A 3.3 fold increase in the ratio of reduced BH4 to oxidized pterins was seen in BH4 fed DOCA-salt animals as compared to hypertensive mice without BH4 feeding (p=NS; Figure 3, d). cardiac BH4 stores, phosphorylated phospholamban levels, and diastolic dysfunction. Isolated cardiomyocyte experiments revealed impaired relaxation that was normalized with acute BH4 treatment. Targeted cardiac overexpression of angiotensin converting enzyme also resulted in cardiac oxidation, NOS uncoupling, and diastolic dysfunction in the absence of hypertension. Conclusions Cardiac oxidation, independent of vascular changes, can lead to uncoupled cardiac NOS and diastolic dysfunction. BH4 may represent a possible treatment for diastolic dysfunction. Left ventricular inflow propagation velocity (Vp) interrogated with color M-mode Doppler. A control mouse shows a steeper isovelocity line slope, corresponding to a higher Vp compared with a hypertensive DOCA mouse. Septal mitral annulus velocities interrogated with tissue Doppler imaging (TDI). The control animal has a higher E (early diastolic velocity), and lower A (late diastolic velocity) than the hypertensive animal. Conventional pulsed wave Doppler shows a normal E/A (early to late diastolic filling velocity ratio) of 1 and 2 for both the control and DOCA mice, a pseudonormal pattern. Invasive hemodynamic evaluation confirmed the echocardiographic findings (Figure 2). As expected, LV end systolic pressure and LV end diastolic pressure were mildly elevated in hypertensive mice as compared to controls (108 3 95 2 mmHg, p=0.002; 7.2 0.7 4.5 0.4 mmHg, p=0.004; Figure 2, aCc ), respectively. Compared to controls, hypertensive mice had prolonged time constants for isovolumic relaxation calculated by two standard methods, Weiss (10.3 0.08 8.1 0.03 ms, p = 0.02) and Glantz (5.9 0.024.9 0.02 ms, p=0.03; Figure 2, d).25 The best fit for the end-diastolic pressure volume-relation (EDPVR) was described by the linear function Pressure end diastole = Rabbit polyclonal to Sp2 EDPVR * Volume end diastole + intercept (median r value 0.99, range 0.91C0.99, for both groups combined; Figure 2, e & f).Hypertensive DOCA-salt mice had a steeper EDPVR compared to controls (1.3 0.1 0.67 0.1 mmHg/L, p=0.0004; Figure 2, e). Open in a separate window Figure 2 Invasive hemodynamic assessment of LV diastolic dysfunction. Baseline pressure-volume loops Amlexanox for hypertensive and control animals. Comparison of LVESP for hypertensive and control animals (p=0.002). Comparison Amlexanox of LVEDP for hypertensive and control animals (7.2 0.7 4.5 0.4 mmHg, p=0.004).The time constant for isovolemic relaxation (Glantz) is increased in hypertensive mice compared to controls (p=0.03).The end-diastolic pressure-volume relation (EDPVR) slope is steeper in hypertensive mice as compared to controls (p=0.0004).Pearson correlation coefficients for linear fitting of the EDPVR.LV contractility assessed by the end-systolic pressure-volume relation (ESPVR) slope (p=NS) and the volume axis intercept Vo (p=NS) are similar between DOCA and control groups. Mean heart rate between groups (p=NS).Arterial elastance (Ea) a measure of vascular stiffness is similar between hypertensive and control mice (p=NS). Diastolic dysfunction did not appear to be the result of changes in Amlexanox myocardial systolic contractile properties. LV systolic function was preserved in hypertensive mice compared to controls based on multiple invasive indices including: the slope of the end-systolic pressure-volume relation (ESPVR; 6.7 0.6 5.3 0.5 mmHg/L, p=NS; Figure 2, Amlexanox f and g ) and its volume axis intercept (Vo; ?2.6 1.3 ?1.6 2.1 mmHg/L, p=NS), LV ejection fraction (52 2.0 45 1.1%, p=NS), stroke volume (16.0 0.4 14.4 0.4 L, p=0.009), and peak rate of pressure rise (dp/dtmax; 10690 459 11680 470 mmHg/s, p=NS).Body weight was similar between the two groups (23.1 0.2 23.3 0.2 g, p=NS). These changes were unexplained by differences in heart rate (553 17 547 10 beats/min, p=NS; Amlexanox Figure 2, h) and arterial elastance, a measure of vascular stiffness that is calculated by dividing the end-systolic pressure by stroke volume, was similar between hypertensive mice and controls.