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onsdag 7 juni 2017

candesartan, hm


Volume-sensitive chloride current in human cardiac fibroblasts

The current with outward rectification shown in Fig. 1D was insensitive to inhibition of K+ channel blockers including 5 mM tetraethylammonium (TEA), 5 mM 4-AP, or 0.5 mM Ba2+ (n = 4−6), suggesting that the outwardly-rectifying current is not carried by K+ ion. We then employed the Cl channel inhibitor DIDS to determine whether the current is carried by chloride ions. Figure 5A shows the current traces recorded in a representative cell with the protocol shown in the inset; DIDS (150 µM) suppressed the current. The I-V relationship (Fig. 5B) of the DIDS-sensitive current obtained by subtracting control currents by the current recorded after DIDS application displayed outward rectification and had a reversal potential at −35 mV, which is close to Cl equilibrium potential (ECl, −46.8 mV). Similar results were obtained in a total of 6 cells. This result suggests that the recorded current under isotonic conditions is carried by Cl ions.
To investigate whether the Cl channel is volume sensitive in human cardiac fibroblasts, we employed a 0.7T tonic solution and recorded membrane current using a K+-free pipette solution, symmetrical Cl ion in pipette and bath medium as described in the Methods section. The membrane conductance was remarkably enhanced by exposure to 0.7T (20 min), and the increased current was highly suppressed by the Cl channel blocker NPPB (Fig. 5C). The I-V relationship of 0.7T-induced Cl current is linear under symmetrical Cl conditions Fig. 5D), similar to the previous report [21]. These results indicate that volume-sensitive Cl channel (ICl.vol) is present in human cardiac fibroblasts

Angiotensin II, EGF receptors, and reactive oxygen species

Stretch of cardiac myocytes has long been known to release angiotensin II (AngII) [81], which acts on myocytes in an autocrine-paracrine loop and signals via Src and EGFR kinase in a multistep pathway ultimately leading to the formation of reactive oxygen species (ROS) [47, 90, 99]. AngII and ROS are implicated in cardiac remodelling and the development of heart failure, where ICl,swell is chronically activated [22, 23], and in hypertrophy of vascular smooth muscle [5, 14, 47, 90, 91, 99].

This raised a question: Does activation of the AngII signalling cascade modulate ICl,swell?
The role of AngII signalling was investigated for ICl,swell elicited both by stretching β1 integrins [10, 12] and by osmotic swelling [75, 76]. 
 Block of AT1 receptors by losartan prevents activation of ICl,swell by either stimulus, and exogenous AngII activates a comparable Cl- current. Thus, activation of ICl,swell appears likely to result from the autocrine-paracrine action of AngII. AngII release may not be required, however. Native cardiac and heterologously expressed AT1 receptors are activated by stretch both in the presence of AngII neutralizing antibodies that block responses to exogenous AngII and in the absence of AngII in an expression system [113]. While AT1 receptors are not activated by AngII in these studies, stretch-induced signalling still is blocked by candesartan, an AT1 antagonist.

Other components of the AngII signalling cascade [14, 47, 90, 91] are also implicated in the upregulation of ICl,swell in response to both stretch and swelling [10, 12, 33, 75, 76], and the signalling scheme is shown in Figure 4.
 Figure 4. Simplified diagram of autocrine-paracrine signalling cascade that controls ICl,swell.

 Simplified diagram of autocrine-paracrine signalling cascade that controls ICl,swell. Swelling and stretch initiate the cascade via integrins and one or more downstream molecules. Exogenous AngII and EGF also active ICl,swell. Src family PTK and ROS are likely to interact at additional sites. It is unclear whether ROS activates ICl,swell directly or via intermediates.

AT1 receptor activation causes transactivation of EGF receptors, which possess intrinsic EGFR kinase activity. ICl,swell is blocked by EGFR kinase inhibitors in human atria and rabbit ventricle [12, 33, 75, 76] and is activated by exogenous EGF [12]. EGFR kinase signals via PI-3K, and PI-3K inhibitors wortmannin and LY294002 block ICl,swell. Ultimately this signalling cascade stimulates sarcolemmal NAD(P)H oxidase, which produces ·O2-, and ·O2- rapidly undergoes dismutation to H2O2 a longer-lived, membrane permeant ROS.

Cardiac muscle expresses two NAD(P)H oxidase isoforms, NOX2, the classical phagocyte isoform, and NOX4 [13, 52, 106]. As expected, ICl,swell is blocked by organic inhibitors of NAD(P)H oxidase, including DPI (diphenylene iodinium),

CaT alternans

Channels (Austin). 2016 Nov;10(6):507-17. doi: 10.1080/19336950.2016.1207020. Epub 2016 Jun 29.

Ca(2+)-activated chloride channel activity during Ca(2+) alternans in ventricular myocytes. Kanaporis G1, Blatter LA1.

Cardiac alternans, defined beat-to-beat alternations in contraction, action potential (AP) morphology or cytosolic Ca transient (CaT) amplitude, is a high risk indicator for cardiac arrhythmias.

 We investigated mechanisms of cardiac alternans in single rabbit ventricular myocytes. CaTs were monitored simultaneously with membrane currents or APs recorded with the patch clamp technique. A strong correlation between beat-to-beat alternations of AP morphology and CaT alternans was observed.

During CaT alternans application of voltage clamp protocols in form of pre-recorded APs revealed a prominent Ca(2+)-dependent membrane current consisting of a large outward component coinciding with AP phases 1 and 2, followed by an inward current during AP repolarization.

Approximately 85% of the initial outward current was blocked by Cl(-) channel blocker DIDS or lowering external Cl(-) concentration identifying it as a Ca(2+)-activated Cl(-) current (ICaCC).
The data suggest that ICaCC plays a critical role in shaping beat-to-beat alternations in AP morphology during alternans.


action potential; alternans; arrhythmias; calcium; calcium-activated chloride channels; excitation-contraction coupling; heart

Kuiva yskä ilman syytä?

Voi olla kloridin puutetta. On olemasa kloridia joka ei ole natriumin kansa yhdesä.  esim  salmiakit ja yskänlääkkeiden osana oleva ammoniumkloridi, mtua tässä on tas se ammonium joni, jota ei pitäisi ladata turhia, ksoka keho muodostaa sitä itse. Lysiinikloridi mainitaan eräässä artikkelissa  tuossa edellä.  Ei mikään herkku varmaankaan, mutta käytetty kloridin antajana tieteellisessä kokeessa. Täytyy vähän pohtia mistä saa puhdasta kloridia, ilman että lataa kehoon natriumia ja ammoniumia.Tietysti monet diureettipotilaat saavat kaliumkloridia, mutta siinä muodossa suurina tabletteina minsuta kloridin  hankinta on  epämiellyttävä ajatus ja mahalaukku  ei oikein pidä siitä.  Pitäisi löytää jokin  dietääri tie. Kloridin puute voi olla kuivan yskän syy. Apteekin salmiakki  varsinkin kesäkuumalla on  hyvä kloridilisä.

Hypokloreminen EKG

 21 Citations
  • Abstract
  • A case of profound hypochloremic alkalosis with hypopotassemia is reported, showing electrocardiographic changes of electrical alternans of the repolarization wave (probably the U wave) without any change in the QRS complex. Transient concomitant P-pulmonale was noted. Hypopotassemia is discussed as a possible mechanism for the development of the electrical alternans.

Hypochloremia ja sydän

Circ Heart Fail. 2016 Aug;9(8). pii: e003180. doi: 10.1161/CIRCHEARTFAILURE.116.003180.

Hypochloremia and Diuretic Resistance in Heart Failure: Mechanistic Insights.



Recent epidemiological studies have implicated chloride, rather than sodium, as the driver of poor survival previously attributed to hyponatremia in heart failure. Accumulating basic science evidence has identified chloride as a critical factor in renal salt sensing. Our goal was to probe the physiology bridging this basic and epidemiological literature.


Two heart failure cohorts were included: (1) observational: patients receiving loop diuretics at the Yale Transitional Care Center (N=162) and (2) interventional pilot: stable outpatients receiving ≥80 mg furosemide equivalents were studied before and after 3 days of 115 mmol/d supplemental lysine chloride (N=10). At the Yale Transitional Care Center, 31.5% of patients had hypochloremia (chloride ≤96 mmol/L). Plasma renin concentration correlated with serum chloride (r=-0.46; P<0 .001="" b=""> with no incremental contribution from serum sodium
(P=0.49).  Hypochloremic versus nonhypochloremic patients exhibited renal wasting of chloride (P=0.04) and of chloride relative to sodium (P=0.01), despite better renal free water excretion (urine osmolality 343±101 mOsm/kg versus 475±136; P<0 .001="" b="">Hypochloremia was associated with poor diuretic
response (odds ratio, 7.3; 95% confidence interval, 3.3-16.1; P<0 .001="" b="" in="" interventional="" pilot="" the="">lysine chloride supplementation was associated with an increase in serum chloride levels of 2.2±2.3 mmol/L, and the majority of participants experienced findings such as hemoconcentration, weight loss, reduction in amino terminal, pro B-type natriuretic peptide, increased plasma renin activity, and increased blood urea nitrogen to creatinine ratio.


Hypochloremia is associated with neurohormonal activation and diuretic resistance with chloride depletion as a candidate mechanism. Sodium-free chloride supplementation was associated with increases in serum chloride and changes in several cardiorenal parameters.


URL: http://www.clinicaltrials.gov. Unique identifier: NCT02031354.


cardiorenal syndrome; chloride; diuretics
[Available on 2017-08-01]

Keliakian vaaroja pitkäaikaisdieetissä

Kun keliakia on jo ehtinyt vaurioitaa suoliston imeyttmisapparaattia -inidividuellisti, kaikilla omatyyppsiesti- pitkän ajan kuluessa voi ilemtä mm EKG- muutoksia. Saataa olla että henkilölää on mm  spreua tapaista tilaa, steathorreaa jäännöksenä  akuutista suolivauriosta- niin sitten voi olla joitain kumuloituvia  ravintoainepuutoksia, josta näkee jotain merkki EKG:ssä.
Tyypillsitä mielestäni on merkit puutteesta eikä esim  liiallisista ravintoaineista, paitsi mit- tulee painoon.
Loogista on hypokalemia, hypokalsemia, hypomagnesemia.
Asia kolplisoituu, jos lisäksi kehittyy mm verenpainetta ja lääkkeitä, jotka edelleen  vähentävät näitä essentiellejä mineraaleja. Suolaakin NaCl  luonnollisesti keliakiass menetetään, mutta siitähän on tavallaan etuakin hypertensiossa,  eikä suolan varsinainen rajoitus tarvitsisi olla aivan liiallisen tehokasta.  Suolahan tuo myös kloridia, joka jakaantuu  Mg, Ca, Na ja K kesken kehossa.
Asia ei ole mitenkään  helppo.
 Jos on sekä hypomagnesemiaa, hypokalemiaa ja hypokalsemiaa EKG.ssa on qt pitenemää ja lattea R-piikin jälkeinen kumpumaisema. 
Mielestäni kannattaa syödä sellaista missä on kalium ja magnesiumpitoisuutta, jopa kakao ja suklaa , siement ym kuuluvat tähän joukkoon.  niissä ei tule kloridia.
Kalsiumia tulee maitotuotteista fosfaatin kanssa.  Juustoissa on lisäksi NaCl runsahkosti.
Saa pohtia miten saa vaikutettua sitä membraanipotentiaalia.  Jos kuitenkin  tulee  angina pectorista, siihenkin tyyppiin auttaa nitro. vaikka kyse ei olisikaan varsinaisista koronaarisuonten  operatiivisesti korjattavasta taudista. Ehkä endoteelifunktiosta, jota taas ei korjaa operaatiolla, koska se on kehossa globaalia, myös aortassa.  Jos on kuitenkin syytä  syödä jokin perinteinen suolainen pala. ettei varsinaissesta klorididistribuutiosta tule  ongelmaa. Täytyy pohtia asiaa.