Role of Secretory Phospholipase A₂ in Rhythmic Contraction of Pulmonary Arteries of Rats With Monocrotaline-Induced Pulmonary Arterial Hypertension

Abstract

Excessive stretching of the vascular wall in accordance with pulmonary arterial hypertension (PAH) induces a variety of pathogenic cellular events in the pulmonary arteries. We previously reported that indoxam, a selective inhibitor for secretory phospholipase A₂ (sPLA₂), blocked the stretch-induced contraction of rabbit pulmonary arteries by inhibition of untransformed prostaglandin H₂ (PGH₂) production. The present study was undertaken to investigate involvement of sPLA₂ and untransformed PGH₂ in the enhanced contractility of pulmonary arteries of experimental PAH in rats. Among all the known isoforms of sPLA₂, sPLA₂-X transcript was most significantly augmented in the pulmonary arteries of rats with monocrotaline-induced pulmonary hypertension (MCT-PHR). The pulmonary arteries of MCT-PHR frequently showed two types of spontaneous contraction in response to stretch; 27% showed rhythmic contraction, which was sensitive to indoxam and SC-560 (selective COX-1 inhibitor), but less sensitive to NS-398 (selective COX-2 inhibitor); and 47% showed sustained incremental tension (tonic contraction), which was insensitive to indoxam and SC-560, but sensitive to NS-398 and was attenuated to 45% of the control. Only the rhythmically contracting pulmonary arteries of MCT-PHR produced a substantial amount of untransformed PGH₂, which was abolished by indoxam. These results suggest that sPLA₂-mediated PGH₂ synthesis plays an important role in the rhythmic contraction of pulmonary arteries of MCT-PHR.