CONTRACTILE FUNCTION AND MYOPLASMIC FREE Ca2+ (Cam) IN CORONARY AND MESENTERIC ARTERIES OF ENDOTOXEMIC GUINEA PIGS

Jj, Jones; Ja, Rapps; Sturek, Michael; Ml, Mattox; Hr, Adams; Jl, Parker

doi:10.1097/00024382-199901000-00010

Cited by 8 publications

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“…Since removal of external Ca 2ϩ abolishes this difference in basal [Ca 2ϩ ] i levels, it is unlikely to result from an impairment of [Ca 2ϩ ] i storage (7,15), but probably from enhanced Ca 2ϩ influx through VOCCs (40) or other Ca 2ϩ channels. The ET-1-induced biphasic increase in Ca 2ϩ levels, comprising transient and sustained components, has been previously shown (18,42 , as previously demonstrated (20,42). Since LPS treatment had no effect on the transient phase increase in [Ca 2ϩ ] i , it is unlikely that Ca 2ϩ mobilization from intracellular stores was affected under our experimental conditions.…”

Section: Discussionsupporting

confidence: 77%

“…For example, mesenteric hyporeactivity to the ␣-adrenergic agonist methoxamine in rat (7) or hyperreactivity to ET-1 in pig (18) were not associated with changes in [Ca 2ϩ ] i , while aortic vascular hyporeactivity to KCl was associated with enhanced Ca 2ϩ uptake (39) or with no change in [Ca 2ϩ ] i release (1). In the present study, we investigated the mechanisms of LPS-induced hyporesponsiveness to ET-1 in rat aorta using an organ culture method by measuring changes in isometric force generation, expression levels of mRNA of ET-1, ET A , and ET B ; expression levels of PKC; phosphorylation of ROK␣, CPI-17, and MYPT1; and changes in [Ca 2ϩ ] i .…”

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confidence: 99%

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Voltage-independent calcium channels mediate lipopolysaccharide-induced hyporeactivity to endothelin-1 in the rat aorta

El‐Awady¹,

Smirnov²,

Watson³

2009

American Journal of Physiology-Heart and Circulatory Physiology

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El-Awady MS, Smirnov SV, Watson ML. Voltage-independent calcium channels mediate lipopolysaccharide-induced hyporeactivity to endothelin-1 in the rat aorta. Am J Physiol Heart Circ Physiol 296: H1408 -H1415, 2009. First published March 13, 2009 doi:10.1152/ajpheart.01305.2008.-The roles of intracellular calcium concentration ([Ca 2ϩ ]i) and Ca 2ϩ sensitization in lipopolysaccharide (LPS)-induced vascular smooth muscle (VSM) hyporesponsiveness are incompletely understood. To investigate these roles, contraction responses to endothelin-1 (ET-1) and 80 mM KCl; relaxation responses to nifedipine; the expression levels of mRNAs of ET-1 and its receptors (ET A or ETB); the expression levels of protein kinase C (PKC) and phosphorylation of Rho kinase (ROK␣), CPI-17, and myosin phosphatase target subunit-1 (MYPT1); and changes in aortic VSM cell [Ca 2ϩ ]i were measured in LPS-treated aortic rings from male Wistar rats (250 -300 g). LPS (10 g/ml, 20 h) decreased contraction induced by ET-1 (0.3-100 nM) or 80 mM KCl. LPSinduced hypocontractility was not observed in the absence of external Ca 2ϩ , but LPS-treated aorta remained hypocontractile on subsequent stepwise restoration of extracellular Ca 2ϩ (0.01-10 mM). Vascular relaxation to nifedipine; mRNA expression levels of ET-1, ET A, or ET B; protein expression levels of PKC; and phosphorylation levels of ROK␣, CPI-17, and MYPT1 were not affected by LPS. In isolated aortic VSM cells, ET-1 caused a transient initial increase in [Ca 2ϩ ]i, followed by a maintained tonic increase in [Ca 2ϩ ]i, which was decreased by LPS pretreatment and was dependent on external Ca 2ϩ . Subsequent restoration of extracellular Ca 2ϩ increased [Ca 2ϩ ]i, but this increase was lower in the LPS-treated group. This difference in response to extracellular Ca 2ϩ addition was not affected by diltiazem, but was abolished by SKF-96365. Therefore, LPS induces hyporeactivity to ET-1 in rat aorta that depends on external Ca 2ϩ influx through non-voltage-operated Ca 2ϩ channels, but not on ET-1 receptor expression or Ca 2ϩ sensitization. calcium sensitization; sepsis; vascular smooth muscle SEPTIC SHOCK IS A COMPLEX pathological state characterized by systemic vasodilation and hyporesponsiveness to vasoconstrictor agents (12,32,38,39). Numerous experimental studies of sepsis have clearly documented the presence of both in vivo and in vitro vascular hyporesponsiveness to different vasoconstrictors, including ␣-adrenergic agonists (7, 12), angiotensin II (38), KCl (38, 39), endothelin-1 (ET-1) (4, 17), and thromboxane A 2 (2). Vascular hyporesponsiveness could be mediated either by an increase in vasodilating or a decrease in vasoconstricting mechanisms. Excessive production of vasodilator molecules, such as nitric oxide or prostacyclin, has been shown to contribute to the hypotension and vasoplegia in septic shock (23,24,36); however, inhibition of their production yields conflicting results. We previously showed that lipopolysaccharide (LPS) causes a selective hypocontractility of rat aorta to E...

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Section: Discussionsupporting

confidence: 77%

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confidence: 99%

Voltage-independent calcium channels mediate lipopolysaccharide-induced hyporeactivity to endothelin-1 in the rat aorta

El‐Awady¹,

Smirnov²,

Watson³

2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…The transient increases in MAP might be due to elevated peripheral resistance which would further reduce perfusion of ischemia-sensitive organs via non-adrenergic vascular tone, possibly via enhanced Ca 2+ channel activity since blocking L-type Ca 2+ channels improves survival in septic shock. 27–30 Dysregulated L-type Ca 2+ channel function would be more predominant in BK β1-KO mice because of the absence of feedback regulation by BK channels. 18 This suggestion is consistent with data from LPS-treated BK β1-KO mice which displayed more severe lung and intestinal damage, and higher mortality with a more rapid onset than WT mice.…”

Section: Discussionmentioning

confidence: 99%

Vascular BK Channel Deficiency Exacerbates Organ Damage and Mortality in Endotoxemic Mice

Wang

Garver

et al. 2012

Journal of Cardiovascular Pharmacology

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We determined the contribution of vascular BK channels to endotoxin (lipopolysaccharide, LPS)-induced hypotension, organ damage, and mortality using smooth muscle BK channel deficiency (BK channel β1-subunit knockout, BK β1-KO) mice. BK β1-KO mice were more sensitive to LPS-induced mortality compared to wild-type mice. After LPS (20 mg/kg, intraperitoneally), BK β1-KO mice had a more rapid fall in heart rate and blood pressure (measured by radiotelemetry), shorter latency to mortality, and higher mortality rate than wild-type mice. Twenty-two hours after LPS treatment, wild-type and BK β1-KO mice had reduced norepinephrine reactivity and impaired constrictor responses to the BK channel blocker paxilline in mesenteric arteries in vitro; and higher iNOS expression in the heart, but not in mesenteric arteries. Endotoxemic BK β1-KO mice also showed more severe lung and intestinal injury, higher myeloperoxidase activity and polymorphonuclear neutrophil infiltration in lung and liver. Endotoxemic BK β1-KO mice had higher plasma tumor necrosis α and interleukin 6 levels at 22 hours, but not 6 hours post-LPS. Exaggerated mortality in BK β1-KO mice also occurred in the cecal ligation/puncture model of septic shock. Reduced vascular BK channel function does not protect against hypotension in the early stage of septic shock; in the later stage, smooth muscle BK channel deficiency enhances organ damage and mortality.

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“…Ca 2ϩ channel blockers improved blood pressure, organ perfusion, and survival in endotoxemic animals (15,17,22,35,40), suggesting that enhanced vascular Ca 2ϩ channel activity might partly contribute to higher peripheral vascular resistance and lower perfusion of ischemia-sensitive organs during the late stage of septic shock (19,36). Since vascular BK channel deficiency increases arterial L-type Ca 2ϩ channel activity and vascular tone (2,31,42), we hypothesized that BK channel deficiency would promote high vascular smooth muscle cell Ca 2ϩ channel activity.…”

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Altered L-type Ca²⁺channel activity contributes to exacerbated hypoperfusion and mortality in smooth muscle cell BK channel-deficient septic mice

Xu¹,

Garver²,

Fernandes³

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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We determined the contribution of vascular large conductance Ca2+-activated K+ (BK) and L-type Ca2+ channel dysregulation to exaggerated mortality in cecal ligation/puncture (CLP)-induced septic BK channel β1-subunit knockout (BK β1-KO, smooth muscle specific) mice. CLP-induced hemodynamic changes and mortality were assessed over 7 days in wild-type (WT) and BK β1-KO mice that were either untreated, given volume resuscitation (saline), or saline + calcium channel blocker nicardipine. Some mice were euthanized 24 h post-CLP to measure tissue injury and vascular and immune responses. CLP-induced hypotension was similar in untreated WT and BK β1-KO mice, but BK β1-KO mice died sooner. At 24 h post-CLP (mortality latency in BK β1-KO mice), untreated CLP-BK β1-KO mice showed more severe hypothermia, lower tissue perfusion, polymorphonuclear neutrophil infiltration-independent severe intestinal necrosis, and higher serum cytokine levels than CLP-WT mice. Saline resuscitation improved survival in CLP-WT but not CLP-BK β1-KO mice. Saline + nicardipine-treated CLP-BK β1-KO mice exhibited longer survival times, higher tissue perfusion, less intestinal injury, and lower cytokines versus untreated CLP-BK β1-KO mice. These improvements were absent in treated CLP-WT mice, although saline + nicardipine improved blood pressure similarly in both septic mice. At 24 h post-CLP, BK and L-type Ca2+ channel functions in vitro were maintained in mesenteric arteries from WT mice. Mesenteric arteries from BK β1-KO mice had blunted BK/enhanced L-type Ca2+ channel function. We conclude that vascular BK channel deficiency exaggerates mortality in septic BK β1-KO mice by activating L-type Ca2+ channels leading to blood pressure-independent tissue ischemia.

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CONTRACTILE FUNCTION AND MYOPLASMIC FREE Ca2+ (Cam) IN CORONARY AND MESENTERIC ARTERIES OF ENDOTOXEMIC GUINEA PIGS

Cited by 8 publications

References 0 publications

Voltage-independent calcium channels mediate lipopolysaccharide-induced hyporeactivity to endothelin-1 in the rat aorta

Voltage-independent calcium channels mediate lipopolysaccharide-induced hyporeactivity to endothelin-1 in the rat aorta

Vascular BK Channel Deficiency Exacerbates Organ Damage and Mortality in Endotoxemic Mice

Altered L-type Ca²⁺channel activity contributes to exacerbated hypoperfusion and mortality in smooth muscle cell BK channel-deficient septic mice

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CONTRACTILE FUNCTION AND MYOPLASMIC FREE Ca2+ (Cam) IN CORONARY AND MESENTERIC ARTERIES OF ENDOTOXEMIC GUINEA PIGS

Cited by 8 publications

References 0 publications

Voltage-independent calcium channels mediate lipopolysaccharide-induced hyporeactivity to endothelin-1 in the rat aorta

Voltage-independent calcium channels mediate lipopolysaccharide-induced hyporeactivity to endothelin-1 in the rat aorta

Vascular BK Channel Deficiency Exacerbates Organ Damage and Mortality in Endotoxemic Mice

Altered L-type Ca2+channel activity contributes to exacerbated hypoperfusion and mortality in smooth muscle cell BK channel-deficient septic mice

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Altered L-type Ca²⁺channel activity contributes to exacerbated hypoperfusion and mortality in smooth muscle cell BK channel-deficient septic mice