Effect of ibuprofen upon denervated skeletal muscle resistance and compliance vessels during endotoxemia.

The primary aim of these studies was to specifically evaluate the non-neural role of the cyclooxygenase products on the peripheral vascular decompensation associated with endotoxemia. The constant-flow perfused, vascularly isolated, denervated double-canine gracilis muscle preparation in which one muscle is used as a control for the contralateral side was employed. The experimental muscle (GMi) received ibuprofen while the control (GMc) was infused with the vehicle. The results of these studies suggest that endotoxin increases the arterial conductance (i.e., arterial dilation) by 100% and venous compliance (i.e., venoconstriction) by 40%. These observations, which are consistent with venous pooling, were not significantly altered by the continuous intra-arterial infusion of ibuprofen at a peripheral blood concentration of 160 microM. Ibuprofen caused a small but statistically significant increase in the conductance/compliance ratio at 60, 75, and 90 min post endotoxin, suggesting that cyclooxygenase products may play a minor role in the non-neural regulation of capillary fluid dynamics during endotoxemia. Consequently, these studies do not provide convincing evidence that would support a non-neural cyclooxygenase role in the peripheral vascular decompensation reported to occur during systemic endotoxemia.

Influence of histaminergic receptors on denervated canine gracilis muscle vascular tone during endotoxemia.

The purpose of this study was to determine if endogenously released histamine and its non-neural interaction with the H1- and H2-histaminergic receptors in the peripheral vasculature can account for the decompensatory loss of peripheral vascular tone associated with the hypotension occurring during endotoxemia. A denervated in situ constant flow double canine gracilis muscle preparation that permitted one muscle to serve as a control (GMc) for the contralateral experimental muscle (GMe) was used. Endotoxemia was induced by intravenous infusion of 2 mg.kg-1.30 min-1 endotoxin. The specific H1 and H2 antagonists diphen-hydramine and cimetidine were infused either together or separately in both high and low dosages into the GMe. Blockades were validated by intra-arterial injection of histamine or the specific agonists betahistine for H1 and dimaprit for H2 receptors. The results suggest that the high-dose diphenhydramine produced a nonspecific dilation not seen with the lower dose. Because both the blocked and unblocked vascular beds exhibited the same degree of vasodilation after endotoxin, these studies do not support the hypothesis that endogenously released histamine is responsible for the loss of vascular tone. These studies do verify, however, that a nonneurally mediated loss of skeletal muscle vascular tone is an important factor to consider in the overall cardiovascular hypotension occurring during endotoxin shock.

Systemic and local effects of endotoxin on canine gracilis muscle vascular conductance.

To define the site and mechanism of action that endotoxin has on the peripheral vasculature, an in situ constant-flow double-canine gracilis muscle (GM) preparation was utilized. During systemic endotoxemia, one GM was innervated and the other was denervated during a 30-min intravenous infusion of 2 mg/kg endotoxin. Significantly increased vascular conductance (URP) in the denervated GM (106 +/- 26%) occurred compared with the innervated GM (50 +/- 7%), which suggests that decompensation is not totally dependent on neural depression. During local endotoxemia, with both GMs either intact or denervated, one GM was infused intra-arterially for 30 min with a dose of endotoxin calculated to provide a blood concentration similar to that achieved during systemic endotoxemia, whereas the other GM was infused with the vehicle. The URPs did not change significantly in either the saline or endotoxin GMs. Therefore, endotoxin does not act directly on peripheral vasculature or totally through depression of the autonomic nervous system. It apparently interacts with a systemically dependent mechanism to release a vasodepressor substance that is transported to the peripheral vasculature causing relaxation of vascular tone.