Changes in cellular Ca2+ and Na+ regulation during the progression towards heart failure in the guinea pig.

KEY POINTS: During compensated hypertrophy in vivo fractional shortening (FS) remains constant until heart failure (HF) develops, when FS decreases from 70% to 39%. Compensated hypertrophy is accompanied by an increase in INa,late and a decrease in Na+ ,K+ -ATPase current. These changes persist as HF develops. SR Ca2+ content increases during compensated hypertrophy then decreases in HF. In healthy cells, increases in SR Ca2+ content and Ca2+ transients can be achieved by the same amount of inhibition of the Na+ ,K+ -ATPase as measured in the diseased cells. SERCA function remains constant during compensated hypertrophy then decreases in HF, when there is also an increase in spark frequency and spark-mediated Ca2+ leak. We suggest an increase in INa,late and a decrease in Na+ ,K+ -ATPase current and function alters the balance of Ca2+ flux mediated by the Na+ /Ca2+ exchange that limits early contractile impairment. ABSTRACT: We followed changes in cardiac myocyte Ca2+ and Na+ regulation from the formation of compensated hypertrophy (CH) until signs of heart failure (HF) are apparent using a trans-aortic pressure overload (TAC) model. In this model, in vivo fractional shortening (FS) remained constant despite HW:BW ratio increasing by 39% (CH) until HF developed 150 days post-TAC when FS decreased from 70% to 39%. Using live and fixed fluorescence imaging and electrophysiological techniques, we found an increase in INa,late from -0.34 to -0.59 A F-1 and a decrease in Na+ ,K+ -ATPase current from 1.09 A F-1 to 0.54 A F-1 during CH. These changes persisted as HF developed (INa,late increased to -0.82 A F-1 and Na+ ,K+ -ATPase current decreased to 0.51 A F-1 ). Sarcoplasmic reticulum (SR) Ca2+ content increased during CH then decreased in HF (from 32 to 15 µm l-1 ) potentially supporting the maintenance of FS in the whole heart and Ca2+ transients in single myocytes during the former stage. We showed using glycoside blockade in healthy myocytes that increases in SR Ca2+ content and Ca2+ transients can be driven by the same amount of inhibition of the Na+ ,K+ -ATPase as measured in the diseased cells. SERCA function remains constant in CH but decreases (τ for SERCA-mediated Ca2+ removal changed from 6.3 to 3.0 s-1 ) in HF. In HF there was an increase in spark frequency and spark-mediated Ca2+ leak. We suggest an increase in INa,late and a decrease in Na+ ,K+ -ATPase current and function alters the balance of Ca2+ flux mediated by the Na+ /Ca2+ exchange that limits early contractile impairment.

A computational fluid dynamics study of inspiratory flow in orotracheal geometries.

Computational fluid dynamics (CFD) has been used to investigate the flow of air through the human orotracheal system. Results from an idealised geometry, and from a patient-specific geometry created from MRI scans were compared. The results showed a significant difference in the flow structures between the two geometries. Inert particles with diameters in the range 1-9 microm were tracked through the two geometries. Particle diameter has proved to be an important factor in defining the eventual destinations of inhaled particles. Results from our calculations match other experimental and computational results in the literature, and differences between the idealised and patient-specific geometries are less significant.

Adrenalectomy increases reduced nicotinamide adenine dinucleotide phosphate-diaphorase activity in the rat spinal trigeminal subnucleus caudalis.

Neurons exhibiting reduced nicotinamide adenine dinucleotide phosphate-diaphorase activity (NADPHd) were quantified at 500 microns rostrocaudal intervals in spinal trigeminal nucleus (Vsp) of adenalectomized (ADX), ADX + corticosterone, and sham-ADX rats 6-12 days after surgery. NADPHd neurons were found predominantly in Vsp subnucleus caudalis (Vc) and in dorsomedial subnucleus oralis. ADX significantly increased the number of NADPHd neurons in superficial laminae of Vc, an effect reversed by chronic corticosterone replacement. ADX effects on NADPHd in superficial laminae of Vc but not in deep laminae of Vc or in the periobex region of Vsp paralleled previously observed sites of ADX enhancement of noxious stimulus-induced Fos-like immunoreactivity. The results indicate that chronic changes in adrenal steroid status regulate NADPHd, a mechanism that may both derive from changes in nitric oxide synthase expression and influence the processing of nociceptive information by central trigeminal neurons.