Absence of flow-mediated vasodilation in the rabbit femoral artery.

The purpose of this study was to determine if there is flow-mediated vasodilation of the femoral artery in response to progressive increases in flow within a physiological range observed in the in vivo experiments. Femoral artery blood flow was determined in conscious rabbits (n = 5) using chronically implanted flowprobes. Resting blood flow was 8.3 +/- 0.6 ml/min and increased to 39.9 +/- 5.4 ml/min during high intensity exercise. Femoral arteries (n = 12, 1705 +/- 43 microm outer diameter) harvested from a separate group of rabbits were mounted on cannulas and diameter was continuously monitored by video system. Functional integrity of the endothelium was tested with acetylcholine. The arteries were set at a transmural pressure of 100 mm Hg and preconstricted with phenylephrine to 73 +/- 3% of initial diameter. Using a roller pump with pressure held constant, the arteries were perfused intraluminally with warmed, oxygenated Krebs' solution (pH = 7.4) over a physiological range of flows up to 35 ml/min. As flow increased from 5 ml/min to 35 ml/min, diameter decreased significantly (p < 0.05) from 1285 +/- 58 microm to 1100 +/- 49 microm. Thus, in vessels with a functional endothelium, increasing intraluminal flow over a physiological range of flows produced constriction, not dilation. Based on these results, it seems unlikely that flow-mediated vasodilation in the rabbit femoral artery contributes to exercise hyperemia.

Inhaled bronchodilators for acute chest syndrome in people with sickle cell disease.

BACKGROUND: Bronchodilators are used to treat bronchial hyper-responsiveness in asthma. Bronchial hyper-responsiveness may be a component of the acute chest syndrome in people with sickle cell disease. Therefore, bronchodilators may be useful in the treatment of acute chest syndrome. OBJECTIVES: To assess the benefits and risks associated with the use of bronchodilators in people with acute chest syndrome. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group trials register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. Additional searches were carried out on MEDLINE (1966 to 2002) and EMBASE (1981 to 2002).Date of the most recent search of the Group's haemoglobinopathies register: May 2002. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials. Trials using quasi-randomisation methods will be included in future updates of this review if there is sufficient evidence that the treatment and control groups are similar at baseline. DATA COLLECTION AND ANALYSIS: We found no trials investigating the use of bronchodilators for acute chest syndrome in people with sickle cell disease. MAIN RESULTS: We found no trials investigating the use of bronchodilators for acute chest syndrome in people with sickle cell disease. REVIEWER'S CONCLUSIONS: If bronchial hyper-responsiveness is an important component of some episodes of acute chest syndrome in people with sickle cell disease, the use of inhaled bronchodilators may be indicated. There is need for a well-designed, adequately powered randomised controlled trial to assess the benefits and risks of the addition of inhaled bronchodilators to established therapies for acute chest syndrome in people with sickle cell disease.

A review of the role of the gut microflora in irritable bowel syndrome and the effects of probiotics.

Irritable bowel syndrome (IBS) is a multi-factorial gastrointestinal condition affecting 8-22 % of the population with a higher prevalence in women and accounting for 20-50 % of referrals to gastroenterology clinics. It is characterised by abdominal pain, excessive flatus, variable bowel habit and abdominal bloating for which there is no evidence of detectable organic disease. Suggested aetiologies include gut motility and psychological disorders, psychophysiological phenomena and colonic malfermentation. The faecal microflora in IBS has been shown to be abnormal with higher numbers of facultative organisms and low numbers of lactobacilli and bifidobacteria. Although there is no evidence of food allergy in IBS, food intolerance has been identified and exclusion diets are beneficial to many IBS patients. Food intolerance may be due to abnormal fermentation of food residues in the colon, as a result of disruption of the normal flora. The role of probiotics in IBS has not been clearly defined. Some studies have shown improvements in pain and flatulence in response to probiotic administration, whilst others have shown no symptomatic improvement. It is possible that the future role of probiotics in IBS will lie in prevention, rather than cure.

Ion exchange activity in pulmonary artery smooth muscle cells: the response to hypoxia.

The purposes of this study were to determine 1) the presence of the major ion transport activities that regulate cytoplasmic pH (pH(c)) in cat pulmonary artery smooth muscle cells, i.e., Na+/H+ and the Na+-dependent and -independent Cl-/HCO3- exchange, 2) whether pH(c) changes in cells from small (SPAs) and large (LPAs) pulmonary arteries during hypoxia, and 3) whether changes in pH(c) are due to changes in the balance of exchange activities. Exchange activities as defined by physiological maneuvers rather than molecular identity were ascertained with fluorescence microscopy to document changes in the ratio of the pH(c) indicator 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein. Steady-state pH(c) was higher in LPA than in SPA normoxic smooth muscle cells. SPAs and LPAs possessed all three transport activities; in HCO3- containing normoxic solutions, Cl-/HCO3- exchange rather than Na+/H+ exchange set the level of pH(c); in HCO3- containing hypoxic solutions, pH(c) increased in SPA and decreased in LPA cells; altering the baseline pH(c) of a cell type to that of the other did not change the direction of the pH(c) response during hypoxia. The absence of Na+ prevented hypoxia-induced alkalinization in SPA cells; in both cell types, inhibiting the Cl-/HCO3- exchange activities reversed the normal direction of pH(c) changes during hypoxia.

Multiple Ca(2+)-dependent modulators mediate alkalosis-induced vasodilation in newborn piglet lungs.

We previously found that alkalosis-induced vasodilation was mediated by endothelium-derived nitric oxide (EDNO) in newborn piglet pulmonary artery and vein rings precontracted with the thromboxane mimetic U-46619. In contrast, prostacyclin or K(+) channel activation contributed to the response in other preparations. This study was undertaken to determine whether EDNO alone also mediates alkalosis-induced pulmonary vasodilation in piglet lungs vasoconstricted with hypoxia and, if not, to identify the mediator(s) involved. Responses to alkalosis were measured during hypoxia under control conditions after blocking nitric oxide synthase (N(omega)-nitro-L-arginine), cyclooxygenase (meclofenamate), or both endothelium-derived modulators (Dual); after blocking voltage-dependent (4-aminopyridine), ATP- dependent (glibenclamide), or Ca(2+)-dependent K(+) (K(Ca); tetraethylammonium) K(+) channels; and after blocking both endothelium-derived modulators and K(Ca) channels (Triple). Vasodilator responses measured after 20 min of alkalosis were blunted in Dual and tetraethylammonium lungs and abolished in Triple lungs. Thus alkalosis-induced vasodilation in hypoxic lungs appeared to be mediated by three Ca(2+)-dependent modulators: EDNO, prostacyclin, and K(Ca) channels. In addition, a transient, unidentified modulator contributed to the nadir of the vasodilator response measured at 10 min of alkalosis. Future studies are needed to identify factors that contribute to the discordance between isolated vessels and whole lungs.

Mediators of alkalosis-induced relaxation of piglet pulmonary veins.

Pulmonary venous constriction leads to significant pulmonary hypertension and increased edema formation in several models using newborns. Although alkalosis is widely used in treating neonatal and pediatric pulmonary hypertension, its effects on pulmonary venous tone have not previously been directly measured. This study sought to determine whether alkalosis caused pulmonary venous relaxation and, if so, to identify the mediator(s) involved. Pulmonary venous rings (500-microm external diameter) were isolated from 1-wk-old piglets and precontracted with the thromboxane mimetic U-46619. Responses to hypocapnic alkalosis were then measured under control conditions after inhibition of endothelium-derived modulator activity or K(+) channels. In control rings, alkalosis caused a 34.4 +/- 4.8% decrease in the U-46619-induced contraction. This relaxation was significantly blunted in rings without functional endothelium and in rings treated with nitric oxide synthase or guanylate cyclase inhibitors. However, neither cyclooxygenase inhibition nor voltage-dependent, calcium-dependent, or ATP-dependent K(+)-channel inhibitors altered alkalosis-induced relaxation. These data suggest that alkalosis caused significant dilation of piglet pulmonary veins that was mediated by the nitric oxide-cGMP pathway.

Changes in smooth muscle cell pH during hypoxic pulmonary vasoconstriction: a possible role for ion transporters.

Hypoxic pulmonary vasoconstriction (HPV) occurs in smooth muscle cells (SMC) from small pulmonary arteries (SPA) and is accompanied by increases in free cytoplasmic calcium ([Ca2+]i) and cytoplasmic pH (pHi). SMC from large pulmonary arteries (LPA) relax during hypoxia, and [Ca2+]i and pHi decrease. Increases in pHi and [Ca2+]i in cat SPA SMC during hypoxia and the augmentation of hypoxic pulmonary vasoconstriction by alkalosis seen in isolated arteries and lungs suggest that cellular mechanisms, which regulate inward and outward movement of Ca2+ and H+, may participate in the generation of HPV. SMC transport systems that regulate pHi include the Na+ - H+ transporter which regulates intracellular Na+ and H+ and aids in recovery from acid loads, and the Na+ -dependent and Na+ -independent Cl-/HCO3- transporters which regulate intracellular chloride. The Na+ -dependent Cl-/HCO3- transporter also aids in recovery from acidosis in the presence of CO2 and HCO3-. The Na+ -independent Cl-/HCO3- transporter aids in recovery from cellular alkalosis. The Na+ - H+ transporter was present in SMC from SPA and LPA of the cat, but it seemed to have little if any role in regulating pHi in the presence of CO2 and HCO3-. Inhibiting the Cl-/HCO3- transporters reversed the normal direction of pHi change during hypoxia, suggesting a role for these transporters in the hypoxic response. Future studies to determine the interaction between pHi, [Ca2+]i and HPV should ascertain whether pHi and [Ca2+]i changes are linked and how they may interact to promote or inhibit SMC contraction.

Integrin signaling, free radicals, and tyrosine kinase mediate flow constriction in isolated cerebral arteries.

Isolated, cannulated, and pressurized (100 mmHg) middle cerebral arteries from adult cats were perfused intraluminally at rates from 0 to 4 ml/min with heated and gassed physiological saline solution. An electronic system held pressure constant by changing outflow resistance. The arteries constricted 18.1 +/- 0.95% in response to flow and depolarized from -54 +/- 0.51 to -40 +/- 1.26 mV (P < 0.05). Constriction was independent of a functional endothelium but was eliminated by superoxide dismutase or tyrosine kinase inhibitors. Luminal perfusion with a synthetic extracellular matrix Arg-Gly-ASP (RGD) peptide that binds with integrin significantly reduced constriction to flow. Neither reducing intraluminal pressure nor increasing tone or shear stresses altered constriction to flow. Flow-induced constriction did not impede the ability of the arteries to dilate to hypercapnia, and inhibiting flow-induced constriction did not alter contractile responses to other agonists. These data suggest that, in vitro, middle cerebral arteries constrict to flow through a mechanism involving free radicals and tyrosine kinase and that flow shear stresses resulting in constriction are transduced by integrin signaling.

Discordant effects of alkalosis on elevated pulmonary vascular resistance and vascular reactivity in lamb lungs.

OBJECTIVES: After an initial vasodilator response to alkalosis, many children with pulmonary hypertension exhibit marked pulmonary vascular reactivity despite continued alkalosis therapy. This study sought to a) identify the mediator of alkalosis-induced pulmonary vasodilation in isolated lamb lungs; b) determine whether alkalosis-induced pulmonary vasodilation decreases over time in this model; and c) determine whether alkalosis enhanced vascular reactivity to subsequent pressor stimuli. DESIGN: Prospective, interventional study. SUBJECTS: Isolated perfused lungs from 1-month-old lambs. INTERVENTIONS: Hypocarbic alkalosis, hypoxia, and infusion of the thromboxane mimetic agent U46619 MEASUREMENTS AND MAIN RESULTS: Pulmonary artery pressure was measured at constant flow, so a change in pressure reflects change in resistance. Hypoxic pulmonary artery pressure was compared after 20 and 100 mins of hypocarbic alkalosis or normocarbia in control and cyclooxygenase-inhibited lungs. Pulmonary artery dose responses to U46619 were then measured in control lungs. Responses to hypoxia and U46619 were also compared after 60-80 mins of hypocarbic or normocarbic normoxia. Hypocarbic alkalosis acutely reduced hypoxic pulmonary vascular resistance, and this was sustained for at least 100 mins. Cyclooxygenase inhibition blocked this vasodilation, suggesting that it was mediated by dilator prostaglandins. However, subsequent reactivity to U46619 was enhanced in hypoxic alkalotic lungs, and both hypoxia and U46619 caused significant vasoconstriction in normoxic alkalotic lungs. CONCLUSIONS: Alkalosis caused sustained vasodilation when pulmonary vascular resistance was high but either failed to attenuate or enhanced vascular reactivity to subsequent pressor stimuli.

Mediators of alkalosis-induced relaxation in pulmonary arteries from normoxic and chronically hypoxic piglets.

Alkalosis-induced relaxation was measured in precontracted arterial rings from 1-wk-old piglets exposed to normoxia or to 3 days of chronic hypoxia. In normoxic piglet arteries, alkalosis-induced relaxation was blunted in arteries without functional endothelium and in arteries treated with nitric oxide synthase or guanylate cyclase inhibitors but not in arteries treated with cyclooxygenase inhibitors or Ca2+- and ATP-dependent K+-channel inhibitors. Inhibition of voltage-dependent K+ channels with 10(-3) M 4-aminopyridine also failed to block alkalosis-induced relaxation. 4-Aminopyridine at 10(-2) M did block the response, but this may have been due to sustained vascular smooth muscle depolarization. Arteries from hypoxic piglets exhibited greater contraction to the thromboxane mimetic U-46619, decreased endothelium-dependent relaxation, and blunted alkalosis-induced relaxation. The residual relaxation was eliminated by nitric oxide synthase but not by cyclooxygenase or voltage-dependent K+-channel inhibition. Alkalosis-induced relaxation of newborn piglet pulmonary arteries appears to be mediated by the nitric oxide-cGMP pathway and is attenuated after 3 days of hypoxia, likely because of decreased nitric oxide activity.

Responses to pulsatile flow in piglet isolated cerebral arteries.

Because cerebrovascular hemorrhage in newborns is often associated with fluctuations in cerebral blood flow, this study was designed to investigate the effects of pulsatile flow in isolated cerebral arteries from neonatal piglets. Arteries mounted on cannulas were bathed in and perfused with a physiologic saline solution. An electronic system produced pulsations, the amplitude and frequency of which were independently controlled. At constant mean transmural pressure (20 mm Hg), increasing flow in steps from 0 to 1.6 mL/min under steady flow conditions caused a biphasic response, constriction at low flow, and dilation at high flow. Under pulsatile flow conditions (pulse amplitude 16-24 mm Hg; 2 Hz), the arteries dilated upon flow initiation and continued to dilate as mean flow increased. Dilation to pulsatile flow did not depend on the level of mean flow because switching from steady to pulsatile flow at each flow step also caused dilation. Arteries dilated further upon increasing either pulse amplitude (12-28 mm Hg; 2 Hz) or frequency (16-24 mm Hg; 4 Hz). Inhibiting nitric oxide synthesis with Nomega-nitro-L-arginine or perfusing with glutaraldehyde to decrease endothelial cell deformability significantly reduced dilations to pulsatile flow and to increased amplitude and frequency. These data suggest that the arterial response to flow is highly dependent on the mode of flow. Dilation induced by initiating pulsatile flow or increasing either pulse amplitude or frequency appears to be mediated by augmented nitric oxide release as result of shear stress-induced deformation of the endothelial cells.

Flow-induced responses in cat isolated pulmonary arteries.

Isolated, cannulated, endothelium-intact cat pulmonary arteries, averaging 692 +/- 104 microns in diameter, were set at a transmural pressure of 10 mmHg and monitored with a video system. Intraluminal flow was increased in steps from 0 to 1.6 ml/min by using a syringe pump. An electronic system held pressure constant by changing outflow resistance. Flow-diameter curves were generated in physiological saline solution. At constant transmural pressure, the arteries constricted in response to increased intraluminal flow. Constriction was not affected by removing extracellular Ca2+ but was abolished after treatment with ryanodine to deplete intracellular Ca2+ stores, with the endothelin-1 synthesis inhibitor phosphoramidon, with the endothelin A-receptor antagonist BQ-123, with the protein kinase C inhibitor staurosporine, or with glutaraldehyde to reduce endothelial cell deformability. The results indicate that isolated pulmonary arteries can constrict in response to intraluminal flow and suggest that constriction is mediated by endothelin-1 and depends on intracellular Ca2+ release and protein kinase C activation.

Flow-induced responses in piglet isolated cerebral arteries.

Although cerebral hemorrhage is a widely occurring neurologic disorder thought to be caused by fluctuating blood flow, the response to flow in the neonatal cerebrovasculature has not been characterized. In the present study, we examined the effect of changing flow on middle cerebral artery diameter and pathways by which flow modulates cerebrovascular tone. Arteries from 2-14-d-old piglets were mounted on cannulas and bathed in and perfused with physiologic saline solution. An electronic system controlled pressure and a syringe pump provided constant flow. The transmural pressure was held constant at 20 mm Hg, and changes in vessel diameter were measured as flow was increased in steps from 0 to 1.60 mL/min (flow/diameter curves). Increasing flow at constant pressure resulted in constriction at flows from 0.077 to 0.152 mL/min and dilation at flows from 0.212 to 1.60 mL/min. The flow/diameter curves were repeated in arteries bathed in Na(+)-reduced or Ca(2+)-free physiologic saline solution; denervated with 6-hydroxydopamine; or treated with indomethacin, N-nitro-L-arginine methyl ester, N omega-nitro-L-arginine (NLA), and L-arginine), ryanodine, or glutaraldehyde. In Na(+)-reduced and in Ca(2+)-free physiologic saline solution, flow constriction was eliminated. Neither indomethacin nor 6-hydroxydopamine affected the biphasic response. N-Nitro-L-arginineL, NLA, and ryanodine blocked dilation, whereas L-arginine restored dilation in NLA-treated arteries. These data suggest that neither prostaglandins nor adrenergic nerve endings participate in flow-induced responses in piglet cerebral arteries. Elimination of flow-constriction by Na+ reduction or Ca2+ removal is consistent with findings in other artery types. The elimination of dilation by N-nitro-L-arginine methyl ester, NLA, and ryanodine suggests that dilation is mediated by nitric oxide and intracellular Ca2+. Whereas the contractile and dilatory responses to agonists remained intact after glutaraldehyde perfusion, both flow-induced constriction and dilation were eliminated, indicating that both types of flow responses result from endothelial cell deformation.

Intrinsic tone and distensibility of in vitro and in situ cat pulmonary arteries.

This study was designed to determine the in vitro and in situ diameter vs pressure relationship of 200- to 1,200-microns diameter pulmonary arteries in the cat. Diameter vs pressure relationships of these arteries were obtained using two methods, microscopic observation of in vitro cannulated and pressurized arteries and X-ray angiography of in situ arteries. Both in vitro and in situ arteries were studied first under normal conditions and then after reducing tone with Ca(2+)-free solution (in vitro) or papaverine (in situ). In vitro arteries commonly increased their tone in response to elevated transmural pressure, and in some cases, the diameter actually decreased as pressure increased. This behavior was not observed in the in situ arteries. The major difference between in vitro and in situ arteries was that when the in vitro arteries were relaxed, the slope of the diameter vs pressure curves increased, whereas the slope was not altered significantly by relaxation of the in situ arteries. This difference is emphasized by the increased distensibility with relaxation of the in vitro arteries but the decreased distensibility with relaxation of the in situ arteries. The results of this study suggest that, at least in the cat, small pulmonary arteries possess a mechanism that is dormant in the in situ environment within the normal lung. However, the potential for pressure-induced constriction may be unmasked by changing the vessel history and/or environment. Extrapolating results obtained from in vitro pulmonary arteries to the in situ situation should therefore be done with caution. Studies directed at what factors contribute to differences in the responses of in vitro and in situ arteries might help in understanding pulmonary vascular pathophysiology.

Effect of cocaine metabolites on behavior: possible neuroendocrine mechanisms.

The predominant cocaine metabolites were tested for central nervous system effects by intracerebroventricular (ICV) administration in rats. We found two types of responses: cocaine, norcocaine (NC), benzoylecgonine (BE), and benzoylnorecgonine (Nor BE) produced stimulatory effects, whereas ecgonine methyl ester (EME) and ecgonine (EC) resulted in no specific effect or sedation. A novel metabolite interaction was revealed when rats were pretreated with EME, which inhibited both analgesia and seizures by subsequently administered cocaine. Pretreatment with EC inhibited both cocaine and BE seizures and seizure-associated death. Direct injection of EME into the nucleus accumbens significantly suppressed systemic cocaine potentiation of intracranial electrical self-stimulation of the ventral tegmental area, whereas corticotropin releasing hormone injected ICV selectively potentiated BE-induced seizures and death. These results confirm multiple, metabolite-mediated activities in the central nervous system. Pharmacological interactions of the metabolites with each other and/or with neurohormones may help explain some of the pathophysiological effects seen in human chronic cocaine abuse.

Cocaine analgesia: an in vivo structure-activity study.

Hot plate testing of rats was performed to determine the optimal analgesic doses of intracerebroventricularly (ICV) administered cocaine, significant cocaine metabolites, and selected structurally similar molecules. Optimal, (subseizure) analgesic doses for cocaine and selected cocaine analogues were (in microM): cocaine, 0.37; cocaethylene, 0.09; benzoylecgonine, 0.35; norcocaine, 0.43; and ecgonine, 2.1. Ecgonine methyl ester was not analgesic at < or = 3.7 microM. These results, in conjunction with findings on other structurally similar molecules suggest that, of the molecules tested, (a) a hydrophobic group at the C-3 attached carbon is critical for analgesia; (b) a hydrophobic C-2 ester group can enhance analgesic activity (e.g., cocaethylene); (c) the N-methyl position is minimally important for analgesia; and (d) isomeric configurational changes can influence analgesia.

L-arginine-related responses to pressure and vasoactive agents in monocrotaline-treated rat pulmonary arteries.

To determine whether altered NO production contributes to attenuated distensibility (alpha), vasoreactivity, and acetylcholine (ACh) dilation in pulmonary arteries from monocrotaline (MCT)-treated rats (J.A. Madden, P.A. Keller, R. M. Effrosa, C. Sequitte, J.S. Choy, and A.D. Hacker. J. Appl. Physiol. 76: 1589-1593, 1994), intralobar and sidebranch arteries from rats 21 days after MCT treatment were cannulated and pressurized and their diameter changes in response to KCl, norepinephrine, angiotensin II, and pressure were measured in the presence of N omega-nitro-L-arginine (NLA) and L-arginine. NLA treatment decreased MCT artery diameters more than normal arteries (P < 0.05) and abolished ACh dilation in both. Agonist responses were greater in normal but not MCT arteries. The alpha increased in NLA-treated normal (P < 0.05) but not MCT arteries. After L-arginine, normal and MCT arteries returned to control diameters and dilated to ACh. Agonist responses returned to control in normal but not MCT arteries. Normal but not MCT arteries dilated in calcium-free solution (P < 0.05). These results suggest that pulmonary arteries from rats with MCT-induced pulmonary hypertension produce more NO than do pulmonary arteries; inhibiting NO does not increase contractility; and decreased vasoreactivity and alpha values are not due to smooth muscle cell tone but may be due to abnormal vascular remodeling.

Concentration-dependent effects of cocaine on monoamine-induced constriction of cannulated, pressurized cerebral arteries from fetal sheep.

Drugs, such as cocaine, which may alter monoamine neurotransmitter responsiveness, could adversely affect the regulation of cerebral vasculature. Cocaine exhibits at least two mechanisms that may alter vascular responsiveness: synaptic uptake inhibition, which may augment response to stimulation, and Na+ channel inhibition, which may attenuate response. To help elicit the concentration-dependent effects of cocaine, the effects of cocaine on monoamine neurotransmitter responsiveness were studied in vitro on fetal sheep cerebral arteries (120 days gestation). The changes in diameter of segments of cannulated, pressurized fetal sheep cerebral artery were measured with a videomicroscaler system. Cumulative concentration-response curves (10(-10) to 10(-4)M) were generated for two monoamines, norepinephrine and serotonin, alone and in the presence of cocaine (10(-5) or 10(-4)M). Cocaine caused concentration-dependent alteration of response. At 10(-4)M, cocaine attenuated mean maximal norepinephrine-induced vasoconstriction 46.2% (P < 0.05). At 10(-5)M, cocaine increased sensitivity to norepinephrine (log EC50 decreased -6.63 +/- 0.09 to -7.11 +/- 0.03) and to serotonin (log EC50 decreased -7.24 +/- 0.04 to -7.81 +/- 0.09) (P < 0.05). The higher concentration of cocaine (10(-4)M) did not significantly decrease log EC50 norepinephrine. Cocaine (10(-4)M) also attenuated the response to single doses of norepinephrine (10(-6)M) and serotonin (10(-6)M) by 26.5% and 40.0%, respectively (P < or = 0.05). It is concluded that cocaine has concentration-dependent effects on vasoconstriction of the fetal sheep cerebral artery in vitro. This cocaine-induced alteration of cerebral vascular responsiveness to monoamines may be important in the regulation of fetal cerebral blood flow.

Cocaine and benzoylecgonine constrict cerebral arteries by different mechanisms.

This study was designed to determine possible mechanisms underlying the vasoconstrictor activity of cocaine and its principal metabolite, benzoylecgonine (BE) in cat isolated cerebral arteries. The arteries constricted significantly in response to single doses of cocaine, BE and norepinephrine (NE; (P < 0.05). After 6-OHDA treatment to remove adrenergic nerve endings, NE-induced constrictions were essentially unchanged from those before treatment. Denervated arteries exposed to cocaine dilated significantly (P < 0.05) but those exposed to BE constricted as much as before denervation. Following exposure to prazosin and yohimbine, arterial constrictions to NE and cocaine were significantly reduced from control (P < 0.05) but the BE-induced constriction was unchanged. Ryanodine eliminated the cocaine-induced contraction (P < 0.05) whereas verapamil eliminated the BE response (P < 0.05). These data suggest that while cocaine's vasoconstrictor action may be significantly mediated through adrenergic transmission, BE may act through a mechanism involving calcium (Ca2+) channels. Cocaine levels peak and decline in the body more rapidly than BE levels which can remain detectable for days. This study suggests there may also be different pharmacological mechanisms as well as temporal differences underlying the vasoreactivity of these two substances. Our findings may have implications for pharmacological management of cocaine-induced toxic vascular events.