The ovine chronotropic response t o i n j e c t i o n of catecholamines i s reported to increase during gestation, exhibit denervation s u p e r s e n s i t i v i t y , but i s s i m i l a r to the adult a f t e r b i r t h . This study examined the developmental changes i n the h e a r t r a t e response t o beta adrenergic stimulation with IS. Dose response s t u d i e s were carried out i n chronically c a t h e t e r i z e d , sheep --5 near-term f e t u s e s , 4 newborn, and 5 pregnant adults. IS was infused f o r 15-30 min u n t i l a steady s t a t e response was obtained f o r each dosage of the s e r i e s . Results a r e shown below.ISOPROTERENOL DOSE % CHANCE HEART RATE (meankSEM) (ug/kg/min) 69.858.7 These s t u d i e s indicate t h a t the ovine chronotropic response t o beta adrenergic stimulation increases not only during gestat i o n but from the newborn period t o adulthood. This may repres e n t a maturational increase in cardiac beta receptor number, a f f i n i t y or responsiveness. ONTOGENY OF 8-ADRENERGIC RECEPTORS IN MAMMALIAN378 LUNG. J.A. WhjJ_s_e_tt, Dept. Peds. Cincinnati, 0.The ontogeny o f 6-adrenergic receptors (BAR) i n lung was described i n the r a b b i t , r a t , sheep and guinea pig. Developmental increases i n binding capacity were demonstrated i g a l l species, f o r examp e, r a b b i t lung membrane bound ( -) - 3[ HI-di hydroalprenolol , [ HIDHA t o a single class o f sites, was stereoselective, r e v e r s i b l e and saturable; KD 1.78~0.30 nM. Binding a t a l l ages was i n h i b i t e d by agonists i n the order o f potency: I s o > Epi=Norepi c h a r a c t e r i s t i c o f a 8lAR subtype. Studies w i t h metoprolol (0 ) and z i n t e r o l (8 selective) revealed 60% 81-and 4h% 8 adrenergic suitypes a t a l l ages. Bmax increased 11.5 f o l % from day 25 o f gestation t o adulthood, increasing during the l a t t e r days o f gestation and the e a r l y neonatal period, from 3 7~1 0 fmolemg-1 p r o t e i n t o 4 2 5~5 1 i n the adult, mkSD. Gpp(NH)p decreased agonist a f f i n i t y more e f f e c t i v e l y i n adult than i n f e t a l lung and we hypothesize t h a t a "coupling" defect e x i s t s i n f e t a l lung BAR. The s e n s i t i v i t y o f adenylate cyclase a c t i v i t y t o catecholami ne was maximal i n adult r a b b i t lung increasing w i t h age from 23% a t day 25 gestation t o 255% stimulation i n the adult. Pulmonary BAR numbers a t term gestation were higher i n animals which are r e l a t i v e l y more mature a t b i r t h (guinea p i g and sheep) as compared t o less mature ( r a b b i t and r a t ) . I n conclusion, padrenergic receptors appear t o be a sensitive i n d i c a t o r of pulmonary maturation and the increase i n BAR during development i n mammalian lung and supports the r o l e of padrenergic receptors i n the regulation o f pulmonary function. PHARMACOKINETICS OF PIPERACILLIN I N INFANTS AND CHILD- 379REN. Chris B. Wilson, Terry I..Stull, Kent Opheim,Jcff Koup, Lee Adelman, Arnold L; Smith. Univ. of Wash. :Sch. of ~e d . ...

Introduction: It is unclear if individuals with very low mean low-density lipoprotein cholesterol (LDL-C) during midlife experience significant absolute risk (AR) for coronary heart disease (CHD). Hypothesis: Individuals with LDL-C ≤80mg/dL from ages 20-60 years (y) do not develop significant AR for CHD over 30 y of follow-up. Methods: Our objective was to quantify and compare the 30-year AR for fatal or nonfatal CHD from index ages 20-40 y and 40-60 y in participants (ppts) with LDL-C ≤80, 81-130, and >130 mg/dL using data from the Lifetime Risk Pooling Project. We included ppts who were free from lipid lowering medications and CHD at baseline. Mean LDL-C was an average of multiple (2-5) fasting LDL-C measurements within 10 years prior to the baseline age. We used a modified Kaplan Meier analysis, adjusted for competing risks of death, to quantify the 30-year CHD AR by LDL-C strata. Results: 3,781 men and 4,995 women were followed for a combined 110,431 person*years and experienced 778 events. Among all ppts, tobacco use ranged from 20-40% and hypertension prevalence ranged from 13-40%. Non-lipid risk factor profiles were generally more favorable in the low-LDL-C strata. At index ages 20-40, men and women with LDL-C ≤80mg/dL did not experience risk for CHD over 20 and 25 years, respectively (Figure). A similar pattern was seen in the LDL-C 80-130mg/dL strata. At index ages 40-60, men and women with LDL-C ≤80mg/dL experienced no risk for CHD for 5 to 15 years, respectively. However, both sex groups saw a gradual increase in risk up to 13.7% (95% confidence interval [CI] 1.9-25.4%) for men and 5.2% (95% CI 2.0-8.4%) for women at year 30 of follow-up. Conclusion: Young ppts with LDL-C ≤80mg/dL had very low CHD risks across midlife despite significant risk factor burden. At older ages, ppts with low LDL-C develop modest AR for CHD suggesting adverse lipid changes over time or alternative mediators of CHD in this age group.