Disruption of growth hormone secretion alters [Ca.sup.2+] current density and expression of [Ca.sup.2+] channel and insulin-like growth factor genes in rat atria

The influence of the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis on expression of low-voltage-activated (LVA) [Ca.sup.2+] current in atrial tissue was investigated using spontaneous dwarf (SpDwf) rats, a mutant strain that lacks GH. Atrial myocytes from SpDwf rats express LVA and high-voltage-activated (HVA) [Ca.sup.2+] currents and the [Ca.sup.2+] channel [[alpha].sub.1]-subunit genes [Ca.sub.v] 1.2, [Ca.sub.v]2.3, [Ca.sub.v]3.1, and [Ca.sub.v]3.2. LVA current density decreases significantly beginning at, or shortly after, birth in normal animals; however, its density is maintained in SpDwf rats at 1 pA/pF for [greater than or equal to] 12 wk after birth. The abundance of mRNAs encoding [Ca.sub.v]2.3 and [Ca.sub.v]3.2 declines with advancing age in normal atrial development, yet expression of [Ca.sub.v]2.3 mRNA remains significantly elevated in older SpDwf animals. Quantitation of local transcript levels for mRNAs encoding IGF-I and IGF-I receptor (IGF-IR) also reveals significant differences in expression of these transcripts in atrial tissue of SpDwf animals compared with controls. In SpDwf rats, the abundance of IGF-IR mRNA remains elevated at many postnatal ages, whereas mRNA encoding IGF-I is maintained only in older animals. Physiological concentrations of IGF-I cause two- to threefold increases in LVA current density in primary cultures of atrial myocytes, and this effect is blocked by an antisense oligonucleotide targeting the IGF-IR. Thus disruption of GH production in SpDwf animals alters expression of atrial LVA [Ca.sup.2+] channel and IGF genes as well as postnatal regulation of LVA [Ca.sup.2+] current density, most likely acting through compensatory mechanisms via the local IGF-IR. low-voltage-activated calcium current; electrophysiology; spontaneous dwarf rats; quantitative reverse transcription-polymerase chain reaction