Addition of sildenafil citrate for treatment of severe intrauterine growth restriction: a double blind randomized placebo controlled trial.

Background: Severe intrauterine growth restriction complicates approximately 0.4% of the pregnancies. It increases the risk of perinatal morbidity and mortality.Subjects and methods: A double blind placebo controlled trial was conducted in Beni Suef University hospitals during 2017. It included 46 pregnant women with severe intrauterine growth restriction. Women were randomly allocated into two groups each included 23 patients. Intervention group received sildenafil citrate 20 mg orally three times a day, in addition to fish oil and zinc supplementation. Control group received tablets similar to sildenafil and the same treatment as intervention group. Primary outcomes included improvement in umbilical and middle cerebral arteries pulsatility indices and abdominal circumference.Results: Umbilical and middle cerebral arteries Doppler indices showed significant difference between groups after intake of sildenafil. Umbilical artery pulsatility index decreased significantly (p value = .001) while middle cerebral artery pulsatility index increased significantly in intervention group (p value0.001). Moreover, abdominal circumference growth velocity improved after two weeks of sildenafil intake (p value = .001).Conclusions: Sildenafil citrate may improve uteroplacental and fetal cerebral perfusion in pregnancies complicated by severe intrauterine growth restriction. It also improves abdominal circumference growth velocity. A wide scale randomized trials are needed for evaluation of neonatal and long term morbidity and mortality outcomes of pregnancies treated by sildenafil citrate.

An effect of maternal nifedipine therapy on fetoplacental blood flow: a prospective study.

PURPOSE: The aim of this study is to assess the effects of maternal nifedipine administration on placental and fetal blood flow. METHODS: A total of 29 patients with preterm labor diagnosis admitted to the tertiary care center, Zeynep Kamil Hospital, were evaluated. Before and 24-48 h after administration of oral nifedipine, Doppler ultrasound scan was carried out to measure fetal middle cerebral artery, ductus venosus, umbilical artery, and maternal uterine artery blood flow. RESULTS: After 24 and 48 h of therapy, there were no changes in mean PI and RI in the umbilical arteries and ductus venosus (p > 0.05). Fetal middle cerebral artery and maternal uterine artery PI and RI values showed a significant reduction 24-48 h after oral nifedipine therapy (p < 0.05). CONCLUSIONS: Our study showed that 24 and 48 h after oral nifedipine therapy, there is a significant increase in fetal MCA and maternal uterine artery blood flow, while fetal umbilical artery and ductus venosus Doppler values do not change.

Evaluation function of transcranial two-dimensional and color Doppler ultrasonography (TCCS) for patients with different degrees of cerebral vasospasm before and after the nimodipine treatment.

OBJECTIVE: To evaluate the changes in cerebral hemodynamics of patients with different degrees of cerebral vasospasm before and after the nimodipine treatment using transcranial two-dimensional and color Doppler ultrasonography (TCCS). PATIENTS AND METHODS: A total of 77 patients with subarachnoid hemorrhage was collected; and the maximum peak systolic velocity (Vs), end diastolic velocity (Vd), time averaged maximum velocity (Vm), pulsatility index (PI) and resistance index (RI) of middle cerebral artery (MCA) were measured by spectral Doppler technique. The standard-dose nimodipine was given for clinical treatment, and changes in blood flow velocity of MCA were monitored by TCCS, and the therapeutic effect was observed. RESULTS: 68 out of 77 patients (88.3%) with subarachnoid hemorrhage were diagnosed as cerebral vasospasm (CVS), including 53 cases (77.9%) of mild spasm, 11 cases (16.2%) of moderate spasm and 4 cases (5.9%) of severe spasm. The sensibility of CVS detected by TCCS after operation was 88.3%. Color Doppler flow imaging (CDFI) showed that the blood flow was multicolored. After the nimodipine treatment, the measured values of MCA-Vs and RI were decreased in different degrees compared with those before treatment. CONCLUSIONS: Nimodipine has improving effects on CVS in different degrees, and TCCS can be used to evaluate the therapeutic effects on CVS.

Acute effect of coffee drinking on dynamic cerebral autoregulation.

PURPOSE: Drinking coffee causes caffeine-induced physiological alterations such as increases in arterial blood pressure, sympathetic nerve activity, cerebral vasoconstriction, etc., and these physiological alterations may be associated with a reduced risk of cerebral vascular disease. However, the effect of coffee drinking on dynamic cerebral blood flow (CBF) regulation remains unclear. The aim of this study was to test our hypothesis that coffee drinking enhances dynamic cerebral autoregulation. METHOD: Twelve healthy young subjects participated in the present study. After a 5 min baseline measurement in a semi-recumbent position on the hospital bed, each subject drank water (CON) as a placebo condition or coffee beverage (Coffee INT). Arterial blood pressure and middle cerebral artery blood velocity (MCAv) were measured continuously throughout the experiment. At 30 min after the intake of either water or coffee, dynamic cerebral autoregulation was examined using a thigh cuffs occlusion and release technique. Each condition was randomly performed on a different day. RESULT: Under Coffee INT condition, mean arterial blood pressure was increased (P = 0.01) and mean MCAv was decreased (P = 0.01) from the baseline. The rate of regulation (RoR), as an index of dynamic cerebral autoregulation, during coffee condition was significantly higher than that during CON (P = 0.0009). CONCLUSION: The findings of the present study suggest that coffee drinking augments dynamic CBF regulation with cerebral vasoconstriction. This phenomenon may be associated with a reduction in the risk of cerebral vascular disease.

What Do Anticoagulants Say about Microemboli?

BACKGROUND: In this study, we evaluated the microembolic signals (MES) frequency with transcranial Doppler ultrasound (TCD) in patients with atrial fibrillation (AF) under anticoagulant therapy, and we compared the treatment groups. METHODS: Ninety-nine patients with nonvalvular AF with a history of stroke using warfarin (46%), 67 patients using rivaroxaban (31%), and 49 patients using dabigatran (23%), that is, a total of 215 patients, who have been referred to the stroke outpatient section of our department from May 2013 to November 2014, were included in the study. CHA(2)DS(2)VASc scoring was made for all patients, and International Normalized Ratio (INR) value was evaluated in patients using warfarin. All patients were monitored with TCD on the middle cerebral arteries bilaterally for 30 minutes. Embolic signals were evaluated according to their density and the mean number of signals in 2 consecutive recordings. RESULTS: The incidence of emboli in the treatment group was 32 (32%) for warfarin, 24 (36%) for rivaroxaban, and 17 (35%) for dabigatran. The analysis of variance revealed that there was no statistically significant differences between the treatment groups in terms of patients' age (P = .145), CHA(2)DS(2)VASc scores (P = .968), and the number of emboli (P = .783). As CHA(2)DS(2)VASc score increases, number of emboli increase. A statistically significant negative correlation between the number of emboli and INR scores was found in the warfarin group. The number of emboli decreases as INR decreases. CONCLUSIONS: As we aim to reduce the risk of emboli to a minimum with anticoagulant therapy, this screening for MES can give us an idea for the risk of stroke.

Impact of short-term treatment with telmisartan on cerebral arterial remodeling in SHR.

BACKGROUND AND PURPOSE: Chronic hypertension decreases internal diameter of cerebral arteries and arterioles. We recently showed that short-term treatment with the angiotensin II receptor blocker telmisartan restored baseline internal diameter of small cerebral arterioles in spontaneously hypertensive rats (SHR), via reversal of structural remodeling and inhibition of the angiotensin II vasoconstrictor response. As larger arteries also participate in the regulation of cerebral circulation, we evaluated whether similar short-term treatment affects middle cerebral arteries of SHR. METHODS: Baseline internal diameters of pressurised middle cerebral arteries from SHR and their respective controls, Wistar Kyoto rats (WKY) and responses to angiotensin II were studied in a small vessel arteriograph. Pressure myogenic curves and passive internal diameters were measured following EDTA deactivation, and elastic modulus from stress-strain relationships. RESULTS: Active baseline internal diameter was 23% lower in SHR compared to WKY, passive internal diameter (EDTA) 28% lower and elastic modulus unchanged. Pressure myogenic curves were shifted to higher pressure values in SHR. Telmisartan lowered blood pressure but had no effect on baseline internal diameter nor on structural remodeling (passive internal diameter and elastic modulus remained unchanged compared to SHR). Telmisartan shifted the pressure myogenic curve to lower pressure values than SHR. CONCLUSION: In the middle cerebral arteries of SHR, short-term treatment with telmisartan had no effect on structural remodeling and did not restore baseline internal diameter, but allowed myogenic tone to adapt towards lower pressure values.

Neuroprotective effect of guggulipid alone and in combination with aspirin on middle cerebral artery occlusion (MCAO) model of focal cerebral ischemia in rats.

This study was designed to test the pre-treatment doses of guggulipid (50 mg/kg), aspirin (100 mg/kg) per orally and co-administration of both drugs for 28 days followed by middle cerebral artery occlusion - a model of focal cerebral ischemia in rats. Middle cerebral artery was occluded for two hours, followed by reperfusion for 22 hours for the induction of focal cerebral ischemia in rats. Neurobehavioral tests like locomotor activity and grip strength tests were performed before sacrificing the animal. After neurobehavioral tests, the animals were sacrificed for the measurement of infarction areas and biochemical estimations in brain. Locomotor activity and grip strength were significantly improved in guggulipid and aspirin pre-treated rats. Guggulipid and aspirin pre-treatment reduced the infarction areas as compared with middle cerebral occluded (MCAO) rats. An elevation of nitrite, thiobarbituric acid reactive substance (TBARS), acetylcholine esterase activity (AchE) and reduction in antioxidant enzymes like superoxide dismutase (SOD), glutathione (GSH) and catalase were observed following MCAO. Pre-treatment with guggulipid and aspirin caused a reduction in TBARS and nitrite levels, AchE, but elevated GSH level, SOD and catalase activities as compared with MCAO rats. The protective effects observed in this study were due to antioxidant, anti-inflammatory and anti-hyperlipidemic properties of guggulipid. The protective effect of guggulipid in cerebral ischemia, that it may have a role in reversing the symptoms and may offer significant neuroprotection in stroke.

Ischemic stroke penumbra and extracorporeal ozone treatment.

The course of events in ischemic strokes is normally seen from a point in which the penumbra is already in place. Since there is no known treatment for edema reduction, mainstream medicine focuses on re-opening the occluded vessel. Here we show that reducing the penumbra saves neuronal units from undergoing apoptosis.

Efficacy and safety of MLC601 (NeuroAiD®), a traditional Chinese medicine, in poststroke recovery: a systematic review.

BACKGROUND: Subsequent to a pooled analysis of 2 trials, several more studies have been published assessing the benefit of MLC601 in stroke patients. Hence, it is timely to conduct an updated meta-analysis to frame the interpretation of the results of an ongoing large multicenter, randomized, double-blind, placebo-controlled study. Therefore, we conducted a systematic review of the efficacy of MLC601 in improving the recovery of stroke patients. METHODS: PubMed® and the Cochrane Library® databases were searched for trials evaluating MLC601 in stroke patients. Primary outcome was functional independence, assessed by the Barthel Index or the Diagnostic Therapeutic Effects of Apoplexy scoring system, item 8. Secondary outcomes were improvement in functional independence scores, motor recovery, reduction in visual field defect and increase in cerebral blood flow. Two authors performed the article selection, appraisal and data extraction while resolving differences through discussion or consulting a third author. Data were analyzed in RevMan5®. Meta-analysis was conducted using a random effects model. RESULTS: This review included 6 studies with overall low risk of bias but some clinical heterogeneity. MLC601 increased the chances of achieving functional independence after stroke compared to control treatments (risk ratio, 2.35; 95% CI, 1.31-4.23). No deaths and 4 serious adverse events were reported in the MLC601 group, although detail was sparse with inconsistent reporting. CONCLUSIONS: There is evidence that MLC601 as an add-on to standard treatment could be effective in improving functional independence and motor recovery and is safe for patients with primarily nonacute stable stroke.

High-dose argatroban therapy for stroke: novel treatment for delayed treatment and the recanalization mechanism.

BACKGROUND: There has been little effective treatment in patients with cerebral infarction at >24 hours after onset. We assessed the effects of high-dose argatroban therapy in delayed administration, and investigated the mechanism based on our clinical findings. METHODS: Argatroban 30 mg was first administered for 15 minutes intravenously, and then 90 mg for 60 minutes followed by 60 mg for 60 minutes were infused continuously. The change of vascular obstruction caused by the treatment was assessed with magnetic resonance angiography. RESULTS: In 4 patients studied, high-dose argatroban resulted in 100% recanalization of occluded vessels (5/5), even though argatroban was administrated >24 hours after onset. On the other hand, when an inadequate dose of argatroban was administered, a hemorrhage was identified. This supports our hypothesis that high-dose argatroban promotes recanalization by deactivating thrombin and exerting an anticoagulant effect on the vascular endothelium. CONCLUSIONS: High-dose argatroban is an effective treatment for cerebral infarction and offers a novel therapeutic approach for delayed hospitalized patients at >24 hours after onset. Additional studies are necessary to identify the cellular and molecular mechanisms and determine the adequate dose in order to reduce risks of complication.

Inhibitory effects of Qushuanling Capsule () on thrombus formation and platelet aggregation in rats.

OBJECTIVE: To investigate the effects of Qushuanling Capsule ( QSLC) on thrombus formation and platelet aggregation in rats. METHODS: Arteriovenous bypass, venous thrombosis, and middle cerebral artery thrombosis models were used in rats to investigate the anti-thrombotic effects of QSLC, a compound of nine Chinese herbs. The platelet aggregation induced by adenosine diphosphate (ADP), thrombin or arachidonic acid (AA), as well as the contents of thromboxane B(2) (TXB(2)) and 6-keto-prostaglandin F1α (6-keto-PGF1α) in rat plasma and aortic walls, were determined to investigate the possible mechanisms of the anti-thrombotic effects of QSLC. RESULTS: After oral administration with QSLC for 7 days, arteriovenous bypass thrombosis was obviously suppressed compared with the model group, venous thrombosis was also obviously suppressed, rat behaviors were obviously improved, and brain infarct size as well as water content were also reduced. The platelet aggregation induced by ADP or thrombin was inhibited by QSLC, but the drug had no effect on AA-induced platelet aggregation and content of TXB(2) and 6-keto-PGF1α in plasma and the aortic wall. CONCLUSION: These results suggest that QSLC can be used in the prevention and treatment of thrombotic diseases, and that its mechanism of action may be related to inhibition of platelet aggregation.

High-dose atorvastatin enhances impaired cerebral vasomotor reactivity.

The influence of statin therapy on cerebral vasomotor function has not been fully characterized. We report the effects of high-dose atorvastatin therapy on cerebral vasomotor reactivity (VMR) in patients with controlled hypertension and dyslipidemia. We prospectively enrolled 36 patients with controlled hypertension and a low-density lipoprotein (LDL) cholesterol concentration >100 mg/dL. Atorvastatin 80 mg was given daily for 6 months and then discontinued. VMR was assessed by hypercapnic and hypocapnic transcranial Doppler challenge in both the right and left middle cerebral artery (MCA) at baseline, and after 3 and 6 months of therapy. Forty-five days after statin cessation, a repeat VMR was performed. VMR impairment was defined as ≤70%. Blood pressure, lipid levels, liver function, and creatine kinase level were monitored. Mean patient age was 60 years, 16 were men, and 13 had a previous history of subcortical infarction. Mean LDL cholesterol level before treatment was 154 ± 30 mg/dL. Atorvastatin lowered LDL by 53% at 3 months and by 46% at 6 months. Baseline VMR was 71% ± 21% in the right MCA and 70% ± 19% in the left MCA. No significant effect of atorvastatin on VMR was seen at 3 months and 6 months in the study population as a whole. In the subgroup of patients with baseline VMR impairment, atorvastatin therapy was associated with significantly improved VMR at both 3 and 6 months. This effect persisted for at least 45 days after discontinuation of therapy. Our findings indicate that high-dose atorvastatin therapy can significantly improve impaired cerebral VMR, and that the effects of atorvastatin on VMR persist for 1.5 months after discontinuation of therapy. We found no benefit of atorvastatin therapy in patients with preserved baseline vasoreactivity.

Capsaicin pre-treatment provides neurovascular protection against neonatal hypoxic-ischemic brain injury in rats.

Capsaicin, a transient receptor potential vanilloid 1 (TRPV1) agonist, has recently been shown to provide neuroprotection against brain injury in experimental adult models of cerebral ischemia. Accordingly, in this study, we investigated the way in which capsaicin-mediated TRPV1 modulation could attenuate damage in an experimental hypoxic-ischemic (HI) neonatal brain injury model. The Rice-Vannucci method was used in 10-day-old rat pups by performing unilateral carotid artery ligation followed by 2 h of hypoxia (8% O2 at 37°C). Capsaicin was administered intraperitoneally (0.2 mg/kg or 2.0 mg/kg) at 3 h pre-HI or 1 h post-HI. Post assessment included measurement of infarction volume at 24 and 72 h in addition to an assessment of the vascular dynamics of the middle cerebral artery (MCA) at 6 h post-HI. The results indicated that pre-treatment with capsaicin reduced infarction volume significantly with either low-dose or high-dose treatment. Pre-treatment also improved myogenic tone and decreased apoptotic changes in the distal MCA. We concluded that capsaicin pre-treatment may provide neurovascular protection against neonatal HI.

The effects of sevoflurane on cerebral blood flow autoregulation and flow-metabolism coupling during cardiopulmonary bypass.

BACKGROUND: previous studies on non-cardiac surgical patients have shown that cerebral pressure-flow autoregulation and cerebral flow-metabolism coupling are maintained with sevoflurane. The effects of sevoflurane on cerebral blood flow (CBF) autoregulation and flow-metabolism coupling during cardiopulmonary bypass (CPB) have not been studied previously. METHODS: the effects of sevoflurane-induced burst suppression, monitored with electroencephalography (EEG), on cerebral blood flow velocity (CBFV), cerebral oxygen extraction (COE) and flow autoregulation, were studied in 16 patients undergoing cardiac surgery. The experimental procedure was performed during non-pulsatile CPB with mild hypothermia (34 degreesC) in fentanyl/droperidol-anesthetized patients. Middle cerebral artery transcranial Doppler flow velocity, right jugular vein bulb oxygen saturation and jugular venous pressure were measured continuously. Autoregulation was tested during changes in the mean arterial pressure (40-90 mmHg), induced by sodium nitroprusside and norepinephrine before (control), and during additional sevoflurane administration, in a dose that resulted in an EEG burst-suppression level of 4-6/min. RESULTS: sevoflurane, at an inspired concentration of 3.36 ± 0.03%, induced a 17% decrease in CBFV (P<0.05) and a 22% decrease in COE (P<0.05) compared with the control. The slope of the positive relationship between CBFV and cerebral perfusion pressure was steeper with sevoflurane (p<0.01) compared with control measurements, as was the slope of the negative relationship between cpp and coe (p<0.01). CONCLUSION: burst-suppression doses of sevoflurane exert an intrinsic cerebral vasodilatory effect, which impairs CBF autoregulation during mildly hypothermic CPB. Furthermore, during sevoflurane administration, CBF is in excess relative to oxygen demand, indicating a partial loss of the cerebral flow-metabolism coupling.

Alterations in the modulation of cerebrovascular tone and blood flow by nitric oxide synthases in SHRsp with stroke.

AIMS: The modulation of myogenic function and cerebral blood flow (CBF) by nitric oxide (NO) synthases (NOS) was assessed in the middle cerebral arteries (MCAs) of Kyoto Wistar stroke prone hypertensive rats (SHRsp) in relation to haemorrhagic stroke development. METHODS AND RESULTS: MCAs were studied with a pressure myograph. CBF in MCA perfusion domain was measured using laser Doppler techniques. NOS isozymes were identified using immunohistochemistry. MCAs expressed endothelial, neuronal, and inducible NOS (eNOS, nNOS, and iNOS, respectively) in the endothelium, nNOS and traces of iNOS in smooth muscle and adventitial cells. Before stroke, MCA pressure-dependent constriction (PDC) was superimposed over basal non-pressure-dependent tone (BNPDT). Endothelial NO generation and non-endothelial nNOS but not iNOS reduced BNPDT and increased the lumen diameter at which PDC initiated without altering the amplitude of PDC. NOS inhibition decreased CBF and increased the upper blood pressure limit of autoregulation. PDC, CBF autoregulation, and NOS dilatory influence were lost, and BNPDT was increased in MCAs from SHRsp with stroke. The expression of NOS isozymes and MCA reactivity to NO donors was not altered. NOS activity was not recovered by in vitro l-arginine or tetrahydrobiopterin supplementation, l-arginase inhibition or superoxide scavengers. CONCLUSION: The loss of PDC and CBF autoregulation during hypertension may facilitate over-perfusion and cerebral haemorrhage formation in SHRsp. NOS dysfunction in MCAs preceded stroke and involved the inactivation of eNOS and nNOS in areas not subjected to hyper-distension. The elevation in BNPDT due to NOS inactivation may oppose over-perfusion in the absence of CBF autoregulation.

Doppler velocimetry of the uterine, umbilical and fetal middle cerebral arteries in pregnant women undergoing tocolysis with oral nifedipine.

OBJECTIVES: To evaluate Doppler velocimetry (resistance index (RI) and peak systolic velocity (PSV)) in the maternal-fetal circulation before and 5 and 24 h after tocolysis with oral nifedipine. METHODS: This was a prospective, observational, analytic cohort study performed in 47 pregnant women undergoing nifedipine tocolysis, each subject acting as her own control. Doppler assessment of uterine, umbilical and fetal middle cerebral (MCA) arteries was performed before and 5 and 24 h after an initial 20-mg sublingual dose, which was repeated twice at 20-min intervals if contractions failed to diminish. The maintenance dose consisted of 20 mg orally every 6 h for 24 h up to a total of 100-120 mg nifedipine. We analyzed whether there was a time effect and compared values at the different time-points. RESULTS: The MCA-RI had decreased significantly after 24 h of tocolysis (0 h = 0.85; 5 h = 0.85; 24 h = 0.81; P = 0.001), with no differences in uterine or umbilical arteries or in the MCA to umbilical artery ratio. The MCA-PSV had reduced significantly after 5 h (0 h = 41.5 cm/s; 5 h = 34.7 cm/s; P = 0.001), returning close to baseline levels between 5 and 24 h. The PSV increased significantly between 5 and 24 h in the right uterine artery (5 h = 55.1 cm/s; 24 h = 65.0 cm/s; P = 0.037) and in the umbilical artery (5 h = 28.4 cm/s; 24 h = 33.1 cm/s; P = 0.038). CONCLUSIONS: Nifedipine tocolysis is associated with a reduction in RI in the MCA but not in the uterine or umbilical arteries, a reduction in PSV in the MCA after 5 h but returning to baseline within 24 h, and an increase in PSV between 5 and 24 h in the umbilical and right uterine arteries.

Direct regulation of BK channels by phosphatidylinositol 4,5-bisphosphate as a novel signaling pathway.

Large conductance, calcium- and voltage-gated potassium (BK) channels are ubiquitous and critical for neuronal function, immunity, and smooth muscle contractility. BK channels are thought to be regulated by phosphatidylinositol 4,5-bisphosphate (PIP(2)) only through phospholipase C (PLC)-generated PIP(2) metabolites that target Ca(2+) stores and protein kinase C and, eventually, the BK channel. Here, we report that PIP(2) activates BK channels independently of PIP(2) metabolites. PIP(2) enhances Ca(2+)-driven gating and alters both open and closed channel distributions without affecting voltage gating and unitary conductance. Recovery from activation was strongly dependent on PIP(2) acyl chain length, with channels exposed to water-soluble diC4 and diC8 showing much faster recovery than those exposed to PIP(2) (diC16). The PIP(2)-channel interaction requires negative charge and the inositol moiety in the phospholipid headgroup, and the sequence RKK in the S6-S7 cytosolic linker of the BK channel-forming (cbv1) subunit. PIP(2)-induced activation is drastically potentiated by accessory beta(1) (but not beta(4)) channel subunits. Moreover, PIP(2) robustly activates BK channels in vascular myocytes, where beta(1) subunits are abundantly expressed, but not in skeletal myocytes, where these subunits are barely detectable. These data demonstrate that the final PIP(2) effect is determined by channel accessory subunits, and such mechanism is subunit specific. In HEK293 cells, cotransfection of cbv1+beta(1) and PI4-kinaseIIalpha robustly activates BK channels, suggesting a role for endogenous PIP(2) in modulating channel activity. Indeed, in membrane patches excised from vascular myocytes, BK channel activity runs down and Mg-ATP recovers it, this recovery being abolished by PIP(2) antibodies applied to the cytosolic membrane surface. Moreover, in intact arterial myocytes under physiological conditions, PLC inhibition on top of blockade of downstream signaling leads to drastic BK channel activation. Finally, pharmacological treatment that raises PIP(2) levels and activates BK channels dilates de-endothelized arteries that regulate cerebral blood flow. These data indicate that endogenous PIP(2) directly activates vascular myocyte BK channels to control vascular tone.

Effects of oral L-arginine on the pulsatility indices of umbilical artery and middle cerebral artery in preterm labor.

OBJECTIVE: The objective of the study was the estimation of the influence of oral supplementation with low-dose l-arginine on feto-placental circulation in women with threatened preterm labor. STUDY DESIGN: Oral administration of 3g of L-arginine daily or placebo as a supplement to standard tocolytic therapy was tried in 70 women with threatened preterm delivery, randomly assigned to the L-arginine (n=37) or placebo (n=33) groups. Twenty-five and 20 completed the study, respectively. Doppler velocimetry of pulsatility indices (PI) of the umbilical (UA) and middle cerebral (MCA) arteries as well as pregnancy outcome and biochemical markers of nitric oxide synthesis (plasma amino acid and nitrite/nitrate levels, as well as 24 h nitrite/nitrate excretion with urine) were estimated. RESULTS: Starting from the second week of therapy, the UA PI values were significantly lower in the L-arginine group than in the placebo group. Moreover, treatment with L-arginine caused a significant increase in MCA PI and cerebro-placental ratio (CPR) values. The changes in feto-placental circulation in the L-arginine group were not associated with any signs of increased nitric oxide synthesis. CONCLUSION: Oral supplementation with low doses of L-arginine changed feto-placental blood flow distribution in patients with threatened preterm labor. The exact mechanism of L-arginine action on feto-placental circulation requires further investigation.

Physiological and pathological observations on rat middle cerebral arteries and human AVM tissue cultures following single high-dose gamma irradiation.

In vitro isometric myograph and histopathological studies were performed on rat middle cerebral arteries (MCAs) to explore changes in contractile capacity following experimental Gamma Knife radiosurgery. Right MCAs were treated with 25 Gy and 50 Gy at the 50% isodose line, while contralateral vessels received 15 Gy and 20 Gy at the 20% isodose region. Survival period varied from 3 to 18 months. Reduction in contractile capacity of irradiated normal rat MCAs was detected but their lumina remained patent. In another study, we investigated human AVM tissue cultures in order to detect genetic and phenotypic modifications contributing to vessel occlusion after irradiation. In culture, the proliferation index decreased considerably following 15-, 20-, 25- or 50-Gy irradiation at the 5th posttreatment day and remained depressed during the observation period of 14 days. P53, p21Waf-1 and mdm-2 mRNA contents were elevated significantly after irradiation, indicating enhanced apoptosis. Immunohistochemistry revealed vigorous vimentin positivity in the nonirradiated control AVM cultures, which gradually decreased by the time in the irradiated specimens. Smooth muscle alpha-actin positivity was prominent in the irradiated cultivated samples, suggesting transformation of resting fibroblasts onto activated myofibroblastic elements with contractile capacity. This transformation process was confirmed by the appearance of TGF-Beta in the irradiated AVM cell lines also. These data support the hypothesis that one of the contributing factors to AVM shrinkage and obliteration after radiosurgery might be fibrocyte-myofibroblastic cell transformation in the vessel wall.

Pharmacological and molecular comparison of K(ATP) channels in rat basilar and middle cerebral arteries.

ATP-sensitive potassium (K(ATP)) channels play an important role in the regulation of cerebral vascular tone. In vitro studies using synthetic K(ATP) channel openers suggest that the pharmacological profiles differ between rat basilar arteries and rat middle cerebral arteries. To address this issue, we studied the possible involvement of endothelial K(ATP) channels by pressurized arteriography after luminal administration of synthetic K(ATP) channel openers to rat basilar and middle cerebral arteries. Furthermore, we examined the mRNA and protein expression profile of K(ATP) channels to rat basilar and middle cerebral arteries using quantitative real-time PCR (Polymerase Chain Reaction) and Western blotting, respectively. In the perfusion system, we found no significant responses after luminal application of three K(ATP) channel openers to rat basilar and middle cerebral arteries. In contrast, abluminal application caused a concentration-dependent dilatation of both arteries, that was more potent in basilar than in middle cerebral arteries. Quantitative real-time PCR detected the presence of mRNA transcripts of the K(ATP) channel subunits Kir6.1, Kir6.2, SUR1 and SUR2B, while SUR2A mRNA was barely detected in both rat basilar and middle cerebral arteries. Of the five mRNAs, the expression levels of Kir6.1 and SUR2B transcripts were predominant in both rat basilar and middle cerebral arteries. Western blotting detected the presence of Kir6.1, Kir6.2, SUR1 and SUR2B proteins in both arteries. Densitometric measurements of the Western blot signals further showed higher expression levels of Kir6.1 and SUR2B proteins in rat middle cerebral arteries than was found in rat basilar arteries. In conclusion, our in vitro pharmacological studies showed no evidence for functional endothelial K(ATP) channels in either artery. Furthermore, the results indicate that Kir6.1/SUR2B is the major K(ATP) channel complex in rat basilar and middle cerebral arteries.