Sexual dimorphism in prostacyclin-mimetic responses of rat mesenteric
and coronary arteries.
Background and purpose- Prostacyclin mimetics are widely used
clinically. As such it is pertinent to understand the mechanisms
underlying the vasoactive response to such agents, yet to date, no study
has considered sex as a factor. The aim of this study was to
characterise the effect of prostacyclin mimetics, Iloprost and MRE-269,
on precontracted arterial tone from male and female Wistar arteries. As
a secondary consideration, we investigated Kcnq-encoded KV7 channels as
potential downstream targets of prostacyclin-IP-receptor mediated
signalling. Experimental approach- Relative mRNA transcript and protein
abundance were determined by RT-qPCR and immunocytochemistry
respectively. The effect of Iloprost and MRE-269 was determined on
pre-contracted arterial tone in the presence of pharmacological
modulators of potassium channels and molecular interreference of KV7.1
within 2nd order mesenteric and left anterior descending arteries from
male and female Wistar rats. Key results- Iloprost evoked a bi-phasic
response in male mesenteric arteries, at low concentrations relaxing,
then contracting the vessel at high concentration in a process
attributed to IP and EP3 receptors respectively. Secondary contraction
was absent in the females, potentially underpinned by a reduction in
Ptger3. Pharmacological inhibition and molecular interference of KV7.1
significantly attenuated MRE-269 mediated relaxation in male and female
Wistar in Diestrus / Metoestrous, but not Pro-oestrus / Oestrus.
Conclusions and implications- Stark sexual dimorphisms in Iloprost
mediated vasoactive responses are present within mesenteric arteries.
KV7.1 is implicated in IP-receptor mediated vasorelaxation and is
impaired by the Oestrus cycle.