkileri hakkinda cok az bilgi mevcuttur. Bu in vitro calisma, EGb-761'in izole insan umbilikal arter uzerindeki vaskuler etkilerini ve bu etkilerde nitrik oksit (NO) ve prostaglandinlerin rolunu degerlendirmeyi amaclamaktadir. Gerecler ve Yontem: Izole edilmis insan umbilikal arter seritleri, Krebs-Henseleit solusyonu iceren organ banyolarinda asilarak, surekli olarak %95 O2-%5 CO2 ile gazlandirildi. Dinlenme suresinden sonra uygulanan ajanlarin olusturdugu izometrik vazoaktif degisiklikler kaydedildi. Farkli doku gruplarinda (n=9) su deneysel prosedurler yapildi; 1) Kumulatif uygulanan EGb-761'in (50-500 µg/ml) umbilikal arter seritlerinin bazal tonusu uzerindeki etkisi. 2) Kumulatif EGb-761'in 10-6 M 5-HT ile arter seritlerinde olusturulan kasilma yaniti uzerindeki gevsetici etkisi. 3) Kumulatif EGb-761'in L-NAME ile inkubasyon sonrasi 5-HT ile arter seritlerinde olusturulan kasilma yaniti uzerindeki gevsetici etkisi 4) Kumulatif EGb-761'in indometazin ile inkubasyon sonrasi 5-HT ile arter seritlerinde olusturulan kasilma yaniti uzerindeki gevsetici etkisi ve 5) Kumulatif EGb-761'in L-NAME ve indometazin ile inkubasyonu sonrasi 5-HT ile arter seritlerinde olusturulan kasilma yaniti uzerindeki gevsetici etkisi. Verilerin istatistiksel analizinde karma etki modelleri kullanildi. p<0.05 anlamli olarak kabul edildi. Bulgular: Kumulatif EGb-761 uygulamasi (50-500 µg/ml) arter seritlerinin bazal tonunu degistirmedi (p>0.05). Kumulatif EGb-761 (50-500 µg/ml), 5-HT kaynakli kasilma cevaplarinda konsantrasyona bagli gevseme olusturdu (p<0.05). L-NAME, EGb-761'in (50-500 µg/ml) tum konsantrasyonlarinda 5-HT kasilmalari uzerinde olusturdugu gevseme yanitlarini onemli olcude azaltti (p<0.05). L-NAME, EGb-761'in dusuk konsantrasyonlarinda (50-100 µg/ml) olusturdugu gevseme yanitlarini ise tamamen inhibe etti. Indometazin ise bu yanitlari daha yuksek EGb-761 konsantrasyonlarinda (200-500 µg/ml) anlamli sekilde inhibe etti (p<0.05). L-NAME + indometazin, tum EGb-761 konsantrasyonlarinin (50-500 µg/ml) olusturdugu yanitlarda anlamli sekilde inhibisyona neden oldu (p<0.05). Dahasi, L-NAME ve indometazinin birlikte uygulanmasi, bu gevseme yanitlarinda belirli EGb-761 konsantrasyonlarinda tek basina L-NAME ve indometazinden daha guclu bir inhibisyon ile sonuclandi. Sonuc: EGb-761, insan umbilikal arterinin bazal tonusunu etkilememektedir. EGb-761’in 5-HT ile onceden kasilma olusturulan insan umbilikal arter seritlerine kumulatif olarak uygulanmasi anlamli sekilde konsantrasyona bagli gevseme yaniti olusturmaktadir. NO ve prostaglandinler, bu vazodilatasyon mekanizmasinda EGb-761 konsantrasyonuna bagli olarak degisen potansiyelde katkida bulunmaktadir. Ayrica prostaglandinler bu yanitlarda NO ile sinerjik etki yaratmaktadir.

Remodeling of Arterial Tone Regulation in Postnatal Development: Focus on Smooth Muscle Cell Potassium Channels.

Maturation of the cardiovascular system is associated with crucial structural and functional remodeling. Thickening of the arterial wall, maturation of the sympathetic innervation, and switching of the mechanisms of arterial contraction from calcium-independent to calcium-dependent occur during postnatal development. All these processes promote an almost doubling of blood pressure from the moment of birth to reaching adulthood. This review focuses on the developmental alterations of potassium channels functioning as key smooth muscle membrane potential determinants and, consequently, vascular tone regulators. We present evidence that the pattern of potassium channel contribution to vascular control changes from Kir2, Kv1, Kv7 and TASK-1 channels to BKCa channels with maturation. The differences in the contribution of potassium channels to vasomotor tone at different stages of postnatal life should be considered in treatment strategies of cardiovascular diseases associated with potassium channel malfunction.

Blocking FcγRIIB in Smooth Muscle Cells Reduces Hypertension.

[Figure: see text].

Prenatal High-Sucrose Diet Induced Vascular Dysfunction in Thoracic Artery of Fetal Offspring.

Maternal nutrition during pregnancy is related to intrauterine fetal development. The authors' previous work reports that prenatal high sucrose (HS) diet impaired micro-vascular functions in postnatal offspring. It is unclear whether/how prenatal HS causes vascular injury during fetal life. Pregnant rats are fed with normal drinking water or 20% high-sucrose solution during the whole gestational period. Pregnant HS increases maternal weight before delivery. Fetal thoracic aorta is separated for experiments. Angiotensin II (AII)-stimulated vascular contraction of fetal thoracic arteries in HS group is greater, which mainly results from the enhanced AT1 receptor (AT1R) function and the downstream signaling. Nifedipine significantly increases vascular tension in HS group, indicating that the L-type calcium channels (LTCCs) function is strengthened. 2-Aminoethyl diphenylborinate (2-APB), inositol 1,4,5-trisphosphate receptors (IP3Rs) inhibitor, increases vascular tension induced by AII in HS group and ryanodine receptors-sensitive vascular tone shows no difference in the two groups, which suggested that the activity of IP3Rs-operated calcium channels is increased. These findings suggest that prenatal HS induces vascular dysfunction of thoracic arteries in fetal offspring by enhancing AT1R, LTCCs function and IP3Rs-associated calcium channels, providing new information regarding the impact of prenatal HS on the functional development of fetal vascular systems.

Methylglyoxal augments uridine diphosphate-induced contraction via activation of p38 mitogen-activated protein kinase in rat carotid artery

The methylglyoxal elicits diverse adverse effects on the body. Uridine diphosphate, an extracellular nucleotide, plays an important role as a signaling molecule controlling vascular tone. This study aimed to evaluate the relationship between methylglyoxal and uridine diphosphate-induced carotid arterial contraction in rats. Additionally, we examined whether p38 mitogen-activated protein kinase (MAPK) would involve such responses. Organ baths were conducted to determine vascular reactivity in isolated carotid arterial rings, and western blotting was used for protein analysis. Treatment with methylglyoxal to carotid arterial rings showed concentration-dependent augmentation to uridine diphosphate-induced contraction in the absence and presence of NG-nitro-L-arginine, which is a nitric oxide synthase inhibitor, whereas, methylglyoxal did not affect serotonin- or isotonic high K+-induced contraction in the presence of a nitric oxide synthase inhibitor. Under nitric oxide synthase inhibition, SB203580, which is a selective p38 MAPK inhibitor, suppressed uridine diphosphate-induced contraction in both the control and methylglyoxal-treated groups, and the difference in uridine diphosphate-induced contraction was abolished by SB203580 treatment. The levels of phosphorylated p38 MAPK were increased by methylglyoxal in carotid arteries, not only under the basal condition but also under uridine diphosphate stimulation. The suppression of uridine diphosphate-induced contraction by a highly selective cell-permeable protein kinase C inhibitor bisindolylmaleimide I was observed in the methylglyoxal-treated group but not in the controls. Moreover, methylglyoxal-induced augmentation of uridine diphosphate-induced contraction was prevented by N-acetyl-L-cysteine. These results suggest that methylglyoxal could enhance uridine diphosphate-induced contraction in rat carotid arteries and may be caused by activation of p38 MAPK and protein kinase C and increased oxidative stress.

Pro‐Resolving Lipid Mediators Reduce Acetylcholine‐Induced Contractions in Resistance Arteries from Hypertensive Rats

Aims It is well known that low-grade chronic inflammation induces vascular dysfunction and contributes to hypertension. On the other hand, resolution of inflammation is an active phenomenon to switch off the inflammatory processes once the harmful stimuli is removed and facilitate the return to homeostasis. Increasing the levels of pro-resolving mediators to promote the resolution of inflammation is emerging as a novel therapeutic approach. Arachidonic acid, docosahexaenoic acid, and eicosapentaenoic acid produce pro-resolving lipid mediators lipoxin A4 (LXA4), resolvin D1 (RvD1), and resolvin E1 (RvE1), respectively, through the 5-lipoxygenase enzymatic pathway. However, it is unknown if pro-resolving lipid mediators can ameliorate dysfunction in arteries from hypertensive animals. Therefore, we hypothesized that pro-resolving lipid mediators decrease acetylcholine-induced contractions in arteries from spontaneously hypertensive rats (SHR). Methods Mesenteric resistance arteries (MRA) (lumen diameter ~ 250 µm) from male SHR and Wistar Kyoto (WKY) (14-weeks old, n=3) were collected to assess vascular function via wire myograph. After testing vascular smooth muscle cell integrity, MRA were incubated with either RvD1, RvE1, or LXA4 (10 nM, 1 hour) or vehicle prior to concentration response curves to acetylcholine (1 nM - 3 µM). Phenylephrine (10 µM) was used to contract the arteries prior relaxation curves. Results As expected, low concentrations (≤ 100 nM) of acetylcholine induced relaxation in arteries from both groups, however high concentrations (≥ 1 µM) of acetylcholine induced contraction in arteries from SHR, but not in WKY [Maximum response (Emax): WKY: 94.5 ± 3.3 vs. SHR-control: 44.9 ± 12.5* %, t-test *vs. WKY, p=0.01). Treatment with the pro-resolving lipid mediators did not change acetylcholine-induced relaxation in arteries from WKY (Vehicle: 94.5 ±3.3 vs. RvD1: 95.8 ± 0.8; RvE1: 90.1 ± 7.1; LXA4: 93.5 ± 3.9 %, p>0.05). However, incubation with RvE1 abolished acetylcholine induced-contraction in arteries from SHR and promoted relaxation (Vehicle: 44.9 ± 12.5 vs. RvE1: 94.1 ± 3.5%,* t-test *vs. vehicle, p<0.05). While acetylcholine-induced contraction abolishment from incubation with RvD1 and LXA4 did not reach significance due to small sample size in arteries from SHR, we did observe a tendency towards improvement. Conclusion Overall, these results suggest that pro-resolving lipid mediators biosynthesized from the 5-lipoxygenase enzymatic pathway improved endothelium-dependent relaxation in arteries from hypertensive animals. As docosahexaenoic acid and eicosapentaenoic acid are already recommended to protect against many cardiovascular diseases, our work suggests that RvD1, RvE1, or LXA4 may also be used as a new therapeutic tool to specifically improve vascular function in hypertension.

Control of Arterial Ca V 1.2 Clustering and Coupled Gating by a Single Amino Acid

The L-type Ca2+ channel CaV1.2 plays key roles in cell excitability, muscle contraction and gene expression. These channels have been shown to gate in unison (e.g. coupled gating) in several cell types. CaV1.2 coupling amplifies Ca2+ influx, which can regulate cell function. In arterial myocytes, CaV1.2 coupling is increased upon elevations in extracellular glucose (HG) and in cells from diabetic patients and animal models of diabetes. Yet, the mechanisms for induction of this gating modality in CaV1.2 channels are poorly understood. Here, we tested the hypothesis that phosphorylation of CaV1.2 at S1928 is critical for induction of CaV1.2 clustering, which contributes to CaV1.2 coupling, amplification of Ca2+ influx and arterial myocyte contraction in response to HG and diabetes. Using a multiscale approach, we found that HG induced an increase in CaV1.2-mediated activity, open probability, and coupling frequency and strength in WT arterial myocytes, but not cells from a mouse in which S1928 was mutated to alanine to prevent the phosphorylation of this site (e.g. S1928A). Wild type-like CaV1.2 response to HG was observed in arterial myocytes from a mouse in which S1700 (another key CaV1.2 phosphorylation site) was prevented (e.g. S1700A), thus underscoring the importance S1928 phosphorylation on CaV1.2 function. Super-resolution nanoscopy and proximity ligation assay (PLA) revealed an increase in CaV1.2 clustering at the surface membrane of WT, but not S1928A arterial myocytes after acute HG incubation. Similar HG-induced CaV1.2 biophysical and structural alterations were recapitulated in arterial myocytes from WT diabetic mice (streptozotocin model) and human with diabetes, and these changes were completely absent in cells from diabetic S1928A mice. These results suggest a key role for S1928 phosphorylation in modulating CaV1.2 spatial distribution and gating mode upon HG and diabetes. We propose that our work may lay the foundation for novel therapeutic strategies with single amino acid accuracy to correct channel function and vascular reactivity during pathological conditions.

Anti‐contractile activity of SIRT1 in the perivascular adipose tissue

Background ˗ Perivascular adipose tissue (PVAT) reduces the contraction of blood vessel at least in part by secreting transferable relaxing factors. Nevertheless, the molecular mechanisms underlying PVAT-mediated anti-contractile activity remain uncharacterized. The present study examined the role of SIRT1, a longevity regulator, in modulating the anti-contractile effects of PVAT. Methods and Results ˗ Mesenteric arteries with or without the attached PVAT were isolated from wild type animals (WT), or mice with selective overexpression of human SIRT1 in adipose tissues (Adipo-SIRT1). Wire myography was performed to examine phenylephrine-induced arterial contractions. PVAT derived from Adipo-SIRT1 exhibited dose- and time-dependent anti-contractile activity, which was not affected by feeding the animals with high fat diet. Molecular analyses revealed that overexpression of SIRT1 decreased the expression of Triadin, an important component of the calcium-releasing ryanodine receptor (RyR) channels. Treatment with dantrolene sodium, an inhibitor of RyR, increased the anti-contractile activity of PVAT derived from WT. Mechanistically, SIRT1-triggered mitochondrial hormesis via modulating the calcium flux from endoplasmic reticulum. The increased production of mitochondrial reactive oxygen species (mtROS) was critically involved in SIRT1-mediated anti-contractile activity of PVAT. The beneficial function of SIRT1 in PVAT was abolished in transgenic mice with selective overexpression of Triadin in adipose tissues (Adipo-TRDN). Conclusions ˗Increased SIRT1 expression in PVAT promotes vascular anti-contraction at least partly through down regulation of Triadin-mediated calcium signaling.

Picotamide inhibits a wide spectrum of agonist‐induced smooth muscle contractions in porcine renal interlobar and coronary arteries

Picotamide is a thromboxane A2 (TXA2) receptor antagonist and TXA2 synthase inhibitor. In clinical studies, it has been considered as a platelet aggregation inhibitor and improved renal function. In vitro studies suggested inhibition of smooth muscle contraction by picotamide, which is poorly understood. Here, we examined effects of picotamide on contractions of renal interlobar and coronary porcine arteries, induced by different vasoconstrictors. Contractions were induced in an organ bath by agonists or electric field stimulation (EFS). Picotamide inhibited EFS‐induced contractions of interlobar arteries around 50% using concentrations of 100 and 300 µM. In interlobar arteries, concentration response curves for contractions induced by three different α1‐adrenoceptor agonists were shifted to the right by picotamide (2–10‐fold increases in EC50). In coronary arteries, α1‐adrenergic contractions were inhibited without right shift (approx. 50%). Contractions induced by two different cholinergic agonists in coronary arteries were inhibited by picotamide (≥50%) withouth right shift. Inhibition of serotonin‐induced contractions by picotamide showed features of a right shift, whereas contractions induced by the TXA2 analog U46619, angiotensin‐II, and endothelin‐1 were inhibited by picotamide in interlobar and coronary arteries without right shifts and to different degree. Picotamide inhibits a wide spectrum of vasoconstrictor‐induced contractions in porcine interlobar and coronary arteries. Inhibition of vasocontraction may contribute to beneficial effects of picotamide in the cardiovascular system and kidney.

Signalling pathway of U46619-induced vascular smooth muscle contraction in mouse coronary artery.

Thromboxane A2 (TXA2 ) participates in many pathophysiological processes of coronary artery disease. However, its mechanism of TXA2 -induced contraction in the coronary artery remains to be clarified. A multi myograph system was used to measure the isometric tension of the mouse coronary arteries and identify the effect and pathway of TXA2 analogues U46619. Confocal laser scanning microscopy was used to measure the intracellular calcium concentration ([Ca2+ ]i ) in mouse coronary artery smooth muscle cells. Results from the experiment had shown that contraction in coronary artery was generated by U46619 in a concentration-dependent manner, which was completely abolished by a specific TXA2 receptor blocker, GR32191. PI-PLC inhibitors U73122 and D609 and Rho-Kinase inhibitor Y-27632 can block the U46619 elicited coronary artery contraction in a dose-dependent manner. Then, the vasoconstriction response to U46619 was obviously inhibited by two pan-PKC inhibitors chelerythrine or Gӧ6983, and a selective PKCδ inhibitor rottlerin, but was not blocked by a selective PKCζ inhibitor PKC-PS or a selective PKCβ inhibitor hispidin. Meanwhile, the PKC activator PDBu-induced vasoconstriction was significantly inhibited by 1μmol/L nifedipine, then mostly inhibited by 100μmol/L 2-APB and 10μmol/L Y27632. We further found that the response to U46619 was inhibited, respectively, by three calcium channel blockers nifedipine, SKF96356 or 2-APB in a concentration-dependent manner. Although Store-operated Ca2+ (SOC) channels generated the increase of [Ca2+ ]i in mouse coronary artery smooth muscle cells, SOC channels did not contribute to the vasoconstriction in mouse coronary arteries. Caffeine-induced sarcoplasmic reticulum (SR) Ca2+ release could obviously induce coronal vasoconstriction. In addition, NPPB, a cell membrane Ca2+ activated C1- channel blocker, could obviously inhibit the U46619-induced vasoconstriction. The U46619-induced mouse coronary artery contraction was involved in the increase in [Ca2+ ]i mediated by Cav1.2, TRPC channels and SR release through the activation of G-protein-coupled TP receptors and the kinases signalling pathway in TP downstream proteins, while SOC channels did not participate in the vasoconstriction.

A Pilot Evaluation Study of Diffuse Coronary Arterial Contraction Causing Ischemia by Double Measurement of Left Ventriculography Before and After Intracoronary Administration of Nitrates.

Background: Abnormal diffuse coronary artery contraction is not easily diagnosed. In order to evaluate its true risk, we performed double left ventriculography (LVG) before and after intracoronary administration of isosorbide dinitrate (ISDN). We also investigated the relationship between changes in coronary lumen area and changes in left ventricular ejection fraction (LVEF) after ISDN.Methods and Results: The study included 53 patients who underwent an acetylcholine (ACh) provocation test after coronary angiogram and LVG. The second LVG was performed after intracoronary ISDN administration. Coronary lumen area was measured by quantitative coronary arteriography (QCA). Simple and multiple regression analyses showed a significant correlation between changes in total QCA area before and after ISDN administration (pre-and post-total QCA area, respectively) and changes in LVEF. Using structural equation modeling, we observed a negative effect of pre-total QCA area and a positive effect of post-total QCA area on LVEF improvement. Importantly, LVEF improvement was similar between the ACh-positive and -negative groups on the coronary artery spasm test. Receiver operating characteristic curves indicated that the cut-off value at which changes in total QCA area affected changes in LVEF was 5%.Conclusions: Performing double LVG tests before and after ISDN administration may detect myocardial ischemia caused by diffuse coronary artery contraction. The addition of this method to the conventional ACh provocation test may detect the presence of local and/or global myocardial ischemia.

Carbonic anhydrase inhibition improves pulmonary artery reactivity and nitric oxide-mediated relaxation in sugen-hypoxia model of pulmonary hypertension.

Pulmonary hypertension (PH) is a serious disease with pulmonary arterial fibrotic remodeling and limited responsiveness to vasodilators. Our data suggest that mild acidosis induced by carbonic anhydrase inhibition could ameliorate PH, but the vascular mechanisms are unclear. We tested the hypothesis that carbonic anhydrase inhibition ameliorates PH by improving pulmonary vascular reactivity and relaxation mechanisms. Male Sprague-Dawley rats were either control normoxic (Nx), or injected with Sugen 5416 (20 mg/kg, sc) and subjected to hypoxia (9% O2) (Su+Hx), or Su+Hx treated with acetazolamide (ACTZ, 100 mg/kg/day, in drinking water). After measuring the hemodynamics, right ventricular hypertrophy was assessed by Fulton's Index; vascular function was measured in pulmonary artery, aorta, and mesenteric arteries; and pulmonary arteriolar remodeling was assessed in lung sections. Right ventricular systolic pressure and Fulton's Index were increased in Su+Hx and reduced in Su+Hx + ACTZ rats. Pulmonary artery contraction to KCl and phenylephrine were reduced in Su+Hx and improved in Su+Hx + ACTZ. Acetylcholine (ACh)-induced relaxation and nitrate/nitrite production were reduced in pulmonary artery of Su+Hx and improved in Su+Hx + ACTZ. ACh relaxation was blocked by nitric oxide (NO) synthase and guanylate cyclase inhibitors, supporting a role of NO-cGMP. Sodium nitroprusside (SNP)-induced relaxation was reduced in pulmonary artery of Su+Hx, and ACTZ enhanced relaxation to SNP. Contraction/relaxation were not different in aorta or mesenteric arteries of all groups. Pulmonary arterioles showed wall thickening in Su+Hx that was ameliorated in Su+Hx + ACTZ. Thus, amelioration of pulmonary hemodynamics during carbonic anhydrase inhibition involves improved pulmonary artery reactivity and NO-mediated relaxation and may enhance responsiveness to vasodilator therapies in PH.