OBJECTIVE-To determine whether maternal intrauterine endotoxin administration leads to neurobehavioral deficits in newborn rabbits. STUDY DESIGN-PregnantNew Zealand white rabbits were injected with 1ml saline (n=8) or 20μg/kg of lipolysaccharide in saline (LPS) (n=8) into the uterine wall on day 28/31 of gestation. On postnatal day 1, kits [saline (n=30) and LPS (n=18) from 4 consecutive litters] underwent neurobehavioral testing. Neonatal brains were stained for microglial cells and myelin.RESULTS-LPS-group kits were hypertonic and demonstrated significant impairment in posture, righting reflex, locomotion and feeding, along with neuroinflammation indicated by activated microglia, and hypomyelination in the periventricular regions. A greater mortality was noted in the LPS group (16 stillbirths from 3 litters vs. 3 from 1 litter).CONCLUSION-Maternal intrauterine endotoxin administration leads to white matter injury and motor deficits in the newborn rabbit resulting in a phenotype that resembles those found in periventricular leukomalacia and cerebral palsy.

Muscle metaboreflex activation (MMA) during dynamic exercise increases cardiac work and myocardial O2 demand via increases in heart rate, ventricular contractility, and afterload. This increase in cardiac work should lead to metabolic coronary vasodilation; however, no change in coronary vascular conductance occurs. This indicates that the MMA-induced increase in sympathetic activity to the heart, which raises heart rate, ventricular contractility, and cardiac output, also elicits coronary vasoconstriction. In heart failure, cardiac output does not increase with MMA presumably due to impaired ability to improve left ventricular contractility. In this setting actual coronary vasoconstriction is observed. We tested whether this coronary vasoconstriction could explain, in part, the reduced ability to increase cardiac performance during MMA. In conscious, chronically instrumented dogs before and after pacing-induced heart failure, MMA responses during mild exercise were observed before and after α1-adrenergic blockade (prazosin 20-50 μg/kg). During MMA, the increases in coronary vascular conductance, coronary blood flow, maximal rate of left ventricular pressure change, and cardiac output were significantly greater after α1-adrenergic blockade. We conclude that in subjects with heart failure, coronary vasoconstriction during MMA limits the ability to increase left ventricular contractility.

Muscle metaboreflex activation during dynamic exercise induces a substantial increase in cardiac work and oxygen demand via a significant increase in heart rate, ventricular contractility, and afterload. This increase in cardiac work should cause coronary metabolic vasodilation. However, little if any coronary vasodilation is observed due to concomitant sympathetically induced coronary vasoconstriction. The purpose of the present study is to determine whether the restraint of coronary vasodilation functionally limits increases in left ventricular contractility. Using chronically instrumented, conscious dogs (n = 9), we measured mean arterial pressure, cardiac output, and circumflex blood flow and calculated coronary vascular conductance, maximal derivative of ventricular pressure (dp/dt(max)), and preload recruitable stroke work (PRSW) at rest and during mild exercise (2 mph) before and during activation of the muscle metaboreflex. Experiments were repeated after systemic alpha(1)-adrenergic blockade ( approximately 50 microg/kg prazosin). During prazosin administration, we observed significantly greater increases in coronary vascular conductance (0.64 + or - 0.06 vs. 0.46 + or - 0.03 ml x min(-1) x mmHg(-1); P < 0.05), circumflex blood flow (77.9 + or - 6.6 vs. 63.0 + or - 4.5 ml/min; P < 0.05), cardiac output (7.38 + or - 0.52 vs. 6.02 + or - 0.42 l/min; P < 0.05), dP/dt(max) (5,449 + or - 339 vs. 3,888 + or - 243 mmHg/s; P < 0.05), and PRSW (160.1 + or - 10.3 vs. 183.8 + or - 9.2 erg.10(3)/ml; P < 0.05) with metaboreflex activation vs. those seen in control experiments. We conclude that the sympathetic restraint of coronary vasodilation functionally limits further reflex increases in left ventricular contractility.

Muscle metaboreflex activation during submaximal dynamic exercise in normal subjects elicits a pressor response primarily due to increased cardiac output (CO). However, when the ability to increase CO is limited, such as in heart failure or during maximal exercise, the muscle metaboreflex-induced increases in arterial pressure occur via peripheral vasoconstriction. How the mechanisms of this pressor response are altered is unknown. We tested the hypothesis that this change in metaboreflex function is dependent on the level of CO. The muscle metaboreflex was activated in dogs during mild dynamic exercise (3.2 km/h) via a partial reduction of hindlimb blood flow. Muscle metaboreflex activation increased CO and arterial pressure, whereas vascular conductance of all areas other than the hindlimbs did not change. CO was then reduced to the same level observed during exercise before the muscle metaboreflex activation via partial occlusion of the inferior and superior vena cavae. Arterial pressure dropped rapidly with the reduction in CO but, subsequently, nearly completely recovered. With the removal of the muscle metaboreflex-induced rise in CO, substantial peripheral vasoconstriction occurred that maintained arterial pressure at the same levels as before CO reduction. Therefore, the muscle metaboreflex function is nearly instantaneously shifted from increased CO to increased vasoconstriction when the muscle metaboreflex-induced rise in CO is removed. We conclude that whether vasoconstriction occurs with muscle metaboreflex depends on whether CO rises.

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