The influence of sympathoadrenal activation on skeletal muscle oxygen extraction during endotoxemia.

We have previously shown a direct relationship (r = .97) between the fall in arterial blood pressure and the increase in skeletal muscle oxygen extraction (MVO2) during canine endotoxemia. Since it is well known that hypotension activates the sympathetic system, the primary aim of these experiments was to determine if the increase in MVO2 during endotoxemia is a result of elevated levels of catecholamines due to increased sympathetic neural and/or humoral activity (sympathoadrenal system). Canine gracilis muscles were vascularly isolated and perfused in situ at a constant flow (6-7 ml/min/100 g). Endotoxemia was induced by a 30 min intravenous infusion of Escherichia coli endotoxin (2 mg/kg), which induced a 50% reduction in arterial pressure. Perfusion pressure, mean arterial pressure, and arteriovenous oxygen difference (a-v O2) were continuously measured. We found 1) no significant difference between the amount of O2 extracted by an innervated or a denervated muscle during endotoxemia; 2) the intra-arterial infusion of norepinephrine or epinephrine into a denervated gracilis muscle (plasma molar concentrations of; 10(-11), 10(-9), 10(-7), and 10(-5) failed to increase MVO2 to the level observed during endotoxemia; 3) pretreatment of a muscle with propranolol to block skeletal muscle beta-adrenergic receptors, did not suppress the endotoxin-induced rise in MVO2. We concluded that the increase in MVO2 seen after the administration of endotoxin is not due to either increased sympathetic nerve activity or elevated levels of circulating catecholamines. We speculate that the increased MVO2 during endotoxemia is caused by nonadrenergic mediators released by endotoxin rather than the hypotensive stimulus.

Calcium-activated potassium channel-mediated arteriolar relaxation during endotoxic shock.

The role of calcium-activated potassium (KCa) channels in the in vivo relaxation of arterioles was investigated before endotoxin shock (Pre-ENDT) and during endotoxin shock at 180 min (Post-ENDT). Diameters of 2nd and 3rd order (A2 and A3) arterioles in the left cremaster muscle of male Sprague-Dawley rats anesthetized with pentobarbital sodium were measured using videomicroscopy. Adenosine (ADO) at 534 micrograms intraarterially, topical ADO at 10(-3) M, and the endothelium-dependent agonist topical acetylcholine (ACH) at 10(-4) M significantly dilated both A2 and A3 arterioles Pre-ENDT and Post-ENDT. Topical tetraethylammonium chloride (TEA) at 1 mM blocked ADO (intraarterially and topical)-induced A2 and A3 arteriolar dilations Pre-ENDT and Post-ENDT. Arteriolar dilation to ACH was maintained Pre-ENDT, but was blocked by TEA in A2 and A3 arterioles Post-ENDT. The endothelium-independent agonist sodium nitroprusside (10(-5) M), when topically applied, caused maximal arteriolar dilation Pre-ENDT and Post-ENDT in the presence of TEA. The data show that vascular smooth muscle KCa channels are a significant factor in ADO-induced relaxation of cremaster microvessels and are not significantly affected by ENDT. The results also suggest that the mechanism for endothelium-dependent ACH vasodilation changes from a non-KCa channel-mediated mechanism Pre-ENDT to a KCa-mediated mechanism Post-ENDT.

Needle holder damage to surgical needles.

Clamping surgical needles between the jaws of needle holders with teeth markedly weaken the needles, making them prone to breakage. In contrast, clamping surgical needles between either smooth needle holder jaws or jaws embedded with tungsten carbide particles did not alter the ductility of surgical needles.

Correlation between skeletal muscle free fatty acid extraction and vascular decompensation during hemorrhagic hypotension.

The objective of this study was to determine whether or not a relationship exists between free fatty acid (FFA) extraction by skeletal muscle and onset of irreversible shock. Hind limb skeletal muscle vasculature of anesthetized dogs was surgically isolated from cutaneous tissue and subjected to a modified Wigger's hemorrhage shock protocol which was divided into five stages (I-V). Since the first signs of irreversibility began in stage II, this stage of hypovolemic hypotension was subdivided into IIa, IIb and IIc. Arterial and venous blood samples were taken during each stage for subsequent blood gas and FFA analysis. The data indicated that the onset of severe tissue ischemia and metabolic acidosis occurs concurrently with increased uptake of FFA and skeletal muscle vasodilation (decompensation). A possible physiological explanation for these observations could be related to an increased synthesis and release of PGE1. This agent has been shown by others to inhibit adrenergic neurotransmitter release causing loss of vascular tone.

Influence of cutting edge configuration on surgical needle penetration forces.

A standardized test for measuring the needle penetration forces has been developed that can be easily replicated in any laboratory. Using this test, conventional cutting edge needles utilized in the test produced lower penetration forces than reverse cutting edge needles. The lower penetration forces encountered by the conventional cutting edge needles imply that the physician should be able to handle these needles with more dexterity and precision than the reverse cutting edge needle.

Peripheral vascular adrenergic depression during hypotension induced by E coli endotoxin.

Previous studies support the concept that most vascular beds exhibit some degree of blood flow autoregulation (ie, vasodilation) in response to a fall in local perfusion pressure. However, when systemic pressure is reduced by acute hemorrhage, this vasodilation is converted to vasoconstriction. This response is due to extrinsic influences (ie, elevated adrenergic activity) which overwhelm the intrinsic autoregulatory response. The objective of the present investigation was to compare the regional vascular behavior in selected tissues (ie, skeletal muscle, skin, mesenteric and renal) during local hypotension and systemic hypotension induced by stepwise hemorrhage and endotoxin. Previously published data on local hypotension accomplished by gradual occlusion of the arterial inflow, and systemic hypotension induced by stepwise hemorrhage were compared to systemic hypotension induced by IV administration of 2 mg/kg E coli endotoxin. The pressure/vascular conductance data suggest the following: 1) Skeletal muscle, mesenteric, and renal vasculature respond to local hypotension by autoregulating while skin exhibits passive vasoconstriction; 2) all four vascular beds respond to hemorrhage by intense vasoconstriction; and 3) all four vascular beds respond to endotoxin by vasodilating. The data are compatible with the concept that endotoxin inhibits the extrinsic compensatory vasoconstrictor response to systemic hypotension in all of these vascular beds.

Cardiovascular-compensatory and decompensatory responses in rats anesthetized with pentobarbital compared to chloralose-urethane.

The data presented in these studies suggests that rats anesthetized with pentobarbital are better able to compensate for acute blood loss, but are less able to sustain the compensatory effort during hemorrhagic hypotension than rats anesthetized with chloralose-urethane. However, following reinfusion of shed blood the pentobarbital rats are better able to maintain their blood pressure.

A review of the skin and muscle hemodynamics during hemorrhagic hypotension and shock.

The primary objective of this study was to compare the hemodynamic responses in a vascular bed known to exhibit decompensation (ie, skeletal muscle) with a nondecompensating bed such as the cutaneous vascular bed during systemic and local reductions in perfusion pressure induced by hemorrhage and sequential inflow arterial occlusion. The secondary objective was to examine the mechanisms which may be responsible for skeletal muscle vascular decompensation. Systemic hypotension was produced by a stepwise hemorrhage of 5 ml/kg body weight with 5-minute intervals between bleedings. The carotid sinus impact was examined during bilateral carotid artery occlusion. The intrinsic effects were evaluated during reductions in local perfusion pressure. The data show that skeletal muscle vasculature exhibits autoregulation but skin vasculature does not. Both vascular beds respond to acute hemorrhage by vasoconstriction; however, the vasoconstriction in the skin occurs as a result of increased plasma levels of catecholamines acting on alpha receptors with no neural component, whereas the vasoconstriction in skeletal muscle occurs as a result of both neural and humoral hyperactivity. The data presented also suggest that the skeletal muscle vascular decompensation occurring late in shock is the result of prostaglandin inhibition of a hyperactive sympathetic nervous system.

Oxygen extraction and vascular dilation are dependently increased in skeletal muscle during canine endotoxemia.

The principal aim of these experiments was to evaluate the ability of a skeletal muscle to extract oxygen during endotoxemia, and determine if the decompensatory decrease in skeletal muscle vascular resistance that occurs after exposure to endotoxin is related to muscle oxygen uptake (VO2). A vascularly isolated denervated canine gracilis muscle was perfused in situ at a constant flow (5-7 mL/min/100 g). Endotoxemia was induced by a 30-min intravenous infusion of Escherichia coli endotoxin (2 mg/kg). Perfusion pressure and arteriovenous oxygen difference (a-v O2) were continuously measured, and muscle O2 extraction was calculated (VO2 = flow x a-v O2). These studies found that gracilis muscle oxygen uptake increased from a resting value of 0.30 mL O2/min/100 g to 0.63 mL O2/min/100 g (111% increase) by 90 min post-endotoxin. The arterial conductance (i.e., arterial dilation) increased 58% during this time. The amount of oxygen the muscle extracts was found to be directly related to the degree of vasodilation (r = .97), and inversely correlated to mean arterial pressure (r = .97). Pre-dilating the muscle with sodium nitroprusside did not alter oxygen extraction. However, after the introduction of endotoxin, a pre-dilated muscle increased VO2 94% by 90 min. These observations support the concept that endotoxin causes an increase in VO2 without producing a defect in the ability of muscle to extract oxygen. The vasodilation typically observed in skeletal muscle during endotoxemia is not the cause of the increased oxygen uptake. It seems likely that mediators released by endotoxin metabolically stimulate skeletal muscle cells, which increases oxygen demand, thus promoting vasodilation.

Endotoxin induces metabolic dysregulation of vascular tone.

The goals of this study were to determine 1) if endotoxin alters vascular responsiveness to metabolic stimuli and 2) if the decompensatory loss of skeletal muscle vascular tone that occurs during endotoxemia is induced by increased muscle metabolism. Vascularly isolated and denervated canine gracilis muscles were perfused in situ at a constant flow. In the first set of experiments, gracilis muscle O2 extraction (MVO2) and perfusion pressure were continuously measured during direct electrical stimulation of the muscle mass. Endotoxemia was induced by a 30-min intravenous infusion of Escherichia coli endotoxin (2 mg/kg), and the stimulations were repeated 60 min postendotoxemia. Compared with the nonendotoxic control, the endotoxemic muscle stimulation resulted in a decreased MVO2, and the vascular response (dilation) was potentiated. In the second set of experiments, the MVO2 of the experimental muscle (GMe) was lowered by cooling the temperature of the blood perfusing the muscle to 22-24 degrees C while maintaining the temperature of the contralateral control muscle (GMc) at 34-35 degrees C. After the administration of endotoxin, arterial pressure fell and the GMc showed a progressive increase in MVO2 and loss of vascular tone (decompensation). Coincidently, the GMe showed no significant change in MVO2 and did not vasodilate. The major findings of this study are 1) endotoxin induces the vasculature to become more reactive to metabolic vasodilation, and 2) the decompensatory vasodilation typically observed during endotoxemia can be abolished if MVO2 (i.e., metabolism) is kept low by cooling the muscle. The data suggest that endotoxemia increases vascular sensitivity to vasodilatory metabolites, which allows local mechanisms to dominate extrinsic nonneural forces and control vascular tone, thus inducing vasodilation.

Cardiovascular adrenoreceptor function during compensatory and decompensatory hemorrhagic shock.

Prior reports by Dr. Bond [1] have described the occurrence of an initial compensatory vasoconstriction followed by a decompensatory vasodilation response in animals that progress to irreversible shock induced by blood loss. Further analysis suggests that the secondary vascular decompensation is the result of sympathetic inhibition of adrenergic neurotransmission. The primary purpose of the present studies was to elucidate the roles of the alpha 1 and alpha 2 adrenoreceptors during initial compensatory and secondary decompensatory phases of hemorrhagic shock. This was accomplished by subjecting rat pairs to a modified Wiggers hemorrhagic shock protocol. One of these rats served as an untreated control (Rc) while the other (Re) received either an adrenergic antagonist or was bilaterally adrenal medullectomized 1-2 days prior to induction of shock. The adrenergic antagonists were: (1) propranolol, a nonspecific beta blocker; (2) phenoxybenzamine, a nonspecific alpha blocker; (3) tiodazosin, a specific alpha 1 blocker; and (4) yohimbine, a specific alpha 2 blocker. The results of these studies suggest that the beta receptors do not play a major role in either the compensatory or decompensatory response. Specific blockade of the alpha 2 adrenoreceptors accentuates decompensation by approximately 35%, while blockade of the alpha 1 adrenoreceptors may offer some degree of protection against the vascular decompensatory processes. These data support the conclusion that the extrasynaptic alpha 2 adrenoreceptors are better able to maintain the vascular compensatory effort than the alpha 1 adrenoreceptors.

Vascular adrenergic interactions during hemorrhagic shock.

The objective of this paper is to review the sequence of vascular events that follows severe hemorrhage. The initial cardiovascular imbalance is a fall in the volume/vascular capacity relationship that leads to reductions in cardiac output and mean arterial pressure (MAP). Peripheral sensors detect the fall in MAP and changes in blood chemistry that cause withdrawal of the normal inhibitory tone from the cardiovascular control centers in the central nervous system. The resulting increased sympathetic activity initiates a series of events that include stimulation of peripheral adrenergic nerves and the adrenal medulla. The magnitude of the compensatory vasoconstriction that follows is the net result of the interaction of the epinephrine (E) from the adrenal medulla and norepinephrine (NE) from the peripheral nerves on the peripheral vascular adrenoreceptors as well as other nonadrenergic mechanisms not discussed here (i.e., angiotensin endogenous opiates). By using pharmacological blocking agents, these adrenoreceptors have been subclassified as: innervated postsynaptic alpha 1; presynaptic alpha 2 (Ps alpha 2); and extrasynaptic alpha 2 (Es alpha 2) adrenoreceptors. The action of E and NE on the alpha 1 and Es alpha 2 receptors initiates the compensatory vasoconstriction, whereas action of these catecholamines on the Ps alpha 2 located on the presynaptic membrane inhibits further release of NE from peripheral nerve terminals, thereby reducing the effect of the innervated alpha 1 receptors. This autoinhibition together with a similar action by prostaglandin E on NE release is thought to be, at least in part, responsible for the vascular decompensation known to occur in the skeletal muscle after hemorrhage. Thus, one of the factors determining survival after hemorrhage may be related to the relative dominance of alpha 1 and Es alpha 2 receptors during the initial compensatory response.

Alpha 1- and alpha 2-adrenoreceptor relationships in SHRs during hypotension.

Previous studies have suggested that spontaneously hypertensive rats (SHRs) are less able to tolerate the cardiovascular stress of hemorrhagic hypotension than normotensive WKYs. The present studies were designed to determine whether or not this deficiency on the part of the SHRs is related to a genetically derived inappropriate balance between the alpha 1- and alpha 2-adrenoreceptors in the peripheral vasculature. To answer this question, SHRs were divided into untreated controls and experimental rats, which were pretreated with either the relatively specific alpha 1-antagonist prazosin or the alpha 2-antagonist yohimbine. In another series, the adrenal medullae were removed 2-3 days before hemorrhage. The data indicate that alpha 1-receptor blockade might offer some degree of protection to SHRs subjected to hemorrhagic hypotension, whereas inhibition of the alpha 2-adrenoreceptors proved detrimental. We conclude that the innervated alpha 1-adrenoreceptors play a more dominant role in SHR blood pressure regulation than the extrasynaptic alpha 2-adrenoreceptors but that these alpha 1-receptors are unable to maintain the compensatory vasoconstrictor response as effectively as the alpha 2-adrenoreceptors.

The influence of hypertension upon the normal cardiovascular responses to hemorrhagic hypotension and shock.

The data suggest that rats genetically inbred to be hypertensive (SHR) are less able to compensate for hemorrhage and shock than their normotensive controls (WKY). Two reasons for this genetic dysfunction are: 1) SHRs seem to depend more on innervated alpha 1 than noninnervated alpha 2 adrenoreceptors for vasoconstriction; and 2) the vascular smooth muscle hypertrophy noted in SHRs may interfere with effective vasoconstriction.

Cardiovascular adrenoreceptor balance during hemorrhagic hypotension and shock.

The primary aim of this study was to examine the hypothesis that the ability of the cardiovascular system to compensate for hemorrhagic hypotension is controlled by a balance between the relative influence of the alpha 1 and extrasynaptic alpha 2 adrenoreceptors. Previous studies have implied that, although both receptors participate in the baroreceptor response to hypotension, only the extrasynaptic alpha 2 receptors are able to maintain the compensatory vasoconstrictor effort for a prolonged period of time. In each experiment two Sprague-Dawley rats were anesthetized and subjected to a modified Wiggers hemorrhagic shock protocol. One rat in each pair was pretreated with either 25 mg/kg of the cyclooxygenase inhibitor sodium meclofenamate or 0.5 mg/kg of the selective alpha 1 antagonist prazosin. The results indicate that neither drug interfered with the normal maximum compensatory effort as defined by the maximum blood loss (ie, reduced total vascular capacitance) when mean arterial pressure (MAP) was reduced to 30 mmHg by hemorrhage. In fact, when normalized for pre-hemorrhage MAP, it was apparent that prazosin, which lowered pre-hemorrhage MAP, may have actually improved the compensatory response. Sodium meclofenamate increased the time to reach the maximum compensatory effort (comp time), while prazosin increased the time to reach 20% uptake from the blood reservoirs (decomp time). Since both drugs enhanced the total time (comp + decomp) and both are known to interfere with alpha 1 function, these studies support the hypothesis stated above.

Intrinsic versus extrinsic regional vascular control during hemorrhagic hypotension and shock.

An analysis of both intrinsic (eg, autoregulatory) and extrinsic adrenoreceptor regulation of the vascular smooth muscle within skeletal muscle (SM), cutaneous (C), and mesenteric (M) tissues obtained during local tissue hypotension (LH), hemorrhagic hypotension (HH), and shock (S) is presented. A series of pressure/conductance curves show that the intrinsic regulation of vascular tone remains down to LH values of 40 mm Hg in M to 60 mm Hg in SM and does not occur in C; all three vascular beds respond to HH by exhibiting strong extrinsic vasoconstriction, the elevated tone persists throughout HH in C but lasts only a few minutes in M while SM vasoconstriction may last up to 45 min; and during the terminal phase of S, vascular tone was best maintained in C. In vitro studies suggest that the prehemorrhage alpha 1 adrenoreceptor control is greatest in M and least in SM. During compensatory and early decompensatory HH, alpha 1 receptors are depressed in SM. M vessels show this alpha 1 receptor hyposensitivity only during compensatory HH. All vessels show strong responsiveness to NE during all stages of HH and S, yet M vessels demonstrate a progressive increase in the NE concentrations required to elicit and ED50, suggesting some degree of adrenoreceptor desensitization or down regulation. This is in contrast to the adrenoreceptor hypersensitivity noted in SM during both compensatory and decompensatory stages. C vessels show this pattern in all stages except S. These data verify that each vascular bed has its own unique set of vascular control mechanisms that can act independently during HH and S.