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.

Key pointsr Local regulation of vascular resistance adjusts coronary blood flow to metabolic demand, although the mechanisms involved are not comprehensively understood r We show that heart tissue surrounding rat coronary arteries releases diffusible factors that regulate vasoconstriction and relaxation r Perivascular tissue reduces rho-kinase-dependent smooth muscle Ca 2+ sensitivity and constriction of coronary arteries to serotonin, the thromboxane analogue U46619 and the α 1 -adrenergic agonist phenylephrine r Endothelium-dependent relaxation of coronary arteries in response to cholinergic stimulation is inhibited by perivascular tissue as a result of reduced endothelial Ca 2+ responses and attenuated H 2 S-dependent signalling r These results establish cellular mechanisms by which perivascular heart tissue can modify local vascular tone and coronary blood flow Abstract Interactions between perivascular tissue (PVT) and the vascular wall modify artery tone and contribute to local blood flow regulation. Using isometric myography, fluorescence microscopy, membrane potential recordings and phosphospecific immunoblotting, we investigated the cellular mechanisms by which PVT affects constriction and relaxation of rat coronary septal arteries. PVT inhibited vasoconstriction to thromboxane, serotonin and α 1 -adrenergic stimulation but not to depolarization with elevated extracellular [K + ]. When PVT was wrapped around isolated arteries or placed at the bottom of the myograph chamber, a smaller yet significant inhibition of vasoconstriction was observed. Resting membrane potential, depolarization to serotonin or thromboxane stimulation, and resting and serotonin-stimulated vascular smooth muscle [Ca 2+ ]-levels were unaffected by PVT. Serotonin-induced vasoconstriction was almost abolished by rho-kinase inhibitor Y-27632 and modestly reduced by protein kinase C inhibitor bisindolylmaleimide X. PVT reduced phosphorylation of myosin phosphatase targeting subunit (MYPT) at Thr850 by ß40% in serotonin-stimulated arteries but had no effect on MYPT-phosphorylation in arteries depolarized with elevated extracellular [K + ]. The net anti-contractile effect of PVT was accentuated after endothelial denudation. PVT also impaired vasorelaxation and endothelial Ca 2+ responses to cholinergic stimulation. Methacholine-induced vasorelaxation was mediated by NO and H 2 S, and particularly the H 2 S-dependent (DL-propargylglycine-and XE991-sensitive) component was attenuated by PVT. Vasorelaxation to NO-and H 2 S-donors was maintained in arteries with PVT. In conclusion, cardiomyocyte-rich PVT surrounding coronary arteries releases diffusible factors that reduce rho-kinase-dependent smooth muscle Ca 2+ sensitivity and endothelial Ca 2+ responses. These mechanisms inhibit agonist-induced vasoconstriction and endothelium-dependent vasorelaxation and suggest new signalling pathways for metabolic regulation of blood flow.

Several studies have suggested that psychological stress may increase the risk of stroke. However, this link remains a controversial issue because of conflicting findings. Bereavement, the loss of a close relative, is considered a severely stressful life event. Increased risk of stroke could thus be expected after bereavement if stress plays a causal role. We aimed to evaluate the association between bereavement and stroke by performing a systematic review of the existing literature. The literature search was conducted according to the PRISMA guidelines for systematic reviews. A search in Medline and Embase identified eligible studies, which were reviewed by two researchers independently according to specific inclusion criteria. We included six studies: five cohort studies and one case-crossover study. Five studies found that loss of a first-degree relative was associated with a 1.1- to 2.4-fold higher risk of stroke. However, one study found a statistically significant overall risk only for women. Five studies evaluated the risk of stroke according to time since the loss; one study found no association, two studies indicated short-term effect, one study indicated long-term effect, and one study indicated both short-term and long-term effect. Three studies stratified their analysis by sex; two found higher association in bereaved women than men. Our systematic review suggests that bereavement-related stress is associated with a higher risk of stroke. As relatively few studies were identified, new studies are needed to verify this association. These should aim to quantify the risk, describe the effect of time since bereavement, and identify risk-modifying factors.

The effect of smooth muscle (VSMC) and endothelial cell pH (pHi) on myogenic tone is unknown. Here the role of Na+,HCO3‐‐cotransporter NBCn1 for pHi in these cells, and the influence of low pHi on myogenic tone and vasomotion were determined in intact mouse middle cerebral arteries. Na+,HCO3‐‐cotransport contributed to extrusion of acid from wildtype arteries but not from arteries where NBCn1 was knocked out. pHi of VSMCs was approximately 0.3 units lower in arteries from NBCn1 knockout than wildtype mice. Substantial myogenic tone developed after inhibition of NO‐synthase with L‐NAME in wildtype arteries. Less tone developed in arteries from NBCn1 knockout mice. This myogenic tone was in both type of arteries abolished by the rho‐kinase inhibitor Y‐27632. The arteries displayed vasomotion, which was attenuated in arteries from NBCn1 knockout mice. No differences in membrane potential or [Ca2+]i were seen between VSMC in arteries from NBCn1 knockout and wildtype mice. We propose that NO production and rho‐kinase‐dependent VSMC Ca2+‐sensitivity are reduced at low pHi in mouse middle cerebral arteries, which likely impedes the ability of these arteries to adjust to changes in perfusion pressure.