Prenatal exposure to carbon monoxide delays postnatal cardiac electrophysiological maturation: Focus on functional and molecular properties of f-current.

Introduction: Prenatal exposure to a mild concentration of carbon monoxide (CO), a component of cigarette smoke, delays postnatal electrophysiological maturation of rat ventricular myocytes (VM). This may establish a period of vulnerability for cardiac arrhythmias predisposing to sudden infant death (SIDS). In rats, the pacemaker current If undergoes typical postnatal changes, being highly expressed in neonatal VM and strongly reduced thereafter. We investigated whether prenatal exposure to CO affects developmental changes of If. Methods and Results: Rats prenatally exposed to 0 (CTR) or 150 ppm CO (CO) were studied over the first 2 months of life. In patch-clamped VM, membrane capacitance and ANP expression, taken as markers of electrical and molecular cell growth respectively, underwent similar postnatal changes in the two groups. During growth, If density decreased in both groups, but the process was significantly delayed in CO rats: at 4 weeks, If density was 0.8±0.4 pA/pF in CTR (n=23) and 2.4±0.3 pA/pF in CO (n=17; p<0.01) and equalled at 8 weeks. mRNA expression of channel α (HCN isoforms) and β (MiRP-1) subunits was quantified by real-time PCR. At 2 days after birth, HCN4 was significantly more expressed in CO than in CTR rats (A.U.: 25±6 vs. 12±4; p<0.05). At 7 days, HCN2 was less expressed in CO than in CTR (56±5 vs. 100±9; p<0.01). MiRP-1, which significantly decreased in the two groups during postnatal growth, was more expressed in CO than in CTR at 7 days (4.7±0.4 vs. 3.1±0.5; p<0.05). cDNA microarrays revealed that prenatal CO exposure induces alterations in multiple signaling pathways, including thyroid hormone receptors and renin-angiotensin system. Conclusions: Prenatal exposure to CO hinders postnatal decrease of If, which persisted in VM from 4-week old treated-rats. This process is accompanied by changes in genes coding for f-channel subunits, as well as for thyroid hormone and renin-angiotensin signaling pathways. This study provides new insights into the molecular and functional mechanisms underlying cardiac electrophysiological maturation ant its impairment by CO.