H. R. Adams

Endotoxin-induced myocardial dysfunction: is there a role for nitric oxide?

Nitric oxide has been implicated in the regulation of cardiac contractile function as well as the depressed myocardial contractility associated with sepsis and endotoxemia. We examined the effects of nitric oxide synthase (NOS) inhibitors and a nitric oxide generator on contractile responses of left atrial preparations and ventricular myocytes isolated from endotoxemic guinea pigs, which exhibit depressed myocardial contractile function. The NOS inhibitor L-NAME had no effect on contractile tension developed by control atria or atria isolated from guinea pigs 4 or 16 h after an intraperitoneal injection of endotoxin. Similarly, contraction of ventricular myocytes isolated from control or endotoxemic guinea pigs (4 h after endotoxin injection) was unchanged by exposure to several NOS inhibitors. In addition, neither Ca(2+)-dependent nor Ca(2+)-independent ventricular NOS activity was affected by endotoxemia. These data suggest that nitric oxide alone is not responsible for the cardiac contractile dysfunction of endotoxemic guinea pigs.

Contractile function and myoplasmic free Ca2+ (Cam) in coronary and mesenteric arteries of endotoxemic guinea pigs

Endotoxin-induced vascular hyporesponsiveness could potentially involve alterations of vascular smooth muscle (VSM) myoplasmic free calcium (Ca(m)) mobilization mechanisms. Contractile function and Ca(m)(fura-2 microfluorometry) regulation were evaluated in vitro using coronary (COR) and mesenteric (MES) artery preparations (100-250 microm inner diameter) isolated from guinea pigs 16 h after intraperitoneal (i.p.) injection of either saline (control; CON) or Escherichia coli endotoxin lipopolysaccharide (LPS; 4 mg/kg). Concentration-response relationships to K+ (5-100 mM) were significantly enhanced in both COR and MES arteries isolated from LPS-treated animals. In contrast, contractile responses to prostaglandin F2alpha (PGF2alpha; 1-100 microM) were markedly impaired in COR and MES arteries from LPS-treated animals, while endothelin-1 (ET; 1-100 nM)-mediated contractile responses of these arteries were enhanced at the maximal dose (100 nM). In COR arteries, PGF2alpha (1-100 microM) and ET (1-100 nM) produced biphasic increases in Ca(m) in both CON and LPS groups. No significant differences were observed in either the initial transient peak or secondary sustained Ca(m) responses between groups, suggesting a lack of effect of LPS upon intracellular Ca2+ release or Ca2+ influx mechanisms in COR arteries. Exposure of MES arteries to PGF2alpha and ET produced concentration-dependent increases in Ca(m) in both groups. However, Ca(m) responses of MES arteries lacked initial peak responses, suggesting potential differences in Ca(m) mobilization between COR and MES arteries. Ca(m) responses to K+ (80 mM) and PGF2alpha (1-100 microM) were similar in MES arteries from both groups; however, ET-mediated increases in Ca(m) were significantly blunted in LPS compared with CON MES arteries. Thus, endotoxemia produced differential effects upon depolarization (K4) and receptor (PGF2alpha, ET)-mediated contractile responses in both COR and MES arteries. Reductions in VSM Ca(m) mobilization appear unlikely as a mechanism for LPS-induced impairment of contractile function of COR and MES arteries; other mechanisms (i.e., decreased Ca2+ sensitivity of contractile proteins) may be involved in effects of LPS upon VSM function of COR and MES arteries.

CHRONIC ENDOTOXEMIA AND ENDOTHELIUM-DEPENDENT VASODILATION IN CORONARY ARTERIES

ABSTRACT Endotoxin acutely decreases the production of nitric oxide, leading to abnormal regulation of coronary vascular tone; however, the effects of chronic endotoxemia on vasomotion are unknown. We therefore tested the hypothesis that chronic, low-level endotoxemia inhibits endothelium-dependent vasodilation. Rabbits were continuously infused with a subclinical dose of Escherichia coli endotoxin (.6 μg/kg/24 h, intraperitoneal) or saline for 5 wk. Endotoxin at this concentration elicited no significant sustained pyretic or hemodynamic responses. Both endothelium-dependent and independent vasomotor responses were determined in coronary arteries (250–500 μ). Vasorelaxation in response to acetylcholine, but not adenosine diphosphate (ADP), was significantly enhanced in endotoxin-challenged animals (EC50 = 62.6 ±11.1 nM, control vs. 33.97 ± 5.7 nM, endotoxin-challenged; p < .05). Vasoconstriction to PGF2±, but not KCI, was significantly decreased in endotoxin-challenged animals. These results indicate that endothelium-dependent and independent vasomotor responses are altered during chronic endotoxemia and are due, in part, to alterations in signal-transduction mechanisms specific for certain types of receptors.