Protein kinase Cα (PKCα) regulates multiple cell signaling pathways, including those that impact blood pressure. PKCα activation increases vascular smooth muscle contractility, yet reduces cardiac contractility. PKCα has also been shown to modulate nephron ion transport. We have shown that PKCα deletion leads to hypotension, with compensatory increases in sodium retention. Here, we hypothesized that PKCα deficiency reduces vascular contractility, leading to decreased mean arterial pressure (MAP). MAP, measured by telemetry, was decreased in PKC KO (≈12 mmHg) compared to PKC control (PKC CTL) mice. Aorta and mesenteric arteries were isolated, and concentration response curves (CRCs) to phenylephrine (Phe), acetylcholine (ACh) or sodium nitroprusside (SNP) were performed in the presence of vehicle or the following inhibitors: L-NAME or indomethacin (NOS, COX inhibitor,
resp.
). CRCs to KCL were performed to assess receptor-independent vascular responses. In aorta, we observed a striking reduction in KCl-mediated contraction (5.8±0.3mN
vs.
10.4±1.1mN control, **p<0.01). PKC KO aorta and mesenteric arteries had decreased contractile responses to Phe, as compared to control (aorta, 12.7±0.5mN
R
max
vs.
16.3±0.5mN
R
max
, and mesenteric 9.9±0.3mN
R
max
vs.
11.8±0.6mN
R
max
; n=4, **p<0.01), revealing a role for reduced vascular contractility. Endothelium-mediated relaxation responses to ACh were also increased in PKC KO mice, as compared to control (59.3±6.8%
R
max
vs.
45.4±3.2%
R
max
, n=4, *p<0.05). Interestingly, NOS inhibition increased contractility in mesenteric arteries from PKC KO mice (8.55±2.65mN
R
max
vs.
6.95±0.39mN
R
max
control, n=4, ***p<0.001). However, PKC KO aorta had an enhanced response to COX inhibition (12.2±0.7mN
R
max
vs.
10.1±0.6mN
R
max
control, n=4, *p<0.05) suggesting that PKCα may be negatively regulating NOS in mesenteric arteries, and COX-mediated prostaglandin production in the aorta. No differences were observed in the relaxation responses to SNP. These data suggest that global deletion of PKCα results in hypotension due to decreased vascular contractility, and loss of PKCα-mediated inhibition of endothelial relaxing factors. Thus, systemic targeting of PKCα may be beneficial for the reduction of MAP.
Acetylcholine produces contraction mediated by cyclooxigenase pathway in arterial vessels in the marine fish (Isacia conceptionis)
