Excess dietary sodium is a major contributing factor to the incidence and severity of hypertension. However, the precise mechanism or mechanisms by which salt contributes to the severity of hypertension are unknown. The region of the rostral ventrolateral medulla (RVLM) is a principal brain stem locus critical for the regulation of arterial blood pressure by the sympathetic nervous system. The purpose of this study was to determine if excess dietary sodium chloride might alter the function or responsiveness of neurons In the RVLM. Male Sprague-Dawiey rats were given either tap water or 0.9% sodium chloride solution to drink for 10 to 14 days. Excess sodium chloride did not affect baseline blood pressure. However, when neurons of the RVLM were stimulated by microinjections of L-glutamate, evoked increases in arterial pressure were potentiated in rats given sodium chloride. Augmented pressor responses could not be accounted for by increased vascular reactivity because both groups responded similarly to intravenously administered phenylephrine and norepinephrine. Additionally, electrical stimulation of descending spinal sympathoexcitatory axons produced identical pressor responses in both groups, indicating that altered synaptic transmission at central or peripheral neuroeffector junctions distal to the RVLM could not explain enhanced pressor responses produced by direct stimulation of RVLM cell somata. Finally, impaired arterial baroreceptor reflexes could not account for augmented RVLM pressor responses, as depressor and bradycardic responses produced by electrical stimulation of aortic baroreceptor afferents were not reduced in rats given excess dietary sodium chloride. These results indicate that increased dietary salt intake sensitizes RVLM sympathoexcitatory neurons and may predispose toward the exaggerated expression of hypertension, suggesting a potential link between salt, hypertension, and the brain. (NaCl) to the pathogenesis of hypertension has been debated for almost half a century. 12 Although an increase in NaCl intake is not invariably associated with elevated arterial blood pressure, a large subset of individuals exhibits fluctuations in arterial pressure when daily salt intake is varied. 35 However, a diet high in salt alone is not sufficient to produce hypertension in otherwise normotensive individuals but instead plays a permissive role in enabling the exaggerated expression of hypertension.3 Salt sensitivity of blood pressure has been studied intensively, but the mechanism or mechanisms by which increased dietary salt imparts enhanced sensitivity to hypertensive stimuli are not known.In several experimental models of hypertension, excess NaCl intake is essential for either the development or full expression of hypertension.611 Additionally, the central nervous system (CNS) and peripheral sympathetic nervous system contribute significantly to the maintenance of elevated arterial pressure in many of
Previous studies have shown that pharmacological blockade of ionotropic excitatory amino acid (EAA) receptors in the nucleus tractus solitarii (NTS) with kynurenate (Kyn) abolishes baroreceptor reflexes but fails to affect cardiovascular responses evoked by microinjections of L-glutamate (Glu) into the NTS. These observations have raised doubts as to whether Glu is a neurotransmitter of baroreceptor information in the NTS because the pharmacological actions of exogenously administered Glu are not identical to those of the neurotransmitter released in the NTS coincident with baroreceptor activation. One possible explanation for these results is that exogenously administered Glu might act at receptors that are not blocked by Kyn and are not accessible to synaptically released Glu in the NTS baroreflex pathway. The purpose of this study was to determine if Kyn-insensitive Glu receptors are present in the NTS. One candidate for this Kyn-insensitive receptor is the metabotropic EAA receptor that is selectively activated by trans-DL-1-amino-1,3-cyclopentane-dicarboxylic acid (ACPD). Microinjections of ACPD into the NTS of anesthetized rats produced dose-related depressor responses that were not reduced by Kyn or by pretreatment with the putative ACPD receptor antagonist L-2-amino-3-phosphonopropionate (L-AP-3). Similarly, depressor responses produced by Glu also were not affected by Kyn or by L-AP-3. These data demonstrate the presence of a Kyn-insensitive Glu receptor in the NTS. Moreover, they suggest that the failure of Kyn to reduce cardiovascular responses evoked by Glu injections into the NTS can be explained by an action of Glu at Kyn-insensitive ACPD receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
MLC2v modulates chamber-specific contractility by enhanced calcium sensitivity and/or improved cross-bridge cycling of the thin and thick filaments of the cardiomyocyte.
Although targeted alterations of the mouse genome are used increasingly to identify the mechanisms underlying cardiac function, the methods used to study the phenotypic expression of these alterations in vivo are limited. To derive a relatively noninvasive, load-independent measure of left ventricular (LV) contractility in mice, we cannulated the femoral artery and performed two-dimensional directed M-mode echo studies in 28 anesthetized FVB/N mice, using a 9-MHz transducer. Loading conditions were altered by intraarterial methoxamine (3-12 microg/g), and LV shortening fraction was determined at several steady states, both before and after myocardial contractility was altered by either 4 microg/g intraperitoneal dobutamine (n = 16) or 1-2 microg/g verapamil (n = 12). The relation between LV systolic meridional stress and fractional shortening derived from pooled baseline data was inverse and linear [r = 0.80, slope = -0.19, intercept = 48%, standard error of estimate (SEE) = 5.5%, P < 0.001]. Dobutamine produced a parallel upward shift of the relation (r = 0.87, slope = -0.21, intercept = 61%, SEE = 4.5%, P < 0.001), and verapamil produced a downward shift of the relation (r = 0.48, slope = -0.05, intercept = 24%, SEE = 3.7%, P < 0.05). At matched levels of end-systolic stress, dobutamine increased and verapamil decreased the LV shortening fraction. We conclude that 1) inverse stress-shortening relations can be assessed noninvasively in mice; and 2) these relations are sensitive to alterations in inotropic state, independent of loading conditions.
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