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Biomedical subjects

J A Will

Publications and source records attributed to J A Will.

At least 19 recordsLinked to original sources
PubMed2003

In vivo measurements of heat transfer on the endocardial surface.

A catheter-based instrument was used to measure the heat transfer on the right atrial and ventricular endocardial surfaces of two pigs in vivo. The heat transfer parameters will assist in calculating the proper dose for radio-frequency ablation. The time constant of the device was 0.05 s. It was found that the average heat convection coefficient varies significantly both spatially and temporally on the endocardium. The average heat convection coefficients found were between 510 and 4800 W m(-2) K(-1).

Animals↗
PubMed2001

Comparative vasodilation of peroxynitrite and 3-morpholinosydnonimine.

Vasorelaxation mediated by peroxynitrite (ONOO-) and 3-morpholinosydnonimine (SIN-1) were investigated in isolated bovine intramammary arteries. Both ONOO- and SIN-1 relaxed U 46619-precontracted rings in a dose-dependent, endothelium-independent manner. Pretreatment with an adenylyl cyclase inhibitor, SQ 22536 [(9-tetrahydro-2-furyl)adenine], resulted in an enhanced ONOO--mediated relaxation, but did not modulate the response to SIN-1. ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), a potent and selective inhibitor of soluble guanylyl cyclase (sGC), did not significantly affect relaxant actions of ONOO-, but ODQ markedly attenuated SIN-1-elicited relaxation with a rightward shift in the dose-response curve and an unaltered maximal response. In the presence of carboxy-PTIO (2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide), a putative nitric oxide scavenger and ONOO- inactivator, the relaxant response to ONOO- was abolished, while relaxant actions of SIN-1 appeared to be unaffected. The results reveal a difference between ONOO- and SIN-1-mediated relaxation with regards to the role of the sGC and suggest that ONOO--evoked relaxation may not be associated with sGC activity, but rather depends on an sGC-independent mechanism triggered by ONOO- and/or NO itself. It also re-emphasizes that SIN-1 induces a vasorelaxant response, in part, via stimulation of sGC.

Adenine↗
PubMed2000

A new catheter design using needle electrode for subendocardial RF ablation of ventricular muscles: finite element analysis and in vitro experiments.

Radio-frequency (RF) cardiac ablation has been very successful for treating arrhythmias related with atrioventricular junction and accessory pathways with successful cure rates of more than 90%. Even though ventricular tachycardia (VT) is a more serious problem, it is known to be rather difficult to cure VT using RF ablation. In order to apply RF ablation to VT, we usually need to create a deeper and wider lesion. Conventional RF ablation electrodes often fail to produce such a lesion. We propose a catheter-electrode design including one or more needle electrodes with a diameter of 0.5-1.0 mm and length of 2.0-10 mm to create a lesion large enough to treat VT. One temperature sensor could be placed at the middle of the needle electrode for temperature-controlled RF ablation. From finite element analyses and in vitro experiments, we found that the depth of a lesion is 1-2 mm deeper than the insertion depth of the needle and the width increases as we increase the diameter of the needle and the time duration. We showed that a single needle electrode can produce a lesion with about 10-mm width and any required depth. If a wider lesion is required, more than one needle with suggested structures can be used. Or, repeated RF ablations around a certain area using one needle could produce a cluster of lesions. In some cases, a catheter with both conventional electrode and needle electrode at its tip may be beneficial to take advantage of both types of electrode.

Animals↗
PubMed1997

Comparative regulation of alpha1-adrenergic receptor mediated contraction in urogenitally derived smooth muscle. Effect of epidermal growth factor.

Contractility of smooth muscle within mammalian urogenital organ systems has an established role in physiological/pathophysiological functioning of the component structures. Our aim was to examine the direct effect of epidermal growth factor (EGF) on smooth muscle tone as well as its indirect effects in regulating alpha1-adrenoceptor-mediated contraction of the prostate, the vas deferens and renal arteries. Tissues were mounted isometrically, under controlled conditions, and changes in tension in response to treatment with phenylephrine (PE) with or without pretreatment with EGF were recorded on a physiological recorder via force transducers. In the rabbit prostate, EGF potentiated the magnitude of contraction to PE. The potentiation appeared to be dependent on cyclo-oxygenase products. In the human prostate, EGF potentiated the contractile response to PE. EGF had no effect on the PE-induced contraction of the rabbit renal artery and vas deferens. EGF alone did not alter smooth muscle tone in any of the above-mentioned tissues. The main finding of this study is the difference in the regulation by EGF of the alpha1-adrenoceptor-mediated response in smooth muscle of the prostate, from that by the vas deferens and renal artery. The reasons for this difference in response remain to be elucidated. This study may form the basis for further investigation into receptor transregulation and its relevance to symptomatic benign prostatic hyperplasia (BPH).

Animals↗
PubMed1997

Functional characterization of post-junctional adrenergic receptor subtypes in bovine intra-mammary arteries.

We examined the functional role of adrenergic receptor subtypes (ARs) in bovine intra-mammary arteries (IMAs), 1.5-2.5 mm internal diameter. Norepinephrine (NE) and phenylephrine (PE) produced concentration-dependent increases in tone in segments maintained at a previously determined optimal basal tension in vitro. The sensitivity of the tissue to NE and PE, based on -log molar ED50s was 6.87 +/- 0.17 and 7.05 +/- 0.35, respectively. In addition a Schild analysis yielded antagonist affinities for the receptor mediating contractile responses to NE (pA2 value) of 10.46 +/- 0.85 for prazosin and 6.29 +/- 0.18 for yohimbine. These data indicate a dominance of functional alpha 1 (alpha(1)) over alpha 2 (alpha(2))-ARS in this tissue. Based on the inhibitory effects of chloroethylclonidine (CEC) on PE responses and the further reduction in sensitivity when nifedipine was added to the CEC, also in the presence of PE, we conclude that there is more than one alpha(1)-AR subtype, with a predominant role for alpha(1B)-ARs in phenylephrine responses. Stimulation of beta (beta)-ARs, resulted in relatively small reductions in tone (the highest magnitude of response was 25.94 +/- 6.46% of the papaverine maximum at 3 x 10(-6) M isoproterenol); in addition, propranolol did not significantly alter tissue sensitivity to NE. Additional characterization of functional autonomic receptor populations in this circulatory bed will form a basis for future studies on circulatory dynamics in the mammary gland.

Adrenergic alpha-Antagonists↗
PubMed1997

Comparison of iodinated contrast media-induced renal vasoconstriction in human, rabbit, dog, and pig arteries.

RATIONALE AND OBJECTIVES: Contrast media (CM)-induced renal vasoconstriction is an important factor in the pathogenesis of CM-induced nephrotoxicity. The effects of ionic, high-osmolar CM sodium/meglumine diatrizoate and nonionic, low-osmolar CM iohexol and iopamidol were studied in rabbit, dog, and pig renal arteries and compared with human tissue in an organ bath. METHODS: Isometric contractions were induced by increasing concentrations of CM and high-osmolar glucose solution. RESULTS: Contrast media and glucose elicited contractions in human renal arteries of 32% (diatrizoate), 20% (iohexol), 30% (iopamidol), and 22% (glucose). Rabbit and dog renal arteries demonstrated contractions of 30% and 46% (diatrizoate), 15% and 23% (iohexol), 15% and 26% (iopamidol), and 11% and 40% (glucose), respectively, of the control. There was a vasorelaxing effect of all CM tested on pig renal artery. CONCLUSIONS: Responses in rabbit and dog renal arteries were similar to those in human renal arteries and could serve as models for investigating CM-induced renal vasoconstriction.

Animals↗
PubMed1997

Vaso-reactivity of isolated bovine intra-mammary artery to endogenous prostanoids and nitric oxide.

The modulatory role of locally produced cyclooxygenase products and endothelium-derived nitric oxide in controlling vascular tone was investigated in bovine intra-mammary artery. Vascular reactivity initiated by vasoactive compounds, endothelin-1 (ET-1), bradykinin (BK), and substance P (SP) was measured isometrically in an isolated tissue bath. The effects of a cyclooxygenase inhibitor, indomethacin (10(-5) M) and an inhibitor of nitric oxide production, N omega-Nitro L-Arginine (L-NNA: 3 x 10(-4) M) were determined during agonist-mediated responses. Indomethacin alone markedly enhanced vascular contraction produced by ET-1, while L-NNA did not. Inhibition of endothelium-derived nitric oxide synthesis by L-NNA, however, significantly attenuated BK- and SP-induced vascular relaxations, whereas indomethacin had slight influence. The potentiation between indomethacin and L-NNA in regulating vasomotor tone was not observed in this vascular bed. Thus, it appeared that both the cyclooxygenase and endothelium-derived nitric oxide pathways participated in modifying vascular reactivity. Domination of one pathway over the other depended upon the agonist used to stimulate vascular tissue.

Animals↗
PubMed1995

Effects of hypoxia, mechanical and chemical endothelium denudation on guinea-pig isolated pulmonary arteries.

1. The isolated unstimulated main trunk, extralobar and intralobar branches of the pulmonary artery of the guinea-pig developed well-sustained contractions upon exposure to hypoxia (95% N2-5% CO2 gas mixture; PO2 11-15 mm Hg). The contractions were readily reversible by reoxygenation (95% O2-5% CO2). 2. Mechanical removal of the endothelium did not significantly affect the magnitude of the hypoxia-induced contractions in rings obtained from the main trunk of the pulmonary artery but reduced those of rings obtained from the proximal and distal extralobar branches. 3. Mechanical removal of the endothelium also did not affect the magnitude of contractions induced by BaCl2 in the main but significantly reduced contractions induced by the same agent in the proximal and distal extralobar branches of the pulmonary artery, suggesting that the reduction of hypoxia-induced contractions in the endothelium-denuded rings is due to impairment of vascular reactivity. 4. Pretreatment with L-N-nitro arginine, an inhibitor of the synthesis of the endothelium-derived relaxing factor, did not significantly affect the hypoxia-induced contractions but increased the magnitude of BaCl2-induced contractions in the main and the extralobar branches. 5. These observations demonstrate that isolated pulmonary artery rings of the guinea-pig develop slow contractions in response to hypoxia without prior contraction with an agonist, and that the endothelium plays little role in the hypoxia-induced contractions of guinea-pig isolated large pulmonary arteries. 6. Furthermore, these observations suggest that the effect of mechanical endothelium denudation or pharmacological manipulation, such as EDRF inhibition, on vascular reactivity should be considered when the effect of hypoxia is studied in isolated pulmonary arteries.

Animals↗
PubMed1995

Potentiation of the hypoxic contraction of guinea-pig isolated pulmonary arteries by two inhibitors of superoxide dismutase.

1. Isolated proximal and distal extralobar branches of the pulmonary artery of the guinea-pig develop slow and well-sustained contractions in response to hypoxia (PO2 11-15 mm Hg) without prior stimulation with an agonist. These contractions are readily reversible by readministration of oxygen. 2. Incubation of these preparations with diethyldithiocarbamic acid (DETCA, 5 mM for 30 min), an inhibitor of superoxide dismutase, significantly increased the hypoxic contractions whether DETCA was added before the challenge with hypoxia or after the hypoxic contraction had reached a plateau. This treatment also reduced the oxygen-induced relaxation. 3. Similarly, incubation with triethylenetetramine (TETA, 5 mM for 30 min), another inhibitor of superoxide dismutase, produced larger potentiation of the hypoxic contraction in the two preparations and reduced the oxygen-induced relaxation. 4. Furthermore, addition of H2O2 (10(-5) M-3 x 10(-4) M) caused concentration-dependent relaxation of the hypoxic contraction while larger concentrations (10(-3) M and 3 x 10(-3) M) caused contraction that did not respond to readministration of oxygen. 5. These observations suggest that during hypoxic stress, the accumulation of superoxide anions may participate in the hypoxia-induced contraction and that the metabolism of these radicals into H2O2 by superoxide dismutase maintains the relaxed state during normoxia.

Animals↗
PubMed1994

Smooth muscle tone regulation in rabbit cavernosal and spongiosal tissue by cyclic AMP- and cyclic GMP-dependent mechanisms.

The relaxing effects of several specific and nonspecific inhibitors of phosphodiesterases (PDE) on rabbit isolated corpus cavernosum (CC) and spongiosum (CS) were investigated. Preparations were mounted in organ baths, and isometric tension was recorded. The results were compared with the effects of direct administration of analogs of the second messenger cyclic nucleotides and the effects of forskolin, a direct stimulator of adenylate cyclase, and the nitric oxide donor 3-morpholinosydnonimine (SIN 1). All drugs relaxed the phenylephrine-induced contractions in CC and CS in a dose-dependent fashion. In CC and CS, type III (SK&F 95654) and type V (zaprinast and dipyramidole) PDE inhibitors, as well as the nonspecific inhibitors papaverine and trequinsin, showed no differences in IC50. The type IV inhibitor rolipram relaxed CC and CS at significantly lower concentrations (p < 0.005) than any other PDE inhibitor, and in CC the type III and IV inhibitor zardaverine was more potent (p < 0.05) than SK&F 95654. SIN 1 stimulates guanylate cyclase and effectively inhibits contractions in CC and CS. Activation of adenylate cyclase by forskolin also was highly effective (p < 0.005). It is concluded that PDE inhibition constitutes an effective relaxing mechanism in rabbit CC and CS. The marked effects of the different types of PDE inhibitors support the importance of cyclic guanosine 3',5'-monophosphate and cyclic adenosine 3',5'-monophosphate in smooth muscle relaxation in erectile tissue.

Animals↗
PubMed1994

Mechanisms of the inhibitory effect of ketamine on guinea pig isolated main pulmonary artery.

Although ketamine increases pulmonary vascular resistance of patients, an occasional decrease of resistance in animals and humans has been reported. In addition, ketamine has a direct relaxant effect on isolated smooth muscle. The effects of ketamine on the main pulmonary artery rings isolated from the guinea pig were studied to elucidate the underlying mechanism of the reported relaxant effect of this anesthetic on smooth muscle. Ketamine (10-250 micrograms/mL) caused a concentration-dependent shift to the right of CaCl2 concentration-effect curves on artery rings, suggesting an interference with Ca2+ metabolism. In Ca(2+)-free buffer, ketamine (10-250 micrograms/mL) did not affect the magnitude of epinephrine-induced contractions but inhibited dose-dependent BaCl2-induced contractions. These observations suggest that ketamine inhibits transmembrane Ca2+ influx but does not affect its release from intracellular stores or its binding to intracellular receptor sites on the contractile system. Ketamine (25-500 micrograms/mL) also caused equipotent concentration-dependent relaxation of epinephrine-induced contractions in the absence and the presence of monensin, a Na(+)-ionophore that dissipates the Na+ gradient across the cell membrane, and in Na(+)-free, sucrose-substituted buffer. Ketamine (25-500 micrograms/mL) also relaxed ouabain-induced contractions to the baseline, an effect that was significantly attenuated in the presence of ruthenium red, a Ca2+ adenosine triphosphatase (ATPase) inhibitor. The relaxant effect of ketamine (250-750 micrograms/mL) of epinephrine-induced contraction also was attenuated in the presence of 0.1 mM lanthanum chloride (La3+), an inhibitor of adenosine 5'-triphosphate (ATP)-dependent Ca2+ extrusion, and completely inhibited in the presence of 10 mM La3+.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Pharmacologic modulation of the influence of the epithelium on immunologic- and nonimmunologic-induced histamine release and contraction in guinea pig superfused tracheal strips.

The influence of the epithelium on contractions and histamine release evoked by ovalbumin and d-tubocurarine has been examined in guinea pig superfused tracheal strips under several experimental conditions. Without drug pretreatment, removal of the epithelium resulted in larger (P < .05) total histamine released by ovalbumin, 10(-4) to 10(-1) mg/ml, and by d-tubocurarine, 3 x 10(-3) M. In the presence of indomethacin, 5 x 10(-6) M, epithelium removal resulted in elevated histamine release only at smaller ovalbumin concentrations, 10(-4) and 10(-3) mg/ml. Indomethacin did not change the influence of the epithelium on histamine release by d-tubocurarine. Indomethacin treatment abolished the influence of the epithelium on ovalbumin-induced tracheal contraction. With indomethacin, larger (P < .05) histamine release was seen with ovalbumin, 10(-1) and 1 mg/ml, when the epithelium was intact. The larger histamine release in response to ovalbumin, 10(-1) mg/ml, in the presence of the epithelium was unaltered by pyrilamine, 10(-6) M, cimetidine, 10(-4) M, and thioperamide, 10(-6) M, to block histamine H1, H2 and H3 receptors, respectively. Therefore, histamine released by ovalbumin does not stimulate histamine release through an action on these receptors when the epithelium is intact. In the presence, but not in the absence, of the epithelium, A64077, 10(-5) M, and ICI198615, 10(-8) and 10(-6) M, inhibitors of 5-lipoxygenase and LTD4/E4 receptors, respectively, inhibited histamine release by ovalbumin, 10(-1) mg/ml. Histamine release by ovalbumin, 10(-4) mg/ml, and d-tubocurarine, 3 x 10(-3) M, studied with or without epithelium was not altered by A64077 or ICI198615.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Studies of desensitization and cross-desensitization to immunologic and nonimmunologic stimuli that evoke contraction and histamine release in superfused guinea pig trachea.

This study examined the possibility that there is cross-desensitization between immunologic and nonimmunologic stimuli that evoke contraction and histamine release (HR) in the isolated guinea pig trachea. Compound 48/80 and D-tubocurarine were found to cause homologous and heterologous desensitization for both contraction and HR from superfused trachea. Specific antigen challenge of trachea obtained from animals sensitized with either IgG1 (ovalbumin [OA]) or IgE (oxazalone-human serum albumin [OX-HSA]) also resulted in homologous desensitization for both contraction and HR. However, in experiments with animals sensitized with both IgG1 and IgE antibodies, prechallenge with OA resulted in cross-desensitization to OX-HSA, whereas the reverse sequence was ineffective in eliciting this phenomenon. This may be related to the type of desensitization produced by each antigen (specific versus nonspecific) or to heterogeneity of mast cells in the tissue. Prechallenge of the trachea with compound 48/80 or D-tubocurarine failed to alter subsequent effects of antigen after active sensitization with OA or passive sensitization with either IgG1 or IgE antibodies. Small but statistically significant decreases in tracheal responses to D-tubocurarine were observed after antigen prechallenge to active both IgG1 and IgE antibodies. This is the first study to demonstrate a cross-desensitization between compound 48/80 and D-tubocurarine and the first to examine cross-desensitization with IgG1 and IgE antibodies in the guinea pig trachea. The overall conclusion is that there is no major overlap in the desensitization mechanisms between immunologic and nonimmunologic stimuli in the guinea pig trachea.

Animals↗
PubMed1990

An examination of the influence of the epithelium on contractile responses to peptidoleukotrienes and blockade by ICI 204,219 in isolated guinea pig trachea and human intralobar airways.

The influence of the epithelium on antagonism by ICI 204,219 of contractile responses to peptide leukotriene (LT) agonists was examined in guinea pig tracheal and human bronchial rings. The -log molar KB values for ICI 204,219 were found to be independent of the epithelium in both tissues. Even though uninfluenced by the epithelium, the -log molar KB values for ICI 204,219 were about 10-fold smaller in human airways than in guinea pig trachea. Removal of the epithelium from guinea pig trachea resulted in small leftward shifts of the concentration-response curves to LTC4 and LTD4 and rightward shifts of the concentration-response curves to LTE4 when examined in the presence of indomethacin. The potentiation of LTC4 and LTD4 by epithelium removal was not seen in the presence of inhibitors of the transformation of LTC4 to LTD4 and LTD4 to LTE4. The influence of the epithelium on responses to LTE4 remained in the presence of these metabolic inhibitors. The lipoxygenase inhibitors nordihydroguaiaretic acid, B755C, Rev 5901 and AA861 antagonized responses to LTE4 in the presence, but not in the absence of epithelium. In human airways, epithelium removal resulted in a small leftward shift of the concentration-response curve to LTD4 whereas responses to LTC4 and LTE4 were unaltered. This effect was not observed in the presence of indomethacin, relating it to reduced release of cyclooxygenase products. These data suggest that contractile responses of guinea pig trachea to LTE4 are modulated by LTE4-induced release of 5-lipoxygenase product(s) only when the epithelium is present.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Elimination and tissue distribution of the monosaccharide lipid A precursor, lipid X, in mice and sheep.

Lipid X (2,3-diacylglucosamine 1-phosphate) is a novel monosaccharide precursor of lipid A (the active moiety of gram-negative endotoxin) and has been found to be protective against endotoxin administered to mice and sheep and against life-threatening gram-negative infections in mice. Because of the need to design optimal dosing regimens in experimental models of ovine and murine septicemia, the pharmacokinetic profile of lipid X was investigated in sheep and in two strains of mice by using 32P-labeled lipid X. In sheep, peak whole blood lipid X levels after a bolus injection of 100 micrograms of lipid X per kg were 900 ng/ml. An initial rapid distribution phase of 7.98 +/- 0.1 min was observed, followed by a prolonged elimination phase of 3.0 +/- 0.5 h; the area under the curve from time zero to infinity was 428 +/- 27 ng.h/ml. The serum half-lives of lipid X were slightly shorter than whole blood half-lives, suggesting that lipid X associates with cellular elements. Metabolites of lipid X could not be detected in serum over a 4-h period. Lipid X appears to accumulate mainly in the liver, and the tissue distribution of lipid X resembles that of lipopolysaccharide. The elimination rate of lipid X in mice was approximately four times as rapid as that seen in sheep. Lipid X pharmacokinetics in lipopolysaccharide-sensitive DBA/2J mice were virtually identical with those seen in endotoxin-resistant C3H/HeJ mice. The pharmacokinetics described here should greatly aid in the design and interpretation of animal studies investigating the therapeutic applications of lipid X in gram-negative septicemia.

Animals↗