We have previously described a subpopulation of patients with septic shock who had a reversible depression of radionuclide-determined left ventricular ejection fraction (EF). To investigate the mechanism of this myocardial depression, an in vitro model of mammalian myocardial cell performance was established employing primary spontaneously beating rat myocardial cells. The contraction of a single cardiac cell was quantitated by recording the changes in area occupied by the cell during contraction and relaxation. In 20 septic shock patients during the acute phase, the mean left ventricular EF was decreased (mean = 0.33, normal mean = 0.50), and serum obtained during this acute phase induced a mean (+/- standard error of the mean) 33 +/- 4% decrease in extent and 25 +/- 4% decrease in velocity of myocardial cell shortening during contraction (P less than 0.001). In contrast, serum obtained from 11 of these same patients before shock (n = 2) or after recovery (n = 9) of the left ventricular EF (mean = 0.50) showed a return toward normal in extent and velocity of shortening (P less than 0.001). Sera from 17 critically ill nonseptic patients, from 10 patients with structural heart disease as a cause for a depressed EF, and from 12 healthy laboratory personnel, induced no significant changes in in vitro myocardial cell performance. In 20 patients during the acute phase of septic shock, the decreased EF in vivo demonstrated a significant correlation (r = +0.52, P less than 0.01) with a decrease in the extent of myocardial cell shortening in vitro. The quantitative and temporal correlation between the decreased left ventricular EF and this serum myocardial depressant substance argues for a pathophysiologic role for this depressant substance in producing the reversible cardiomyopathy seen during septic shock in humans.

/pdf/a-circulating-myocardial-depressant-substance-in-humans-with-1p4j92hhvn.pdf

A circulating myocardial depressant substance in humans with septic shock. Septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell performance.

. A cardiodepressant factor (CDF) able to decrease contractile activity of cultured rat heart cells was determined to be located in the lipid-soluble fraction of sera from men in septic shock. This heat-stable CDF has a molecular weight under 1000. Repeated fractionations of sera gave evidence of an oestrone-like chromatographic behaviour.



Oestrone, oestradiol and cortisol were immunologically quantified in two groups (recovery and death) of men in septic shock. All of them were elevated in sera from patients with shock. Highest levels of oestrone 4330 pmol l-1 (SEM pL 851, n= 15), oestradiol 1030 pmol l-1 (SEM pL 220, n= 15) and cortisol 1096 pmol l-1 (SEM pL 94, n= 15), were found in patients who failed to recover from shock. However, oestrone levels were the most striking, especially in the male.



This study gives evidence for a polarity relationship between the CDF and oestrone, but natural oestrone does not appear to be a direct CDF. Moreover, this study shows that radioimmunoassay of oestrone could be an important index evaluating the severeness of septic shock.

Early released lipid-soluble cardiodepressant factor and elevated oestrogenic substances in human septic shock.

UNLABELLED: Pregnancy is associated with altered vascular reactivity. However, the effect of pregnancy on the alpha- and beta-adrenergic responses in the uterine microcirculation remains to be determined. In late-pregnant (Day 20-21, n = 6) and virgin (n = 6) Sprague-Dawley rats, uterine radial arterioles (70-120 microm in internal diameter) were isolated. We studied in vitro arteriolar responses in a pressurized, no-flow state with videomicroscopy. alpha(2)-Adrenergic activation relaxed uterine arterioles; this relaxation was increased with pregnancy and was inhibited after endothelial denudation or inhibition of nitric oxide synthase. Pregnancy significantly increased the contractile response to the alpha(1)-adrenoceptor agonist phenylephrine but decreased the relaxation to the beta-adrenoceptor agonist isoproterenol. The contractile response to the protein kinase C activator phorbol ester and relaxation responses to both the adenylate cyclase activator forskolin and the endothelium-independent cyclic guanosine monophosphate-mediated vaso- dilator nitroprusside were preserved. These results suggest that pregnancy enhances the alpha(2)-adrenoceptor-mediated relaxation of uterine arterioles, probably because of an increase in the release of nitric oxide. The alpha(1)-adrenergic response is upregulated, whereas the beta-adrenergic response is impaired, in the uterine microcirculation of pregnant rats. IMPLICATIONS: Both alpha- and beta-adrenergic responses are important mechanisms for the regulation of uteroplacental perfusion. By use of an in vitromicrovascular technique, we have shown pregnancy-associated alteration in adrenergic responses in the uterine microcirculation of the rat.

Pregnancy alters adrenergic mechanisms in uterine arterioles of rats.

The effect of sepsis on the intrinsic contractile status of the myocardium is best examined in the awake, closed-chest animal with intact circulation because anesthesia, open thoracotomy, and circulatory support are all known to affect hemodynamics. To fulfill these criteria, 18 adult dogs were chronically studied in the awake state after instrumentation with left ventricular high-fidelity pressure catheters and ultrasonic dimension transducers to measure left ventricular transmural pressure and minor axis dimension. This allowed computer assessment of the left ventricular end-systolic pressure-dimension relationship in the control state and at intervals following cecal ligation in one group of dogs. A second group of control animals was studied over variable time intervals without cecal ligation to evaluate the temporal stability and reproducibility of the animal model and the end-systolic pressure-dimension relationship. Evaluation of contractility by use of the end-systolic pressure-dimension relationship was essential because this relationship is a sensitive indicator of the intrinsic myocardial contractile state while remaining insensitive to the wide swings in preload and after load that are commonly seen in sepsis. In the control group of dogs, the temporal consistency and stability of the end-systolic pressure-dimension relationship in this model was confirmed; no significant changes in the slope and dimension-axis intercept were demonstrated over the study interval. In the septic group of dogs, however, the intrinsic myocardial contractility significantly deteriorated as the mean slope of the end-systolic pressure-dimension relationship (mmHg/mm) decreased from 16.87 +/- 0.85 to 12.79 +/- 1.67 over 120 hours following cecal ligation. Intrinsic contractility of the heart during sepsis was therefore isolated for the first time from the widely variant loading conditions seen during sepsis by pressure-dimension analyses in the chronically instrumented, awake, closed-chest canine with intact circulation.

Assessment of the intrinsic contractile status of the heart during sepsis by myocardial pressure-dimension analysis.

A supersensitivity of the beta-adrenoceptor-mediated chronotropic response has been demonstrated in atria isolated from rats subjected to septic shock. Our study was undertaken to investigate whether bacterial endotoxin/LPS affects the increase in heart rate induced by beta-adrenoceptor agonists in the rat also in vivo. In pithed and vagotomized rats, the nonselective beta-adrenoceptor agonist isoprenaline (0.05-0.15 nmol/kg) and agonists at the high- and low-affinity state of beta1-adrenoceptors, that is, prenalterol (0.3-3 nmol/kg) and (+/-)-4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazole-2-one (CGP 12177; 3-6 nmol/kg), respectively, and at beta2-adrenoceptors, that is, fenoterol (1-5 nmol/kg), increased heart rate by 50 to 60 beats/min. Administration of LPS (0.4, 1, and 1.5 mg/kg), under continuous infusion of vasopressin, dose-dependently amplified the chronotropic response to isoprenaline, prenalterol, and fenoterol (by 80%, 50%, and 100%, respectively) but not to CGP 12177. The beta2-adrenoceptor antagonist erythro-(+/-)-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol (ICI 118551 0.1 mumol/kg) did not affect the chronotropic responses of isoprenaline, fenoterol, and prenalterol under non-endotoxic conditions, but abolished the potentiation of tachycardia produced by LPS (1.5 mg/kg). The beta1-adrenoceptor antagonist (+/-)-2-hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]-phenoxy]propyl]-amino]ethoxy]-benzamide CGP 20712A; 0.1 mumol/kg almost completely reduced the chronotropic effects of isoprenaline, fenoterol, and prenalterol both in control rats and in animals exposed to LPS (1.5 mg/kg). We conclude that LPS sensitizes cardiac beta-adrenoceptors by recruiting functionally active beta2-adrenoceptors, but the amplification of tachycardia occurs only when both beta1- and beta2-adrenoceptors are concomitantly activated. The pithed rat may serve as a model to examine the beta-adrenoceptor supersensitivity in vivo.

Recruitment of functionally active heart β2-adrenoceptors in the initial phase of endotoxic shock in pithed rats

Human serum, obtained within 24 hours after the onset of septic shock, was evaluated for its effects on the chronotropic response of cultured rat myocardial cells to isoproterenol. Transmembrane action potential (AP) was measured in some experiments. Sera obtained after the first four to five hours, when central venous pressure (CVP) was normal or high, inhibited increased cell beats, while this property was not evidenced for samples taken soon after septic shock when CVP was low. Sera were also found to alter AP in much the same way as Sotalol, an adrenergic beta-blocking drug. These two effects were never observed with control sera obtained from healthy male adults at rest. These findings demonstrate that sera from patients in septic shock depress the beta-adrenergic response of rat myocardial cells, after the early phase of septic shock characterized by sympathoadrenergic activity. They strongly suggest the mediation of unidentified humoral factors, which might interfere in the pathogenesis of myocardial dysfunction during the intermediate phase of septic shock.

Inhibited response to isoproterenol and altered action potential of beating rat heart cells by human serum in septic shock.

Cultures of beating rat myocardial cells brought into contact with various human sera during 24 hours were infused with isoprenaline. The isoprenaline-induced positive chronotropic effect (IIPCE) was not found with all sera. IIPCE was present in all the male sera, but was absent in the cases of clinically beta-blocked pindolol treated men. IIPCE was present only in about 50% of the female sera, menopaused or not. IIPCE was absent in 95% of the sera of pregnant women in the late phase of pregnancy. This suggests the presence in female sera, especially during pregnancy, of a circulating factor capable of "in vitro" inhibition of isoprenaline-induced positive chronotropic effect.

Inhibitory action of human serum on the isoprenaline-induced chronotropic effect in cultured rat heart cells. Influence of sex and pregnancy.

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Inhibited response to isoproterenol and altered action potential of beating rat heart cells by human serum in septic shock.

Inhibitory action of human serum on the isoprenaline-induced chronotropic effect in cultured rat heart cells. Influence of sex and pregnancy.