Abstract-High-salt diet is often associated with increases in arterial pressure, and a role for endothelin (ET)-1 in salt-sensitive hypertension has been suggested; however, the vascular mechanisms involved are unclear. We investigated whether ET increases the sensitivity of the mechanisms of vascular contraction to changes in dietary salt intake. Active stress and 45 Ca 2ϩ influx were measured in endothelium-denuded aortic strips of male Sprague-Dawley rats not treated or chronically infused intravenously with ET (5 pmol/kg per minute) and fed either normal-sodium diet (NS, 1%) or high-sodium diet (HS, 8%) for 9 days. Phenylephrine (Phe) caused increases in active stress that were similar in NS and HS, but were greater in NS/ET (maximum, 10.5Ϯ0.7) than in NS (maximum, 7.4Ϯ0.9) rats, and further enhanced in HS/ET (maximum, 14.4Ϯ1.1) compared with HS rats (maximum, 8.0Ϯ0.8ϫ10 4 N/m 2 ). Phe was more potent in causing contraction in NS/ET than in NS rats and in HS/ET than in HS rats. In Ca 2ϩ -free (2 mmol/L EGTA) Krebs, stimulation of intracellular Ca 2ϩ release by Phe (10 Ϫ5 mol/L) or caffeine (25 mmol/L) caused a transient contraction that was not significantly different in all groups of rats. In contrast, membrane depolarization by high-KCl solution, which stimulates Ca 2ϩ entry from the extracellular space, caused greater contraction in ET-infused rats, particularly those on HS diet. Phe (10 Ϫ5 mol/L) caused an increase in 45 Ca 2ϩ influx that was greater in NS/ET (27.9Ϯ1.7) than in NS (20.1Ϯ1.8) rats and further enhanced in HS/ET (35.2Ϯ1.8) compared with HS rats (21.8Ϯ1.9 mol/kg/min). The Phe-induced 45 Ca 2ϩ influx-stress relation was not different between NS and HS rats, but was enhanced in ET-infused rats particularly those on HS. The enhancement of the 45 Ca 2ϩ influx-active stress relation in ET-infused rats was not observed in vascular strips treated with the protein kinase C inhibitor GF109203X or calphostin C (10 Ϫ6 mol/L). Thus, low-dose infusion of ET, particularly during HS, is associated with increased vascular reactivity that involves Ca 2ϩ entry from the extracellular space, but not Ca 2ϩ release from the intracellular stores. The ET-induced enhancement of the Ca Key Words: arterial pressure Ⅲ endothelium Ⅲ vascular smooth muscle Ⅲ calcium Ⅲ contraction H igh-salt diet (HS) has been implicated in the pathogenesis of hypertension, particularly in salt-sensitive individuals, 1-4 and salt moderation is often recommended to protect against excessive increases in blood pressure. 1,2,5,6 Studies in salt-sensitive experimental animals such as the Dahl salt-sensitive rat have shown that HS is associated with significant increases in blood pressure. 7,8 Also, in saltsensitive rats, HS is associated with exaggerated vascular reactivity to vasoconstrictor stimuli, which may contribute, at least in part, to the increases in blood pressure. 9 -12 Although the mechanisms of salt-sensitive hypertension have not been clearly identified, several studies point to a possible role of endothelin (ET). 7,[13][14...
The current therapeutic options for acute decompensated heart failure are limited to afterload reducers and positive inotropes. The latter increases myocardial contractility through changes in myocyte calcium (Ca2+) handling (mostly through stimulation of the β-adrenergic pathways [β-ADR]) and is associated with paradoxical effects of arrhythmias, cell death, and subsequently increased mortality. We have previously demonstrated that probenecid can increase cytosolic Ca2+ levels in the cardiomyocyte resulting in an improved inotropic response in vitro and in vivo without activating the β-ADR system. We hypothesize that, in contrast to other commonly used inotropes, probenecid functions through a system separate from that of β-ADR and hence will increase contractility and improve function without damaging the heart. Furthermore, our goal was to evaluate the effect of probenecid on cell death in vitro and its use in vivo as a positive inotrope in a mouse model of ischemic cardiomyopathy. Herein, we demonstrate that probenecid induced an influx of Ca2+ similar to isoproterenol, but does not induce cell death in vitro. Through a series of in vivo experiments we also demonstrate that probenecid can be used at various time points and with various methods of administration in vivo in mice with myocardial ischemia, resulting in improved contractility and no significant difference in infarct size. In conclusion, we provide novel data that probenecid, through its activity on cellular Ca2+ levels, induces an inotropic effect without causing or exacerbating injury. This discovery may be translatable if this mechanism is preserved in man.
An organism's cardiovascular response to sepsis is at least partly dependent on hormonal and neural modulation of myocardial function. We have investigated both intrinsic myocardial performance and one aspect of myocardial sensitivity to beta-adrenergic stimulation in a model of sepsis in which animals, at the time studied, exhibited bacteremia, normal arterial blood pressure and cardiac output, elevated heart rate, and elevated plasma catecholamines. Intrinsic myocardial contractile function, studied with the isolated, perfused working heart preparation, was depressed over a range of preloads in septic animals, whereas heart rate was elevated. To determine whether hearts from septic animals could respond normally to beta-adrenergic stimulation, we studied chronotropic responses to isoproterenol in both Langendorff perfused hearts and in isolated right atria. In langendorff perfused hearts from septic animals, basal rates were significantly increased and lower concentrations of isoproterenol elicited greater increases in heart rate. In isolated right atria from septic animals, basal rates were also elevated and the EC50 for the chronotropic response to isoproterenol was significantly less than in atria from control animals. The maximal heart rate response to isoproterenol was not significantly different from control. These results indicate that in sepsis, despite apparently adequate in vivo cardiac performance, intrinsic myocardial function is depressed, but chronotropic sensitivity to beta-adrenergic stimulation is increased.
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