Summary This study determined whether the membrane-permeable ventilatory stimulant, L-cysteine ethylester (L-CYSee), reversed the deleterious actions of morphine on arterial blood-gas chemistry in isoflurane-anesthetized rats. Morphine (2 mg/kg, i.v.) elicited sustained decreases in arterial blood pH, pO2 and sO2, and increases in pCO2 (all responses indicative of hypoventilation) and Alveolar-arterial gradient (indicative of ventilation-perfusion mismatch). Injections of L-CYSee (100 μmol/kg, i.v.) reversed the effects of morphine in tracheotomized rats but were minimally active in non-tracheotomized rats. L-cysteine or L-serine ethylester (100 μmol/kg, i.v.) were without effect. It is evident that L-CYSee can reverse the negative effects of morphine on arterial blood-gas chemistry and Alveolar-arterial gradient but that this positive activity is negated by increases in upper-airway resistance. Since L-cysteine and L-serine ethylester were ineffective, it is evident that cell penetrability and the sulfur moiety of L-CYSee are essential for activity. Due to its ready penetrability into the lungs, chest wall muscle and brain, the effects of L-CYSee on morphine-induced changes in arterial blood-gas chemistry are likely to involve both central and peripheral sites of action.

Purpose Obstructive sleep apnea (OSA) in children is associated with obesity, insulin resistance, and elevated baseline inflammation as measured by high-sensitivity C-reactive protein (hsCRP). Our goal was to evaluate whether inflammation increases overnight among children suspected of having OSA and to determine whether worsened inflammation is associated with the degree of OSA severity, obesity, and/or insulin resistance. Methods Twenty-three children with clinical suspicion of OSA underwent a sleep study. Levels of hsCRP were tested the evening before and morning after the sleep study. Fasting insulin and glucose levels were measured from which the homeostasis model of insulin resistance (HOMA-IR) was calculated. Linear correlations were performed to evaluate relationships between hsCRP levels at baseline and change overnight (ΔhsCRP) vs. HOMA-IR, body mass index (BMI) z-score, and sleep study parameters related to O2 saturation and the apnea-hypopnea index (AHI). Results Among children with OSA and the entire cohort, hsCRP values were correlated with HOMA-IR and BMI z-scores. HOMA-IR but not BMI z-score correlated with ΔhsCRP overnight in the entire cohort. Sleep study parameters, including AHI mean O2 saturation overnight, REM O2 nadir, and non-REM O2 nadir were not correlated with hsCRP or ΔhsCRP overnight. Conclusion Among children being evaluated for OSA, degree of insulin resistance may be an important determinant of increased systemic inflammation overnight. Sleep study markers did not correlate with ΔhsCRP, leaving uncertain the role of OSA in increasing inflammation overnight. Further studies are needed to explore these associations and their potential mechanisms.

Exposure to hypoxia elicits changes in mean arterial blood pressure (MAP), heart rate, and frequency of breathing (fR). The objective of this study was to determine the role of nitric oxide (NO) in the cardiovascular and ventilatory responses elicited by brief exposures to hypoxia in isoflurane-anesthetized rats. The rats were instrumented to record MAP, heart rate, and fR and then exposed to 90 s episodes of hypoxia (10% O2, 90% N2) before and after injection of vehicle, the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), or the inactive enantiomer D-NAME (both at 50 μmol/kg iv). Each episode of hypoxia elicited a decrease in MAP, bidirectional changes in heart rate (initial increase and then a decrease), and an increase in fR. These responses were similar before and after injection of vehicle or D-NAME. In contrast, the hypoxia-induced decreases in MAP were attenuated after administration of L-NAME. The initial increases in heart rate during hypoxia were amplified whereas the subsequent decreases in heart rate were attenuated in L-NAME-treated rats. Finally, the hypoxia-induced increases in fR were virtually identical before and after administration of L-NAME. These findings suggest that NO factors play a vital role in the expression of the cardiovascular but not the ventilatory responses elicited by brief episodes of hypoxia in isoflurane-anesthetized rats. Based on existing evidence that NO factors play a vital role in carotid body and central responses to hypoxia in conscious rats, our findings raise the novel possibility that isoflurane blunts this NO-dependent signaling.

Objectives: We and others previously demonstrated that activation of the NO-cGMP-Protein Kinase G (PKG) pathway inhibits cardiac hypertrophy and remodeling in vivo. However, it remains untested whether PKG specifically in the cardiac myocyte (CM) mediates these effects. We therefore tested the hypothesis that PKGIα inhibits pathologic cardiac hypertrophy through a specific role in the CM. Methods and Results: We created and characterized mice with CM-restricted excision of PKGIα. Mice were generated in which the PKGI exon 1 (specific for the Iα isoform) was flanked by loxP sites. We crossed these PKGIα fl/fl mice with αMHC-Cre mice which constitutively express Cre recombinase selectively in the CM. The resultant PKGIα fl/fl / αMHC-Cre+/- mice were compared with PKGIα fl/fl / αMHC-Cre-/- littermate controls (termed PKG CMKO and Ctrl, respectively). By age 3 months (n=5 per genotype), male PKG CMKO mice developed atrial and LV hypertrophy compared with Ctrl littermates PKG CMKO atrial weight/tibia length 0.33 ± 0.03 mg/mm vs 0.22 ± .01 in Ctrl, P <0.05; PKG CMKO LV/TL 5.0 ± 0.2 mg/mm vs 4.1 ± 0.4 in Ctrl, P <0.05). LV CM cross sectional area also increased in the 3 month old PKG CMKO mice (9445 ± 282 pixels PKG CMKO vs 8273 ± 213 in Ctrl, n>400 cells/genotype, 5 hearts per genotype; P <0.001). The systolic index end systolic elastance was decreased in 3 month old PKG CMKO mice (PKG CMKO 3.1 ± 0.4 mmHg/μ l vs 6.1 ± 1.0 in Ctrl-; P <0.05). Importantly, blood pressure did not differ between genotypes. By age 6 months, PKG CMKO mice developed early mortality (3 of 4 PKG CMKO males died at 6 months of age vs 0 of 4 Ctrl males). Total heart and atrial weights of male mice (n=3 PKG CMKO , 4 Ctrl) increased in PKG CMKO mice (heart weight/tibia length 10.8 ± 1.7 mg/mm in PKG CMKO vs 7.1 ± 0.6 in Ctrl; P <0.05; atrial weight/tibia length 2.3 ± 1.1 mg/mm in PKG CMKO vs 0.30 ± 0.1 Ctrl, P <0.05). LV fractional shortening percentage, recorded at 6 months age, trended lower in the PKG CMKO mice as well (35 ± 3% PKG CMKO vs 44 ± 4% Ctrl, P 0.09). Conclusions: These data provide the first evidence that PKGIα functions in the CM as a tonic inhibitor of age-dependent pathologic hypertrophy, supporting further study of PKGIα as a therapeutic target in the prevention and treatment of LV remodeling and congestive heart failure.