Bradycardia in serotonin-deficient Pet-1−/− mice: influence of respiratory dysfunction and hyperthermia over the first 2 postnatal weeks

摘要

Neonatal rodents deficient in medullary serotonin neurons have respiratory instability and enhanced spontaneous bradycardias. This study asks if, in Pet-1^−/− mice over development: 1) the respiratory instability leads to hypoxia; 2) greater bradycardia is related to the degree of hypoxia or concomitant hypopnea; and 3) hyperthermia exacerbates bradycardias. Pet-1^+/+, Pet-1^+/−, and Pet-1^−/− mice [postnatal days (P) 4–5, P11–12, P14–15] were held at normal body temperature (Tb) and were then made 2°C hypo- and hyperthermic. Using a pneumotach-mask system with ECG, we measured heart rate, metabolic rate (V̇o2), and ventilation. We also calculated indexes for apnea-induced hypoxia (total hypoxia: apnea incidence × O2 consumed during apnea = μl·g⁻¹·min⁻¹) and bradycardia (total bradycardia: bradycardia incidence × magnitude = beats missed/min). Resting heart rate was significantly lower in all Pet-1^−/− animals, irrespective of Tb. At P4–5, Pet-1^−/− animals had approximately four- to eightfold greater total bradycardia (P < 0.001), owing to an approximately two- to threefold increase in bradycardia magnitude and a near doubling in bradycardia incidence. Pet-1^−/− animals had a significantly reduced V̇o2 at all Tb; thus there was no genotype effect on total hypoxia. At P11–12, total bradycardia was nearly threefold greater in hyperthermic Pet-1^−/− animals compared with controls (P < 0.01). In both genotypes, bradycardia magnitude was positively related to the degree of hypopnea (P = 0.02), but there was no genotype effect on degree of hypopnea or total hypoxia. At P14–15, genotype had no effect on total bradycardia, but Pet-1^−/− animals had up to seven times more total hypoxia (P < 0.001), owing to longer and more frequent apneas and a normalized V̇o2. We infer from these data that 1) Pet-1^−/− neonates are probably not hypoxic from respiratory dysfunction until P14–15; 2) neither apnea-related hypoxia nor greater hypopnea contribute to the enhanced bradycardias of Pet-1^−/− neonates from approximately P4 to approximately P12; and 3) an enhancement of a temperature-sensitive reflex may contribute to the greater bradycardia in hyperthermic Pet-1^−/− animals at approximately P12.