The incidence of cerebrovascular diseases increases significantly with aging. This study aimed to test the hypothesis that aging may influence the protein kinase A (PKA)-dependent vasodilation via RyR/BKCa pathway in the middle cerebral arteries (MCA). Male Sprague-Dawley rats were randomly divided into control (4-6 month-old) and aged (24-month-old) groups. The functions of MCA and ion channel activities in smooth muscle cells were examined using myograph system and patch-clamp. Aging decreased the isoproterenol/forskolin-induced relaxation in the MCA. Large-conductance Ca2+-activated-K+ (BKCa) channel inhibitor, iberiotoxin, significantly attenuated the forskolininduced vasodilatation and hyperpolarization in the young group, but not in the aged group. The amplitude and frequency of spontaneous transient outward currents (STOCs) were significantly decreased in the aged group. Single channel recording revealed that the mean open time of BKCa channels were decreased, while an increased mean closed time of BKCa channels were found in the aged group. The Ca2+/voltage sensitivity of the channels was decreased accompanied by reduced BKCa α and β1-subunit, the expression of RyR2, PKA-Cα and PKA-Cβ subunits were also declined in the aged group. Aging induced down-regulation of PKA/BKCa pathway in cerebral artery in rats. The results provides new information on further understanding in cerebrovascular diseases resulted from agerelated cerebral vascular dysfunction.
Galanin and galanin receptors (GalRs) have been reported to be
involved in the transmission and modulation of nociceptive
information in the central nervous system (CNS). However, the
underlying mechanism of the antinociception of GalRs in
neuropathic pain remains unclear. This study investigated the
antinociception induced by galanin receptor 1 (GalR1) via protein
kinase A (PKA) signaling pathway in the nucleus accumbens
(NAc) of rats with neuropathic pain. A mononeuropathy model
was replicated by ligation of the left sciatic nerve, following which
the expression of phospho-PKA (p-PKA) in the NAc were
markedly up-regulated at 14th and 28th day after ligation of sciatic
nerve, and p-PKA expression was down-regulated by intra-NAc
injection of GalR1 agonist M617, but the GalR1 antagonist M35
did not have an effect. We also found that M35 in the NAc
blocked the M617-induced increase in the hind paw withdrawal
latencies (HWLs) of rats with mononeuropathy, but M35 alone
had no effect on HWLs, and PKA inhibitor H-89 attenuated the
M617-induced an increase in the HWLs. These results suggested
that GalR1 induced an antinociception via inhibiting PKA
activation, implying that GalR agonists may be potential and
potent therapeutic options to treat chronic neuropathic pain.