The American journal of physiology
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We have previously shown that left ventricular (LV) pacing-induced heart failure is associated with preserved wall thickening in the interventricular septum (IVS) compared with the posterolateral wall (PLW). The current study focuses on the relationship between regional myocardial function and altered beta-adrenergic receptor (beta-AR) signaling. We studied 15 pigs: 6 controls and 9 paced from the left ventricle (225 beats/min, 26 +/- 3 days). ⋯ Adenylyl cyclase activity, beta-AR number, and beta-AR/Gs coupling were markedly reduced in failing LV without regional differences. In animals with heart failure, LV G protein receptor kinase (GRK) isoform 2 content was unchanged and GRK5, the other major GRK isoform, was increased more than threefold (IVS, 0.51 +/- 0.20 vs. 0. 12 +/- 0.12 arbitrary densitometric units, P = 0.01; PLW, 0.47 +/- 0. 15 vs. 0.13 +/- 0.09 arbitrary densitometric units, P = 0.03), but again, there were no regional differences. These data indicate that systemic rather than regional factors govern LV adrenergic signaling and that regional adrenergic signaling abnormalities poorly predict wall thickening in the same regions.
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We hypothesized that acute brain injury results in decreased heart rate (HR) variability and baroreflex sensitivity indicative of uncoupling of the autonomic and cardiovascular systems and that the degree of uncoupling should be proportional to the degree of neurological injury. We used HR and blood pressure (BP) power spectral analysis to measure neuroautonomic regulation of HR and BP and the transfer function magnitude (TF) between BP and HR as a measure of baroreflex modulation of HR. ⋯ Brain-dead patients showed decreased low-frequency HR power [0. 51 +/- 0.36 (SE) vs. 2.54 +/- 0.14 beats/min2, P = 0.03] and TF [0. 61 +/- 0.16 (SE) vs. 1.29 +/- 0.07 beats . min-1 . mmHg-1, P = 0.05] compared with non-brain-dead patients. We conclude that 1) severity of neurological injury and outcome are inversely associated with HR and BP variability and 2) there is direct evidence for cardiovascular and autonomic uncoupling in acute brain injury with complete uncoupling during brain death.
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We investigated whether a complete inhibition of nitric oxide (NO) formation caused by bacterial endotoxin (lipopolysaccharide, LPS) in vivo prevents the hypotension and restores the vascular hyporeactivity to normal in vivo and ex vivo. The combination of dexamethasone (Dex; 3 mg/kg at 30 min before LPS) plus aminoguanidine (AG; 15 mg/kg at 2 h after LPS) inhibited the overproduction of nitrate (an indicator of NO) in the plasma and aortic smooth muscle and also prevented the development of the delayed hypotension in rats treated with LPS for 6 h. However, the vascular hyporeactivity to norepinephrine (NE) was only partially improved either in vivo or ex vivo in endotoxemic rats treated with Dex plus AG. ⋯ Interestingly, we found that in the presence of tetraethylammonium (an inhibitor of K+ channels) plus L-NAME or charybdotoxin [a specific inhibitor of large-conductance Ca2+-activated K+ (KCa) channels] plus ODQ, the vascular hyporeactivity to NE in the LPS-treated group was also completely restored to normal. In addition, in the presence of L-NAME or ODQ, the vascular hyporeactivity to high K+ was abolished in rings from the LPS-treated group. These results suggest that LPS causes the production of other mediator(s), in addition to NO, which also stimulates soluble GC (i.e., increases the formation of cGMP) and then activates the large-conductance KCa channels in the vascular smooth muscle causing vascular hyporeactivity.
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Maternal obesity and genetic background can affect the development of obesity and diabetes in offspring. Here we used selected strains of rats resistant (DR) vs. susceptible to development of diet-induced obesity (DIO) on high-energy (HE) diets to assess this issue. DR and DIO dams were fed either Chow or HE diet for 4 wk. ⋯ After 4 wk on HE diet, all DIO offspring gained more weight and had heavier total adipose depots and higher insulin and leptin levels than DR offspring. Offspring of DIO HE dams also gained more weight and had heavier fat depots and higher leptin levels than DIO Chow offspring. Therefore maternal obesity and hyperinsulinemia were associated with increased obesity in those offspring already genetically predisposed to become obese.