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Background Hyperphosphataemia is strongly associated with cardiovascular disease and mortality. Recently, phosphate binders (PBs), which are used to bind intestinal phosphate, have been shown to bind vitamin K, thereby potentially aggravating vitamin K deficiency. This vitamin K binding by PBs may offset the beneficial effects of phosphate reduction in reducing vascular calcification (VC). Here we assessed whether combining PBs with vitamin K2 supplementation inhibits VC. Methods We performed 3/4 nephrectomy in rats, after which warfarin was given for 3 weeks to induce vitamin K deficiency. Next, animals were fed a high phosphate diet in the presence of low or high vitamin K2 and were randomized to either control or one of four different PBs for 8 weeks. The primary outcome was the amount of thoracic and abdominal aorta VC measured by high-resolution micro-computed tomography (µCT). Vitamin K status was measured by plasma MK7 levels and immunohistochemically analysed in vasculature using uncarboxylated matrix Gla protein (ucMGP) specific antibodies. Results The combination of a high vitamin K2 diet and PB treatment significantly reduced VC as measured by µCT for both the thoracic (P = 0.026) and abdominal aorta (P = 0.023), compared with MK7 or PB treatment alone. UcMGP stain was significantly more present in the low vitamin K2–treated groups in both the thoracic (P < 0.01) and abdominal aorta (P < 0.01) as compared with high vitamin K2–treated groups. Moreover, a high vitamin K diet and PBs led to reduced vascular oxidative stress. Conclusion In an animal model of kidney failure with vitamin K deficiency, neither PB therapy nor vitamin K2 supplementation alone prevented VC. However, the combination of high vitamin K2 with PB treatment significantly attenuated VC. [ABSTRACT FROM AUTHOR]

Recent studies have been directed at modulating the heart failure process through inhibition of activated matrix metalloproteinases (MMPs). We hypothesized that a loss of MMP inhibitory control by tissue inhibitor of MMP (TIMP)-1 deficiency alters the course of postinfarction chamber remodeling and induced chronic myocardial infarction (MI) in wild-type (WT) and TIMP-[1.sup.-/-] mice. Left ventricular (LV) pressure-volume loops obtained from WT and TIMP-[1.sup.-/-] mice demonstrated that LV end-diastolic volume [52 [+ or -] 4 (WT) vs. 71 [+ or -] 6 (TIMP-[1.sup.-/-]) [micro]l] and LV end-diastolic pressure [9.0 [+ or -] 1.2 (WT) vs. 12.7 [+ or -] 1.4 (TIMP-[1.sup.-/-]) mmHg] were significantly increased in the TIMP-[1.sup.-/-] mice 2 wk after MI. LV contractility was reduced to a similar degree in the WT and TIMP-[1.sup.-/-] groups after MI, as indicated by a significant fall in the LV end-systolic pressure-volume relationship. Ventricular weight and cross-sectional areas of LV myocytes were significantly increased in TIMP-[1.sup.-/-] mice, indicating that the hypertrophic response was more pronounced. The observed significant loss of fibriliar collagen in the TIMP-[1.sup.-/-] controls may have been an important contributory factor for the observed LV alterations in the TIMP-[1.sup.-/-] mice after MI. These findings demonstrate that TIMP-1 deficiency amplifies adverse LV remodeling after MI in mice and emphasizes the importance of local endogenous control of cardiac MMP activity by TIMP-1. myocardial remodeling; pressure-volume loops

Background: In humans, type 1 diabetes (T1D) is associated with arterial stiffening as assessed by carotid-femoral pulse wave velocity (cfPWV) [1]. To experimentally study the underlying mechanism of this stiffening, we investigated blood pressure (BP) and cfPWV in streptozotocin (STZ)-induced diabetes in mice. Methods: Twenty-four 9-week-old male C57BL/6 J mice were divided equally among diabetic (induced through once-daily 50 mg/kg STZ injections for five days) and control (sham injections using citrate buffer) groups, and were kept to an age of 24 weeks. Fasting glucose was measured every 4-5 weeks via tail blood collection with levels of 15 mmol/L and higher considered diabetic. Non-invasive tonometric cfPWV was measured in anaesthetised animals (1% isoflurane) 24 h prior to euthanasia; tail-cuff BP was measured directly prior to euthanasia. Results: Diabetic mice exhibited higher fasting glucose than controls (p < 0.0001, two-way ANOVA with Tukey post-hoc test; Fig. A). There was no difference in systolic BP (110 ± 4 vs. 104 ± 3 mmHg, p = 0.26, mean ± SE, unpaired t-test) and cfPWV (2.60 ± 0.14 vs. 2.55 ± 0.11 m/s, p = 0.80) between diabetic and control mice (Fig. B-C). Discussion: In the popular animal model of STZ-induced T1D, existing literature on systolic BP is not consistent [2,3]. Literature about cfPWV is limited: in contrast to our data, one report showed an STZ-induced increase in ultrasound-derived cfPWV [4]. Discrepancies between studies could be due to different methods of measuring BP and cfPWV [5]; the choice of measurement methods therefore needs critical appraisal. Conclusion: In the murine model of STZ-induced T1D, we did not find elevated BP or increased arterial stiffness. [ABSTRACT FROM AUTHOR]

Janssen, Ben J. A., Peter J. A. Leenders, and Jos F. M. Smits. Short-term and long-term blood pressure and heart rate variability in the mouse. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 278: R215-R225, 2000.--Knowledge on murine blood pressure and heart rate control mechanisms is limited. With the use of a tethering system, mean arterial pressure (MAP) and pulse interval (PI) were continuously recorded for periods up to 3 wk in Swiss mice. The day-to-day variation of MAP and PI was stable from 5 days after surgery. Within each mouse (n = 9), MAP and PI varied by 21 [+ or -] 6 mmHg and 17 [+ or -] 4 ms around their respective 24-h averages (97 [+ or -] 3 mmHg and 89 [+ or -] 3 ms). Over 24-h periods, MAP and PI were bimodally distributed and clustered around two preferential states. Short-term variability of MAP and PI was compared between the resting (control) and active states using spectral analysis. In resting conditions, variability of MAP was mainly confined to frequencies [is less than] 1 Hz, whereas variability of PI was predominantly linked to the respiration cycle (3-6 Hz). In the active state, MAP power increased in the 0.08- to 3-Hz range, whereas PI power fell in the 0.08- to 0.4-Hz range. In both conditions, coherence between MAP and PI was high at 0.4 Hz with MAP leading the PI fluctuations by 0.3-0.4 s, suggesting that reflex coupling between MAP and PI occurred at the same frequency range as in rats. Short-term variability of MAP and PI was studied after intravenous injection of autonomic blockers. Compared with the resting control state, MAP fell and PI increased after ganglionic blockade with hexamethonium. Comparable responses of MAP were obtained with the [Alpha]-blocker prazosin, whereas the [Beta]-blocker metoprolol increased PI similarly. Muscarinic blockade with atropine did not significantly alter steady-state levels of MAP and PI. Both hexamethonium and prazosin decreased MAP variability in the 0.08- to 1-Hz range. In contrast, after hexamethonium and metoprolol, PI variability increased in the 0.4- to 3-Hz range. Atropine had no effect on MAP fluctuations but decreased those of PI in the 0.08- to 1-Hz range. These data indicate that, in mice, blood pressure and its variability are predominantly under sympathetic control, whereas both vagal and sympathetic nerves control PI variability. Blockade of endogenous nitric oxide formation by [N.sup.G]-nitro-L-arginine methyl ester increased MAP variability specifically in the 0.08- to 0.4-Hz range, suggesting a role of nitric oxide in buffering blood pressure fluctuations. autonomic control; baroreflex; circadian rhythm; set point; spectral analysis

Objectives: We studied the effects of chronic left coronary artery ligation on cardiac structure and function in the mouse. Methods: Morphometric studies of the left ventricle were performed in coronary artery-ligated and sham-operated animals at one, two, three and five weeks after surgery. The fraction of DNA-synthesizing cells was determined as the fraction of cells incorporating 5′-bromo-2′-deoxyuridine, which was infused by osmotic minipumps one week before sacrifice. Collagen content of the septum was determined morphometrically. Left ventricular pressure and its derivatives were measured in separate groups of animals at one and three weeks after surgery. Results: Ligation of the main left coronary artery resulted in antero-apical infarction of the left ventricular wall, involving ∼40% of left ventricular circumference. Infarction resulted in thinning of the infarcted area and left ventricular dilatation. DNA synthesis increased, peaking between one and two weeks in the border-zone of the infarct (22-fold), septum (ten-fold) and right ventricle (five-fold). At five weeks, DNA synthesis was still increased in the border zone of the infarct. Septal collagen content increased ~eight-fold in infarcted mice at two weeks, and decreased thereafter; it was still significantly elevated at five weeks. Left ventricular systolic pressure, and maximal positive and negative dP/dt decreased following infarction; left ventricular end-diastolic pressure was elevated at three weeks, but this effect was not statistically significant. Conclusion: These data provide basic information on changes in cardiac structure and function in mice following chronic coronary artery ligation. They indicate the feasibility of induction of chronic myocardial infarction in this species. Furthermore, they show the similarity of cardiac structural and functional consequences of chronic myocardial infarction in mice to those previously described in rats. [ABSTRACT FROM PUBLISHER]