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Biomedical subjects

J A Madden

Publications and source records attributed to J A Madden.

At least 37 records · Page 2Linked to original sources
PubMed1994

Effects of cocaine, benzoylecgonine, and cocaine metabolites in cannulated pressurized fetal sheep cerebral arteries.

Prenatal cocaine exposure has been reported to cause neurovascular complications in the developing fetus. To determine the effect of cocaine on the fetal neurovasculature, we studied the in vitro response of fetal sheep cerebral arteries to cocaine and cocaine metabolites. The change in diameter of cannulated pressurized cerebral artery segments from fetal sheep was measured using a video microscaler system. Cumulative dose-response curves (10(-12)-10(-4) M) were generated for cocaine and the major cocaine metabolites in fetal sheep cerebral artery segments. Benzoylecgonine (> 10(-10) M) also caused concentration-dependent constriction, and cerebral artery segments were significantly more sensitive to benzoylecgonine than to cocaine and the other cocaine metabolites. Benzoylecgonine-induced vasoconstriction appeared to be mediated through alpha-adrenergic stimulation, predominantly through stimulation of alpha 1-adrenergic receptor subtypes. We conclude that cocaine and benzoylecgonine cause significant fetal cerebral artery vasoconstriction in vitro. Cocaine and benzoylecgonine-induced cerebral vasoconstriction may contribute to the perinatal neurovascular complications associated with prenatal cocaine exposure.

Adrenergic alpha-Antagonists↗
PubMed1993

The effect of carbon dioxide on cerebral arteries.

The constancy of cerebral blood flow and volume relies heavily upon the cerebral arteries' intrinsic ability to respond to changes in the partial pressure of arterial CO2. The physiologic mechanisms underlying these responses have not been determined, although changes in extracellular and intracellular pH, mediation by prostanoids and neural activity have been suggested. CO2 reactivity can be influenced by oxygen status and blood pressure and can vary according to age and brain region. In certain pathological conditions or diseases, it can be severely altered. Modern techniques, which measure CBF in cases of cerebral hemodynamic insufficiency, head injury or tumor, rely on the inherent ability of the cerebral circulation to respond to changing levels of CO2.

Aging↗
PubMed1993

Effect of hypoxia and norepinephrine on cytoplasmic free Ca2+ in pulmonary and cerebral arterial myocytes.

The fluorescent calcium indicator, fura 2, was used to test whether contraction of primary cultured smooth muscle cells (SMC) from small pulmonary arteries in response to hypoxia and the relaxation by large pulmonary and cerebral artery SMC were mediated by changes in cytoplasmic free Ca2+ (Ca2+c). Because SMC from large pulmonary and cerebral arteries contract to norepinephrine (NE), Ca2+c levels during NE exposure were measured to determine if they differed from those seen with hypoxia. Under hypoxic conditions, Ca2+c increased 64.1 +/- 11.1% above the normoxic baseline in small pulmonary artery SMC. In SMC from large pulmonary and cerebral arteries, Ca2+c decreased 25.2 +/- 9.20 and 28.1 +/- 5.80%. Ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) and ryanodine attenuated the Ca2+c increase in the small pulmonary artery SMC. On exposure to NE, Ca2+c increased markedly in all three SMC types. EGTA and ryanodine treatment also attenuated NE-induced Ca2+c increases in all three SMC types. These results show that the three SMC types mobilize their available Ca2+ stores differently when exposed to hypoxia but similarly when exposed to NE. The data also suggest that a change in the Ca2+c concentration, rather than a change in the Ca2+ sensitivity of the contractile apparatus, is involved in the response to hypoxia.

Animals↗
PubMed1993

Differing effects of acute and prolonged alkalosis on hypoxic pulmonary vasoconstriction.

Animal studies and clinical pediatric practice have shown that acute alkalosis attenuates hypoxic pulmonary vasoconstriction (HPV). However, increased intracellular pH appears to enhance pulmonary vasoreactivity. We therefore hypothesized that prolonged alkalosis augments HPV. This study compares the effects of acute and prolonged alkalosis on HPV in isolated perfused lungs of 1-month-old lambs (n = 5) and the hypoxic responses of 300- to 500-microns diameter segments of pulmonary arteries (n = 7) from mature cats at control pH and after 30 min of alkalosis. In isolated lamb lungs, normocarbic (5% CO2) hypoxia (4% O2) increased the total pressure gradient (delta PT) by 6.0 +/- 2.7 (SEM) mm Hg (p < or = 0.05). Acute hypocarbia (3% CO2) increased the perfusate pH to approximately 7.52 and significantly decreased the hypoxic delta PT to normocarbic, normoxic (28% O2) levels. Subsequent exposure to normoxia (while maintaining alkalosis) further decreased delta PT. However, re-exposure to hypoxia after 60 min of normoxic alkalosis significantly increased delta PT by 11.6 +/- 1.6 mm Hg (p < or = 0.05) to a level similar to that seen during normocarbic hypoxia. The increased hypoxic reactivity (i.e., change in pressure between normoxia and hypoxia) during prolonged alkalosis was due to enhanced HPV of the small vessels within the middle segment of the pulmonary circuit, as defined by an inflow-outflow occlusion technique (p < or = 0.05). The occlusion data also suggested that most of this increase occurred in small arteries. Moreover, the hypoxic response of isolated small arteries from the cat was increased almost threefold (p < or = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1992

Effects of indomethacin on myogenic contractile activation and responses to changes in O2 and CO2 in isolated feline cerebral arteries.

We used an isolated, pressurized, and perfused feline middle cerebral artery preparation to measure how changes in intraluminal pressure and alterations in O2 and CO2 affect vessel diameter and myogenic contractile activation before and after treatment with indomethacin (IND). Vessel diameters were measured over the pressure range 60-140 mm Hg. The arteries were then exposed to low O2 (50 torr) and/or high CO2 (65 torr) and diameters remeasured over the same range. Under control conditions, the arteries exhibited myogenic contractile activation. Exposure to low O2, high CO2, or a mixture of low O2/high CO2, increased vessel diameter but did not change the vessels' myogenic contractile responsiveness to changes in pressure. Arteries exposed to IND decreased in diameter but retained myogenic contractile activity. In the presence of IND, vessels dilated to both low O2 and a mixture of low O2/high CO2, but did not dilate to high CO2 alone. Under all conditions, vessels retained myogenic contractile activity. Results obtained under control conditions and low O2 confirm those of others using similar systems. Myogenic contractile activity in the presence of high CO2 or a mixture of low O2/high CO2 has not been previously reported. The dilation to low O2 but not to high CO2 in the presence of IND suggests that this drug's effects in cerebral arteries are not limited solely to inhibition of prostaglandin synthesis.

Animals↗
PubMed1992

Hepatic insulin and EGF receptor phosphorylation and dephosphorylation in fetal rats.

Hepatic insulin receptor and epidermal growth factor (EGF) receptor phosphorylation and dephosphorylation were studied in normal and growth-retarded fetal rats. Insulin receptor autophosphorylation at a subsaturating ATP concentration (0.5 microM) increased by 10-fold from day 17 to 21 of gestation and decreased by 50% in term growth-retarded fetuses of fasted mothers. In vitro kinase activation at 0.5 mM ATP did not change with gestation or maternal fasting. EGF receptor autophosphorylation increased in parallel with receptor number with advancing gestation and did not change with maternal fasting. Protein tyrosine phosphatases (PTPases), which might attenuate receptor signaling in livers from growth-retarded fetuses, were measured using polybasic and polyacidic artificial substrates as well as the insulin receptor kinase domain. Fetal membrane PTPase activities were twofold higher than in the adult and declined with advancing gestation. However, activities were similar in normal and growth-retarded fetuses. We conclude that decreased hepatic growth in growth-retarded fetuses may involve decreased insulin receptor tyrosine kinase activation in vivo, as indicated by diminished receptor autophosphorylation at subsaturating ATP concentrations. Changes in EGF receptor kinase activity and PTPases could not be implicated based on our in vitro findings.

Animals↗
PubMed1992

Effects of hypoxia and other vasoactive agents on pulmonary and cerebral artery smooth muscle cells.

Smooth muscle cells (SMC) were isolated from cat cerebral arteries and three sizes of pulmonary artery (less than 200-, 200- to 600-, and greater than 800-microns diameter) and used within 72-96 h. Change in cell length in response to hypoxia and other vasoactive agents was measured in a specially constructed cell chamber on an inverted microscope. Pulmonary artery SMC responded to hypoxia differently according to artery size. SMC from less than 200- and 200- to 600-microns-diameter pulmonary arteries shortened 18.6 +/- 4.85 and 24.2 +/- 2.70%, respectively. However, SMC from greater than 800-microns-diameter pulmonary arteries shortened 0.81 +/- 0.44%. Cerebral artery SMC plated on a flexible polydimethyl siloxane membrane showed loss of tension during exposure to hypoxia. The shortening of SMC from the 200- to 600-microns pulmonary arteries was accompanied by myosin phosphorylation. SMC from greater than 800-microns-diameter pulmonary arteries and cerebral arteries contained myosin that did not phosphorylate during hypoxia. The SMC from both artery types responded to norepinephrine, serotonin, prostaglandin F2 alpha and indomethacin and exhibited alpha-adrenergic receptor population patterns similar to those of intact arteries. The pattern of hypoxic responses exhibited by these nondedifferentiated pulmonary and cerebral artery SMC supports the idea that, at least in the cat, the hypoxic sensor is located within the SMC.

Animals↗
PubMed1992

Effects of benzoylecgonine on the behavior of suckling rats: a preliminary report.

A major metabolite of cocaine, benzoylecgonine, causes behavioral activation that progresses to seizures when given intraventricularly to 2-week-old rats. The seizures are characterized by running, hopping, and vocalizing and are mixed with shorter-duration tonic episodes. Pretreatment with haloperidol, at a dose aimed at blocking stereotyped behavior, did not suppress these behaviors. In contrast, seizures were prevented by antiepileptic drugs, with the order of potency being diazepam greater than phenobarbital greater than phenytoin. We hypothesize that the long-lasting cocaine metabolite, benzoylecgonine, contributes to the infant cocaine intoxication syndrome.

Animals↗
PubMed1991

Two nonradioactive assays for phosphotyrosine phosphatases with activity toward the insulin receptor.

Two highly sensitive, nonradiolabeled assays for protein phosphotyrosine phosphatase (PTPase) have been developed. The first assay is based on the use of chemically synthesised phosphotyrosine-containing peptides that can be separated from the dephosphorylated peptide products by HPLC. In this assay, partially purified placental PTPase 1B dephosphorylated three dodecaphosphopeptides (corresponding to insulin receptor autophosphorylation sites at positions PY1146, PY1150, and PY1151) with approximately equal affinity (Km 1.3-2.5 microM), indicating that PTPase 1B shows no distinct preference for the site of dephosphorylation in these peptides. The second assay employs either a phosphopeptide or an autophosphorylated tyrosine kinase domain immobolized on microtiter plate wells. After reaction with PTPase, the remaining unconverted phosphosubstrate is detected in an ELISA using anti-phosphotyrosine antibodies. The latter assay was used to monitor PTPase activity during purification procedures and for characterizing PTPases. Modulation of PTPase activity by orthovanadate, heparin, Zn2+, and EDTA gave similar results in both assays. The immobilized autophosphorylated IR tyrosine kinase domain was a poor substrate for bovine liver alkaline phosphatase and seminal fluid acid phosphatase. The second assay also offers the potential for comparing PTPase activity toward several autophosphorylated tyrosine kinase domains, including those of the insulin, epidermal growth factor, and platelet-derived growth factor receptors.

Amino Acid Sequence↗
PubMed1991

Distensibility of small arteries of the dog lung.

To obtain in situ measurements of the distensibility of small (100- to 1,000-microns-diam) pulmonary arterial vessels of the dog lung, X-ray angiograms were obtained from isolated lung lobes with the vascular pressure adjusted to various levels. The in situ diameter-pressure relationships were compared with the diameter-pressure relationships for small arteries that were dissected free from the lungs and cannulated with small glass pipettes for the measurement of diameter and transmural pressure. The diameter-vascular or diameter-transmural pressure curves from both in situ and cannulated vessels were sufficiently linear in the pressure range studied (0-30 Torr) that they could be characterized by linear regression to obtain estimates of D0, the diameter at zero vascular pressure, and beta, the change in diameter (micron) per Torr change in pressure. The vessel distensibility coefficient (alpha) was defined as alpha = beta/D0. The mean values of alpha were approximately 2.0 +/- 0.8%/Torr (SD) for the in situ vessels and 1.7 +/- 0.6%/Torr for the cannulated vessels, with no statistically significant difference between the two methods. The influence of vasoconstriction elicited by serotonin was evaluated in the in situ vessels. Serotonin-induced vasoconstriction caused a decrease in D0 and little change in alpha.

Animals↗
PubMed1990

Effect of cocaine and cocaine metabolites on cerebral arteries in vitro.

Cocaine has pronounced peripheral vasoconstrictor effects. Despite the short half life of cocaine in the body these effects are relatively long-lived. The role of cocaine metabolites in vasoconstriction attributed to cocaine has not been reported. We evaluated the contractile ability of cocaine and its major metabolites in isolated cat cerebral arteries. The primary cocaine metabolite, benzoylecgonine was a potent contractile agent, causing a 50% decrease in cross sectional area at 10(-5) M. This was less than caused by serotonin, but greater than caused by norepinehrine. Ecgonine and cocaine were less active contractile agents than was benzoylecgonine, and ecgonine methyl ester was a mild relaxant.

Animals↗
PubMed1990

The effect of halothane on norepinephrine responsiveness in rabbit small mesenteric veins.

The effect of halothane on the response of small isolated mesenteric capacitance veins to exogenous norepinephrine and electrically induced endogenous norepinephrine release was studied. The role of extra- and intracellular Ca2+ in norepinephrine-induced contractions was also examined. Two-millimeter-long segments from the second-order branch of the mesenteric vein were stretched to twice their resting diameter, and the generated tension was measured with a force transducer. Dose-dependent effects of norepinephrine on generated tension were examined before and after exposure to 0.75 and 1.5% halothane. (These concentrations produced perfusate halothane concentrations of 0.31 and 0.49 mM respectively.) Norepinephrine produced an increase in the basal vessel tension along with a superimposed rhythmic oscillation in tension. Although the magnitude of the tension increase was not affected by either concentration of halothane, the amplitude of the oscillations was reduced. Ryanodine (a blocker of Ca2+ release from the sarcoplasmic reticulum), like halothane, decreased the amplitude of the oscillations, but did not affect overall tension development. In the Ca2(+)-free medium the contractile response to norepinephrine was greatly attenuated as compared to control, whereas the oscillatory behavior was completely abolished. Norepinephrine release was examined indirectly by measuring the increase in tension during electric field stimulation. Response to endogenously released norepinephrine was significantly decreased by exposure to halothane 1.5% (0.49 mM) and blocked by pretreating the vessel with phentolamine. At concentrations used clinically, halothane did not affect overall developed tension in response to exogenously applied norepinephrine. However, 1.5% (0.49 mM) halothane decreased both sarcoplasmic-reticulum-dependent oscillations in tension and electrically induced release of endogenous norepinephrine.

Animals↗
PubMed1987

Distribution of excitatory junction potential amplitude in cat cerebral arteries: examination of its quantal nature and modulation by opiates.

We used scorpion venom to release small amounts of an excitatory neurotransmitter from adventitial nerves in cat left anterior descending cerebral artery. We used glass microelectrodes to measure and record postsynaptic electrical events of minimal amplitude. These events were similar to postsynaptic spontaneous and electrically evoked excitatory junction potentials (ejp's) seen in skeletal muscle. We performed a frequency analysis of the ejp amplitudes to determine if they fit a unimodal or multimodal distribution. We also investigated the effects of phentolamine, norepinephrine, hydromorphone, and morphine on ejp amplitude and frequency in the artery. Statistical analysis of the ejp frequency and amplitude revealed a multipeaked distribution with decreasing peaks. These results were similar to the distribution reported for acetylcholine release in skeletal muscle. The ejps were inhibited by phentolamine, which suggested that these events were adrenergically mediated. Norepinephrine and the opiates, hydromorphone and morphine, reduced the frequency and amplitude of the ejp's. The vessels also constricted to increasing doses of norepinephrine both under control conditions and in the presence of opiate. These results suggest that norepinephrine blocks the ejp's by a feedback mechanism at the presynaptic membrane and that endorphins and/or enkephalins, also acting at this presynaptic site, may modulate neurotransmission in the cerebral circulation.

Animals↗
PubMed1987

The effect of alkaline pH and transmural pressure on arterial constriction and membrane potential of hypertensive cerebral arteries.

These studies were undertaken to examine the effect of alkalosis to modify "pressure-induced" activation of isolated cerebral arteries from spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto (WKY) controls. At pH 7.4 and PCO2 of 34 torr elevation of transmural pressure from 0-140 mm Hg resulted in myogenic activation preceded by membrane depolarization in both SHR and WKY. The degree of developed myogenic tone in SHR was elevated above WKY. Alkalosis (pH 7.4-7.7) depolarized and activated SHR cerebral arteries to a greater extent than WKY. Furthermore, both the electrical and mechanical responses to elevation in transmural pressure were exaggerated in SHR compared to WKY at pH 7.7 (PCO2 constant at 34 torr). Manipulation of PCO2 at constant pH of 7.4 had similar effects on "pressure-induced" myogenic tone in both SHR and WKY. Thus, cerebral arteries from both SHR and WKY depolarize and develop myogenic tone in response to increasing transmural pressure. This response is augmented in SHR, but to a much greater extent upon elevation of extracellular pH, while PCO2 is maintained within normal limits. The implications of these findings are discussed.

Animals↗
PubMed1987

Electrical stimulation of the endothelial surface of pressurized cat middle cerebral artery results in TTX-sensitive vasoconstriction.

The purpose of this study was to examine the electrical and mechanical responses of cat middle cerebral arteries to electrical stimulation of the adventitial vs. intimal surface of the vessels and to determine the responses as a function of transmural pressure. Middle cerebral arteries were cannulated at both ends. Within each cannula was a stimulating electrode. Electrical stimulation (0.5-msec square current pulses at 0.5 Hz yielding 160 microA of current between electrodes) resulted in significant reduction in diameter that was greater at both 40 and 80 mm Hg vs. 100 or 140 mm Hg. Conversely, adventitial stimulation of perivascular nerves with transmural platinum stimulating electrodes resulted in significant vasodilation. The constrictor response to intimal stimulation, as well as the dilatory response to adventitial stimulation, was blocked by tetrodotoxin. The constrictor response to luminal stimulation was enhanced by scorpion toxin demonstrating a functional role for tissues containing fast Na+ channels. Perfusion with collagenase to disrupt the endothelium also abolished the constrictor response to luminal stimulation. The divergence of responses between adventitial and luminal surface stimulation may suggest that different cell layers within a blood vessel serve different functions, one to increase resistance and another to decrease resistance. For example, in cat middle cerebral arteries, the adventitial nerves (i.e., via reflexes) may increase flow, while blood-borne substances may mediate release of agents that reduce flow.

Animals↗
PubMed1986

Effect of reduced oxygen availability upon myogenic depolarization and contraction of cat middle cerebral artery.

The goal of this study was to determine whether electrophysiological mechanisms contribute to the relaxation of cat middle cerebral artery in response to decreased ambient Po2 and whether decreased Po2 alters the myogenic depolarization and contraction of this vessel in response to elevations in transmural pressure. In one series of experiments, arterial segments (200-500 micron outer diameter) were isolated and mounted in an in vitro tension transducer to allow continuous measurement of active tension as bath Po2 was reduced. In these experiments, vessel relaxation occurred primarily between 150 mm Hg Po2 and 40 mm Hg Po2, suggesting that cerebral arteries are sensitive to alterations of Po2 in the physiological range. Relaxation did not result from the activation of dilator nerves in the vessel wall, since it was unaffected by tetrodotoxin. Arterial segments were also cannulated with micropipettes and subjected to elevations in transmural pressure during 300 mm Hg Po2 and 50 mm Hg Po2 superfusion. During 300 mm Hg Po2 superfusion, cannulated vessels exhibited myogenic depolarization and maintained their diameter as transmural pressure was increased; 50 mm Hg Po2 superfusion inhibited spontaneous spike activity, decreased the slope of the myogenic depolarization, and partially inhibited vessel contraction in response to elevated transmural pressure. These effects are independent of the parenchymal cell environment and appear to be mediated, at least in part, by electrophysiological mechanisms.

Animals↗
PubMed1985

Cellular mechanism of force development in cat middle cerebral artery by reduced PCO2.

These studies were undertaken to determine the effect of reducing a PCO2 below physiological levels on cat middle cerebral artery. Upon reduction of PCO2 from 37 to 14 torr (pH 7.4) we observed membrane depolarization and force development. Reducing PCO2 decreased the slope of the Em vs. log [K]o curve and increased the slope of the steady-state I/V relationship suggesting that the change in Em was due to reduction of outward K+ conductance (gk). Elevation of pH from 7.37 to 7.6 had a very similar effect on these cerebral arterial muscle cells, depolarizing the muscle membrane (reducing the Em vs. log [K]o curve) and increasing the slope of the I/V relationship to statistically equivalent values as reduction of PCO2. Returning PCO2 from 14 to 37 torr rapidly relaxed these preparations, but only transiently. This relaxation was followed by a rebound contraction within 3 min, demonstrating a transient nature for the action of elevating PCO2 in cerebral arteries. The response to changing pHo followed a slower time course but did not change with time. These studies demonstrate that both elevated pHo and reduced PCO2 activate cerebral arterial muscle by a mechanism which includes reduction in gk. However, it can not be determined if these similar responses and reduction of gk are mediated by changing pHi or mediated through different mechanisms. It is possible that pHo and PCO2 can modify cerebral arterial tone by direct mechanisms and not necessarily by their effect on pHi. It is clear, however, that reduction of PCO2 and elevation of pHo both activate cerebral arterial muscle by a mechanism which includes reduction of gk.

Animals↗