Intracellular Acidification Alters Myogenic Responsiveness and Vasomotion of Mouse Middle Cerebral Arteries

Abstract

Intracellular pH (pHi) in the vascular wall modulates agonist-induced vasocontractile and vasorelaxant responses in mesenteric arteries, whereas effects on myogenic tone have been unsettled. We studied the role of Na(+),HCO3(-) cotransporter NBCn1 in mouse isolated middle cerebral arteries and the influence of pHi disturbances on myogenic tone. Na(+),HCO3(-) cotransport was abolished in arteries from NBCn1 knockout mice and steady-state pHi ∼0.3 units reduced compared with wild-type mice. Myogenic tone development was low under control conditions but increased on treatment with the NO-synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME). This effect of L-NAME was smaller in arteries from NBCn1 knockout than wild-type mice. Myogenic tone with L-NAME present was significantly lower in arteries from NBCn1 knockout than wild-type mice and was abolished by rho-kinase inhibitor Y-27632. The arteries displayed vasomotion, and this rhythmic contractile pattern was also attenuated in arteries from NBCn1 knockout mice. No differences in membrane potential or intracellular [Ca(2+)] were seen between arteries from NBCn1 knockout and wild-type mice. We propose that NO production and rho-kinase-dependent Ca(2+) sensitivity are reduced at low pHi in pressurized mouse middle cerebral arteries. This likely impedes the ability to adjust to changes in perfusion pressure and regulate cerebral blood flow.

Renal Autoregulation in Health and Disease

“…Both NO and ROS in VSMCs regulated RyR-mediated Ca 2ϩ mobilization (384, 1645), but by distinct signaling pathways (752,861,866,1224). NO dilated gracilis muscle arteries and afferent arterioles by activating MLCP (129, 1499,1503), and attenuated myogenic tone of nonrenal vessels by inhibiting Rho kinase in VSMCs (475,1214,1458). This may also occur in the renal microcirculation (1358).…”

Pulse pressure-dependent cerebrovascular eNOS regulation in mice

“…In SP conditions, which is the classical methodological approach to investigate MT and FMD ex vivo, C57Bl6 mouse cerebral arteries with an intact endothelium develop little tone 44,45 when compared to other species including human cerebral arteries. [46][47][48][49][50][51] The vascular endothelium, however, is known to potently inhibit MT: indeed, after eNOS inhibition, MT is magnified under static pressure (Figure 1), as previously reported in mouse and rat cerebral arteries.…”

Extracellular ʜ ᴄ ᴏ3̅ is sensed by mouse cerebral arteries: Regulation of tone by receptor protein tyrosine phosphatase γ

“…Although a selective decrease in pCO 2 also has no effect on artery tone at pH o 7.1 (Figure 3d), a selective increase in pCO 2 lowers tension development (Figure 3d) with no effect on VSMC Ca 2þ dynamics (Figure 3e). The inhibitory effect of intracellular acidification on VSMC Ca 2þ sensitivity 5,12,18,26 likely contributes to the lower tension development observed at pH o 7.1 compared to 7.4 in the presence of low [HCO …”

“…5,12,18,26 To explore mechanisms of vasomotor control additional to RPTPg-dependent signaling, we next investigate whether metabolic acidosis interferes with VSMC Ca 2þ -sensitivity in basilar arteries from RPTPg-knockout mice (Figure 6(f) and (h)). Because U46619 is expected to increase VSMC Ca 2þ -sensitivity, 29 we determine the contractile response to varying levels of [Ca 2þ ] i during constant exposure to a maximal stimulatory level of U46619 (10 mM).…”

“…Photodamage during BCECF excitation was minimized by reducing light exposure to the last 30 s of each experimental condition. 18 The BCECF fluorescence ratio was calibrated to pH values using the high-[K þ ] nigericin method, as previously described. 19 …”