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Chemical exchange saturation transfer (CEST) potentially provides the ability to detect small solute pools through indirect measurements of attenuated water signals. However, CEST effects may be diluted by various competing effects, such as non-specific magnetization transfer (MT) and asymmetric MT effects, water longitudinal relaxation (T1 ) and direct water saturation (radiofrequency spillover). In the current study, CEST images were acquired in rats following ischemic stroke and analyzed by comparing the reciprocals of the CEST signals at three different saturation offsets. This combined approach corrects the above competing effects and provides a more robust signal metric sensitive specifically to the proton exchange rate constant. The corrected amide proton transfer (APT) data show greater differences between the ischemic and contralateral (non-ischemic) hemispheres. By contrast, corrected nuclear Overhauser enhancements (NOEs) around -3.5 ppm from water change over time in both hemispheres, indicating whole-brain changes that have not been reported previously. This study may help us to better understand the contrast mechanisms of APT and NOE imaging in ischemic stroke, and may also establish a framework for future stroke measurements using CEST imaging with spillover, MT and T1 corrections.
Copyright © 2014 John Wiley & Sons, Ltd.
Although the development of abnormal myocardial mechanics represents a key step during the transition from hypertension to overt heart failure (HF), the underlying ultrastructural and cellular basis of abnormal myocardial mechanics remains unclear. We therefore investigated how changes in transverse (T)-tubule organization and the resulting altered intracellular Ca(2+) cycling in large cell populations underlie the development of abnormal myocardial mechanics in a model of chronic hypertension. Hearts from spontaneously hypertensive rats (SHRs; n = 72) were studied at different ages and stages of hypertensive heart disease and early HF and were compared with age-matched control (Wistar-Kyoto) rats (n = 34). Echocardiography, including tissue Doppler and speckle-tracking analysis, was performed just before euthanization, after which T-tubule organization and Ca(2+) transients were studied using confocal microscopy. In SHRs, abnormalities in myocardial mechanics occurred early in response to hypertension, before the development of overt systolic dysfunction and HF. Reduced longitudinal, circumferential, and radial strain as well as reduced tissue Doppler early diastolic tissue velocities occurred in concert with T-tubule disorganization and impaired Ca(2+) cycling, all of which preceded the development of cardiac fibrosis. The time to peak of intracellular Ca(2+) transients was slowed due to T-tubule disruption, providing a link between declining cell ultrastructure and abnormal myocardial mechanics. In conclusion, subclinical abnormalities in myocardial mechanics occur early in response to hypertension and coincide with the development of T-tubule disorganization and impaired intracellular Ca(2+) cycling. These changes occur before the development of significant cardiac fibrosis and precede the development of overt cardiac dysfunction and HF.
The treatment of heart failure (HF) is challenging and morbidity and mortality are high. The goal of this study was to determine if inhibition of the late Na(+) current with ranolazine during early hypertensive heart disease might slow or stop disease progression. Spontaneously hypertensive rats (aged 7 mo) were subjected to echocardiographic study and then fed either control chow (CON) or chow containing 0.5% ranolazine (RAN) for 3 mo. Animals were then restudied, and each heart was removed for measurements of t-tubule organization and Ca(2+) transients using confocal microscopy of the intact heart. RAN halted left ventricular hypertrophy as determined from both echocardiographic and cell dimension (length but not width) measurements. RAN reduced the number of myocytes with t-tubule disruption and the proportion of myocytes with defects in intracellular Ca(2+) cycling. RAN also prevented the slowing of the rate of restitution of Ca(2+) release and the increased vulnerability to rate-induced Ca(2+) alternans. Differences between CON- and RAN-treated animals were not a result of different expression levels of voltage-dependent Ca(2+) channel 1.2, sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a, ryanodine receptor type 2, Na(+)/Ca(2+) exchanger-1, or voltage-gated Na(+) channel 1.5. Furthermore, myocytes with defective Ca(2+) transients in CON rats showed improved Ca(2+) cycling immediately upon acute exposure to RAN. Increased late Na(+) current likely plays a role in the progression of cardiac hypertrophy, a key pathological step in the development of HF. Early, chronic inhibition of this current slows both hypertrophy and development of ultrastructural and physiological defects associated with the progression to HF.
Induction of hemeoxygenase-1 (HO-1) lowers blood pressure and reduces organ damage in hypertensive animal models; however, a potential protective role for HO-1 induction against diabetic-induced glomerular injury remains unclear. We hypothesize that HO-1 induction will protect against diabetes-induced glomerular injury by maintaining glomerular integrity and inhibiting renal apoptosis, inflammation, and oxidative stress. Diabetes was induced with streptozotocin in spontaneously hypertensive rats (SHR) as a model where the coexistence of hypertension and diabetes aggravates the progression of diabetic renal injury. Control and diabetic SHR were randomized to receive vehicle or the HO-1 inducer cobalt protoporphyrin (CoPP). Glomerular albumin permeability was significantly greater in diabetic SHR compared with control, consistent with an increase in apoptosis and decreased glomerular nephrin and α(3)β(1)-integrin protein expression in diabetic SHR. CoPP significantly reduced albumin permeability and apoptosis and restored nephrin and α(3)β(1)-integrin protein expression levels in diabetic SHR. Glomerular injury in diabetic SHR was also associated with increases in NF-κB-induced inflammation and oxidative stress relative to vehicle-treated SHR, and CoPP significantly blunted diabetes-induced increases in glomerular inflammation and oxidative stress in diabetic SHR. These effects were specific to exogenous stimulation of HO-1, since incubation with the HO inhibitor stannous mesoporphyrin alone did not alter glomerular inflammatory markers or oxidative stress yet was able to prevent CoPP-mediated decreases in these parameters. These data suggest that induction of HO-1 reduces diabetic induced-glomerular injury and apoptosis and these effects are associated with decreased NF-κB-induced inflammation and oxidative stress.
Clinical use of prostaglandin synthase-inhibiting NSAIDs is associated with the development of hypertension; however, the cardiovascular effects of antagonists for individual prostaglandin receptors remain uncharacterized. The present studies were aimed at elucidating the role of prostaglandin E2 (PGE2) E-prostanoid receptor subtype 1 (EP1) in regulating blood pressure. Oral administration of the EP1 receptor antagonist SC51322 reduced blood pressure in spontaneously hypertensive rats. To define whether this antihypertensive effect was caused by EP1 receptor inhibition, an EP1-null mouse was generated using a "hit-and-run" strategy that disrupted the gene encoding EP1 but spared expression of protein kinase N (PKN) encoded at the EP1 locus on the antiparallel DNA strand. Selective genetic disruption of the EP1 receptor blunted the acute pressor response to Ang II and reduced chronic Ang II-driven hypertension. SC51322 blunted the constricting effect of Ang II on in vitro-perfused preglomerular renal arterioles and mesenteric arteriolar rings. Similarly, the pressor response to EP1-selective agonists sulprostone and 17-phenyltrinor PGE2 were blunted by SC51322 and in EP1-null mice. These data support the possibility of targeting the EP1 receptor for antihypertensive therapy.
Blood pressure (BP) increases in postmenopausal women. The mechanisms responsible are unknown. The present study was performed to characterize a model of postmenopausal hypertension in the rat and to determine the role that oxidative stress may play in mediating the postmenopausal hypertension. Spontaneously hypertensive rats were ovariectomized (ovx) or left intact (PMR) at 8 months and were aged to 18 months. These animals were compared with young females (YF; 4 or 8 months of age) and old males (18 months) for some measurements. Estradiol levels were decreased in PMR rats to levels not different from YF rats in proestrous or from old males. BP increased progressively with age in PMR rats but not in ovx or male rats, such that the gender difference in hypertension disappeared by 18 months. Glomerular filtration rate was lower in ovx and PMR rats than in YF rats. Renal plasma flow and renal vascular resistance were similar between YF and ovx rats, but lower and higher, respectively, in PMR rats. Serum testosterone increased by 60% in ovx rats and 400% in PMR rats compared with YF rats. Plasma renin activity also increased in PMR rats but not in ovx rats. Chronic treatment (for 8 months beginning at 8 months of age) of PMR rats with vitamins E and C, but not tempol, resulted in a significant reduction in BP and excretion of F2-isoprostanes. In contrast, tempol, but not vitamins E and C, reduced BP in old males. These data suggest that the PMR rats, but not ovx rats, may be a suitable model for the study of postmenopausal hypertension, and that oxidative stress plays a role in the increased BP.
PURPOSE OF THE REVIEW - Inappropriate sympathetic overactivity is consistently observed in patients with essential hypertension. The present review summarizes the recent advances that have been made in our understanding of the role of the sympathetic nervous system in hypertension.
RECENT FINDINGS - Studies in patients with autonomic disorders underscore the role of the sympathetic nervous system in the long-term maintenance of hypertension. Abnormalities in the afferent limb of the sympathetic nervous system, in the regulation of central neurons where sympathetic outflow originates, and in the modulation of efferent sympathetic function, can all produce autonomic disorders that are associated with hypertension. More subtle dysfunctions in any of these components have been described in essential hypertension and can contribute to its pathogenesis. These include impaired buffering capacity of arterial baroreflexes, increased central sympathetic outflow, and enhanced norepinephrine release (or decrease reuptake) from sympathetic nerve terminals. Whether genetic polymorphisms of adrenoreceptors are associated with essential hypertension is an area of active research.
SUMMARY - Increased sympathetic activity can contribute to sustained hypertension not only because of its hemodynamic effects (increased cardiac output and vascular resistance), but also by altering renal and water handling by the kidney, and by inducing cardiac and vascular remodeling. Antihypertensive agents that directly or indirectly target this sympathetic overactivity may be particularly useful in long-term treatment of essential hypertension.
Heterogeneity of structure and function among nephrons is a well-recognized feature of chronic renal diseases. However, only a small number of superficial nephrons per kidney are accessible for micropuncture analysis and relationships of proteinuria to structural change in individual nephrons of experimental models are not clearly established. To directly evaluate proteinuria in many individual nephrons, we developed an immunomorphometric method of analysis. This method is based on the uniformly abundant renal synthesis of Tamm-Horsfall protein (THP) in the thick ascending limb of Henle's loop (TAL). Luminal rabbit immunoglobulin G (IgG) deposits are formed in TALs of proteinuric nephrons in rats injected with heterologous IgG anti-THP antibodies. This immunomorphometric luminal deposit method of assessing proteinuria was previously validated through analysis of heterologous immune complex nephropathy. Glomerular dysfunction in several models-spontaneously hypertensive rats (SHR), aging Sprague-Dawley (SD) rats, rats with adriamycin nephropathy (ADR), and rats subjected to subtotal nephrectomy (NX)-was characterized by immunomorphometric analysis after injection of anti-THP antibodies. Luminal IgG deposits were used to identify nephrons with increased proteinuria. Nephrons were identified histologically as either long looped (LL) or short looped (SL), and frequency of luminal deposits in these nephrons was determined. Glomerular size and sclerosis in deep and superficial zones of renal cortex were determined. Luminal deposits in LL nephrons were more frequent than luminal deposits in SL nephrons in SHRs (p < .001) and aging rats (p < .001) and SL nephrons in ADR rats (p < .02). Whole kidney levels of albuminuria correlated closely with the frequency of luminal deposits in both LL and SL nephrons of SHRs and ADR rats and in LL nephrons of aging rats (p < .005). In contrast, LL and SL deposits were equal in NX rats and did not correlate with albuminuria. A majority of luminal deposits extended beyond the first medullary TAL zone of NX rats, but was confined to this zone in the other 3 models. Deep cortical glomeruli were larger with more glomerulosclerosis than superficial cortical glomeruli. Albuminuria correlated with sclerosis of both deep (p < .002) and superficial (p < .01) glomeruli in NX rats, but not in the other three models. These studies provide a detailed characterization of a new method that allows comparison of proteinuria derived from deep and superficial nephrons. They also provide evidence that pathogenesis of the glomerulosclerosis in NX rats differs from that of the other three models. Glomerulosclerosis was closely linked to the overall level of albuminuria in NX rats, but not to luminal deposits. In the other three models, albuminuria and luminal deposits were closely linked but did not correlate with glomerulosclerosis. Furthermore, LL and SL nephron proteinuria of NX rats was comparable while LL proteinuria was markedly greater than SL proteinuria in the other three models. The luminal deposit method provides a new way to analyze heterogeneity of proteinuria among nephrons and the mechanisms underlying structural change in experimental glomerular diseases.
A potential role for the renin-angiotensin system (RAS) in the development and/or maintenance of hypertension in the genetic model of rat hypertension, spontaneously hypertensive rats (SHR), has been suggested by studies indicating that treatment of immature animals with angiotensin-converting enzyme (ACE) inhibitors prevents subsequent development of hypertension. Because young SHR also demonstrate RAS-dependent increased sodium retention, we examined proximal tubule type 1 angiotensin II receptor (AT1R) mRNA expression in young (4 wk) or adult (14 wk) SHR compared with age-matched Wistar-Kyoto (WKY) rats. Proximal tubules were isolated by Percoll gradient centrifugation, and AT1R mRNA expression was measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR). At 14 wk, when SHR had established hypertension [mean arterial blood pressure (MAP) of SHR vs. WKY: 145 +/- 6 vs. 85 +/- 5 mmHg, n = 14-15], there were no differences in proximal tubule AT1R mRNA levels [SHR vs. WKY: 79 +/- 14 vs. 72 +/- 14 counts/min (cpm) per cpm mutant AT1R per cpm beta-actin x 10(-6), n = 6; not significant (NS)]. In contrast, in 4 wk SHR, at a time of minimal elevations in blood pressure (MAP: 70 +/- 8 vs. 63 +/- 3), SHR proximal tubule AT1R mRNA levels were 263 +/- 30% that of WKY (143 +/- 18 vs. 60 +/- 11 cpm per cpm of mutant AT1R per cpm beta-actin x 10(-6), n = 8; P < 0.005). We have recently shown that chronic ACE inhibition decreases proximal tubule AT1R expression and have also shown that chronic L-3,4-dihydroxyphenylalamine (L-DOPA) administration inhibits AT1R expression in adult Sprague-Dawley proximal tubule and cultured proximal tubule, and this inhibition is mediated via Gs-coupled DA1 receptors. When 3-wk-old animals were given L-DOPA or captopril for 1 wk, MAP was not altered (70 +/- 8 vs. 60 +/- 4 or 61 +/- 5 mmHg), but proximal tubule AT1R mRNA was no longer significantly different between SHR and WKY (68 +/- 9 vs. 38 +/- 7 or 20 +/- 3 vs. 47 +/- 15 cpm per cpm of mutant AT1R per cpm beta-actin x 10(-6)), due to a significant decrease in proximal tubule AT1R expression in SHR (P < 0.005, compared with untreated SHR). Immunoreactive proximal tubule AT1R expression also was increased in 4 wk SHR and was reversed with captopril or L-DOPA treatment. Therefore, these results indicate that young, but not adult, SHR have increased expression of proximal tubule AT1R and that chronic L-DOPA or captopril treatment decreased the elevated AT1R expression to control levels. These results provide further support for an important role of the RAS in the development of hypertension in SHR.
Low density lipoprotein receptor-related protein (LRP) is a multifunctional receptor, expressed by vascular smooth muscle cells (VSMCs) in normal arteries and in atherosclerotic lesions. In this investigation, we demonstrate a novel mechanism for the regulation of LRP activity in cultured rat aortic VSMCs. Cells that were treated with platelet-derived growth factor-BB (PDGF-BB) or epidermal growth factor (EGF) for 24 h bound increased amounts of the LRP ligand, activated alpha2-macroglobulin (alpha2M), at 4 degrees C. The Bmax for activated alpha2M was increased from 56 +/- 5 to 178 +/- 24 and 143 +/- 11 fmol/mg cell protein by PDGF-BB and EGF, respectively, while the KD was unchanged. Northern and Western blot analyses demonstrated that neither PDGF-BB nor EGF increase LRP mRNA or protein levels. Instead, LRP was redistributed to the cell surface and remained localized primarily in coated pits, as determined by surface protein biotinylation, affinity labeling, and immunoelectron microscopy studies. The increase in cell-surface LRP was partially explained by a 50% decrease in receptor endocytosis rate; however, at 37 degrees C, PDGF-BB- and EGF-treated VSMCs still bound/internalized increased amounts of activated alpha2M and subsequently released increased amounts of trichloroacetic acid-soluble radioactivity. The cytokine-induced shifts in LRP subcellular distribution were stable when VSMCs were challenged with a saturating concentration of ligand and then incubated, in the absence of cytokine, for 2.5 h at 37 degrees C. Regulation of LRP distribution and activity may be an important aspect of the VSMC response to the atherogenic cytokines, PDGF-BB and EGF.