Intracellular vascular muscle Ca2+ modulation in genetic hypertension.

Erné, Paul; Hermsmeyer, Kent

doi:10.1161/01.hyp.14.2.145

Cited by 68 publications

(21 citation statements)

References 18 publications

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“…Ion channel changes such as these are thought to underlie increased vascular reactivity in hypertension (11,20). It is generally agreed that depolarization (17,18), enhanced Ca 2ϩ current (15,32,35), and increased intracellular free Ca 2ϩ (13,21,31) contribute to augmented vasoconstriction in hypertension. Importantly, however, roles for smooth muscle K ϩ channels in producing or opposing hypertension are less clear.…”

Section: Discussionmentioning

confidence: 99%

Reduced functional expression of K⁺channels in vascular smooth muscle cells from rats made hypertensive withN^ω-nitro-l-arginine

Bratz¹,

Swafford²,

Kanagy³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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, we demonstrated that superior mesenteric arteries from rats made hypertensive with N -nitro-L-arginine (L-NNA) are depolarized and express less K ϩ channel protein compared with those from normotensive rats. In the present study, we used patch-clamp techniques to test the hypothesis that L-NNA-induced hypertension reduces the functional expression of K ϩ channels in smooth muscle. In whole cell experiments using a Ca 2ϩ -free pipette solution, current at 0 mV, largely due to voltage-dependent K ϩ (KV) channels, was reduced ϳ60% by hypertension (2.7 Ϯ 0.4 vs. 1.1 Ϯ 0.2 pA/pF). Current at ϩ100 mV with 300 nM free Ca 2ϩ , largely due to large-conductance Ca 2ϩ -activated K ϩ (BKCa) channels, was reduced ϳ40% by hypertension (181 Ϯ 24 vs. 101 Ϯ 28 pA/pF). Current blocked by 3 mM 4-aminopyridine, an inhibitor of many K V channel types, was reduced ϳ50% by hypertension (1.0 Ϯ 0.4 vs. 0.5 Ϯ 0.2 pA/pF). Current blocked by 1 mM tetraethylammonium, an inhibitor of BK Ca channels, was reduced ϳ40% by hypertension (86 Ϯ 14 vs. 53 Ϯ 19 pA/pF). Differences in BK Ca current magnitude are not attributable to changes in single-channel conductance or Ca 2ϩ /voltage sensitivity. The data support the hypothesis that L-NNAinduced hypertension reduces K ϩ current in vascular smooth muscle. Reduced molecular and functional expression of K ϩ channels may partly explain the depolarization and augmented contractile sensitivity of smooth muscle from L-NNA-treated rats. , and contraction are intimately intertwined in a phenomenon referred to as electromechanical coupling (20,30). K ϩ channels play an important role in electromechanical coupling, functioning to set a negative membrane potential and limit the activation of L-type Ca 2ϩ channels. The loss of proper K ϩ channel function results in altered vascular reactivity and hypertension (5, 33). Conversely, hypertension alters the expression of ion channels involved in the electromechanical coupling of smooth muscle (11,20). Recently, interesting light has been shed on concepts of cause and effect between hypertension and alterations in smooth muscle K ϩ channels (1, 2), and it remains to be determined in what scenarios ion channel changes precede hypertension and vice versa.We previously demonstrated a variety of vascular changes in male rats made hypertensive with the nitric oxide synthase inhibitor N -nitro-L-arginine (L-NNA). Smooth muscle changes associated with L-NNA-induced hypertension include increased contractility (22), enhanced Ca 2ϩ sensitivity (6), and augmented responses to dihydropyridines (29). In the companion paper to this article (3), we demonstrated that L-NNAinduced hypertension depolarizes the smooth muscle membrane potential and diminishes expression of K ϩ channel proteins. In the present study, we tested the hypothesis that L-NNA-induced hypertension reduces the functional expression of K ϩ channels in vascular myocytes from hypertensive rats. Smooth muscle cells were isolated from the superior mesenteric artery of normotensive and hypertensive rats and studied...

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Section: Discussionmentioning

confidence: 99%

Reduced functional expression of K⁺channels in vascular smooth muscle cells from rats made hypertensive withN^ω-nitro-l-arginine

Bratz¹,

Swafford²,

Kanagy³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…On the other hand, it was reported that impaired insulin sensitivity or associated hyperinsulinemia can depress the activity of the Na-K pump [16], augment Na-H exchange [17], and impair Ca-ATPase [18], suggesting that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of hypertension [2,19]. Blood pressure in the present subjects was decreased to normal by VLCD therapy, but there was no difference between blood pressure before and after mazindol therapy.…”

Section: Discussionmentioning

confidence: 99%

Effect of Mazindol on Body Weight and Insulin Sensitivity in Severely Obese Patients after a Very-Low-Calorie Diet Therapy.

et al. 1996

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Abstract. The present investigations were performed in order to clarify the effects of mazindol on body weight and insulin sensitivity in patients with morbid obesity who had already been treated with a verylow-calorie diet containing 480 kcal food (VLCD) with various amino acids. We attempted to study whether a further decrease in body weight would be achieved by the administration of mazindol, because it is difficult to obtain sufficient and continuous reduction of body weight after VLCD therapy. Thirteen female severely obese subjects were 51.0 ± 13.9 years old (25-73 years old), with a mean height of 154.7 ± 5.6 cm (146.0-160.5 cm), mean weight of 84.5 ± 9.4 kg (69-98 kg) and a mean body mass index (BMI) of 35.3 ± 3.6 kg/m2 (29.2-41.0 kg/m2). Their mean body weight decreased to 76.7 ± 2.2 kg (net decrease: 6.3 ± 0.9 kg) after VLCD therapy for 2-4 weeks. Then they were treated by the administration of mazindol with diet restriction (1000-1200 kal/day). Mazindol administration resulted in a further weight reduction of 2.9 ± 0.5 kg after 4 weeks, 4.9 ± 0.5 kg after 8 weeks and 6.9 ± 0.9 kg after 12 weeks. Their blood pressure was not changed after mazindol treatment. The responses of blood glucose and insulin levels in a 75 g oral glucose tolerance test (OGTT) were not significantly different before and after mazindol administration.The blood glucose area calculated from the data obtained during OGTT for 120 min did not significantly differ before and after mazindol administration, while the insulin area significantly decreased after mazindol treatment (from 98.0 ± 12.1 before administration to 70.1 ± 7.8). The mean M value reflecting insulin sensitivity in the whole body determined by euglycemic glucose clamping was increased significantly after mazindol treatment (from 4.92 ± 0.30 mg/kg/min to 6.36 ± 0.43 mg/kg/min).The results demonstrated that mazindol administration with diet restriction further reduced body weight in the morbidly obese subjects after treatment with VLCD, with an increase in the M value and a decrease in insulin release. The results suggest that mazindol is useful for reducing body weight as well as improving insulin sensitivity.

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“…However, increased PLC activity and increased intracellular calcium are already observed in prehypertensive spontaneously hypertensive rats (24,26 (27) reported that the shear stress-induced increase in 'P3 in human umbilical vein endothelial cells persists for several minutes after an increase in shear stress, although other agonist-induced IP3 levels, such as those induced by histamine, thrombin, and bradykinin, return to near basal levels within 1 to 2 min after exposure to the agonist. Pressure-induced calcium responses were sustained and also differed from those of norepinephrine.…”

Section: Discussionmentioning

confidence: 99%

Pressure promotes DNA synthesis in rat cultured vascular smooth muscle cells.

Hishikawa¹,

Nakaki²,

Marumo³

et al. 1994

J. Clin. Invest.

117

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High blood pressure is one of the major risk factors for atherosclerosis. In this study, we examined the effects of pressure on cell proliferation and DNA synthesis in cultured rat vascular smooth muscle cells. Pressure without shear stress and stretch promotes cell proliferation and DNA synthesis in a pressuredependent manner. Pressure-induced DNA synthesis was inhibited significantly by the phospholipase C (PLC) inhibitor 2-nitro4-carboxyphenyl-N,N-diphenylcarbamate, the protein kinase C inhibitor H-7, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, staurosporine, and the tyrosine kinase inhibitor (l3,4,5-trihydroxyphenyljmethylene) propanedinitrile. Toclarify whether activation of PLC and calcium mobilization are involved in pressure-induced DNA synthesis, production of 1,4,5-inositol trisphosphate (IP3) and intracellular Ca2" was measured. Pure pressure increased IP3 and intracellular Ca2"

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Intracellular vascular muscle Ca2+ modulation in genetic hypertension.

Cited by 68 publications

References 18 publications

Reduced functional expression of K⁺channels in vascular smooth muscle cells from rats made hypertensive withN^ω-nitro-l-arginine

Reduced functional expression of K⁺channels in vascular smooth muscle cells from rats made hypertensive withN^ω-nitro-l-arginine

Effect of Mazindol on Body Weight and Insulin Sensitivity in Severely Obese Patients after a Very-Low-Calorie Diet Therapy.

Pressure promotes DNA synthesis in rat cultured vascular smooth muscle cells.

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Intracellular vascular muscle Ca2+ modulation in genetic hypertension.

Cited by 68 publications

References 18 publications

Reduced functional expression of K+channels in vascular smooth muscle cells from rats made hypertensive withNω-nitro-l-arginine

Reduced functional expression of K+channels in vascular smooth muscle cells from rats made hypertensive withNω-nitro-l-arginine

Effect of Mazindol on Body Weight and Insulin Sensitivity in Severely Obese Patients after a Very-Low-Calorie Diet Therapy.

Pressure promotes DNA synthesis in rat cultured vascular smooth muscle cells.

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Reduced functional expression of K⁺channels in vascular smooth muscle cells from rats made hypertensive withN^ω-nitro-l-arginine

Reduced functional expression of K⁺channels in vascular smooth muscle cells from rats made hypertensive withN^ω-nitro-l-arginine