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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the possible involvement of brain amiloride-sensitive Na+ channels in Na(+)-induced hypertension, we investigated the effects of benzamil hydrochloride, a specific blocker of these Na+ channels, on the acute pressor mechanisms of intracerebroventricular infusion of hypertonic NaCl and the continuous pressor mechanisms of Na(+)-induced chronic hypertension, such as deoxycorticosterone acetate-salt hypertensive or stroke-prone spontaneous hypertensive rats, and of non-Na(+)-induced hypertension, such as renovascular hypertensive rats. Intracerebroventricular preinjection with benzamil (1 or 10 nmol/kg) abolished the increase in mean arterial pressure, heart rate, abdominal sympathetic discharge, and plasma vasopressin concentration induced by an acute increase in cerebrospinal Na+ concentrations at intracerebroventricular infusion of 1.5 M hypertonic NaCl. Continuous intracerebroventricular infusion of benzamil (1 or 10 nmol.kg-1.day-1) for 7 days attenuated Na(+)-induced chronic hypertension in both deoxycorticosterone acetate-salt and stroke-prone spontaneous hypertensive rats, accompanied by reduction of urinary excretion of vasopressin and norepinephrine but not in renovascular hypertensive rats. Intravenous infusion of benzamil (10 nmol.kg-1.day-1) for 7 days affected neither arterial pressure nor urinary excretion of vasopressin and norepinephrine in either model of hypertension. Benzamil-blockable brain amiloride-sensitive Na+ channels are expected to function as one of the Na+ receptors in the brain and to be involved in the pressor mechanism of Na(+)-induced hypertension.
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PMID:Benzamil blockade of brain Na+ channels averts Na(+)-induced hypertension in rats. 953 Feb 28

Intracerebroventricular infusions of an amiloride analog, benzamil, reduce blood pressure in several rat models of hypertension. This effect has been attributed to an inhibition of amiloride-sensitive Na+ channels in the brain. This study examines whether intracerebroventricular benzamil would prevent the onset of deoxycorticosterone acetate (DOCA)-salt-induced hypertension in rats and whether this effect correlates with an inhibition of ion transport through the known amiloride-sensitive cation channels at the blood-brain barrier. We also examine whether the effects of benzamil on blood pressure are mediated by a Na+ channel by comparing the effects of different amiloride analogs. Benzamil (0.15 and 0.5 microgram/h icv) did significantly attenuate the increase in blood pressure induced by DOCA treatment. This antihypertensive effect, however, was not associated with an alteration in a blood-brain barrier ion transport as assessed by measurements of blood-to-brain 22Na transport and cerebral spinal fluid Na+ and K+ concentrations. Indeed, intracerebroventricular infusion of dimethyl amiloride, an amiloride analog with low affinity for Na+ channels, also attenuated the increase in blood pressure induced by DOCA-salt treatment. Comparisons of the effects of benzamil, dimethyl amiloride, and 3,4-dichlorobenzamil, another amiloride analog, suggest that these antihypertensive effects are mediated by an inhibition of Na+/Ca2+ exchange in the brain.
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PMID:Effect of amiloride analogs on DOCA-salt-induced hypertension in rats. 1036 6

Central infusions of benzamil prevent/reverse salt-induced hypertension in genetic models of salt-sensitive hypertension. Benzamil acts by blockade of ion--presumably sodium--channels. In the present study, we assessed in Dahl salt-sensitive (S) rats on high salt intake whether these channels mediate increases in brain "ouabain" and, thereby, hypertension. Intracerebroventricular (icv) infusions of a low (1.2 microg/kg per hour) or high (4.0 microg/kg per hour) dose of benzamil were given to Dahl S rats on high salt diet (1370 micromol Na+/g food) for 2 or 4 weeks. "Ouabain" content was measured using a specific enzyme-linked immunosorbent assay (ELISA). Systolic blood pressure (BP) in Dahl S rats on high salt for 4 weeks increased markedly (188+/-10 versus 128+/-4 mm Hg, n=8, P<0.05). Benzamil fully blocked this increase (131+/-7 mm Hg after the high dose of benzamil). Hypothalamic and pituitary "ouabain" increased significantly (22+/-7 versus 12+/-3 and 151+/-38 versus 69+/-6 ng/g tissue, respectively, P<0.05) in Dahl S rats on high salt versus regular salt diet for 2 weeks. Benzamil blocked these increases of brain "ouabain" to high salt intake. Similarly, high salt intake for 4 weeks increased hypothalamic (18+/-2 versus 13+/-1 ng/g tissue, P<0.05) and pituitary (183+/-30 versus 78+/-8 ng/g tissue, P<0.05) "ouabain." Benzamil also inhibited these increases of brain "ouabain." Both hypothalamic and pituitary "ouabain" showed significant positive correlations with BP. In contrast, high salt intake did not affect "ouabain" levels in the adrenal gland or plasma in Dahl S rats on high salt for either 2 or 4 weeks. These findings indicate that in Dahl S rats high salt intake only increases brain and not peripheral "ouabain" and that benzamil-blockable brain sodium channels mediate the increases in brain "ouabain" and the subsequent hypertension.
Hypertension 2002 Jul
PMID:Brain sodium channels mediate increases in brain "ouabain" and blood pressure in Dahl S rats. 1210 45

Central nervous system (CNS) effects of mineralocorticoids participate in the development of salt-sensitive hypertension. In the brain, mineralocorticoids activate amiloride-sensitive sodium channels, and we hypothesized that this would lead to increased release of ouabainlike compounds (OLC) and thereby sympathetic hyperactivity and hypertension. In conscious Wistar rats, intracerebroventricular infusion of aldosterone at 300 or 900 ng/h in artificial cerebrospinal fluid (aCSF) with 0.145 M Na+ for 2 h did not change baseline mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), or heart rate (HR). Intracerebroventricular infusion of aCSF containing 0.16 M Na+ (versus 0.145 M Na+ in regular aCSF) did not change MAP or RSNA, but significant increases in MAP, RSNA, and HR were observed after intracerebroventricular infusion of aldosterone at 300 ng/h for 2 h. Intracerebroventricular infusion of aCSF containing 0.3 M Na+ increased MAP, RSNA, and HR significantly more after intracerebroventricular infusion of aldosterone versus vehicle. After intracerebroventricular infusion of aldosterone, the MAP, RSNA, and HR responses to intracerebroventricular infusion of aCSF containing 0.16 M Na+ were blocked by blockade of brain OLC with intracerebroventricular infusion of Fab fragments or of brain sodium channels with intracerebroventricular benzamil. Chronic intracerebroventricular infusion of aldosterone at 25 ng/h in aCSF with 0.15 M Na+ for 2 wk increased MAP by 15-20 mmHg and increased hypothalamic OLC by 30% and pituitary OLC by 60%. Benzamil blocked all these responses to aldosterone. These findings indicate that in the brain, mineralocorticoids activate brain sodium channels, with small increases in CSF Na+ leading to increases in brain OLC, sympathetic outflow, and blood pressure.
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PMID:Brain sodium channels and ouabainlike compounds mediate central aldosterone-induced hypertension. 1293 42

To elucidate the role of epithelial sodium channels (ENaCs) and Na(+)-K(+)-ATPase in Na(+) transport by the choroid plexus, we studied ENaC expression and Na(+) transport in the choroid plexus. Lateral ventricle choroid plexuses were obtained from young male Wistar, Dahl salt-resistant (SS.BN13), and Dahl salt-sensitive (SS/MCW) rats on a regular (0.3%) or high- (8.0%) salt diet. The effects of ENaC blocker benzamil and Na(+)-K(+)-ATPase blocker ouabain on sodium transport were evaluated by measuring the amounts of retained (22)Na(+) and by evaluating intracellular [Na(+)] with Sodium Green fluorescence. In Wistar rats, ENaC distribution was as follows: microvilli, 10% to 30%; cytoplasm, 60% to 80%; and basolateral membrane, 5% to 10%. Benzamil (10(-8) m) decreased (22)Na(+) retention by 20% and ouabain (10(-3) m) increased retention by 40%, whereas ouabain and benzamil combined caused no change. Similar changes were noted in intracellular [Na(+)]. In Dahl rats on a regular salt diet, intracellular [Na(+)] was similar, but the amount of retained (22)Na(+) was less in sensitive versus resistant rats. High salt did not affect ENaC mRNA or protein, nor the benzamil induced decreases in retained (22)Na(+) or intracellular [Na(+)] in either strain. However, high salt increased intracellular [Na(+)] and attenuated the increase in uptake of (22)Na(+) by ouabain in resistant but not sensitive rats, suggesting a decrease in Na(+)-K(+)-ATPase activity only in resistant rats. These findings suggest that both ENaC and Na(+)-K(+)-ATPase regulate Na(+) transport in the choroid plexus. Aberrant regulation of Na(+) transport and of Na(+)-K(+)-ATPase activity, but not of ENaCs, might contribute to the increase in cerebrospinal fluid [Na(+)] in Dahl salt-sensitive rats on a high-salt diet.
Hypertension 2009 Oct
PMID:Sodium transport in the choroid plexus and salt-sensitive hypertension. 1963 91

Supplementing diets with high potassium helps reduce hypertension in humans. Inwardly rectifying K+ channels Kir4.1 (Kcnj10) and Kir5.1 (Kcnj16) are highly expressed in the basolateral membrane of distal renal tubules and contribute to Na+ reabsorption and K+ secretion through the direct control of transepithelial voltage. To define the importance of Kir5.1 in blood pressure control under conditions of salt-induced hypertension, we generated a Kcnj16 knockout in Dahl salt-sensitive (SS) rats (SSKcnj16-/-). SSKcnj16-/- rats exhibited hypokalemia and reduced blood pressure, and when fed a high-salt diet (4% NaCl), experienced 100% mortality within a few days triggered by salt wasting and severe hypokalemia. Electrophysiological recordings of basolateral K+ channels in the collecting ducts isolated from SSKcnj16-/- rats revealed activity of only homomeric Kir4.1 channels. Kir4.1 expression was upregulated in SSKcnj16-/- rats, but the protein was predominantly localized in the cytosol in SSKcnj16-/- rats. Benzamil, but not hydrochlorothiazide or furosemide, rescued this phenotype from mortality on a high-salt diet. Supplementation of high-salt diet with increased potassium (2% KCl) prevented mortality in SSKcnj16-/- rats and prevented or mitigated hypertension in SSKcnj16-/- or control SS rats, respectively. Our results demonstrate that Kir5.1 channels are key regulators of renal salt handling in SS hypertension.
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PMID:Essential role of Kir5.1 channels in renal salt handling and blood pressure control. 2893 51

Increased generation of reactive oxygen species (ROS) and altered Ca2+ handling cause vascular damage in hypertension. Mechanisms linking these systems are unclear, but TRPM2 (transient receptor potential melastatin 2) could be important because TRPM2 is a ROS sensor and a regulator of Ca2+ and Na+ transport. We hypothesized that TRPM2 is a point of cross-talk between redox and Ca2+ signaling in vascular smooth muscle cells (VSMC) and that in hypertension ROS mediated-TRPM2 activation increases [Ca2+]i through processes involving NCX (Na+/Ca2+ exchanger). VSMCs from hypertensive and normotensive individuals and isolated arteries from wild type and hypertensive mice (LinA3) were studied. Generation of superoxide anion and hydrogen peroxide (H2O2) was increased in hypertensive VSMCs, effects associated with activation of redox-sensitive PARP1 (poly [ADP-ribose] polymerase 1), a TRPM2 regulator. Ang II (angiotensin II) increased Ca2+ and Na+ influx with exaggerated responses in hypertension. These effects were attenuated by catalase-polyethylene glycol -catalase and TRPM2 inhibitors (2-APB, 8-Br-cADPR olaparib). TRPM2 siRNA decreased Ca2+ in hypertensive VSMCs. NCX inhibitors (Benzamil, KB-R7943, YM244769) normalized Ca2+ hyper-responsiveness and MLC20 phosphorylation in hypertensive VSMCs. In arteries from LinA3 mice, exaggerated agonist (U46619, Ang II, phenylephrine)-induced vasoconstriction was decreased by TRPM2 and NCX inhibitors. In conclusion, activation of ROS-dependent PARP1-regulated TRPM2 contributes to vascular Ca2+ and Na+ influx in part through NCX. We identify a novel pathway linking ROS to Ca2+ signaling through TRPM2/NCX in human VSMCs and suggest that oxidative stress-induced upregulation of this pathway may be a new player in hypertension-associated vascular dysfunction.
Hypertension 2020 01
PMID:Crosstalk Between Vascular Redox and Calcium Signaling in Hypertension Involves TRPM2 (Transient Receptor Potential Melastatin 2) Cation Channel. 3173 84