Hemodynamic Aspects of Hemorrhagic and Septic Shock

Hopkins, Robert W.

doi:10.1001/jama.1965.03080090045010

Cited by 50 publications

(7 citation statements)

References 6 publications

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“…However, the structurally dissimilar glimepiride showed little effect on arterial pressure (Fig. 2 b) It is of interest that inadequate tissue oxygenation with anaerobic metabolism and lactic acidosis are features common to shock of any etiology (18), and it appears likely that activation ofKATP channels is a general mechanism involved in the hypotension of shock. For example, severe hypovolemia is initially associated with systemic vasoconstriction, but as tissue hypoxia persists, lactic acidosis develops and systemic vascular resistance falls (38,39), suggesting activation of the KATP channel.…”

Section: Resultsmentioning

confidence: 99%

“…Opening ofthis channel hyperpo-larizes vascular smooth muscle and reduces Ca2" entry through voltage-gated Ca2" channels, thereby inducing relaxation. The KAZT channel is activated by decreased intracellular ATP (1 1, 12) by cytosolic acidosis (13,14), and increased cytosolic lactate (15) conditions that may present in septic shock, which is characterized by inadequate tissue oxygenation (16, 17), anaerobic metabolism, and lactic acidosis (18,19). Thus, we examined the role of KATp channel activation in the hypotension of sepsis by means of an animal model (4) for septic shock.…”

Section: Introductionmentioning

confidence: 99%

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The ATP-sensitive K+ channel mediates hypotension in endotoxemia and hypoxic lactic acidosis in dog.

Landry¹,

Oliver²

1992

J. Clin. Invest.

200

111

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Endotoxemia causes hypotension characterized by vasodilation and resistance to vasopressor agents. The molecular mechanisms responsible for these changes are unclear. The ATPregulated K+ (KATP) channel has recently been found to be an important modulator of vascular smooth muscle tone which may transduce local metabolic changes into alterations ofvascular flow. We report here that in endotoxic hypotension, the sulfonylurea glyburide, a specific inhibitor for the KATP channel, caused vasoconstriction and restoration of blood pressure. Glyburide also induced vasoconstriction and restoration of blood pressure in the vasodilatory hypotension caused by hypoxic lactic acidosis, while it was ineffective in the hypotension induced by sodium nitroprusside. Thus, vasodilation and hypotension in septic shock are, at least in part, due to activation of the KATP channel in vascular smooth muscle, and anaerobic metabolism with acidosis is a sufficient stimulus for channel activation. Because anaerobic metabolism and acidosis are common features in shock ofany etiology, sulfonylureas may be effective therapeutic agents in the treatment of shock. (J. Clin.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The ATP-sensitive K+ channel mediates hypotension in endotoxemia and hypoxic lactic acidosis in dog.

Landry¹,

Oliver²

1992

J. Clin. Invest.

200

111

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“…Moreover, the beneficial haemodynamic effects in animal models of septic shock given by dexamethasone (Wright et al, 1992), PAF-receptor antagonists (Szabo et al, 1993e), antibodies to TNFa (Thiemermann et al, 1993), IL-1 receptor antagonists (Szabo et al, 1993d) or dihydropyridinetype calcium channel antagonists (Szabo et al, 1993c) Thiemermann, 1994). Moreover, agents which prevent the induction of iNOS including dexamethasone (Szabo et al, 1993b), antibodies to TNFz (Thiemermann et al, 1993), IL-1 receptor antagonists (Szabo et al, 1993d), PAF receptor antagonists (Szabo et al, 1993e) or dihydropyridine-type calcium channel antagonists (Szabo et al, 1993c) (Hopkins et al, 1965;Kaufman et al, 1984;Keung & Li, 1991); (ii) a decrease in intracellular ATP (anaerobic metabolism) (Noma, 1983;Deutsch et al, 1991) or intracellular acidosis (Davies, 1990;Cuevas et al, 1991) facilitates the activation of K'ATP channels; and (iii) activation of K+ATP channels results in vasodilatation (Standen et al, 1989). Thus, it has been suggested that the beneficial haemodynamic effects of glibenclamide in dogs with septic shock are due to inhibition of the activation of K'ATP channels occurring secondary to lactic acidosis (Landry & Oliver, 1992 Endotoxaemia in the rat causes the expression of cyclooxygenase-2 (COX-2) (Swierkosz et al, 1994), which results in an enhanced formation of prostaglandins (PGs) and/or thromboxane A2.…”

Section: Discussionmentioning

confidence: 99%

Glibenclamide‐induced inhibition of the expression of inducible nitric oxide synthase in cultured macrophages and in the anaesthetized rat

Thiemermann

Vane

1995

British J Pharmacology

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1 We have investigated whether glibenclamide, an inhibitor of ATP-sensitive potassium channels, influences the induction of the calcium-independent isoform of nitric oxide synthase (iNOS) in cultured J774.2 macrophages activated by bacterial endotoxin (E.coli lipopolysaccharide; LPS), as well as in the lung and aorta of rats with endotoxic shock.2 Pretreatment of J774.2 macrophages with glibenclamide (10-' to 10-1 M for 30 min) dosedependently inhibited the accumulation of nitrite caused by LPS (1 pg ml-'). In contrast, pretreatment of macrophages with tetraethylammonium (10-4 to 10-2M for 30min), a non-selective inhibitor of potassium channels, did not affect the rise in nitrite caused by LPS. At the highest concentration (10-5 M) used, cromakalim, an opener of ATP-sensitive potassium channels, caused a small, but significant inhibition of nitrite formation in macrophages activated with LPS, while lower concentrations (10-7 to 3 x 10-6 M) were without effect.3 The inhibition by glibenclamide (3 JM) of the increase in nitrite induced by LPS in J774.2 macrophages was weaker when glibenclamide was given several hours after LPS, indicating that glibenclamide inhibits the induction, but not the activity, of iNOS. In contrast, the degree of inhibition of nitrite formation caused by the nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME) was similar when this agent was given up to 10 h after LPS. 4 In anaesthetized rats, LPS caused a fall in mean arterial blood pressure (MAP) from 120 ± 4 (time 0) to 98 ± 4 mmHg at 180 min (P<0.05, n = 6). Treatment of LPS-rats with glibenclamide (1 mg kg-', i.v.at 60 min after LPS) caused a rapid and sustained rise in MAP (e.g. MAP at 180 min after LPS: 122±4 mmHg; n =6, P <0.05 when compared to LPS-rats). The maximum of the rise in MAP produced by glibenclamide (1 mg kg-, i.v.) was similar when the drug was given either at 60 or 180 min after LPS. However, the duration of the pressor response was significantly longer when glibenclamide was given at 60 min, rather than at 180 min after LPS. 5 LPS-treatment caused a significant reduction of the pressor responses elicited by noradrenaline (NA, 1 jig kg-', i.v.) from 35 ± 2 to 19 ± 1 mmHg at 60 min and 20 ± 2 mmHg at 180 min (P<0.05).Treatment of LPS-rats with glibenclamide (1 mg kg-', i.v. at 60 min) caused a significant restoration of the pressor responses elicited by NA from 19 ± 1 mmHg at 60 min (prior to glibenclamide injection) to 29± 3 mmHg at 180 min (P<0.05). 6 Endotoxaemia for 180 min resulted in a significant increase in a calcium-independent NOS activity (which was taken to represent iNOS activity) in the lung from 0.17 ± 0.1 (control, n =4) to 6.21 ± 0.48 pmol mg-' min-' (n =6, P<0.05). Injection of glibenclamide (1 mg kg ', i.v.) at 60 min after LPS attenuated the increase in iNOS activity caused by endotoxaemia in the lung by 43 ± 7% (n = 6, P <0.05). In contrast, injection of glibenclamide at 180 min after LPS did not result in a significant inhibition of iNOS activity (n = 6, P <0.05). 7 Thor...

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“…Bei Hyperventilation mit Abfall des pCO 2 auf 20 mm Hg wurden nur geringffigige Anstiege des Lactats gefunden (unter 1 mmol/1). Die metabolische Azidose beim hfimorrhagischen, kardiogenen und septischen Schock wurde in sp~iteren Untersuchungen[35,53,62] als Lactat-Azidose erkannt. Diese Lactazidhmie ist auf eine f2berproduktion von Lactat zurfickzuffihren, die wahrscheinlich vorzugsweise in Erythrozyten erfolgt.…”

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Lactat-Azidose ? Eine m�gliche Komplikation der Buformin-Therapie

et al. 1978

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Lactic acidosis is defined as a state of metabolic acidosis (arterial pH below 7.36) due to an increase in the blood concentration of lactate above 2 mEq/l. Lactic acidosis may occur under a variety of conditions; the biguanide-induced lactic acidosis is due to the toxic effects of biguanides (buformin, metformin, phenformin). The clinical picture is characterized by the occurrence of disturbances of consciousness, severe acidosis with Kussmaul's respiration, shock, hypothermia and in about 30% of all cases hypoglycemia. Apart from the general principles of intensive medical care, therapy should comprise correction of the acid-base-disturbances and elimination of the offending biguanide. The efficacy of hemodialysis in the treatment of biguanide-induced lactic acidosis is difficult to evaluate. By a more sensible use of biguanides, lactic acidosis secondary to drug administration should become a rare event.

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Hemodynamic Aspects of Hemorrhagic and Septic Shock

Cited by 50 publications

References 6 publications

The ATP-sensitive K+ channel mediates hypotension in endotoxemia and hypoxic lactic acidosis in dog.

The ATP-sensitive K+ channel mediates hypotension in endotoxemia and hypoxic lactic acidosis in dog.

Glibenclamide‐induced inhibition of the expression of inducible nitric oxide synthase in cultured macrophages and in the anaesthetized rat

Lactat-Azidose ? Eine m�gliche Komplikation der Buformin-Therapie

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