Showing papers by "Philip A. Poole-Wilson published in 1993"

Reduced content of connexin43 gap junctions in ventricular myocardium from hypertrophied and ischemic human hearts.

Abstract: BACKGROUNDGap junctions are a determinant of myocardial conduction. Disturbances of gap-junctional content may account for abnormalities of impulse propagation, contributing to the arrhythmic tendency and mechanical inefficiency of ischemic and hypertrophied myocardium. The aim of this study was to characterize gap junction organization in normal human ventricular myocardium and to establish whether abnormalities exist in myocardium of chronically ischemic and hypertrophied hearts.METHODS AND RESULTSCardiac gap-junctional connexin43 antibodies and confocal microscopy were used in a quantitative immunohistochemical study of surgical myocardial samples to explore the structural basis of electromechanical ventricular dysfunction in chronic ischemic and hypertrophic heart diseases. Normal adult human left ventricular myocardium had a gap-junctional surface area of 0.0051 micron2/micron3 myocyte volume; gap junctions were confined to intercalated disks, of which there was a mean of 11.6 per cell. The right ven...

Nitric oxide attenuates cardiac myocyte contraction

Abstract: Cardiac muscle fibers have microvessels in close proximity, the distance from the nearest capillary being no greater than 8 microns. We performed experiments on isolated, electrically stimulated, c...

Pathogenesis of oedema in chronic severe anaemia: studies of body water and sodium, renal function, haemodynamic variables, and plasma hormones.

Abstract: BACKGROUND--Patients with chronic severe anaemia often retain salt and water. Fluid retention in these patients is not caused by heart failure and the exact mechanisms remain unclear. This study was designed to examine some of the possible mechanisms. METHODS AND RESULTS--Haemodynamic variables, body fluid compartments, renal function, and plasma hormones were measured in four patients with oedema caused by chronic severe anaemia (mean (SE) haematocrit 13 (1.7)) who had never received any treatment. Cardiac output was increased (6.1 (0.6) l/min/m2) and right atrial (7.8 (1) mm Hg), mean pulmonary arterial (20.5 (2.0) mm Hg), and mean pulmonary arterial wedge (13 (2.7) mm Hg) pressures were slightly increased. The mean systemic arterial pressure (81 (1.3) mm Hg) and systemic vascular resistance (12.3 (1.1) mm Hg x min x m2/l were low. There were significant increases in total body water (+14%), extracellular volume (+32%), plasma volume (+70%), and total body exchangeable sodium (+30%). Renal blood flow was moderately decreased (-46%) and the glomerular filtration rate was slightly reduced (-24%). There were significant increases in plasma noradrenaline (2.1-fold), renin activity (15-fold), aldosterone (3.2-fold), growth hormone (6.3-fold), and atrial natriuretic peptide (12-fold). CONCLUSION--In patients with oedema caused by chronic severe anaemia there is retention of salt and water, reduction of renal blood flow and glomerular filtration rate, and neurohormonal activation similar to that seen in patients with oedema caused by myocardial disease. However, unlike patients with myocardial disease, patients with anaemia have a high cardiac output and a low systemic vascular resistance and blood pressure. It is suggested that the low concentration of haemoglobin in patients with anaemia causes a reduced inhibition of basal endothelium-derived relaxing factor activity and leads to generalised vasodilatation. The consequent low blood pressure may be the stimulus for neurohormonal activation and salt and water retention.

Coexistence of functioning beta 1- and beta 2-adrenoceptors in single myocytes from human ventricle.

Abstract: BACKGROUNDBoth beta 1- and beta 2-adrenoceptors (beta 1 AR and beta 2 AR) are present in human ventricle. This study was designed to determine whether the two subtypes contribute to contraction in single myocytes from human heart.METHODS AND RESULTS(-)-Epinephrine increased the contraction amplitude and velocity of single myocytes isolated from the ventricles of failing and nonfailing human hearts. Concentration-response curves to (-)-epinephrine were constructed in the presence and absence of selective antagonists for beta 1 AR (CGP 20712A) and beta 2 AR (ICI 118,551). Responses to (-)-epinephrine were antagonized to a variable degree by the blockers, suggesting heterogeneous contribution of beta 1AR and beta 2AR among cells. The most common response in single myocytes was that ICI 118,551 (50 nmol/L) shifted the concentration-response curve less than 10-fold: this was lower than the 100-fold shift expected for a pure beta 2AR effect. Inclusion of CGP 20712A (300 nmol/L) with ICI 118,551 shifted the (-)-...

Incomplete reversal of β‐adrenoceptor desensitization in human and guinea‐pig cardiomyocytes by cyclic nucleotide phosphodiesterase inhibitors

Abstract: 1. The decreased response to beta-adrenoceptor stimulation seen in heart failure may be related to a defect in cyclic AMP production. The inotropic effects of the selective phosphodiesterase (PDE) III inhibitors, SKF either at threshold or maximum inotropic concentrations, or by CPT cyclic AMP, an analogue of cyclic AMP.6. A significant potentiation of the maximum isoprenaline response by threshold inotropic concentrations was observed with SK&F 94120 (P<0.05), but not with IBMX or SK&F 94836, in myocytes isolated from noradrenaline-treated guinea-pig hearts. This potentiation, however, did not completely restore the response to levels seen in control myocytes.7. The extent of potentiation of the maximum isoprenaline response by maximum inotropic concentrations of either IBMX or CPT cyclic AMP, was no greater than that by threshold concentrations of IBMX, in myocytes isolated from noradrenaline-treated guinea-pig hearts.8. In cardiac myocytes isolated from the explanted hearts of 16 patients with heart failure, threshold concentrations of IBMX and SK&F 94120 decreased the isoprenaline EC50 by a factor of four and six,respectively, but potentiation of the maximum isoprenaline response occurred only with SK&F 94120.The attenuated isoprenaline response was increased from 60.3 +/- 4.5% to 74.3 +/- 4.2% as a % maximum calcium (P<0.05, n = 6), but remained substantially lower than the 116 +/- 7% (P<0.001, n = 6) seen in myocytes isolated from non-failing hearts.9. We conclude that the reduced maximum contraction amplitude with isoprenaline in cardiac myocytes from either patients in end-stage failure, or noradrenaline-treated guinea-pigs, is partly but not solely due to insufficient cyclic AMP levels, since inhibition of cyclic AMP degradation does not result incomplete reversal of the beta-adrenoceptor desensitization.

Skeletal muscle blood flow in heart failure measured by ultrafast computed tomography: validation by comparison with plethysmography

Abstract: Objectives: Abnormalities of skeletal muscle perfusion and metabolism may be important in the symptomatic limitation of patients with chronic heart failure. A method for assessing both skeletal muscle blood flow and mass would be useful in clinical practice and research. Ultrafast computed tomography has the potential to make these measurements. The aim was to determine the accuracy with which skeletal muscle blood flow could be measured by ultrafast computed tomography in patients with chronic heart failure. Methods: Leg blood flow measured by venous occlusion plethysmography was compared with skeletal muscle blood flow by ultrafast computed tomography. Fourteen patients with chronic heart failure (aged 51 to 76 years) were investigated. Plethysmography and ultrafast computed tomography measurements were performed at rest and during hyperaemic flow induced by symptom limited bicycle exercise followed by five minutes of leg ischaemia. The ultrafast computed tomography measurements were made by analysing the opacification of the blood pool and of the muscle after an intravenous bolus of non-ionic radio-opaque contrast. Results: Flows assessed by plethysmography ranged from 1.5 to 38.1 ml·100 ml−1·min−1. The slope of the line relating the two methods was 1.1 (95% confidence interval 0.91 to 1.31), and the mean (95% limits of agreement) of the differences between the two methods was 2.5(10.6) ml·100 ml−1·min−1. Conclusions: Ultrafast computed tomography is a useful tool in the measurement of both skeletal muscle mass and perfusion in humans. Cardiovascular Research 1993; 27 :1109-1115