MODULATION OF CALCIUM CHANNELS IN ARTERIAL SMOOTH-MUSCLE CELLS BY DIHYDROPYRIDINE ENANTIOMERS

The actions of the optical enantiomers of BAY K 8644 and Sandoz 202,791 were studied on barium inward currents recorded using the whole-cell configuration of the patch clamp technique from enzymatically isolated smooth muscle cells from the rabbit ear artery. The enantiomers were applied by bath perfusion or rapidly by a concentration jump technique, which enabled the study of drug action under equilibrium and nonequilibrium conditions. A larger effect of agonists was seen on peak inward current in 110 mM Ba when small rather than large depolarizations were applied. The midpoint voltage of the steady-state inactivation curve of IBa was -12.8 +/- 1.9 mV (n = 4) in the absence of drug, -16.4 +/- 2.5 mV (n = 4) in 1 microM (+)202,791, and -31.4 +/- 0.4 mV (n = 4) in 1 microM (-)202,791. The rate of onset of action of the agonist and antagonist enantiomers of BAY K 8644 and Sandoz 202,791 was studied by rapid application during 20-ms depolarizing steps from different holding potentials to +30 mV at 1 or 0.2 Hz. The drugs were applied as concentration jumps between two single pulses of a pulse train. The rates of onset of drug action on peak IBa during a 1-Hz pulse train were concentration dependent over the range of 100 nM-3 microM for both (+) and (-)202,791. The rate of onset of inhibition of peak current by antagonist enantiomers was not significantly influenced by the test pulse frequency. At a holding potential of -60 mV, the onset rate of the increase in peak IBa on application of 1 microM of agonist enantiomers (+)202,791 or (-)BAY K 8644 during a train of pulses occurred with mean time constants of 2.1 +/- 0.7 s (n = 7) and 2.3 +/- 0.2 s (n = 4), respectively. The onset of current increase on application of 1 microM (+)202,791 during a single voltage clamp step to 20 mV was faster, with a mean time constant of 380 +/- 80 ms (n = 3)

Estimation of maximal oxygen consumption and heart rate recovery using the Tecumseh sub-maximal step test and their relationship to cardiovascular risk factors

BACKGROUND: Maximum aerobic capacity (VO2max) is associated with lower cardiovascular and total mortality. Step tests can be used to provide an estimate of (VO2max) in epidemiological or home-based studies. We compared different methods of estimation of VO2max and heart rate recovery and evaluated the relationship of these estimates with cardiovascular risk factors. METHODS: Data were analysed from 2286 participants in the Tecumseh Community Health Study (>16 y and <70 y) who performed a step test. VO2max was estimated from heart rate using three methods and the results compared. The magnitude of heart rate recovery (HRR) and the time constant of recovery based on different time intervals post-exercise were also estimated. RESULTS: Estimated VO2max showed good or poor agreement depending on the method used. VO2max correlated inversely with systolic blood pressure (SBP), body mass index (BMI), total cholesterol, blood glucose following a 100 g oral load (PLG) and Framingham risk score. In a multivariable model age sex, cigarette smoking, SBP, BMI and PLG were significantly inversely associated with VO2max. Correlations with risk factors were strongest for HRR measured over the first 30 s of recovery. Only the time constant calculated from the 3 min post-exercise period correlated significantly with risk factors. CONCLUSIONS: The Tecumseh step test can be used to provide estimates of VO2max and heart rate recovery. Estimated VO2max was inversely associated with higher systolic BP, higher BMI and worse glucose tolerance. Measurements of HRR over the first 30 s and the time constant calculate from the first 3 min of recovery correlate most closely with risk factors

The modified arterial reservoir: An update with consideration of asymptotic pressure (P∞) and zero-flow pressure (Pzf)

This article describes the modified arterial reservoir in detail. The modified arterial reservoir makes explicit the wave nature of both reservoir (Pres) and excess pressure (Pxs). The mathematical derivation and methods for estimating Pres in the absence of flow velocity data are described. There is also discussion of zero-flow pressure (Pzf), the pressure at which flow through the circulation ceases; its relationship to asymptotic pressure (P∞) estimated by the reservoir model; and the physiological interpretation of Pzf . A systematic review and meta-analysis provides evidence that Pzf differs from mean circulatory filling pressure

Wave intensity analysis: A novel non-invasive method for determining arterial wave transmission

Wave intensity analysis is a novel technique for assessing wavelet transmission in the cardiovascular system. Using this tool, we have developed non-invasive techniques to study wave transmission in both central & peripheral arteries in man. The aim of this study was to determine the reproducibility of various haemodynamic measures in the carotid, brachial and radial arteries. 12 treated hypertensive men underwent applanation tonometry and pulsed Doppler ultrasound studies of the carotid, brachial and radial arteries on 2 occasions. Coefficients of variation for the local wave speed, cardiac compression wave intensity and main reflected wave intensity ranged between 3.7-6.6%, 8.2-11.4% and 12.5-19.6% respectively. We conclude that non-invasive methods used for wave intensity analysis are reproducible & provide additional information regarding the complex phenomenon of arterial wave transmission in man

Reproducibility of Left Ventricular Dyssynchrony Indices by Three-Dimensional Speckle-Tracking Echocardiography: The Impact of Sub-optimal Image Quality

Background: 3D speckle-tracking echocardiography (3D-STE) is a novel method to quantify left ventricular (LV) mechanical dyssynchrony. 3D-STE is influenced by image quality, but studies on the magnitude of its effect on 3D-STE derived LV systolic dyssynchrony indices (SDIs) and their test-retest reproducibility are limited. Methods: 3D-STE was performed in two groups, each comprising 18 healthy volunteers with good echocardiographic windows. In study 1, optimal and inferior-quality images, by intentionally poor echocardiographic technique, were acquired. In study 2, sub-optimal quality images were acquired by impairing ultrasound propagation using neoprene rubber sheets (thickness 2, 3, and 4 mm) mimicking mildly, moderately, and severely impaired images, respectively. Measures (normalized to cardiac cycle duration) were volume- and strain-based SDIs defined as the standard deviation of time to minimum segmental values, and volume- and strain-derived dispersion indices. For both studies test-retest reproducibility was assessed. Results: Test-retest reproducibility was better for most indices when restricting the analysis to good quality images; nevertheless, only volume-, circumferential strain-, and principal tangential strain-derived LV dyssynchrony indices achieved fair to good reliability. There was no evidence of systematic bias due to sub-optimal quality image. Volume-, circumferential strain-, and principal tangential strain-derived SDIs correlated closely. Radial strain- and longitudinal strain-SDI correlated moderately or weakly with volume-SDI, respectively. Conclusions: Sub-optimal image quality compromised the reliability of 3D-STE derived dyssynchrony indices but did not introduce systematic bias in healthy individuals. Even with optimal quality images, only 3D-STE indices based on volume, circumferential strain and principal tangential strain showed acceptable test-retest reliability

Ethnic Differences in Associations Between Blood Pressure and Stroke in South Asian and European Men.

It is unknown whether associations between blood pressure (BP) and stroke vary between Europeans and South Asians, despite higher stroke rates in the latter. We report findings from a UK cohort study of 1375 European and 1074 South Asian men, not receiving antihypertensive medication, aged 40 to 69 years at baseline (1988-1991). Assessment included BP, blood tests, anthropometry, and questionnaires. Incident stroke was established at 20 years from death certification, hospital and primary care records, and participant report. South Asians had higher systolic BP, diastolic BP, and mean arterial pressure than Europeans, and similar pulse pressure. Associations between systolic BP or diastolic BP and stroke were stronger in South Asians than Europeans, after adjustment for age, smoking status, waist/hip ratio, total/high-density lipoprotein-cholesterol ratio, diabetes mellitus, fasting glucose, physical activity, and heart rate (systolic BP: Europeans [odds ratio, 1.22; 95% confidence interval, 0.98-1.51], South Asians [1.56; 1.24-1.95]; ethnic difference P=0.04; diastolic BP: Europeans [0.90; 0.71-1.13], South Asians [1.68; 1.32-2.15]; P<0.001). Hemodynamic correlates of stroke risk differed by ethnicity: in combined models, mean arterial pressure but not pulse pressure was detrimentally associated with stroke in South Asians, whereas the converse was true for Europeans. The combination of hyperglycemia and hypertension appeared particularly detrimental for South Asians. There are marked ethnic differences in associations between BP parameters and stroke. Undue focus on systolic BP for risk prediction, and current age and treatment thresholds may be inappropriate for individuals of South Asian ancestry

Mechanism of the Vasodilator Action of Pinacidil

The mechanism of the vasodilator action of pinacidil has been studied in rat mesenteric small arteries. The results show, first, that the use of flux studies to make measurements of ion permeability requires knowledge of the membrane potential, especially as regards K+ permeability. Second, the results confirm that the vasodilator effect of pinacidil is due to an increase in K+ permeability. Lastly, the results suggest that the K+ channels involved are sensitive to glibenclamide

Optimality, cost minimization and the design of arterial networks

The arterial circulation acts as a network to deliver nutrients and oxygen to cells. The design of the cardiovascular system is subject to a variety of constraints and costs. It has been postulated that the design of the arterial network might be understood in terms of the need to minimize competing 'costs' within the context of physical or material limits to the system. These designs can also be envisaged as being subservient to space filling or fractal considerations. The signalling mechanisms underlying these designs remain to be fully characterized although shear stress, wall tensile stress and metabolic stimuli are likely candidates. I will also review evidence that deviations from a minimal cost condition or optimal design may provide both a measure of disease severity and insights into the underlying disease mechanism

Thigh fat and muscle each contribute to excess cardiometabolic risk in South Asians, independent of visceral adipose tissue.

OBJECTIVE: To compare fat distribution and associations between fat depots and cardiometabolic traits in South Asians and Europeans. METHODS: Five hundred and fourteen South Asians and 669 Europeans, aged 56-86. Questionnaires, record review, blood testing, and coronary artery calcification scores provided diabetes and clinical plus subclinical coronary heart disease (CHD) diagnoses. Abdominal visceral (VAT) and subcutaneous adipose tissue, thigh subcutaneous adipose tissue (TSAT), intermuscular and intramuscular thigh fat and thigh muscle were measured by CT. RESULTS: Accounting for body size, South Asians had greater VAT and TSAT than Europeans, but less thigh muscle. Associations between depots and disease were stronger in South Asians than Europeans. In multivariable analyses in South Asians, VAT was positively associated with diabetes and CHD, while TSAT and thigh muscle were protective for diabetes, and thigh muscle for CHD. Differences in VAT and thigh muscle only partially explained the excess diabetes and CHD in South Asians versus Europeans. Insulin resistance did not account for the effects of TSAT or thigh muscle. CONCLUSIONS: Greater VAT and TSAT and lesser thigh muscle in South Asians contributed to ethnic differences in cardiometabolic disease. Effects of TSAT and thigh muscle were independent of insulin resistance

Associations and clinical relevance of aortic-brachial artery stiffness mismatch, aortic reservoir function, and central pressure augmentation

Central augmentation pressure (AP) and index (AIx) predict cardiovascular events and mortality, but underlying physiological mechanisms remain disputed. While traditionally believed to relate to wave reflections arising from proximal arterial impedance (and stiffness) mismatching, recent evidence suggests aortic reservoir function may be a more dominant contributor to AP and AIx. Our aim was therefore to determine relationships among aortic-brachial stiffness mismatching, AP, AIx, aortic reservoir function, and end-organ disease. Aortic (aPWV) and brachial (bPWV) pulse wave velocity were measured in 359 individuals (aged 61 ± 9, 49% male). Central AP, AIx, and aortic reservoir indexes were derived from radial tonometry. Participants were stratified by positive (bPWV > aPWV), negligible (bPWV ≈ aPWV), or negative stiffness mismatch (bPWV < aPWV). Left-ventricular mass index (LVMI) was measured by two-dimensional-echocardiography. Central AP and AIx were higher with negative stiffness mismatch vs. negligible or positive stiffness mismatch (11 ± 6 vs. 10 ± 6 vs. 8 ± 6 mmHg, P < 0.001 and 24 ± 10 vs. 24 ± 11 vs. 21 ± 13%, P = 0.042). Stiffness mismatch (bPWV-aPWV) was negatively associated with AP (r = −0.18, P = 0.001) but not AIx (r = −0.06, P = 0.27). Aortic reservoir pressure strongly correlated to AP (r = 0.81, P < 0.001) and AIx (r = 0.62, P < 0.001) independent of age, sex, heart rate, mean arterial pressure, and height (standardized β = 0.61 and 0.12, P ≤ 0.001). Aortic reservoir pressure independently predicted abnormal LVMI (β = 0.13, P = 0.024). Positive aortic-brachial stiffness mismatch does not result in higher AP or AIx. Aortic reservoir function, rather than discrete wave reflection from proximal arterial stiffness mismatching, provides a better model description of AP and AIx and also has clinical relevance as evidenced by an independent association of aortic reservoir pressure with LVMI