scholarly journals Secondhand smoke exposure impairs ion channel function and contractility of mesenteric arteries

Function ◽  
2021 ◽  
Author(s):  
Thanhmai Le ◽  
Miguel Martín-Aragón Baudel ◽  
Arsalan Syed ◽  
Navid Singhrao ◽  
Shiyue Pan ◽  
...  

Abstract 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 hours/day, 5 days/week) 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 weeks but not for 4 or 8 weeks. These results were correlated with an increase in L-type Ca2+ channel activity in mesenteric arterial myocytes after 12 weeks of SHS exposure. Moreover, 12 weeks 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.

2015 ◽  
Vol 308 (12) ◽  
pp. H1517-H1524 ◽  
Author(s):  
Joseph R. H. Mauban ◽  
Joseph Zacharia ◽  
Seth Fairfax ◽  
Withrow Gil Wier

Myogenic tone is an intrinsic property of the vasculature that contributes to blood pressure control and tissue perfusion. Earlier investigations assigned a key role in myogenic tone to phospholipase C (PLC) and its products, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). Here, we used the PLC inhibitor, U-73122, and two other, specific inhibitors of PLC subtypes (PI-PLC and PC-PLC) to delineate the role of PLC in myogenic tone of pressurized murine mesenteric arteries. U-73122 inhibited depolarization-induced contractions (high external K+ concentration), thus confirming reports of nonspecific actions of U-73122 and its limited utility for studies of myogenic tone. Edelfosine, a specific inhibitor of PI-PLC, did not affect depolarization-induced contractions but modulated myogenic tone. Because PI-PLC produces IP3, we investigated the effect of blocking IP3 receptor-mediated Ca2+ release on myogenic tone. Incubation of arteries with xestospongin C did not affect tone, consistent with the virtual absence of Ca2+ waves in arteries with myogenic tone. D-609, an inhibitor of PC-PLC and sphingomyelin synthase, strongly inhibited myogenic tone and had no effect on depolarization-induced contraction. D-609 appeared to act by lowering cytoplasmic Ca2+ concentration to levels below those that activate contraction. Importantly, incubation of pressurized arteries with a membrane-permeable analog of DAG induced vasoconstriction. The results therefore mandate a reexamination of the signaling pathways activated by the Bayliss mechanism. Our results suggest that PI-PLC and IP3 are not required in maintaining myogenic tone, but DAG, produced by PC-PLC and/or SM synthase, is likely through multiple mechanisms to increase Ca2+ entry and promote vasoconstriction.


2010 ◽  
Vol 298 (3) ◽  
pp. F625-F633 ◽  
Author(s):  
Peter Ochodnický ◽  
Robert H. Henning ◽  
Hendrik J. Buikema ◽  
Dick de Zeeuw ◽  
Abraham P. Provoost ◽  
...  

It is unknown whether generalized vascular dysfunction precedes the development of kidney disease. Therefore, we studied myogenic constriction and endothelium-mediated dilatory responses in two inbred Fawn-Hooded (FH) rat strains, one of which spontaneously develops hypertension, proteinuria, and glomerulosclerosis (FHH), whereas the other (FHL) does not. Small renal, mesenteric resistance arteries and thoracic aorta isolated from FH rats before (7 wk old) and after the development of mild proteinuria (12 wks old) were mounted in perfused and isometric set-ups, respectively. Myogenic response, endothelium-dependent relaxation, and the contribution of endothelium-mediated dilatory compounds were studied using their respective inhibitors. Myogenic reactivity was assessed constructing pressure-diameter curves in the presence and absence of calcium. At the age of 7 wk, renal arteries isolated from kidneys of FHH rats developed significantly lower myogenic tone compared with FHL, most likely because of excessive cyclo-oxygenase 1-mediated production of constrictive prostaglandins. Consequently, young FHH demonstrated reduced maximal myogenic tone (22 ± 4.8 vs. 10.8 ± 2.0%, P = 0.03) and the peak myogenic index (−6.9 ± 4.8 vs. 0.6 ± 0.8%/mmHg, P = 0.07 for FHL vs. FHH, respectively). Active myogenic curves obtained in mesenteric arteries isolated from 7-wk-old rats did not differ between either strain, demonstrating a similar level of systemic myogenic tone in FHL and FHH rats. Therefore, before any renal end-organ damage is present, myogenic response seems selectively impaired in renal vasculature of FHH rats. Aortic reactivity did not differ between FHL and FHH at the time points studied. The present study shows that vascular dysfunction in both small renal and systemic arteries precedes renal end-organ damage in a spontaneous model of hypertension-associated renal damage. These early vascular changes might be potentially involved in the increased susceptibility of FHH rats to renal injury.


Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Cody R Kilar ◽  
YanPeng Diao ◽  
Larysa Sautina ◽  
Sivakumar Sekharan ◽  
Shahar Keinan ◽  
...  

Erythropoietin (EPO) increases systemic vascular resistance and blood pressure. However, endothelial cells cultured in the presence of EPO demonstrate increased production of the potent vasodilator, nitric oxide (NO). The mechanism by which EPO causes vasoconstriction despite stimulating NO production may be dependent on its ability to differentially activate the two receptor complexes, the homodimeric EPO (EPOR 2 ) and the heterodimeric EPOR/β-common receptor (βCR). Objective: The purpose of this study was to investigate the contribution of the EPOR 2 and βCR receptor to the vasoactive properties of EPO. Methods: First order, mesenteric arteries isolated from 16-week old male C57BL/6 mice were cannulated and perfused using a pressure arteriography system. To determine the contribution of each receptor complex, arteries were incubated with EPO stimulating peptide (ESP) which binds and activates only the heterodimeric EPOR/βCR complex or EPO which activates both receptors, 20 min prior to evaluation of vasoconstrictor (phenylephrine and potassium chloride), endothelium-dependent (acetylcholine, bradykinin, A23187) and -independent (sodium nitroprusside) vasodilator responses. Additionally, we studied the effect of a novel βCR inhibitory peptide (βIP) which was developed in silico and validated by demonstrating that it selectively inhibits binding of ligands to the βCR. Results: Acetylcholine induced vasodilation was impaired in arteries pretreated with EPO or ESP by 100% and 60%, respectively. EPO and ESP did not affect endothelium-dependent vasodilation by Bradykinin or A23187, endothelium-independent vasodilation by sodium nitroprusside, or vasoconstriction by phenylephrine and KCl. The βIP prevented the impairment of acetylcholine-induced vasodilation by EPO and ESP. Conclusion: Together, our findings suggest that activation of the heterodimeric EPOR/βCR leads to selective impairment of ACh-mediated vasodilator response in mouse mesenteric resistance arteries. Thus the βCR might have a role in mediating hypertensive effects of EPO. Therapeutic inhibition of the βCR might prevent vascular complications of EPO without affecting erythropoiesis.


Hypertension ◽  
2020 ◽  
Vol 76 (3) ◽  
pp. 785-794
Author(s):  
Josh F. Smith ◽  
Hamish A.L. Lemmey ◽  
Lyudmyla Borysova ◽  
C. Robin Hiley ◽  
Kim A. Dora ◽  
...  

Endothelial dysfunction in small arteries is a ubiquitous, early feature of cardiovascular disease, including hypertension. Dysfunction reflects reduced bioavailability of endothelium-derived nitric oxide (NO) and depressed endothelium-dependent hyperpolarization that enhances vasoreactivity. We measured smooth muscle membrane potential and tension, smooth muscle calcium, and used real-time quantitative polymerase chain reaction in small arteries and isolated tubes of endothelium to investigate how dysfunction enhances vasoreactivity. Rat nonmyogenic mesenteric resistance arteries developed vasomotion to micromolar phenylephrine (α 1 -adrenoceptor agonist); symmetrical vasoconstrictor oscillations mediated by L-type voltage-gated Ca 2+ channels (VGCCs). Inhibiting NO synthesis abolished vasomotion so nanomolar phenylephrine now stimulated rapid, transient depolarizing spikes in the smooth muscle associated with chaotic vasomotion/vasospasm. Endothelium-dependent hyperpolarization block also enabled phenylephrine-vasospasm but without spikes or chaotic vasomotion. Depolarizing spikes were Ca 2+ -based and abolished by either T-type or L-type VGCCs blockers with depressed vasoconstriction. Removing NO also enabled transient spikes/vasoconstriction to Bay K-8644 (L-type VGCC activator). However, these were abolished by the L-type VGCC blocker nifedipine but not T-type VGCC block. Phenylephrine also initiated T-type VGCC-transient spikes and enhanced vasoconstriction after NO loss in nonmyogenic arteries from spontaneously hypertensive rats. In contrast to mesenteric arteries, myogenic coronary arteries displayed transient spikes and further vasoconstriction spontaneously on loss of NO. T-type VGCC block abolished these spikes and additional vasoconstriction but not myogenic tone. Therefore, in myogenic and nonmyogenic small arteries, reduced NO bioavailability engages T-type VGCCs, triggering transient depolarizing spikes in normally quiescent vascular smooth muscle to cause vasospasm. T-type block may offer a means to suppress vasospasm without inhibiting myogenic tone mediated by L-type VGCCs.


2011 ◽  
Vol 89 (6) ◽  
pp. 435-443 ◽  
Author(s):  
Tlili Barhoumi ◽  
Isabelle Jallat ◽  
Alain Berthelot ◽  
Pascal Laurant

Chronic use of human recombinant erythropoietin (r-HuEPO) is accompanied by serious vascular side effects related to the rise in blood viscosity and shear stress. We investigated the direct effects of r-HuEPO on endothelium and nitric oxide (NO)-dependent vasodilatation induced by shear stress of cannulated and pressurized rat mesenteric resistance arteries. Intravascular flow was increased in the presence or absence of the NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME; 10−4 mol/L). In the presence of r-HuEPO, the flow-dependent vasodilatation was attenuated, while L-NAME completely inhibited it. The association of r-HuEPO and L-NAME caused a vasoconstriction in response to the rise in intravascular flow. Bosentan (10−5 mol/L), an inhibitor of endothelin-1 (ET-1) receptors, corrected the attenuated vasodilatation observed with r-HuEPO and inhibited the vasoconstriction induced by flow in the presence of r-HuEPO and L-NAME. r-HuEPO and L-NAME exacerbated ET-1 vasoconstriction. At shear stress values of 2 and 14 dyn/cm2 (1 dyn = 10–5 N), cultured EA.hy926 endothelial cells incubated with r-HuEPO, L-NAME, or both released greater ET-1 than untreated cells. In conclusion, r-HuEPO diminishes flow-induced vasodilatation. This inhibitory effect seems to implicate ET-1 release. NO withdrawal exacerbates the vascular effects of ET-1 in the presence of r-HuEPO. These findings support the importance of a balanced endothelial ET-1:NO ratio to avoid the vasopressor effects of r-HuEPO.


1995 ◽  
Vol 88 (5) ◽  
pp. 519-524 ◽  
Author(s):  
P. D. Taylor ◽  
J. E. Graves ◽  
L. Poston

1. There is growing evidence that an impairment in the function of nitric oxide synthase may play a role in the vascular complications of diabetes mellitus. The relaxation of resistance arteries from the mesenteric and hindlimb circulations of streptozotocin-induced diabetic rats and age-matched controls were investigated using two endothelium-dependent vasodilators, bradykinin and acetylcholine, and the endothelium-independent vasodilator sodium nitroprusside. The contractile responses to the α1-adrenergic agonist phenylephrine were also studied. 2. Endothelium-dependent relaxation to acetylcholine was impaired in the diabetic rats in arteries from both mesenteric and hindlimb circulations (hindlimb pEC50, 7.93 ± 0.08 in the control compared with 7.38 ± 0.10 in the diabetic rat; mesenteric pEC50, 7.47 ± 0.04 in the control compared with 6.65 ± 0.06 in the diabetic rat; unpaired t-test P < 0.0001). Bradykinin elicited relaxation in only the mesenteric arteries, and this was not attenuated in the diabetic rats compared with controls. 3. Endothelium-independent relaxation to sodium nitroprusside was similar in the two circulations and was not abnormal in the diabetic rats. There was no significant difference in constrictor responses to phenylephrine between diabetic rats and controls in either the hindlimb or mesenteric arteries, in contrast to an earlier study in which we showed increased sensitivity to noradrenaline. 4. The diabetic rats therefore demonstrated a specific impairment of receptor-mediated endothelium-dependent relaxation to acetylcholine. These results suggest that, in this diabetic model, the ability of the endothelium to relax arteries via nitric oxide may involve a defect of a specific signal transduction pathway, leading to reduced production of nitric oxide.


2010 ◽  
Vol 299 (6) ◽  
pp. H2097-H2106 ◽  
Author(s):  
Youhua Wang ◽  
Shengpeng Wang ◽  
W. Gil Wier ◽  
Quanjiang Zhang ◽  
Hongke Jiang ◽  
...  

Myocardial infarction (MI) has been shown to induce endothelial dysfunction in peripheral resistance arteries and thus increase peripheral resistance. This study was designed to investigate the underlying mechanisms of post-MI-related dysfunctional dilatation of peripheral resistance arteries and, furthermore, to examine whether exercise may restore dysfunctional dilatation of peripheral resistance arteries. Adult male Sprague-Dawley rats were divided into three groups: sham-operated, MI, and MI + exercise. Ultrastructure and relaxation function of the mesenteric arteries, as well as phosphatidylinositol-3 kinase (PI3K), Akt kinases (Akt), endothelial nitric oxide synthase (eNOS) activity, and phosphorylation of PI3K, Akt, and eNOS by ACh were determined. Post-MI rats exhibited pronounced ultrastructural changes in mesenteric artery endothelial cells and endothelial dysfunction. In addition, the activities of PI3K, Akt, and eNOS, and their phosphorylation by ACh were significantly attenuated in mesenteric arteries ( P < 0.05–0.01). After 8 wk of exercise, not only did endothelial cells appeared more normal in structure, but also ameliorated post-MI-associated mesenteric arterial dysfunction, which were accompanied by elevated activities of PI3K, Akt, and eNOS, and their phosphorylation by ACh ( P < 0.05–0.01). Importantly, inhibition of either PI3K or eNOS attenuated exercise-induced restoration of the dilatation function and blocked PI3K, Akt, and eNOS phosphorylation by ACh in the mesenteric arteries. These data demonstrate that MI induces dysfunctional dilation of peripheral resistance arteries by degradation of endothelial structural integrity and attenuating PI3K-Akt-eNOS signaling. Exercise may restore dilatation function of peripheral resistance arteries by protecting endothelial structural integrity and increasing PI3K-Akt-eNOS signaling cascades.


The prevalence of heart failure is markedly increased in individuals with diabetes mellitus. Numerous observational studies suggest that this increased risk for heart failure can be attributed to exacerbated vascular complications and the presence of increased risk factors in diabetic subjects. In addition, experimental studies revealed the presence of a number of distinct molecular alterations in the myocardium that occur independently of vascular disease and hypertension. Many of these molecular alterations are similarly observed in failing hearts of nondiabetic patients and have thus been proposed to contribute to the increased risk for heart failure in diabetes. The interest in understanding the underlying mechanisms of impaired cardio- vascular outcomes in diabetic individuals has much increased since the demonstration of cardioprotective effects of SGLT-2 inhibitors and GLP-1 receptor agonists in recent clinical trials. The current review therefore summarizes the distinct mechanisms that have been proposed to increase the risk for heart failure in diabetes mellitus.


BMJ Open ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. e048590
Author(s):  
Kewei Wang ◽  
Yuanqi Wang ◽  
Ruxing Zhao ◽  
Lei Gong ◽  
Lingshu Wang ◽  
...  

ObjectiveThe objective of this study was to evaluate the influence of secondhand smoke (SHS) exposure during childhood on type 2 diabetes mellitus, hypertension, hyperlipidaemia and coronary heart disease among Chinese non-smoking women.MethodsIn this cross-sectional study, the SHS exposure data in childhood were obtained using a questionnaire survey. Self-reported childhood SHS exposure was defined as the presence of at least one parent who smoked during childhood.ResultsOf the 6522 eligible participants, 2120 Chinese women who had never smoked were assessed. The prevalence of SHS exposure in the entire population was 28.1% (596). SHS exposure during childhood was not significant for the standard risk factors of type 2 diabetes mellitus (p=0.628) and hypertension (p=0.691). However, SHS was positively associated with hyperlipidaemia (p=0.037) after adjusting for age, obesity, education status, physical activity, alcohol consumption, current SHS exposure status, diabetes mellitus and hypertension. In addition, childhood SHS increased the occurrence of coronary heart disease (p=0.045) among non-smokers after further adjusting for hyperlipidaemia.ConclusionSHS exposure during childhood is associated with prevalent hyperlipidaemia and coronary heart disease in adulthood among non-smoking Chinese women.


PEDIATRICS ◽  
1994 ◽  
Vol 94 (2) ◽  
pp. 255-255
Author(s):  
Martin I. Sachs

Since 1986 an increasing awareness of the harmful effects of secondhand smoke has caused parents to smoke fewer cigarettes in the presence of their asthmatic children. This has been associated with a marked reduction in asthma severity of the smokers' children.


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