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Biomedical subjects

J A Osborne

Publications and source records attributed to J A Osborne.

At least 37 records · Page 2Linked to original sources
PubMed1992

S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds.

Endothelium-derived relaxing factor (EDRF) activity has been attributed to the highly labile nitric oxide radical (NO). In view of the fact that the plasma and cellular milieux contain reactive species that can rapidly inactivate NO, it has been postulated that NO is stabilized by a carrier molecule that preserves its biological activity. Reduced thiol species are candidates for this role, reacting readily in the presence of NO to yield biologically active S-nitrosothiols that are more stable than NO itself. Because sulfhydryl groups in proteins represent an abundant source of reduced thiol in biologic systems, we examined the reaction of several sulfhydryl-containing proteins of diverse nature and function upon exposure to authentic NO and EDRF. We demonstrate that S-nitroso proteins form readily under physiologic conditions and possess EDRF-like effects of vasodilation and platelet inhibition. These observations suggest that S-nitrosothiol groups in proteins may serve as intermediates in the cellular metabolism of NO and raise the possibility of an additional type of cellular regulatory mechanism.

Animals↗
PubMed1992

The relaxant properties in guinea pig airways of S-nitrosothiols.

Several cellular constituents of the lung have the capacity to synthesize a factor capable of relaxing smooth muscle which has the physicochemical properties of nitric oxide (NO). In other systems, it has been shown that NO may be stabilized in the plasma and cellular milieu by reduced thiol in the form of an S-nitrosothiol (RS-NO). These compounds have half-lives that are significantly greater than that of NO, and also retain the vasorelaxant activity of NO, which is mediated by activating guanylate cyclase and raising cyclic GMP levels. The effects of RS-NO and their potential mechanism of action on airways, however, have not been previously investigated. In this study, we have examined the smooth muscle relaxant properties of several biological and synthetic RS-NO on guinea pig trachea. Our data reveal that RS-NO are generally potent airway smooth muscle relaxants with at least a partial effect through stimulation of cyclic GMP. Relaxations were attenuated significantly by the guanylate cyclase inhibitor methylene blue (P less than .05), and RS-NO-induced increases in cyclic GMP were demonstrated (P less than .0005). The IC50 values for S-nitroso-glutathione, S-nitroso-cysteine, S-nitroso-homocysteine, S-nitroso-N-acetylcysteine, S-nitroso-penicillamine and S-nitroso-captopril were 0.99 +/- 0.09, 3.2 +/- 0.2, 2.1 +/- 0.3, 2.1 +/- 0.8, 1.8 +/- 0.8 and 20 +/- 0.7 microM (mean +/- S.E.M.), respectively. In this system isoproterenol has an IC50 of 0.016 microM and theophylline an IC50 of 74 microM, making the relaxant properties of these NO derivatives of potential pharmacological and physiological relevance.

Animals↗
PubMed1989

Protective effect of the specific thromboxane receptor antagonist, BM-13505, in reperfusion injury following acute myocardial ischemia in cats.

The ability of BM-13505, 4-[2-(4-chlorobenzenesulfonylamino) ethyl]-benzene acetic acid), a specific thromboxane/endoperoxide receptor antagonist, to protect the myocardium against ischemia and reperfusion injury, was assessed in an anesthetized cat model. Cats were rendered ischemic by left anterior descending (LAD) coronary artery ligation for 1 1/2 hours followed by reperfusion for 4 1/2 hours. BM-13505 or its vehicle (i.e., Na2CO3) was administered intravenously 30 minutes before reperfusion at a rate of 1 mg/kg followed by 1 mg/kg/hr. BM-13505 significantly (p less than 0.001) reduced the area of ischemic tissue as a percent of total left ventricular mass and total area at risk, without altering basic hemodynamics (i.e., arterial blood pressure, heart rate, or their product) and thereby not influencing myocardial oxygen demand. The mechanism of the protective effect of the thromboxane receptor antagonist appears to be cytoprotective but may involve the prevention of neutrophil-induced cellular damage.

Acute Disease↗
PubMed1989

Lack of endothelium-dependent relaxation in coronary resistance arteries of cholesterol-fed rabbits.

The endothelium-dependent contractile responses of subepicardial coronary resistance arteries (286 +/- 18 microns ID, n = 22) from rabbits fed either a 0.5 or 2.0% cholesterol-enriched diet or a control diet for 10-12 wk were determined under isometric conditions at the optimum length for active force production (Lo). After the development of tone with 29 mM K+-Krebs, arteries from control rabbits treated with acetylcholine (0.1-10 microM) showed a concentration-dependent relaxation, with a maximum decrease in tone of 63%. In contrast, coronary arteries from animals fed 0.5 and 2.0% cholesterol contracted to acetylcholine (approximately 210% increase in tone). A similar phenomenon was seen with arteries precontracted with 10 nM 9,11-methanoepoxy-prostaglandin H2 (U 46,619), a thromboxane A2 mimetic. The contractile responses to acetylcholine occurred in arteries in which the endothelium was structurally intact and which were devoid of plaque. Arteries from cholesterol-fed animals were poorly responsive to ADP (0.01-10.0 microM), whereas arteries from normal animals relaxed. All arteries relaxed to an equal degree when exposed to acidified nitrite, which produces nitric oxide (NO). The data suggest that as a result of hypercholesterolemia, there may be a dysfunction in the synthesis or release of endothelium-derived relaxing factor (EDRF) by the endothelial cells of coronary resistance arteries, rather than an abnormality of the smooth muscle cells per se.

Acetylcholine↗
PubMed1989

Cardiovascular effects of acute hypercholesterolemia in rabbits. Reversal with lovastatin treatment.

Hypercholesterolemia was induced in New Zealand white rabbits by feeding them a 0.5% cholesterol-enriched rabbit chow for 2 wk. Half of the cholesterol-fed rabbits were given lovastatin, a potent inhibitor of hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase), the rate limiting enzyme in cholesterol biosynthesis, and the other half were given its vehicle (i.e., DMSO). At the end of 2 wk, the rabbits underwent experimental myocardial ischemia or a sham ischemia procedure. Ischemic animals fed the cholesterol-enriched diet for 2 wk experienced much greater cardiac damage than ischemic rabbits fed the control diet, despite the absence of any atherosclerosis. Lovastatin was shown to protect the ischemic rabbit myocardium by three different indices of ischemic damage: (a) maintenance of creatine kinase (CK) activity in the ischemic myocardium; (b) reduced loss of free amino-nitrogen containing compounds from the ischemic myocardium; and (c) blunting the rise of plasma CK activity. These effects were not due to differences in myocardial oxygen demand between the groups. Arteries isolated from animals fed the cholesterol-enriched diet developed defects in endothelium-dependent relaxation in both large vessels as well as coronary resistance vessels. Acute hypercholesterolemia increases the severity of myocardial ischemia while at the same time impairing endothelium-dependent relaxation. These deleterious changes can be significantly attenuated by treatment with lovastatin.

Animals↗
PubMed1989

Vascular responsiveness of constant flow perfused arteries with intact endothelium.

We have devised a perfused artery preparation, in which one can conveniently assess vasoactivity to agents (a) in the presence and absence of a functionally intact endothelium within the same vessel, and (b) when added to the luminal or abluminal (i.e., adventitial) surface of the vessel. Moreover, utilizing stainless steel cannulas of various calibers, one can routinely perfuse vessels ranging from less than 1 mm to over 4 mm in internal diameter. By moderating the pulsatile nature of the constant flow perfusion, one can retain a functionally intact endothelium (i.e., at totally damped perfusion) or one can abolish endothelial modulation of vasoactive agents (i.e., a pulsatile perfusion). The integrity of the endothelium was confirmed by histological methods. Using perfused cat carotid arteries preconstricted with U-46619, a stable prostaglandin-endoperoxide analog which maintains a stable vasoconstriction, acetylcholine dilated carotid arteries perfused at non-pulsatile flows, but not at pulsatile flows, indicating the endothelium dependent nature of the vasodilation produced by ACh. This was confirmed with the calcium ionophore A-23187, a non-receptor endothelium dependent vasodilator. However, calcium channel blockers (e.g., nimodipine) prostacyclin analogs (e.g., iloprost) or vasodilator nitrates (e.g., sodium nitrite at pH 2.0) produced equivalent dilations in the presence and absence of a functional intact endothelium. This preparation allows for convenient use of single dose application of pharmacologic agents as well as cumulative dose-response relationships.

Acetylcholine↗
PubMed1988

Cardioprotective actions of thromboxane receptor antagonism in ischemic atherosclerotic rabbits.

Atherosclerosis was induced in New Zealand White rabbits by feeding them a 0.5% cholesterol-enriched rabbit chow for 10-12 wk. Half of the cholesterol-fed rabbits were given BM 13505, a specific thromboxane A2/endoperoxide (TxA2/PGH2) receptor antagonist, and the other half were given its vehicle (i.e., 2% Na2CO3). At the end of 10-12 wk, the rabbits underwent experimental myocardial ischemia or an identical sham operation, except that the coronary artery was not occluded. BM 13505 was shown to protect the ischemic rabbit myocardium by three different methods: 1) maintenance of myocardial tissue creatine kinase (CK) activity in the ischemic myocardium; 2) reduced loss of free amino nitrogen-containing compounds from the myocardium; and 3) blunting the rise of plasma CK activity. Part of the mechanism for these effects may be due to inhibition of platelet aggregation and blockade of the vasoconstrictor effect of TxA2. However, these protective effects were not due to differences in myocardial oxygen demand among the groups. Finally, BM 13505 exhibited an antiatherogenic effect by reducing the deposition of cholesterol in the aortic wall and by retarding plaque formation in coronary arteries. However, it does not achieve this antiatherogenic effect by lowering plasma cholesterol concentrations or by scavenging superoxide free radicals. Thus blockade of TxA2 receptors exerts a variety of beneficial effects that reduce the severity of ischemic damage resulting from myocardial ischemia.

Animals↗
PubMed1987

Increased severity of acute myocardial ischemia in experimental atherosclerosis.

We investigated the effects of acute myocardial ischemia (MI) in a rabbit model of atherosclerosis to determine whether atherosclerosis augments the severity of damage produced in the ischemic myocardium. Normal rabbits were fed a control rabbit chow diet or a diet enriched with either 2% cholesterol or 0.5% cholesterol for 10-12 weeks prior to induction of MI. Plasma cholesterol concentrations in the cholesterol-fed rabbits were 1697 +/- 70 mg/dl (2%) and 1056 +/- 51 mg/dl (0.5%) vs. 61 +/- 12 mg/dl for the non-cholesterol-fed rabbits. All rabbits were observed for 5 h following induction of MI or sham MI. At the conclusion of the experiment, tissue biopsies from the MI region and non-MI (NMI) regions were taken and analyzed for two indicators of the severity of MI--myocardial creatine kinase (CK) activity and free amino-nitrogen concentration. Atherosclerosis was confirmed histologically in coronary artery and aortic specimens. No difference was found among any group with respect to heart rate (HR), mean arterial blood pressure (MABP), or pressure-rate index (HR x MABP/1000, a measure of myocardial oxygen demand). Myocardial CK loss (NMI - MI) was significantly greater for the 2% and 0.5% cholesterol groups (7.3 +/- 1.3 and 4.9 +/- 0.7 IU/mg protein, respectively, P less than 0.05) than in the nonatherosclerotic group (2.5 +/- 0.4 IU/mg protein; P less than 0.001 for 2% and P less than 0.01 for 0.5%). Increased severity of MI was confirmed by a significantly greater myocardial loss of free amino-nitrogen (NMI - MI) in the two atherosclerotic groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Influence of atherosclerosis on vascular responsiveness in isolated rabbit vascular smooth muscle.

Coronary arteries and aortic rings were isolated from rabbits fed either a control diet or a high cholesterol (1 to 2%) diet for 8 to 11 weeks and studied for their vasoactive properties to a variety of vasoconstrictor and vasodilator agents. Perfused coronary arteries without intact endothelium constrict markedly to a thromboxane A2 agonist (i.e., carbocyclic thromboxane A2, CTA2) and dilate markedly to iloprost, a prostacyclin analog. No differences occurred between the coronary arteries isolated from control or atherosclerotic rabbits. Additional studies were conducted on rabbit aortic vascular smooth muscle rings containing functionally intact endothelium and in rings denuded of their endothelium. Acetylcholine (20 to 2000 ng/ml) neither constricted nor dilated control aortic rings without endothelium, and markedly dilated aortic rings with intact endothelium in a concentration dependent manner. In atherosclerotic aortic rings, acetylcholine constricted preparations without endothelium, and dilated rings with endothelium to a much lesser extent than that observed in control rings. Similar reductions in responsiveness occurred with adenosine diphosphate (ADP), another endothelium-dependent vasodilator, but not with iloprost, a nonendothelium-dependent dilator. No differences were observed in constrictor responses to norepinephrine. Aortae from atherosclerotic rabbits produced less prostacyclin in response to arachidonic acid than control aortae. These data point to an important role of the endothelium in modulating the vascular response to vasodilators in atherosclerotic rabbit arterial vessels.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Protective actions of a stable prostacyclin analog in ischemia induced membrane damage in rat myocardium.

Myocardial ischemia leads to the damage of cellular membranes and release of intracellular enzymes. We studied the influence of the prostacyclin analog, iloprost, on alterations in membrane phospholipid content and composition in rat myocardium during ischemia. Infusion of iloprost (100 ng/kg/min) or its vehicle started 20 min after coronary artery ligation, and the hearts were analyzed after 6 h. Myocardial creatine kinase activity was significantly reduced by approximately 25% in the ischemic areas of hearts from rats receiving vehicle. This reduction in myocardial creatine kinase activity was totally abolished by infusion of iloprost. Total phospholipid content was significantly reduced by 10% in ischemic areas of hearts obtained from vehicle infused animals. Iloprost infusion also prevented the loss of total phospholipids in the ischemic areas. The data show that coronary artery ligation is associated with a significant loss of total membrane phospholipids in ischemic regions of rat myocardium, characterized by significant decreases in phosphatidylcholine, phosphatidylethanolamine and cardiolipin. The decrease in cardiac phosphatidylcholine and phosphatidylethanolamine content was prevented by iloprost, whereas the decrease in cardiolipin content was unaltered. Infusion of the prostacyclin analog iloprost almost totally inhibited the ischemia induced loss of phospholipids, suggesting that this may be an important component of its cytoprotective mechanism of action.

Animals↗
PubMed1987

Coronary vascular actions of synthetic atrial natriuretic factor in isolated vascular preparations.

Administration of atrial natriuretic factor (ANF) in animals results in increases in renal blood flow, natriuresis, and a decrease in arterial blood pressure, supporting a role for the atrial peptide system in cardiovascular regulation. However, little is known about the vascular effects of synthetic ANF (26 amino acid) on coronary artery smooth muscle. We studied the coronary vascular effects of synthetic ANF in feline artery preparations in vitro. In isolated coronary arteries perfused at constant flow, ANF (3-300 nM) concentration dependently decreased perfusion pressure ranging from 2.6 +/- 0.7 mm Hg (p less than 0.02) at 3 nM to 28.6 +/- 3.7 mm Hg (p less than 0.001) at 300 nM. Perfusion with the prostacyclin analog, iloprost (20-100 nM), failed to alter the coronary vasodilator response to ANF. ANF also relaxed feline coronary helical strips when contracted by U-46,619 (an endoperoxide analog), serotonin, and leukotriene D4. This relaxant effect was independent of the presence of endothelial cells and occurred in the presence of a guanylate cyclase inhibitor, methylene blue. The ANF had no direct effect on electrically driven isolated feline papillary muscles, signifying a lack of direct inotropic activity of ANF in cat cardiac muscle. These results suggest that ANF may produce coronary vasodilation that therefore could contribute to coronary regulation, without directly altering myocardial performance.

Animals↗
PubMed1987

Beneficial actions of the thromboxane receptor antagonist, AH-23,848, in acute myocardial ischemia.

Thromboxane A2 (TxA2) production increases significantly during acute myocardial ischemia. Since TxA2 induces platelet aggregation, coronary vasoconstriction and has a direct cytolytic effect, thromboxane receptor antagonists would be expected to be beneficial in acute myocardial ischemia. A new thromboxane A2 receptor antagonist, AH-23,848, was studied in a cat model of acute myocardial ischemia. Myocardial ischemia was induced by ligation of the left anterior descending (LAD) coronary artery. Thirty minutes later, AH-23,848 or vehicle was given as a bolus (1 mg.kg-1) followed by a continuous infusion (1 mg.kg-1.h-1). AH-23,848 effectively reduced the S-T segment elevation while vehicle treated cats showed an increase. From direct myocardial biopsies, it was also seen that AH-23,848 prevented the loss of creatine kinase (CK) activity from the ischemic myocardium. Furthermore, the loss of amino-nitrogen compounds was also significantly reduced (p less than 0.05) by treatment with the receptor antagonist. This protective effect was not due to an indirect reduction of myocardial oxygen demand since blood pressure, heart rate or their product was unaltered by AH-23,848 administration. Moreover, the specificity of AH-23,848 to thromboxane receptors was confirmed in isolated cat coronary arteries and in cat platelets. These experiments demonstrate that blockade of the thromboxane receptor by AH-23,848 is an effective means of preventing acute myocardial ischemic damage in the cat, and thus thromboxane A2 plays a role in propagating the extension of ischemic damage during acute myocardial ischemia.

Acute Disease↗
PubMed1986

In vivo anti-platelet properties of anipamil, a calcium channel blocker, in the rabbit.

The anti-platelet actions of anipamil, a new calcium channel blocker were studied in anesthetized rabbits using continuous on-line techniques to measure platelet count and platelet secretion by ATP release. Anipamil, at a dose of 0.5 mg/kg twice daily for three days, prior to challenge with collagen (100 micrograms/kg) or arachidonic acid (1.1 mg/kg), was without effect. However, 2 and 5 mg/kg of anipamil significantly retarded the decline in platelet count to both platelet activators, although anipamil failed to significantly diminish the hypotensive effect of these platelet activators, or significantly increase survival to arachidonic acid. Moreover, anipamil was without effect on the platelet effects of platelet activating factor (PAF). Thus, anipamil has the ability to partially inhibit the activation of platelets in vivo.

Adenosine Triphosphate↗
PubMed1980

On deriving the electrocardiogram from vectoradiographic leads.

The issue of whether a traditional or scientifically based system for applying electrodes to the body for routine electrocardiography may be resolved by deriving the 12-lead ECG from the Frank XYZ signals. The result, the ECGD, is sufficiently close to the ECG for serial comparisons to be valid. Reducing data acquisition to the XYZ signals alone has several technical advantages. These have been realized with the introduction of a computer system employing the ECGD at a large general hospital. Plotting the lead vectors of the ECGD on Aitoff's projection of the sphere brings out important relationships between the leads, one to another, and to the spatial directions of the QRS and T vectors. Reversing the polarity of a VR enhances the sequential relationship between the limb leads; this is taken advantage of in an educational display generated by the computer.

Computers↗
PubMed1979

Standardization of electrocardiographic interpretive statements: a menu for word processing.

Standardization of electrocardiographic interpretive statements is a goal of various coding systems, but word processing has not usually been considered. A simple, easily memorized system for clinical electrocardiography has been developed and used for approximately 60 000 interpretations. It takes the form of a "menu", in which boxes stand for various interpretive statements; the boxes are identified by mnemonics and marked by the interpreter when appropriate. The results provide better standardization, significant decreases in the numbers of descriptive statements and words per interpretation and considerable saving in typing time. Acceptance by the interpreters has been good. Features of the system allow for word processing as part of a polarcardiography computing system.

Computers↗
PubMed1977

Polarcardiographic criteria for infarction evaluated by angiocardiography.

Out of a series of 1000 consecutive patients studied by angiocardiography, two groups were selected on the basis of the probability of having suffered myocardial infarction: an infarction group of 324 cases, and a non-infarction group of 112 cases. Members of the infarction group had complete occlusion of at least one major coronary artery; members of the non-infarction group had less than 50% occlusion in all coronary arteries, normal hemodynamics, and negative histories of infarction. The diagnostic performances of the independently-read 12-lead electrocardiograms (ECGs) and the polarcardiograms (PCGs) were evaluated in terms of sensitivity, specificity, validity and risk ratio. The performance of the ECG was significantly lower than the PCG. Corresponding figures were 56%, 99%, 67%, and 1.67 for the ECG, and 75%, 91%, 80%, and 2.23 for the PCG. There is a 99.9% probability that the PCG can detect at least 21% more cases of infarction than the ECG can.

Adult↗