Cardiac function in rats selectively bred for low- and high-capacity running.

Rat genetic models of intrinsic (i.e., untrained) low-capacity runners (LCR) and high-capacity runners (HCR) are being developed by artificial selective breeding for treadmill running. At generation 3, these lines differed in running capacity by 114%. We used generation 3 rats to test the hypotheses that HCR, relative to LCR, have 1) greater isolated cardiac performance and 2) more resistance to myocardial ischemic insult. The LCR ran for 227 +/- 7 m, and the HCR ran 994 +/- 11 m at exhaustion (337% difference, P < 0.001). Isolated heart performance was assessed from cardiac output (CO) generated at constant preload (15 mmHg) and afterload (70 mmHg) using a Langendorff-Neely working heart preparation. CO averaged 33.5 +/- 2.0 ml. min(-1). g(-1) in LCR hearts and 49.9 +/- 1.4 ml. min(-1). g(-1) in HCR hearts (49% difference, P < 0.001). Recovery of CO after 25 min of global ischemia was not different between the lines. These results suggest that 1) increased cardiac performance accounts for part of the difference in running capacity between the lines; and 2) unlike exercise training, genetically determined intrinsic capacity for exercise does not influence the recovery from 25 min of global low-flow cardiac ischemia.

Cardiac performance in inbred rat genetic models of low and high running capacity.

1. Previous work demonstrating that DA inbred rats are superior to COP inbred rats in aerobic treadmill running capacity has indicated their utility as genetic models to explore this trait. We tested the general hypothesis that intermediate phenotypes of cardiac function and calcium metabolism are responsible for the difference in capacity between these strains. 2. Logical cardiac trait differences were estimated at a tissue (isolated papillary muscle), cellular (isolated left ventricular cells), and biochemical level of organization. 3. DA hearts were found to give significantly higher values than COP hearts for: (1) maximal developed tension (38.3 % greater), and rates of tension change in contraction (61 %) or relaxation (59 %) of isolated papillary muscle, (2) fractional shortening (50 %), amplitude of the Ca(2+) transient (78.6 %), and caffeine-induced release of Ca(2+) from the sarcoplasmic reticulum (SR; 260 %) in isolated ventricular myocytes, and (3) Na(+),K(+)-ATPase activity of isolated myocytes (17.3 %). 4. Our results suggest that these trait differences may prove useful for further studies into the genes responsible for natural variations in both ventricular function and aerobic endurance capacity. Understanding the genetic basis of aerobic capacity will help define the continuum between health and disease.

Pyridoxine-dependent seizures responding to extremely low-dose pyridoxine.

We report on a male infant with pyridoxine dependency and seizures from birth, controlled with pharmacological doses of pyridoxine at 4 months of age. Seizures stopped between 30 and 80 days of age when very-low doses of pyridoxine were given in a multivitamin supplement. Daily dose was 0.5 mg that corresponded to 0.08 to 0.16 mg/kg/day when weight gain is considered. In previous reports doses have ranged from 0.2 to 30 mg/kg/day. Another distinctive feature was that this infant went into a coma and developed hypotonia and irregular breathing when pyridoxine was given by enteral tube which has usually been reported when the vitamin is given intravenously. Use of low doses of pyridoxine in multivitamin supplements could be a confounding factor for early diagnosis and appropriate treatment of pyridoxine-dependent seizures.

Randomized, controlled trial of low-dose inhaled nitric oxide in the treatment of term and near-term infants with respiratory failure and pulmonary hypertension.

UNLABELLED: Recent reports indicate that inhaled nitric oxide (iNO) causes selective pulmonary vasodilation, increases arterial oxygen tension, and may decrease the use of extracorporeal membrane oxygenation (ECMO) in infants with persistent pulmonary hypertension of the newborn (PPHN). Despite these reports, the optimal dose and timing of iNO administration in PPHN remains unclear. OBJECTIVES: To test the hypotheses that in PPHN 1) iNO at 2 parts per million (ppm) is effective at acutely increasing oxygenation as measured by oxygenation index (OI); 2) early use of 2 ppm of iNO is more effective than control (0 ppm) in preventing clinical deterioration and need for iNO at 20 ppm; and 3) for those infants who fail the initial treatment protocol (0 or 2 ppm) iNO at 20 ppm is effective at acutely decreasing OI. STUDY DESIGN: A randomized, controlled trial of iNO in 3 nurseries in a single metropolitan area. Thirty-eight children, average gestational age of 37.3 weeks and average age <1 day were enrolled. Thirty-five of 38 infants had echocardiographic evidence of pulmonary hypertension. On enrollment, median OI in the control group, iNO at 0 ppm, (n = 23) was 33.1, compared with 36.9 in the 2-ppm iNO group (n = 15). RESULTS: Initial treatment with iNO at 2 ppm for an average of 1 hour was not associated with a significant decrease in OI. Twenty of 23 (87%) control patients and 14 of 15 (92%) of the low-dose iNO group demonstrated clinical deterioration and were treated with iNO at 20 ppm. In the control group, treatment with iNO at 20 ppm decreased the median OI from 42.6 to 23.8, whereas in the 2-ppm iNO group with a change in iNO from 2 to 20 ppm, the median OI did not change (42.6 to 42.0). Five of 15 patients in the low-dose nitric oxide group required ECMO and 2 died, compared with 7 of 23 requiring ECMO and 5 deaths in the control group. CONCLUSION: In infants with PPHN, iNO 1): at 2 ppm does not acutely improve oxygenation or prevent clinical deterioration, but does attenuate the rate of clinical deterioration; and 2) at 20 ppm acutely improves oxygenation in infants initially treated with 0 ppm, but not in infants previously treated with iNO at 2 ppm. Initial treatment with a subtherapeutic dose of iNO may diminish the clinical response to 20 ppm of iNO and have adverse clinical sequelae.

Phenotypic differences in cardiovascular regulation in inbred rat models of aerobic capacity.

The Dark Aouti (DA) inbred strain of rats has superior aerobic treadmill running capacity compared with the Copenhagen (COP) strain of inbred rats. This difference in aerobic capacity provides a model to explore the genetic basis of variation in this trait. The present study evaluated intermediate phenotypic differences between 10 male COP inbred rats and 10 male DA inbred rats that might contribute to the difference in aerobic capacity between the strains. Five autonomically regulated cardiovascular variables were evaluated during rest or exercise by measuring the response to autonomic antagonists. The DA rat had enhanced autonomic function for the regulation of peripheral blood flow and cardiac output. Specifically, at rest the DA rats had significantly more sympathetic (123 +/- 8 vs. 99 +/- 7 beats/min) and parasympathetic (35 +/- 5 vs. 12 +/- 3 beats/min) tonus for heart rate control and more sympathetic support of blood pressure (70 +/- 7 vs. 38 +/- 6 mmHg) compared with the COP rats. During three graded levels of treadmill exercise the DA rats had higher blood pressures (16% on average) and higher heart rates (4% on average) relative to the COP rats. In addition, the DA rats had a 27% greater heart weight-to-body weight ratio compared with the COP strain of rats (3.63 +/- 0.08 vs. 2.85 +/- 0.07 g/kg). All five of these intermediate phenotypes could participate as variables causative of the difference in treadmill running capacity between the DA and COP strains of rats.

Spectrum of aerobic endurance running performance in eleven inbred strains of rats.

The goal of this study was to identify inbred rat strains that could serve as useful models for exploration of the genetic basis of aerobic endurance performance. Six rats of each gender from 11 different inbred strains were tested for 1) maximal running capacity on a treadmill and 2) isolated cardiac performance. Running performance was estimated from 1) duration of the run, 2) distance run, and 3) vertical work performed. Cardiac output, during constant preload and afterload, was taken as a measure of cardiac performance from an isolated working heart preparation. The COP rats were the lowest performers and the DA rats were the best performers by all estimates of running performance. Across the 11 strains, the distance run correlated positively with isolated cardiac performance (r = 0.87). Estimates of performance were as follows (COP vs. DA strain, respectively): duration of run, 19.9 +/- 1.8 vs. 41.5 +/- 2. 2 min; distance run, 298 +/- 30 vs. 840 +/- 64 m; vertical work, 15 +/- 1.7 vs. 40 +/- 4.4 kg/m. These approximately 2.5-fold differences in running performance between the COP and DA suggest that these strains could serve as models for evaluation of the genetic basis of variance in aerobic performance.

Chemosensory Activation of an Antennular Grooming Behavior in the Spiny Lobster, Panulirus argus, Is Tuned Narrowly to L-Glutamate.

Antennular grooming behavior (AGB) is a stereotyped behavior in crustaceans in which the first pair of antennae, the major olfactory organs, are clasped and wiped repetitively by the third maxillipeds, which also serve as feeding appendages. AGB apparently functions to clear away accumulating debris on or between the antennular aesthetascs (olfactory sensilla). The purpose of this research was to determine whether AGB can be activated by chemicals commonly found in food odors. Lobsters were presented, via headset or handheld pipette, with 27 chemicals found in their food. One chemical, L-glutamate, evoked very high frequencies of wiping. Most chemicals tested were not stimulatory and only a few were weakly stimulatory (adenosine-5'-monophosphate, glycine, D-glutamate). This is surprising because previous studies have shown that other behaviors (antennular flick, search) can be evoked by a much broader array of chemicals found in food odorants. On the basis of these results, we propose that chemosensory neurons that specifically detect L-Glu activate AGB through a recently described non-olfactory pathway. Furthermore, we propose that the role of L-Glu in evoking AGB is based on its electrostatic properties. Because it has a high probability of electrostatic adherence to the antennular cuticle, L-Glu is a sensitive indicator of fouling by food-associated chemicals and thus an appropriate compound to stimulate antennular grooming.

Noninvasive cardiopulmonary monitoring.

Contrast dilution curves have been utilized for evaluation of hemodynamic function. Noninvasive techniques for this purpose usually have been qualitative, expensive, and cumbersome with minimal applicability to the newborn infant. The technique of roentgen densitometry has been utilized to screen children with heart murmurs. Characteristic curve patterns were identified for normal subjects and for patients with shunts with correlation to catheterization data. This technique is now being applied in a quantitative fashion to estimate cardiac output and left-to-right ductal shunts. Cardiac output volumes were inversely proportional to the difference of the second moments of the dilution curves obtained--the second moment being a measurement of the peak dispersion. The estimation of the percent of left-to-right shunt is related to the exponential decay of the left-sided curve.