Enhancement of spontaneous baroreflex by antisense c-fosoligonucleotide treatment in the NTS of the rat

We evaluated the hypothesis that basal Fos protein at the nucleus tractus solitarii (NTS), the primary terminal site for baroreceptor afferents, exerts a tonic inhibitory modulation on the spontaneous baroreceptor reflex (BRR) control machinery, which is responsible for beat-to-beat regulation of resting systemic arterial pressure (SAP). In adult male Sprague-Dawley rats anesthetized and maintained with pentobarbital sodium, microinjection bilaterally into the caudal NTS of a 15-mer antisense oligonucleotide that targets against the initiation codon of c-fos mRNA (5'-129 to 143-3') significantly enhanced the spontaneous BRR response, as determined by transfer function analysis of SAP and heart rate signals. The same treatment also diminished baseline Fos-like immunoreactivity in the absence of acute cardiovascular perturbation. Control treatments with artificial cerebrospinal fluid, sense cDNA, or antisense oligonucleotides that either target against a different site of the c-fos mRNA (5'-135 to 149-3') or with three mismatched nucleotides in the antisense sequence, were ineffective. These observations support the notion that, under minimal cardiovascular perturbation, basal expression of Fos protein in the NTS may represent an early step in the cascade of intracellular events that leads to long-term inhibitory modulation of beat-to-beat baroreflex control of blood pressure.