Inhibition of NO synthesis in septic shock.
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Arginine↗
Biomedical subjects
J L Parker
Publications and source records attributed to J L Parker.
Effects of exercise training on vasomotor reactivity of porcine coronary arteries.
The purpose of this study was to determine whether exercise training induces changes in the contractile behavior of proximal coronary arteries. Female Yucatan miniature swine were either exercise trained (ET) on a motor-driven treadmill or allowed to remain sedentary (SED) for 16-22 wk. Responses to vasoactive compounds were evaluated in vitro using coronary arterial rings (approximately 2 mm diam) isolated from ET and SED pigs. Each ring was stretched to the apex of the length-active tension relationship. Concentration-response relationships for isometric contractions evoked with KCl (5-100 mM), prostaglandin F2 alpha (PGF2 alpha; 10(-8)-3 x 10(-5) M), acetylcholine (ACh; 10(-9)-10(-4) M), and endothelin (10(-10)-10(-7) M) were similar in arteries from SED and ET pigs. In contrast, arteries from the ET group developed 50-60% less maximal tension in response to norepinephrine (NE; 10(-6)-10(-4) M) than did controls. Vasodilator responses of rings precontracted with either KCl or PGF2 alpha were evaluated with adenosine (ADO; 10(-9)-10(-4) M), isoproterenol (10(-9)-10(-4) M), forskolin (10(-9)-10(-4) M), and sodium nitroprusside (NP; 10(-10)-10(-4) M). Vasodilator responses were similar in SED and ET groups for all agents except ADO and NP; arteries from ET pigs were more sensitive to ADO and less sensitive to NP. The ET-induced alterations in vasomotor responses to NE and ADO appear to be due to changes in vascular smooth muscle because they were still present after removal of endothelium. We conclude that chronic exercise training in pigs induces selective alterations in NE and ADO receptor-second messenger coupling and/or postreceptor-related events in epicardial coronary vascular smooth muscle.
Animals↗
Lyme borreliosis in cattle and horses: a review of the literature.
A complete search of the literature concerning Lyme borreliosis as it relates to horses and cattle was done. The epidemiology, pathogenesis, immunological response to the disease, diagnosis and treatment are discussed. A review of clinical cases in horses and cattle is presented. Clinical signs of Lyme borreliosis in horses include: chronic weight loss, sporadic lameness, laminitis, low grade fever, swollen joints, muscle tenderness, and anterior uveitis. In addition to those clinical signs, neurological signs such as depression, behavioral changes, dysphagia, head tilt and encephalitis can be seen in chronic cases. Borreliosis occurs in cattle, usually as a herd problem. In acute Lyme borreliosis, cattle often will show a fever, stiffness, swollen joints, and decreased milk production. Chronic weight loss, laminitis and abortion are also possible outcomes of borreliosis in cattle. Diagnosis of clinical Lyme borreliosis is difficult and depends upon recognition of clinical signs, a history of possible exposure, and identification of the spirochete in the affected animal. Since the spirochete is very difficult to culture, confirmation of B. burgdorferi infection often relies on serologic testing. Subclinical seropositive animals do occur, thus confusing the diagnosis. An approach to treatment of cattle and horses with Lyme borreliosis is outlined.
Animals↗
Coronary vascular smooth muscle function in E. coli endotoxemia in dogs.
The purpose of this study was to determine whether intrinsic contraction-relaxation properties of coronary arteries are altered during acute gram-negative endotoxemia. Coronary vascular smooth muscle (VSM) was evaluated in vitro using large and small left circumflex coronary ring preparations isolated from dogs 4 h after administration of either saline (control; C) or 1.5 mg/kg Escherichia coli endotoxin (ET). ET dogs exhibited marked systemic hypotension and cardiovascular depression throughout the 4-h in vivo phase of the study accompanied by reduction in total left ventricular myocardial blood flow. Isolated coronary vessels were stretched to the apex of the length-contractile tension curve; no differences were observed in length-active or length-passive tension (vessel compliance) relationships between C and ET vessels. Isometric contractions produced by K+ and prostaglandin F2 alpha (PGF2 alpha) were similar in C and ET coronary arteries. VSM relaxant responses to nitroprusside (NP; 10(-10) to 10(-4) M) were also similar in C and ET vessels. In contrast to the apparent lack of effect of ET on directly acting VSM agents, relaxation responses to the endothelial-dependent vasodilator acetylcholine (ACh) were significantly less in ET vessels. Impaired vasodilator response to ACh was not improved by in vivo treatment with the combination antioxidant therapy of allopurinol, superoxide dismutase, and catalase. We conclude that both depolarization (K+) and receptor (PGF2 alpha)-mediated contractile mechanisms, as well as basal cGMP (NP)-mediated vasodilator mechanisms, remained functional in coronary vasculature during acute endotoxemia. Inhibition of ACh-mediated relaxation in ET vessels suggests altered endothelial-dependent vasodilation in coronary arteries during endotoxemia, but this change did not seem to be associated causally with oxygen free radicals.
Acetylcholine↗
Left ventricular dysfunction in early E. coli endotoxemia: effects of naloxone.
Although the opiate receptor antagonist naloxone (NAL) has been reported to improve in vivo systolic performance of the heart in different circulatory shock syndromes, the influence of this drug on intrinsic cardiac mechanical function during hypodynamic circulatory states is unknown. The present study was designed to determine the effects of in vivo NAL on contraction-relaxation properties of isovolumic left ventricular (LV) preparations isolated from guinea pigs 4 h after induction of gram-negative endotoxemia. Animals were given a 1 mg/kg ip injection of Escherichia coli endotoxin and immediately treated intravenously with either NAL (4 mg/kg iv bolus plus 4 mg.kg-1.h-1 infusion) or an equivalent volume of saline. Endotoxin produced significant reduction of LV contractile function in coronary-perfused hearts, a response unaffected by NAL therapy. For example, LV systolic pressure at approximately 10 mmHg end-diastolic pressure averaged 78 +/- 3 and 82 +/- 6 mmHg in hearts from saline and NAL control animals, respectively, but only 41 +/- 2 and 40 +/- 2 mmHg in endotoxin and endotoxin plus NAL groups, respectively. LV end-diastolic pressure-volume relationships in endotoxin hearts were shifted upward and to the left of controls in the direction of decreased diastolic compliance (P less than 0.05). Importantly, in vivo NAL prevented the endotoxin-induced decrease in LV compliance of the isolated heart preparations (P less than 0.05). Thus intrinsic cardiac complications of early (4 h) nonhypotensive endotoxemia included decreased diastolic compliance as well as diminished contractility of the left ventricle. Only the diastolic compliance changes were NAL responsive and therefore may involve endogenous opioid systems in their pathophysiological expression.
Animals↗
Calcium fluxes in cardiac sarcolemma and sarcoplasmic reticulum isolated from endotoxin-shocked guinea pigs.
In vitro examination of cardiac tissues isolated from septic and endotoxin-shocked animals has demonstrated intrinsic decreased contractile function and has suggested calcium-related dysfunction. Both the sarcolemma (SL) and sarcoplasmic reticulum (SR) membranes have important roles in regulating cardiac free Ca2+ concentration. Therefore, calcium fluxes were examined in well-characterized SL and SR fractions isolated from hearts of control and endotoxin-shocked guinea pigs. Calcium pump activity was similar in SL from control and shock animals. No intrinsic alteration in the rate of equilibrium calcium concentration of Na(+)-Ca2+ exchange was observed in SL from shock guinea pigs. The electrogenic nature of the exchange was maintained. Active Ca2+ transport, Ca2(+)-ATPase activity, and Ca2+ efflux were similar in SR from hearts of control and shock animals. Although no intrinsic calcium dysfunction was noted in the sarcolemma or sarcoplasmic reticulum from the shock animals, this does not preclude the possibility that some factor (humoral agent) or condition (acidosis) may alter calcium processing in these membranes in vivo.
Adenosine Triphosphate↗
Intrinsic myocardial dysfunction during endotoxemia: dependent or independent of myocardial ischemia?
The cardiac mechanisms responsible for endotoxin-mediated disruptions in left ventricular (LV) contraction-relaxation dynamics have been controversial. Recently, a combination of clinical cardiodynamic studies in patients along with experimental cardiodynamic studies in endotoxemic/septic animals and isolated heart tissue has yielded corroborating evidence for a consistent deleterious alteration(s) of intrinsic LV contractility during shock syndromes. Cardiac dysfunction in shock patients and intact animals was characterized by reduced LV ejection fraction in the presence of unchanging LV stroke volume, or by reduced LV end-systolic pressure-volume ratio. In hearts isolated from experimental shock subjects, LV contractile abnormality was characterized by reduced isovolumetric intraventricular pressure development and stroke volume, even in the presence of maximally effective increments in end-diastolic volume or preload. Cardiodynamic changes developed early in experimental septicemic shock syndromes (less than 4 hr) and were not irreversible. Furthermore, and this is a key element, both clinical and experimental study indicated that coronary perfusion inadequacy was not an obligatory etiologic factor in the shock-associated loss of cardiac contractile function. Thus, clinical and experimental data are now available to assemble a consensus that 1) intrinsic LV contractile reserves are diminished early during endotoxemia and sepsis and 2) this diminution is not simply a consequence of global myocardial ischemia.
Animals↗
The guinea pig as a model in shock research.
Studies described in this review characterize the guinea pig as useful for modeling pathophysiologic changes associated with a variety of shock states, including thermal injury. There are basic similarities in the hemodynamic and metabolic responsiveness of humans and guinea pigs to thermal trauma. Guinea pigs are readily available, relatively inexpensive, and easily maintained in the laboratory in accordance with specific nutrition-environmental requirements. The inherent tractability of the guinea pig, coupled with small body size, facilitates cardiorespiratory monitoring without anesthetic restraint. A limitation to using the guinea pig is the amount of information that can be obtained from one animal, but we have demonstrated that with the use of microtechnology, both hemodynamic and metabolic alterations in shock can be characterized in individual guinea pigs. Experimental models using guinea pigs can also be successfully utilized to investigate potential resuscitative and therapeutic modalities in shock.
Animals↗
Gram-negative endotoxemia: effects on cardiac Na-Ca exchange and stoichiometry.
We studied the acute effects of gram-negative endotoxemia on Na-Ca exchange activity and stoichiometry in cardiac sarcolemmal (SL) vesicles isolated from pentobarbital-anesthetized dogs. Dogs were given either endotoxin (ET; 1.5 mg/kg IV) or saline vehicle (C; n = 4 dogs/group). Characteristic of endotoxemia, endotoxin produced a decrease in mean arterial pressure from 120 to 60 mmHg, an increase in packed cell volume from 38% to 60%, and an increase in heart rate from 130 to 190 bpm. After 2 hr, hearts were removed and SL vesicles were prepared from left and right ventricular tissue. For ET and C, Na-dependent Ca2+ uptake (left ventricle) was 3.13 and 3.44 (2 sec) and 18.60 and 19.42 (60 sec) nmole Ca2+/mg protein, respectively; ET group values were not significantly different from corresponding C values in either left or right ventricles. The stoichiometry of Na-Ca exchange was determined in left ventricular vesicles by a previously described thermodynamic approach utilizing a K+-valinomycin gradient opposed by Na+ equilibrium potentials (Reeves and Hale: J Biol Chem 259:7733-7739, 1984). The stoichiometry of exchange of Na+ for Ca2+ was 2.84 +/- 0.09 and 2.74 +/- 0.14 for ET and C, respectively. We conclude that during the developmental phase (2 hr) of endotoxemia, there were no ET-mediated changes in cardiac Na-Ca exchange activity in SL vesicles from either left or right ventricular tissue and the exchange process remained electrogenic with a stoichiometry of 3Na+ for 1Ca2+.
Animals↗
Apparent haematuria: an early sign in polymyositis.
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Adult↗
Selective association and transport of Campylobacter jejuni through M cells of rabbit Peyer's patches.
M cells in the Peyer's patches may facilitate transport of pathogens such as Campylobacter jejuni from the intestine. We evaluated this hypothesis by using electron microscopy to examine Peyer's patches in ligated adult rabbit ileal loops inoculated with 5-mL suspensions of 10(9) cfu/mL of Campylobacter jejuni. Peyer's patches taken at intervals from 15 min to 2 h after inoculation of loops in anaesthetized rabbits provided evidence that Campylobacter jejuni selectively adhered to M cells as opposed to absorptive epithelial cells and was transported, apparently intact, into the M cell follicle. Although intercellular organisms were seen within the follicle, many others were phagocytosed by lymphoid cells. The proximity of the lymphatic and blood circulatory systems to the M cell follicle makes this a probable route for systemic spread of Campylobacter jejuni.
Animals↗
Contractile function of aortic smooth muscle in guinea pig endotoxin shock.
Contractile responsiveness of aortic rings from control and endotoxin-shocked guinea pigs was examined in vitro. Aortae were removed 16 h following intraperitoneal administration of 4 mg/kg of Escherichia coli endotoxin or sterile saline. Although no shift in the dose-response curve or maximal contraction to norepinephrine (10(-9)-10(-4) M) was observed, there was an enhanced contractile response to KCl in shock rings. Calcium dose-response curves in both 60 mM and normal (5.4 mM) KCl were shifted upward in shock rings. This upward shift was abolished in normal KCl in the presence of the Ca2+ blocker D 600 (50 microM), suggesting enhanced Ca2+ influx via voltage-dependent Ca2+ channels in shock vascular smooth muscle. A deleterious effect of high cytoplasmic Ca2+ on vascular smooth muscle mitochondrial function may play a role in endotoxin shock.
Animals↗
Reduction of intrinsic contractile reserves of the left ventricle by Escherichia coli endotoxin shock in guinea-pigs.
To test the hypothesis that cardiodynamic responses during endotoxemia are limited by intrinsic myocardial dysfunction, we studied contractile properties of isovolumic left ventricular (LV) preparations isolated from E. coli endotoxin-shocked guinea pigs. Compared to control hearts, shock hearts developed significantly lower LV systolic pressures (54 +/- 7 v. 84 +/- 2 mmHg; P less than 0.001) and maximal rates of LV pressure rise (+dP/dtmax; 886 +/- 106 v. 1246 +/- 39 mmHg/s; P less than 0.006) and fall (-dP/dtmax; 702 +/- 98 v. 1103 +/- 26 mmHg/s; P less than 0.001). The LV mechanical disadvantage of shock hearts was not correlated with changes in beating frequency, active state duration, or tissue water content; neither was it surmounted by pyruvate nor by maximally effective increases in coronary flow, diastolic stretch, or extracellular Ca2+ concentration. These findings suggest that endotoxin pathogenesis encompasses a decrease in intrinsic contractile reserves of the left ventricle, and that the resulting changes in myocardial contractile mechanisms may underlie cardiac involvement in endotoxin shock syndromes.
Animals↗
Development of myocardial dysfunction in endotoxin shock.
Isolated heart muscle preparations were used to investigate the onset and development of myocardial inotropic dysfunction during endotoxin shock in guinea pigs. Left atrial muscles were removed from separate groups of animals at increasing time intervals after administration of either 4 mg/kg purified Escherichia coli endotoxin (shock groups) or an equivalent volume of isotonic saline (control groups). Peak developed contractile tension (CT) and maximal rate of tension development (+dT/dtmax) were significantly depressed in shock tissues as early as 2 h postendotoxin (P less than 0.01), with the magnitude of the contractile deficit progressively increasing during 4, 6, and 12 h postendotoxin. Contractility remained significantly depressed (P less than 0.001) at 16 and 24 h postendotoxin but progressively recovered toward control levels during 16, 24, 48, and 72 h postendotoxin. Shock-induced myocardial dysfunction was characterized by altered contractile responsiveness to low-Ca2+ medium (0.5 mM), gentamicin (4 mM), and hypoxia; altered inotropic reactivity to these interventions followed similar temporal development as the postendotoxin changes in basal contractile parameters. Left ventricular papillary muscles obtained at 16 h postendotoxin corroborated the shock-induced contractile depression observed in atria. These studies provide evidence for early and progressive intrinsic myocardial dysfunction in endotoxin shock and demonstrate that this dysfunction can be unmasked through the study of in vitro atrial and ventricular heart muscle preparations isolated from in vivo shocked animals.
Animals↗
Supraophthalmic carotid infusion for brain chemotherapy. Experience with a new single-lumen catheter and maneuverable tip.
A single-lumen catheter with a maneuverable tip which does not incorporate a balloon has been developed for supraophthalmic intracarotid infusion of chemotherapeutic agents for central nervous system neoplasms. Supraophthalmic carotid catheterization was accomplished in 48 (96%) of the first 50 consecutive infusions in which this catheter was used. None of the 31 patients who underwent this procedure developed optic neuropathy or loss of vision. Ten patients developed Marcus-Gunn pupils, ipsilateral to the infused carotid artery in two and contralateral to the infused carotid artery in eight. Thrombosis of the carotid artery occurred after infusion in one patient. Problems associated with the technique include a tendency for the catheter to retract proximally during infusion in some patients, and the necessity for surgical exposure of the carotid artery. The infusion technique protects the eye from the high-concentration first-pass of chemotherapeutic agents administered via the carotid artery. Since the tip of this catheter can be hydraulically guided, it may prove to be useful in other areas of transarterial neurosurgical procedures.
Antineoplastic Agents↗
Isolated cardiac preparations: models of intrinsic myocardial dysfunction in circulatory shock.
Isolated cardiac preparations have been adapted for modeling intrinsic myocardial responses to circulatory shock syndromes independently of immediate influence from depressive or supportive constraints operative in the intact host. Left atrial and left ventricular (LV) papillary muscles and coronary-perfused hearts were removed from guinea pigs during development of Escherichia coli endotoxin shock. Preparations were then subjected to a battery of functional analyses under conditions of constant perfusate pH, pO2, pCO2, electrolyte and substrate concentrations, osmolality, and temperature. Evidence for contractile depression intrinsic to the myocardium itself was a consistent and reproducible finding in all three tissue models. The LV mechanical disadvantage of shock hearts was not correlated with changes in cardiac cycle length (beating frequency), active state duration (contraction-relaxation intervals), or tissue water content; neither was it surmounted by maximally effective increments in coronary flow, [Ca2+]o, or diastolic fiber length. Taken in concert, studies to date suggest that gram-negative endotoxin leads in some way to a reduction of intrinsic contractile reserves of the myocardium, and we have postulated that this change underlies the circulatory shock phase of endotoxicosis. The experimental approach embodied in these models may yield unique cardiodynamic interpretations that will allow the formulation of testable hypotheses about the pathogenesis and prevention of intrinsic cardiac complications of endotoxin and related shock forms.
Animals↗
Pharmacologic management of circulatory shock: cardiovascular drugs and corticosteroids.
Effective use of cardiovascular drugs in the management of circulatory shock requires knowledge of the pathophysiologic changes occurring in the different types and stages of shock and an understanding of the specific hemodynamic actions of drugs used to correct shock. Objectives of therapy are to: (1) restore circulating blood volume, (2) ensure of increase perfusion of critical organs by selectively reducing arteriolar resistance, (3) augment cardiac output, and (4) increase perfusion pressure. If blood volume is not restored, drugs may be ineffective and can even induce deleterious effects. If reflex sympathetic discharge has induced generalized vasoconstriction, it is irrational to expect beneficial results from administration of exogenous vasconstrictor agents. Instead, selective vasodilatation of vascular beds in critical tissues (eg, myocardium, intestines, and kidneys) accompanied by increased perfusion pressure and cardiac output can prove useful. Large doses of adrenocorticosteroids are used commonly in the therapy of different shock conditions, based primary on empiric tests of efficacy. Although such steroids may not influence the course of shock by direct cardiovascular effects, beneficial actions may result from mechanisms such as protection of cell membrane integrity and stabilization of lysosomes.
Adrenal Cortex Hormones↗
Rhombic particle arrays in gill epithelium of a mollusc, Aplysia californica.
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Animals↗