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

Abstract

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 A 2 (sPLA 2 ), blocked the stretch-induced contraction of rabbit pulmonary arteries by inhibition of untransformed prostaglandin H 2 (PGH 2 ) production. The present study was undertaken to investigate involvement of sPLA 2 and untransformed PGH 2 in the enhanced contractility of pulmonary arteries of experimental PAH in rats. Among all the known isoforms of sPLA 2 , sPLA 2 -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 PGH 2 , which was abolished by indoxam. These results suggest that sPLA 2 -mediated PGH 2 synthesis plays an important role in the rhythmic contraction of pulmonary arteries of MCT-PHR.

Evidence for a common mechanism for spontaneous rhythmic contraction and myogenic contraction induced by quick stretch in detrusor smooth muscle

“…If our hypothesis that SRC and QS-induced contraction are due to the regulation of a shared population of crossbridges is valid, this leads to a secondary hypothesis that the QS-induced myogenic contraction in detrusor is the first contraction of a shifted SRC cycle. Data demonstrating stretch-induced RC in rat pulmonary artery (Tanabe et al 2012) are consistent with this hypothesis. Furthermore, the example in Figure 7 shows a myogenic contraction due to a QS imposed~1 sec after the peak of a SRC cycle with a period of~5.5 sec.…”

“…Data demonstrating stretch‐induced RC in rat pulmonary artery (Tanabe et al. ) are consistent with this hypothesis. Furthermore, the example in Figure shows a myogenic contraction due to a QS imposed ~1 sec after the peak of a SRC cycle with a period of ~5.5 sec.…”

Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension

“…We have demonstrated here that KCNK3 expression was abolished whereas expression of phospholipase A2 was known to be upregulated in the MCT-PH models (more precisely, 3 and 4 weeks after PH initiation by monocrotaline exposure). 46 If the improvement in PH by ONO-RS-082 was caused by decreased phospholipase A2 activity, we would have observed a partial correction of PH as a curative strategy. This was not the case, suggesting that the improvement in PH by long-term ONO-RS-082 treatment was caused mainly by its pharmacological activation of KCNK3 channels.…”