Cell growth and Na-K-Cl cotransport responses of vascular smooth muscle cells of Milan rats.

Canessa, Mitzy; Salazar, Gloria; Werner, Erica; Vallega, Gino; González, Alfonso

doi:10.1161/01.hyp.23.6.1022

Cited by 13 publications

(9 citation statements)

References 22 publications

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“…Milan hypertensive rats have also been shown to have an increased proliferative response to EGF in cultured VSMC when compared to normotensive Milan rats. In this case, however, no difference could be found in the number or affinity of the receptors for EGF [ 11 ].…”

Section: Epidermal Growth Factor and Smooth Muscle Cellsmentioning

confidence: 53%

Novel signaling pathways contributing to vascular changes in hypertension

et al. 2000

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In hypertension, increased peripheral resistance maintains elevated levels of arterial blood pressure. The increase in peripheral resistance results, in part, from abnormal constrictor and dilator responses and vascular remodeling. In this review, we consider four cellular signaling pathways as possible explanations for these abnormal vascular responses: (1) augmented signaling via the epidermal growth factor receptor to cause remodeling of the cerebrovasculature; (2) reduced sphingolipid signaling leading to blunted vasodilation and increased smooth muscle proliferation; (3) increased signaling via Rho/Rho kinase leading to enhanced vasoconstriction, and (4) a relative state of microtubular depolymerization favoring vasoconstriction in hypertension. These novel cell signaling pathways provide new pharmacological targets to reduce total peripheral vascular resistance in hypertension.

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Section: Epidermal Growth Factor and Smooth Muscle Cellsmentioning

confidence: 53%

Novel signaling pathways contributing to vascular changes in hypertension

et al. 2000

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“…Most studies of the relationship between vascular smooth muscle NKCC1 and blood pressure have been limited to cells cultured from hypertensive rats. Its activity is reduced in cells cultured from aortas of spontaneously hypertensive rats (35,39) but increased in cells cultured from Milan hypertensive rats (4). Because of the phenotypic changes these cells undergo in culture (40), such results probably have little relevance to vascular smooth muscle in vivo.…”

Section: Discussionmentioning

confidence: 99%

Blood pressure regulates the activity and function of the Na-K-2Cl cotransporter in vascular smooth muscle

Jiang

Akar

Cobbs

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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The Na-K-2Cl cotransporter (NKCC1) is one of several transporters that have been linked to hypertension, and its inhibition reduces vascular smooth muscle tone and blood pressure. NKCC1 in the rat aorta is stimulated by vasoconstrictors and inhibited by nitrovasodilators, and this is linked to the contractile state of the smooth muscle. To determine whether blood pressure also regulates NKCC1, we examined the acute effect of hypertension on NKCC1 in rats after aortic coarctation. In the hypertensive aorta (28-mmHg rise in mean blood pressure), an increase in NKCC1 activity (measured as bumetanide-sensitive (86)Rb efflux) was apparent by 16 h and reached a plateau of 62% greater than control at 48 h. In contrast, there was a slight decrease in NKCC1 activity in the hypotensive aorta (21% decrease in mean blood pressure). Measurement of NKCC1 mRNA by real-time PCR revealed a fivefold increase in the hypertensive aorta compared with the hypotensive aorta or sham aorta. The inhibition by bumetanide of isometric force response to phenylephrine was significantly greater in the hypertensive aorta than in the control aorta or hypotensive aorta. We conclude that NKCC1 in rat aortic smooth muscle is regulated by blood pressure, most likely through changes in transporter abundance. This upregulation of NKCC1 is associated with a greater contribution to force generation in the hypertensive aorta. This is the first demonstration that NKCC1 in vascular smooth muscle is regulated by blood pressure and indicates that this transporter is important in the acute response of vascular smooth muscle to hypertension.

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“…Inhibition of the NKCC cotransporter by loop diuretics is associated with decreased proliferation of human skin fibroblasts, bovine endothelial cells, and rat vascular smooth muscle cells in culture (3,19,21). Because we have shown that a functional NKCC cotransporter is present in human airway smooth muscle (9, 10), we hypothesized that inhibition of the cotransporter with loop diuretics will also impair proliferation of different cells within the lung.…”

mentioning

confidence: 99%

Na-K-2Cl cotransporter inhibition impairs human lung cellular proliferation

Iwamoto¹,

Fujiwara²,

Nakamura³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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The widespread presence of the Na-K-2Cl (NKCC) cotransporter protein suggests that chronic administration of inhibitors may result in adverse effects. Inhibition of the NKCC cotransporter by loop diuretics is felt to underlie the diuretic and the pulmonary smooth muscle relaxant effects of this drug class. However, the fundamental regulation of salt and water movement by this cotransporter suggests that it may also mediate cell volume changes occurring during cell cycle progression. Thus we hypothesized that NKCC cotransporter inhibition by loop diuretics would decrease cellular proliferation. Normal human bronchial smooth muscle cells (BSMC) showed a significant concentration-dependent decrease in cell counts after 7 days of exposure to both bumetanide (n=5-10) and furosemide (n=6-16) compared with controls. Proliferation was similarly inhibited in normal human lung fibroblasts (n=5-9). To determine whether this was due to loss of cells, we performed apoptosis assays on BSMC. Both annexin V-propidium iodide staining (n=5-10) and single cell gel electrophoresis assays (n=4) were negative for necrosis and apoptosis in BSMC exposed to 10 microM bumetanide. Subsequent analysis of the cell cycle by flow cytometry showed that bumetanide-exposed BSMC were delayed in G1 phase compared with controls (n=4-8). This is the first evidence for loop diuretic inhibition of airway smooth muscle cell proliferation. NKCC cotransporter inhibition impeded G1-S phase transition without facilitating cell death. Thus although inhibition by loop diuretics relaxes airway smooth muscle, the NKCC cotransporter may have a more important role in cell proliferation regulation.

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Cell growth and Na-K-Cl cotransport responses of vascular smooth muscle cells of Milan rats.

Cited by 13 publications

References 22 publications

Novel signaling pathways contributing to vascular changes in hypertension

Novel signaling pathways contributing to vascular changes in hypertension

Blood pressure regulates the activity and function of the Na-K-2Cl cotransporter in vascular smooth muscle

Na-K-2Cl cotransporter inhibition impairs human lung cellular proliferation

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