Accumulation of Intracellular Chloride by (Na-K-Cl) Co-transport in Rat Arterial Smooth Muscle is Enhanced in Deoxycorticosterone Acetate (DOCA)/salt Hypertension

Myogenic tone in mouse mesenteric arteries: evidence for P2Y receptor-mediated, Na+, K+, 2Cl− cotransport-dependent signaling

“…Ca 2+ release from the endoplasmic reticulum elicits activation of Cl − channels, plasma membrane depolarization and activation of long-lasting L-type Ca 2+ channels, whose involvement in MT is well-documented in an overwhelming number of vessels studied so far [3]. Significantly, NKCC inhibition partially blocked the depolarizing action of Cl − channel activation via attenuation of [Cl -] i , as demonstrated in bumetanide-and furosemidetreated smooth muscle cells of different origins [20][21][22], and resulted in the MT suppression documented here (Fig. 6).…”

“…The distinct action of bumetanide on ATP-and UTP-induced contractions is consistent with different mechanisms of action of these nucleotides on excitation-constriction coupling. Indeed, in rat mesenteric arteries, UTP triggered modest and sustained depolarization from −60 to −50 mV [44] that was probably caused by the activation of Ca 2+ -sensitive Cl − channels and could be abolished by the addition of bumetanide that decreases [Cl − ] i and approaches Nernst Cl − equilibrium potential to resting E m [20][21][22]. Unlike UTP, ATP affected VSMC contractions via transient activation of Ca 2+ influx through P2X ion channels and independently of E m modulation [44].…”

“…These data suggest that highceiling diuretics suppress MT of the renal afferent arterioles via NKCC inhibition, attenuation of [Cl − ] i and VSMC hyperpolarization. Indeed, both furosemide and bumetanide decrease [Cl − ] i [20][21][22], hyperpolarize VSMC [21], suppress the activation of L-type Ca 2+ channels [22] and reduce the baseline tone of vascular and non-vascular smooth muscles [23][24][25] as well as contractions triggered by diverse stimuli, including [K + ] o -induced depolarization [22], phenylephrine [22,[26][27][28], histamine [29], angiotensin II [30], thromboxane A 2 [31,32], and oxytocin [33,34]. Recently, it was demonstrated that high-ceiling diuretics, such as bumetanide and furosemide that are known to be potent NKCC inhibitors, almost completely abolished the MT of renal afferent arterioles in perfused hydronephrotic rat kidneys in vitro [32].…”

Aldosterone Regulates the Na-K-2Cl Cotransporter in Vascular Smooth Muscle

“…14 In addition to the increase in Na ϩ flux, stimulation of NKCC1 could also account for the increased K ϩ and Cl Ϫ fluxes 9,15 also observed in vascular smooth muscle from mineralocorticoid-treated animals. In fact, the increase in intracellular [Cl Ϫ ] in femoral artery of mineralocorticoid-treated, hypertensive rats is abolished by bumetanide, 16 a specific inhibitor of NKCC1. Although this indicates an increased Cl Ϫ influx via NKCC1, it is unclear whether this is due to the mineralocorticoid, the high salt diet, or the hypertension.…”

Microvascular & Endothelial with Smooth Muscle

“…Accordingly, the effect of deoxycorticosterone acetate (DOCA) on Em and contractility of rat femoral arterial smooth muscle was studied. Em and [Cl]1 were measured using double-barrelled microelectrodes in an oxygenated physiological saline (PSS) at 37°C (Davis et al 1993). Contractility was estimated from the pressure at the proximal end of cannulated arteries perfused with PSS that had been pre-contracted to > 100 mmHg with 1-8 /LM phenylephrine (Chipperfield et al 1992).…”