Evidence against a systemic arterial defect in patients with inflammatory bowel disease.

BACKGROUND: Despite increasing interest in local microvascular alterations associated with inflammatory bowel disease (IBD), the potential contribution of a primary systemic vascular defect in the etiology of IBD is unknown. We compared reactivity of large diameter mesenteric arteries from segments affected by Crohn disease (CD) or ulcerative colitis (UC) to an uninvolved vascular bed in both IBD and control patients. METHODS: Mesenteric and omental arteries were obtained from UC, CD, and non-IBD patients. Isometric arterial contractions were recorded in response to extracellular potassium (K(+)) and cumulative additions of norepinephrine (NE). In addition, relaxation in response to pinacidil, an activator of adenosine triphosphate-sensitive K(+) channels was examined. RESULTS: Contraction to K(+) and sensitivity to NE were not significantly different in arteries from CD, UC, and controls. Relaxation to pinacidil was also similar between groups. CONCLUSIONS: Potassium-induced contractions and sensitivity to NE and pinacidil were not significantly different in large diameter mesenteric and omental arteries obtained from IBD patients. Furthermore, there was no significant difference in the sensitivity to K(+), NE, and pinacidil between mesenteric and omental arteries of CD and UC patients and those from non-IBD patients. Our results suggest an underlying vascular defect systemic to CD or UC patients is unlikely to contribute to the etiology of IBD.

Inhibition of Ca++ sparks by oxyhemoglobin in rabbit cerebral arteries.

OBJECT: Oxyhemoglobin (HbO2) causes cerebral artery constriction and is one component of blood that likely contributes to the pathogenesis of cerebral vasospasm after aneurysm rupture. This study was designed to examine the acute effect of HbO2 on subcellular Ca(++) release events (Ca(++) sparks) in cerebral artery myocytes. Calcium sparks provide a tonic hyperpolarizing and relaxing influence to vascular smooth muscle by the activation of plasmalemmal large-conductance Ca(++)-activated K+ channels. Evidence is provided that HbO2 may contract cerebral vascular muscle in part by free radical-mediated inhibition of Ca(++) sparks. METHODS: Calcium sparks were visualized in intact pressurized rabbit cerebral arteries by using laser scanning confocal microscopy and a Ca(++) indicator dye. Calcium spark frequency was reduced by approximately 65% after a 15-minute application of HbO2 (10(-4) M). The HbO2-induced decrease in Ca(++) spark frequency was prevented by a combination of the free radical scavengers superoxide dismutase and catalase. Isometric force measurements were used to characterize the role of the vascular endothelium and smooth-muscle Ca(++) channels in HbO2-induced cerebral artery contraction. The HbO2-induced contractions were independent of the vascular endothelium, but were abolished by diltiazem, a blocker of L-type voltage-dependent Ca(++) channels (VDCCs). Ryanodine, a blocker of ryanodine-sensitive Ca(++) release channels located on the sarcoplasmic reticulum, also reduced HbO2-induced contractions by approximately 50%. CONCLUSIONS: These results support the hypothesis that HbO2 may contract cerebral artery segments in part by inhibition of Ca(++) sparks, leading to decreased large-conductance Ca(++)-activated K+ channel activity, membrane potential depolarization, and enhanced Ca(++) entry through VDCCs.

Enhanced myogenic tone in cerebral arteries from a rabbit model of subarachnoid hemorrhage.

Cerebral artery vasospasm is a major cause of death and disability in patients experiencing subarachnoid hemorrhage (SAH). Currently, little is known regarding the impact of SAH on small diameter (100-200 microm) cerebral arteries, which play an important role in the autoregulation of cerebral blood flow. With the use of a rabbit SAH model and in vitro video microscopy, cerebral artery diameter was measured in response to elevations in intravascular pressure. Cerebral arteries from SAH animals constricted more (approximately twofold) to pressure within the physiological range of 60-100 mmHg compared with control or sham-operated animals. Pressure-induced constriction (myogenic tone) was also enhanced in arteries from control animals organ cultured in the presence of oxyhemoglobin, an effect independent of the vascular endothelium or nitric oxide synthesis. Finally, arteries from both control and SAH animals dilated as intravascular pressure was elevated above 140 mmHg. This study provides evidence for a role of oxyhemoglobin in impaired autoregulation (i.e., enhanced myogenic tone) in small diameter cerebral arteries during SAH. Furthermore, therapeutic strategies that improve clinical outcome in SAH patients (e.g., supraphysiological intravascular pressure) are effective in dilating small diameter cerebral arteries isolated from SAH animals.

Ca2+ sparks and their function in human cerebral arteries.

BACKGROUND AND PURPOSE: Local Ca2+ release events (Ca2+ sparks) caused by the opening of ryanodine-sensitive Ca2+ channels in the sarcoplasmic reticulum have been suggested to oppose constriction in cerebral arteries through the activation of large-conductance Ca2+-activated K+ (BK) channels. We report the first identification and characterization of Ca2+ sparks and associated BK channel currents in smooth muscle cells isolated from human cerebral arteries. METHODS: Membrane currents and intracellular Ca2+ were measured with the use of the patch-clamp technique and laser scanning confocal microscopy. RESULTS: Ca2+ sparks with a peak fractional fluorescence change (F/F0) of 2.02 +/- 0.04 and size of 8.2 +/- 0.5 microm2 (n=108) occurred at a frequency of approximately 1 Hz in freshly isolated, cerebral artery myocytes from humans. At a holding potential of -40 mV, the majority of, but not all, Ca2+ sparks (61 of 85 sparks) were associated with transient BK currents. Consistent with a role for Ca2+ sparks in the control of cerebral artery diameter, agents that block Ca2+ sparks (ryanodine) or BK channels (iberiotoxin) were found to contract human cerebral arteries. CONCLUSIONS: This study provides evidence for local Ca2+ signaling in human arterial myocytes and suggests that these events may play an important role in control of cerebral artery diameter in humans.