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

Cummings KJ, Li A, Deneris ES, Nattie EE. Bradycardia in serotonin-deficient Pet-1(-/-) mice: influence of respiratory dysfunction and hyperthermia over the first 2 postnatal weeks. Am J Physiol Regul Integr Comp Physiol 298: R1333-R1342, 2010. First published March 10, 2010; doi: 10.1152/ajpregu.00110.2010.-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 (T-b) and were then made 2 degrees C hypo- and hyperthermic. Using a pneumotach-mask system with ECG, we measured heart rate, metabolic rate ((V)over dotO(2)), and ventilation. We also calculated indexes for apnea-induced hypoxia (total hypoxia: apnea incidence X O-2 consumed during apnea = mu l.g(-1).min(-1)) and bradycardia (total bradycardia: bradycardia incidence X magnitude = beats missed/min). Resting heart rate was significantly lower in all Pet-1(-/-) animals, irrespective of T-b. 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 (V)over dotO(2) at all T-b; 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 (V)over dotO(2). 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.