Circulation research
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Recent evidence suggests a cardioprotective effect of adenosine in myocardial ischemia and reperfusion. The present study was undertaken to determine (1) whether adenosine attenuates myocardial stunning, (2) if so, whether the beneficial effect of adenosine takes place during ischemia or after reperfusion, and (3) whether adenosine preconditions against myocardial stunning. A total of 93 dogs were used. ⋯ In phase B of the study, dogs received an intracoronary infusion of either saline (group IV [control], n = 6) or adenosine (4 mg/min from 40 to 10 minutes before occlusion [group V, n = 6]). Despite pretreatment with adenosine, the recovery of function in group V was indistinguishable from that in the control group. This study demonstrates that (1) continuous administration of adenosine before, during, and after ischemia results in a significant and sustained attenuation of myocardial stunning; (2) this improved recovery of function cannot be attributed to nonspecific variables, such as collateral flow during coronary occlusion, coronary flow after reperfusion, or other hemodynamic factors, and therefore reflects a direct cardioprotective action of adenosine; (3) the protection against stunning is lost or markedly diminished if adenosine is given only at reperfusion; and (4) administration of adenosine before ischemia does not precondition the myocardium against the stunning induced by a 15-minute occlusion.(ABSTRACT TRUNCATED AT 400 WORDS)
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Circulation research · Oct 1994
Comparative StudyKetanserin inhibits depolarization-activated outward potassium current in rat ventricular myocytes.
Ketanserin (KT), an antihypertensive agent, has been shown to prolong action potential duration (APD) and QT interval and to induce torsade de pointes in some patients. We previously suggested that the prolongation of APD could be due to KT inhibition of the fast component of the delayed rectifier current (IKr) in guinea-pig myocytes. However, in other tissue such as human atrium, Purkinje fibers, epicardial cells, and rat ventricular myocytes, the transient outward potassium current (Ito) is one of the major repolarizing currents. ⋯ The inhibitory effect of KT was more prominent on charge areas of the slow component (Qs) than the fast component (Qf) of Ito (Qf = 33.2 +/- 6.2 s.pA and Qs = 235.5 +/- 7.4 s.pA for the control condition; 12.4 +/- 4.3 and 59.6 +/- 17 s.pA for KT at 40 mV; n = 4). The binding association (k) and dissociation (l) constants at 40 mV were 9.0 +/- 0.9x10(6) M-1.s-1 and 86.6 +/- 0.3 s-1, respectively. KT also blocked ISus in a dose-dependent manner with an EC50 of 11.2 mumol/L and had no significant effect on both the inward rectifier potassium current and the L-type calcium current.(ABSTRACT TRUNCATED AT 400 WORDS)
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Hypotension in septic shock is a reflection of unregulated nitric oxide (NO) production and vascular smooth muscle guanylyl cyclase activation. We examined the effect of methylene blue on lipopolysaccharide (LPS)-induced shock in anesthetized rabbits. Shock was induced with 150 micrograms/kg LPS after measurement of mean arterial pressure, platelet cGMP, and total plasma NO (nitrogen monoxide+S-nitrosothiol) content. ⋯ Thus, methylene blue restores normal arterial pressure in rabbits with septic shock. This effect is associated with persistent elevation of intraplatelet cGMP levels and normalization of total plasma NO content. These data are consistent with methylene blue-mediated inhibition of NO synthase and/or degradation of NO in this model and suggest a novel therapeutic approach to the treatment of septic shock.
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Circulation research · Feb 1994
Molecular determinants of reperfusion-induced leukocyte adhesion and vascular protein leakage.
The adherence and emigration of leukocytes have been implicated as a rate-limiting step in the microvascular dysfunction associated with reperfusion of ischemic tissues. The objective of the present study was to define the relation between leukocyte-endothelial cell adhesion and albumin leakage in rat mesenteric venules exposed to ischemia and reperfusion (I/R). Leukocyte adherence and emigration as well as albumin extravasation were monitored in single post-capillary venules using intravital fluorescence microscopy. ⋯ Platelet-leukocyte aggregates were formed in postischemic venules; the number of aggregates was reduced by antibodies against P-selectin, CD11b, CD18, and ICAM-1, but not E- or L-selectin. These results indicate that reperfusion-induced albumin leakage is tightly coupled to the adherence and emigration of leukocytes in postcapillary venules. This adhesion-dependent injury response is primarily mediated by CD11b/CD18 on activated neutrophils and ICAM-1 on venular endothelium and appears to require L-selectin-dependent leukocyte rolling.
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Circulation research · Feb 1993
Comparative StudyInhaled nitric oxide reverses pulmonary vasoconstriction in the hypoxic and acidotic newborn lamb.
We determined whether inhaling low levels of nitric oxide (NO) gas could selectively reverse hypoxic pulmonary vasoconstriction in the near-term newborn lamb and whether vasodilation would be attenuated by respiratory acidosis. To examine the mechanism of air and NO-induced pulmonary vasodilation soon after birth, we measured plasma and lung cGMP levels in the newly ventilated fetal lamb. Breathing at FIO2 0.10 nearly doubled the pulmonary vascular resistance index in newborn lambs and decreased pulmonary blood flow primarily by reducing left-to-right blood flow through the ductus arteriosus. ⋯ Four minutes after initiating ventilation with air in the fetal lamb lung, cGMP concentration nearly doubled without changing preductal plasma cGMP concentration. Ventilation with 80 ppm NO at FIO2 0.21 increased both lung and preductal plasma cGMP concentration threefold. Our data suggest that inhaled NO gas is a rapid and potent selective vasodilator of the newborn pulmonary circulation with an elevated vascular tone due to hypoxia and respiratory acidosis that acts by increasing lung cGMP concentration.