Abnormal Vascular Tone Research Articles

Platelet Activation Is Linked to the Severity of Pulmonary Hypertension in Sickle Cell Disease and Normalizes on Sildenafil Therapy.

Pulmonary hypertension (PHT) is a severe complication of sickle cell disease (SCD) characterized by abnormal vascular tone, vascular proliferation and thrombosis, associated with chronic hemolysis, and nitric oxide (NO) consumption by cell-free hemoglobin. Since platelets are central to the development of large-vessel thrombosis, and increased platelet activation has been described independently in patients with primary PHT and in patients with SCD, we sought to define the degree of platelet activation in SCD patients with secondary PHT. We hypothesized that the degree of platelet activation may be linked to the severity of PHT, hemolytic rate and NO bioavailability; conversely, platelet activation may decrease with therapy directed to PHT by increasing NO-dependent signaling. We obtained blood samples from SCD patients with PHT (n=16) and without PHT (n=17) during steady state (not in pain crisis). PHT was defined by a tricuspid regurgitant jet (TRjet) velocity >= 2.5 m/sec by Doppler echocardiography. Platelet activation was measured by the flow cytometry detection of activated fibrinogen receptors (activated GPIIb/IIIa) and surface expression of P-Selectin. The mean percentage of platelets with activated GPIIb/IIIa was 10.3 ± 1.8%( mean ± SEM) for non-PHT SCD patients vs. 27.2 ± 4.7% for PHT SCD patients (p = 0.001). The percentage of platelets positive for P-Selectin was 2.0 ± 0.8% for non-PHT SCD patients vs. 5.1 ± 2.5% for PHT SCD patients (p = 0.02). The percentage of activated platelets strongly correlated with TR jet velocities (r = 0.63 and p = 0.0006). (Figure 1) In addition, the percentage of activated platelet correlated to surrogate markers of hemolysis LDH and reticulocyte count. This link may not prove causation but it suggests a common pathophysiology. Nitric oxide plays a central role in vascular homeostasis by regulating vascular tone and platelet activation through the generation of cyclic guanosine 5′-monophosphate (cGMP). It is possible that decreased NO bioavailability is responsible for both pulmonary vasculopathy and platelet activation. Our pilot studies indicate sildenafil, which enhances NO responsiveness by promoting the accumulation of its downstream mediator cGMP, may be useful in treating PHT.To verify the effect of this therapy on the degree of platelet activation, we studied a group of 12 SCD patients receiving sildenafil. Platelet activation was determined from blood samples obtained before and after (120–150 minutes) a single dose of 100 mg. of sildenafil. The mean percentage of activated platelets was higher before than after sildenafil; for activated GPIIb/IIIa 31.2 ± 4.7% vs. 17.1 ±3.9% (p = 0.001); for P-Selectin 6.3 ± 1.6% vs. 3.2 ±0.6% (p = 0.11).Our findings show for the first time the association of platelet activation and pulmonary hypertension in SCD. Furthermore, by demonstrating that platelet activation of SCD patients with PHT is decreased by sildenafil, a drug that potentiates the effects of NO, this work suggests a common pathophysiology. Additional research is needed to define whether platelet activation plays a role in the thrombo-vascular events that characterize PHT.

Simvastatin Improved Arterial Compliance in High-Risk Patients

Reduced arterial compliance is associated with arteriosclerosis. In some arteries, this is due in part to abnormal vascular tone, which can be altered by low-density lipoprotein (LDL) cholesterol reduction and statin therapy. We tested the effectiveness of statin therapy in improving arterial compliance in patients with manifest coronary disease (CAD) and/or diabetes. Simvastatin (40 mg/day) was administered to 10 patients with proven CAD for 4 months. As measured by air plethysmography, compliance of the arterial segments in the thigh improved in every patient after 2 months, increasing by 34% by the fourth month. Compliance at the calf was not affected. These results suggest that compliance in the thigh is controlled by smooth muscle tone. Compliance measurements in the thigh and calf may be a useful measurement in evaluating high-risk patients and monitoring cholesterol-lowering therapy.

Nitric oxide and the hyperdynamic circulation in cirrhosis: is there a role for selective intestinal decontamination?

Abnormal vascular tone is responsible for many of the complications seen in cirrhosis making the identification of the pathophysiology of abnormal dilatation a major focus in hepatology research. The study of abnormal vascular tone is complicated by the multiple vascular beds involved (hepatic, splanchnic, peripheral, renal and pulmonary), the differences in the underlying cause of portal hypertension (hepatic versus pre-hepatic) and the slow evolution of the hyperdynamic state. The autonomic nervous system, circulating vasodilators and abnormalities in vascular smooth muscle cells (receptors, ion channels, signalling systems and contraction) have all been implicated. There is overwhelming evidence for an overproduction of NO (nitric oxide) contributing to the peripheral dilatation in both animal models of, and in humans with, cirrhosis and portal hypertension. This review focuses on the proposal that endotoxaemia, possibly from gut-derived bacterial translocation, causes induction of NOS (NO synthase) leading to increased vascular NO production, which is the primary stimulus for the development of vasodilatation in cirrhosis and its accompanying clinical manifestations. The current controversy lies not in whether NO production is elevated, but in which isoform of NOS is responsible. We review the evidence for endotoxaemia in cirrhosis and the factors contributing to gut-derived bacterial translocation, including intestinal motility and permeability, and finally discuss the possible role of selective intestinal decontamination in the management of circulatory abnormalities in cirrhosis.

Parenteral lipids and the preterm infant: between Scylla and Charybdis

Intravenous lipid infusions are a valid option for a dense source of energy and essential fatty acids when the enteral route is unavailable. However, the use of these preparations in neonatal patients has been associated with metabolic concerns such as oxidative stress, and complications such as abnormal vascular tone, intravascular fat deposition and even fat embolism. Metabolic issues related to nutrient accretion and noxious biological reactions should be considered when prescribing parenteral lipids with high PUFA content to the critically ill newborn infant.

Increased expression of regulator of G protein signaling-2 (RGS-2) in Bartter's/Gitelman's syndrome. A role in the control of vascular tone and implication for hypertension.

Regulator of G protein signaling-2 (RGS-2) plays a key role in the G protein-coupled receptor (GPCR) angiotensin II (Ang II) signaling. NO and cGMP exert a vasodilating action also through activation and binding to RGS-2 of cGMP dependent protein kinase 1-alpha, which phosphorylates RGS-2 and dephosphorylates myosin light chain. In Bartter's/Gitelman's patients (BS/GS) Ang II related signaling and vasomotor tone are blunted. Experiments were planned to explore whether RGS-2 may play a role in BS/GS vascular hyporeactivity. NO metabolites and cGMP urinary excretion were also measured. Mononuclear cells (PBM) from six BS/GS patients and six healthy controls were used. PBM RGS-2 mRNA and RGS-2 protein were increased in BS/GS: 0.47 +/- 0.06 d.u. vs 0.32 +/- 0.04, (p < 0.006) (RGS-2 mRNA), and 0.692 +/- 0.02 vs 0.363 +/- 0.06 (p < 0.0001) (RGS2 protein). Incubation of PBM with Ang II increased RGS-2 protein in controls (from 0.363 +/- 0.06 d.u. to 0.602 +/- 0.05; p < 0.0001) but not in BS/GS (from 0.692 +/- 0.02 to 0.711 +/- 0.02). NO(2)(-)/NO(3)(-) and cGMP urinary excretion were increased in BS/GS (0.46 +/- 0.13 vs 0.26 +/- 0.05 micromol/micromol of urinary creatinine, p < 0.005, and 0.060 +/- 0.030 vs 0.020 +/- 0.01 p < 0.009, respectively). These results demonstrate that RGS-2 is increased and maximally stimulated in BS/GS and human RGS-2 system reacts as predicted by knockout mice experiments. This is the first report of RGS-2 level in a human clinical condition characterized by altered vascular tone, underlines the importance of RGS-2 as a key regulator element for Ang II signaling and provides insight into the links between BS/GS genetic abnormalities and abnormal vascular tone regulation.

High blood pressure upregulates arterial L-type Ca2+ channels: is membrane depolarization the signal?

Long-lasting Ca2+ (Ca(L)) channels of the Ca(v)1.2 gene family contribute to the pathogenesis of abnormal arterial tone in hypertension. The physiological stimulus that enhances Ca(L) channel current in the vascular smooth muscle cells (VSMCs) remains unknown. The present study investigated if high blood pressure triggers an upregulation of vascular Ca(L) channel protein. Rat aortae were banded between the origins of the left renal (LR) and right renal (RR) arteries to selectively elevate blood pressure in the proximal RR arteries. After 2 days, the immunoreactivity on Western blots corresponding to the pore-forming alpha1C subunit of the Ca(L) channel was increased 3.25-fold in RR compared with LR arteries. This finding persisted at 28 days and was associated with abnormal Ca2+-dependent tone and higher Ca(L) currents in the VSMCs exposed to high pressure. Based on microelectrode studies indicating that RR arteries were depolarized compared with LR arteries, further studies examined if membrane depolarization, an inherent response of VSMCs to high blood pressure, increased alpha1C expression. Isolated rat renal arteries were cultured for 2 days in low K+ (4 mmol/L) or depolarizing high K+ (30 mmol/L) media. Arteries preconditioned in high K+ showed a 5.47-fold increase in alpha1C expression, enhanced Ca(L) channel current, and elevated Ca2+-dependent tone. These findings provide the first direct evidence that high blood pressure upregulates the Ca(L) channel alpha1C subunit in VSMCs in vivo and suggest that membrane depolarization is a potential signal involved in this interaction that may contribute to the development of abnormal vascular tone.

Abnormal pulmonary vascular tone in canine oleic acid lung injury.

To characterize the endothelium-dependent and endothelium-independent components of abnormal pulmonary vascular tone in canine oleic acid lung injury. Prospective, interventional study. University laboratory. Twenty anesthetized mongrel dogs. Right heart catheterization was performed to measure pulmonary vascular resistance before and after induction of oleic acid lung injury in ten anesthetized and ventilated dogs. Pulmonary and internal mammary artery rings were sampled in these ten dogs with oleic acid injury and in ten anesthetized healthy control dogs. We also studied the responses to acetylcholine, to phenylephrine, and to hypoxia of the intact or endothelium-denuded rings mounted in organ baths. Oleic acid lung injury was associated with an increase in pulmonary vascular resistance from 118 +/- 11 to 245 +/- 47 dyne.sec.cm-5.m-2 and a decrease in the Pao2/Fio2 ratio from 451 +/- 42 to 139 +/- 26 mm Hg (mean +/- se, p <.05 and p <.01, respectively). Acetylcholine-induced relaxation was decreased in the oleic acid pulmonary artery rings compared with the controls (85 +/- 3% vs. 99 +/- 6% of precontraction level, p <.05). Phenylephrine-induced contraction was decreased in denuded oleic acid pulmonary artery rings compared with the controls (81 +/- 8% vs. 102 +/- 10% of contraction to KCl 120 mM, p <.05). In vitro hypoxia induced a small endothelium-dependent contraction followed by an endothelium-independent relaxation. These responses were not different in oleic acid lung artery rings and in controls, except for a decrease in hypoxic contraction in the oleic acid pulmonary artery rings. In vitro hypoxic pulmonary vasoconstriction and relaxation were, respectively, directly (r =.48) and inversely (r = -.67) correlated with oleic acid-induced increase in pulmonary vascular resistance. There was no correlation between in vitro internal mammary artery reactivity and oleic acid-induced increase in pulmonary vascular resistance. Oleic acid-induced lung injury slightly impairs pulmonary arterial endothelium-dependent relaxation and endothelium-independent contraction. In vitro hypoxic pulmonary vasoreactivity is related to in vivo oleic acid-induced increase in pulmonary vascular resistance.

Upregulation of L-type Ca2+ channels in mesenteric and skeletal arteries of SHR.

An increased Ca2+ influx attributed to dihydropyridine-sensitive L-type Ca2+ channels has been demonstrated in mesenteric vascular smooth muscle cells of spontaneously hypertensive rats (SHR). This study examined whether an upregulation of the pore-forming alpha1C subunit of the L-type Ca2+ channel underlies this ionic defect. With the use of mesenteric arcade arteries from 12- to 16-week-old SHR and normotensive Wistar Kyoto (WKY) rats, reverse transcriptase-polymerase chain reaction demonstrated an increased level of amplified cDNA corresponding to the alpha1C subunit mRNA in the SHR arteries. Western blots confirmed that the increased mRNA expression was associated with a 3.4-fold increase in the immunoreactive signal of the alpha1C subunit protein in SHR compared with WKY mesenteric arteries, and immunocytochemistry confirmed this abnormality at the single-cell level. Finally, isolated mesenteric arteries from SHR were highly reactive to Bay K8644 and developed anomalous Ca2+-dependent tone, suggesting a functional role for alpha1C subunit upregulation in vascular hyperreactivity. To determine if these Ca2+ channel abnormalities extended to the SHR skeletal muscle bed, we repeated a similar series of studies in WKY and SHR hind limb arteries. Skeletal muscle arteries from SHR also expressed higher levels of alpha1C subunit mRNA and protein than WKY arteries and developed anomalous Ca2+-dependent tone attributed to L-type Ca2+ channels. Our data provide the first evidence that the alpha1C subunit mRNA and protein are upregulated in SHR arteries and that the increased numbers of L-type Ca2+ channel pores are associated with the generation of abnormal vascular tone.

Cotyledon and binucleate cell nitric oxide synthase expression in an ovine model of fetal growth restriction.

Heat exposure early in ovine pregnancy results in placental insufficiency and intrauterine growth restriction (PI-IUGR). We hypothesized that heat exposure in this model disrupts placental structure and reduces placental endothelial nitric oxide synthase (eNOS) protein expression. We measured eNOS protein content and performed immunohistochemistry for eNOS in placentas from thermoneutral (TN) and hyperthermic (HT) animals killed at midgestation (90 days). Placental histomorphometry was compared between groups. Compared with the TN controls, the HT group showed reduced delivery weights (457 +/- 49 vs. 631 +/- 21 g; P < 0.05) and a trend for reduced placentome weights (288 +/- 61 vs. 554 +/- 122 g; P = 0.09). Cotyledon eNOS protein content was reduced by 50% in the HT group (P < 0.03). eNOS localized similarly to the vascular endothelium and binucleated cells (BNCs) within the trophoblast of both experimental groups. HT cotyledons showed a reduction in the ratio of fetal to maternal stromal tissue (1.36 +/- 0.36 vs. 3.59 +/- 1.2; P< or = 0.03). We conclude that eNOS protein expression is reduced in this model of PI-IUGR and that eNOS localizes to both vascular endothelium and the BNC. We speculate that disruption of normal vascular development and BNC eNOS production and function leads to abnormal placental vascular tone and blood flow in this model of PI-IUGR.

Reduced Na-K pump but increased Na-K-2Cl cotransporter in aorta of streptozotocin-induced diabetic rat.

The activities of Na-K-ATPase and Na-K-2Cl cotransporter (NKCC1) were studied in the aorta, heart, and skeletal muscle of streptozotocin (STZ)-induced diabetic rats and control rats. In the aortic rings of STZ rats, the Na-K-ATPase-dependent (86)Rb/K uptake was reduced to 60.0 +/- 5.5% of the control value (P < 0.01). However, Na-K-ATPase activity in soleus skeletal muscle fibers of STZ rats and paired control rats was similar, showing that the reduction of Na-K-ATPase activity in aortas of STZ rats is tissue specific. To functionally distinguish the contributions of ouabain-resistant (alpha(1)) and ouabain-sensitive (alpha(2) and alpha(3)) isoforms to the Na-K-ATPase activity in aortic rings, we used either a high (10(-3) M) or a low (10(-5) M) ouabain concentration during (86)Rb/K uptake. We found that the reduction in total Na-K-ATPase activity resulted from a dramatic decrement in ouabain-sensitive mediated (86)Rb/K uptake (26.0 +/- 3.9% of control, P < 0.01). Western blot analysis of membrane fractions from aortas of STZ rats demonstrated a significant reduction in protein levels of alpha(1)- and alpha(2)-catalytic isoforms (alpha(1) = 71.3 +/- 9.8% of control values, P < 0.05; alpha(2) = 44.5 +/- 11.3% of control, P < 0.01). In contrast, aortic rings from the STZ rats demonstrated an increase in NKCC1 activity (172.5 +/- 9.5%, P < 0.01); however, in heart tissue no difference in NKCC1 activity was seen between control and diabetic animals. Transport studies of endothelium-denuded or intact aortic rings demonstrated that the endothelium stimulates both Na-K-ATPase and Na-K-2Cl dependent (86)Rb/K uptake. The endothelium-dependent stimulation of Na-K-ATPase and Na-K-2Cl was not hampered by diabetes. We conclude that abnormal vascular vessel tone and function, reported in STZ-induced diabetic rats, may be related to ion transport abnormalities caused by changes in Na-K-ATPase and Na-K-2Cl activities.

Primary pulmonary hypertension: a vascular biology and translational research "Work in progress".

Primary pulmonary hypertension (PPH) is a syndrome of dyspnea, chest pain, and syncope defined by increased pulmonary vascular resistance and the absence of a known cause. It also occurs in a familial form, which is linked to unidentified genes on chromosome 2. This syndrome is characterized by abnormalities of pulmonary vascular biology in each compartment of the blood vessel. The lumen has a prothrombotic diathesis, the endothelium displays an excessive production of vasoconstrictors relative to vasodilators, and the smooth muscle cells are depolarized and calcium-overloaded, which is due in part to reduced expression of voltage-gated potassium channels (Kv). This causes vasoconstriction and may promote cell proliferation. The adventitia displays excessive remodeling, which is associated with exaggerated metalloproteinase and elastase activity. Conceptually, PPH seems to require a permissive genotype, a susceptible phenotype (eg, endothelial dysfunction) and, in many cases, an exogenous trigger (eg, an anorexigen). Although there is not a generally accepted, unifying hypothesis regarding its cause, impaired function and the expression of vascular and platelet Kv channels suggest PPH may be a disease of the ion channels. Abnormal matrix metalloproteinase and elastase activity could also explain the abnormal vascular tone, platelet activation, and remodeling in PPH. Although calcium-channel blockers and prostacyclin, particularly when coadministered with warfarin, improve survival, PPH has a 5-year mortality rate of approximately 50%. Pharmacological and gene therapies aimed at enhancing the activity of prostacyclin, nitric oxide synthases, and Kv channels or at inhibiting endothelin and matrix metalloproteinases are promising areas for future development.

Inhibition of Abnormal Hindquarter Vascular Tone in Spontaneously Hypertensive Rats with Chlorpromazine

The presence of an abnormal sympathetic vascular tone is assumed in the hindquarters of spontaneously hypertensive rats (SHR) on the basis that ganglionic blockade decreases hindquarter vascular resistance (HQR) in them but not in normotensive control rats (NCR). Hindquarter blood flow (HQF) was observed with an electromagnetic flow probe implanted around the terminal aorta in SHR and NCR in the conscious state. Mean arterial pressure (AP) was also recorded with an indwelling catheter. HQR was calculated as AP divided by HQF. Intravenous bolus injection of chlorpromazine-HCl at 0.5 mg/kg significantly decreased HQR in SHR but not in NCR. Thereafter, in SHR, ganglionic blockade with hexamethonium bromide did not decrease HQR further. Chlorpromazine given to SHR after ganglionic blockade did not decrease HQR either. These findings indicate that the abnormal hindquarter tone in SHR was inhibited by chlorpromazine. It is suggested that dopaminergic neurons are involved in the hindquarter sympathetic tone generation.

Nitric oxide: biological role and clinical uses.

Nitric oxide is a product of the conversion of L-arginine by the enzyme nitric oxide synthase. Nitric oxide is involved in a variety of physiological situations and is produced by many different cell types. It is involved in neurotransmission, maintenance of vascular smooth muscle tone, and cytotoxicity. Nitric oxide has been suggested to play an anti-inflammatory role by inhibiting the expression of the genes for inflammatory cytokines. The pathophysiological role of nitric oxide is also evident in a variety of diseases, including septic shock, asthma, reperfusion injury, etc. Nitric oxide, by stimulating the production of cyclic GMP, relaxes smooth muscles of the cardiovascular, respiratory, gastrointestinal, and genito-urinary systems. Recent studies have provided important information on the use of inhaled nitric oxide for the management of several diseases characterized by the presence of abnormal pulmonary vascular tone, such as persistent pulmonary hypertension of the newborn. This review addresses the biology and clinical uses of inhaled nitric oxide.

IGF-I regulation of Na(+)-K(+)-ATPase in rat arterial smooth muscle.

Insulin-like growth factor I (IGF-I) is vasodilatory and mitogenic for vascular smooth muscle cells (VSMC). Alteration in VSMC Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase) activity is hypothesized to underlie abnormal vascular tone and growth in hypertension and diabetes. Therefore, we investigated effects of IGF-I on Na(+)-K(+)-ATPase activity in rat aortic VSMC. IGF-I increases pump activity in a dose- and time-dependent manner: the minimal dose required was 10(-10) M, and the minimal time required was 20 min (at 10(-8) M) to increase activity. Similar effects persisted through 12 h. In Na(+)-loaded cells, IGF-I does not further stimulate activity. Blockade of Na+/H+ exchange attenuates IGF-I-induced increases in activity after 30 min but has no effect after 12 h. Northern blot analyses reveal that expression of the alpha 1- and the alpha 2-subunits of the pump were unaffected by IGF-I. Plasma membrane alpha 1- and alpha 2-protein were also unaffected, suggesting translocation of preformed pools was not responsible for the increases. Inhibitors revealed that neither tyrosine kinase activity, RNA transcription, protein synthesis, nitric oxide synthase activity, or protein kinase C activity mediated this IGF-I effect. Therefore, IGF-I regulates Na pump activity in the short term by an Na+/H+ exchange-dependent but transcription/translocation-independent mechanism. These data suggest that IGF-I, known to be produced by VSMC, may regulate tone and growth responses abnormal in disease states such as hypertension and diabetes.

MECHANISMS OF GAS EXCHANGE IMPAIRMENT IN PATIENTS WITH LIVER CIRRHOSIS

This article reviews the basic pathophysiologic mechanisms underlying the abnormal pulmonary gas exchange often seen in patients with cirrhosis. To summarize, the following keypoints seem appropriate: (1) Patients with cirrhosis have a low pulmonary vascular tone characterized by a poor or absent hypoxic pressor response. This results in a marked dilation of the pulmonary vasculature. (2) This abnormal pulmonary vascular tone, independently of airway disease, causes VA/Q mismatch and mild to moderate hypoxemia. Yet, as liver disease progresses and hepatocellular function deteriorates, more severe degrees of intrapulmonary shunt emerge and, probably, O2 diffusion limitation ensues, causing severe respiratory failure (see Table 1). (3) At rest, the high cardiac output and minute ventilation of cirrhosis minimize the degree of arterial hypoxemia that otherwise would be expected from the observed degree of both VA/Q inequality and intrapulmonary shunt. During exercise, the relative "normalization' (with respect to metabolic demands) of the hemodynamic and ventilatory status of the patient explains the fall in PaO2. (4) A clear pathogenic mechanism of these pathophysiologic abnormalities is still lacking, although available evidence suggests that both the liver and the endothelial cells may play a pivotal role in the regulation of the pulmonary vascular tone in these patients. (5) To date, no pharmacologic intervention has been effective in treating hypoxemia in these patients. Yet liver transplantation helps in most of them. This observation reinforces the functional nature of the gas exchange abnormalities of cirrhosis.

Pathogenesis and treatment of neonatal and postnatal pulmonary hypertension

Recent developments in basic vascular biology have provided new insights into mechanisms contributing to pulmonary hypertension and novel approaches to its treatment. Although it has long been recognized that normal vascular endothelium produces endogenous vasodilators, identification of the so-called endothelium-derived relaxing factor as a gas, nitric oxide, led to extensive studies in several experimental models of pulmonary hypertension and in various clinical settings. Endogenous nitric oxide production modulates vascular tone in the fetal and postnatal lung, and contributes to the normal decline in pulmonary vascular resistance at birth. Exogenous (inhaled) nitric oxide therapy causes potent and selective pulmonary vasodilation in neonates with severe pulmonary hypertension (ie, persistent pulmonary hypertension of the newborn), as well as in patients with pulmonary hypertension due to congenital heart disease, acute hypoxemic respiratory failure, primary or unexplained pulmonary hypertension, and other diseases. The safety and efficacy of inhaled nitric oxide therapy is currently being examined in multicenter trials. Other endothelium-derived products, such as the potent vasoconstrictor peptide endothelin, may contribute to abnormal vascular tone, reactivity, and structure in the pulmonary circulation. Basic studies of mechanisms to altered vessel growth and remodeling may lead to further therapeutic strategies for chronic pulmonary hypertension.

Septic autocannibalism. A failure of exogenous nutritional support.

Forty-six patients with surgical sepsis were studied prospectively until death or survival to evaluate the effect of exogenous metabolic support on the observed plasma substrate levels and on the differential endogenous utilization of branch chain amino acids. There were no effects of administered glucose or colloid load. The administered amino acid load had little effect on substrate levels in patients who died; but significantly effected the observed levels of glycine, isoleucine, and methionine in patients who survived. Evidence is presented which suggests that fatal sepsis is associated with an increased release of endogenous valine and isoleucine into plasma, as well as increased plasma levels of tyrosine, proline, and methionine. These abnormalities are highly correlated with the increased levels of plasma alanine and occur at a time when the nonsurviving septic patient manifests a tendency toward reduced oxygen consumption and abnormal vascular tone relations--the septic B state. These data are consistent with the hypothesis that increased muscle protein catabolism is occurring with a differential utilization of branch chain amino acids and increased use of leucine and isoleucine and reduced use of valine. This autocannibalism of muscle mass appears to be the source of the increased plasma alanine and is little influenced by administered amino acid support in the absence of control of the septic process.

Vasoconstriction and increased blood pressure in the development of accelerated vascular disease.

The pathogenesis of acute vascular lesions has been studied in two types of accelerated vascular disease. Firstly, vascular lesions were induced by a short-term (2 h) infusion of angiotensin II. Low doses of angiotensin II caused only a slight increase in blood pressure and non-destructive lesions. High doses caused a significant elevation of blood pressure and destructive vascular lesions. Secondly, in renovascular hypertension, renal vascular disease was induced by the removal of the stenosing clip from the renal artery. Incidence and severity of destructive vascular lesions were correlated with the calculated gradient between the pressure before and beyond the stenosis. Anaesthesia had a protective effect on the development of destructive vascular lesions in both models. Obviously, this effect is not related to a reduction of the systemic pressure, but rather to the suppression of abnormal vascular tone, characterized by focal constriction alternating with overdilation. Vasomotor changes, which cause a local overdilation, may be responsible for destructive vascular lesions even at normal to subnormal blood-pressure values. Destructive vascular lesions occur as a result of the exceeding of a critical wall tension. The necrosis of medial smooth-muscle cells in non-destructive lesions may be explained by an excessive contraction, which "surpasses" the metabolic capacity of the cells.

The systemic septic response: does the organism matter?

The clinical and physiological responses to septicemia were evaluated in 59 patients with 70 septic episodes. All patients were critically ill, had similar ICU support, and had positive blood cultures as well as a clinical infection when studied by dye dilution cardiac outputs. The overall ratio of gram-negative to gram-positive sepsis was 2.6:1.0. Patients with septicemia caused by gram-positive organisms, gram-negative organisms, anaerobes, and fungi had similar fever, leucocyte, and acid-base responses. There were also no statistical differences in any physiological variables between organism group or between specific organisms. After volume loading, all patients exhibited a hyperdynamic cardiovascular response with abnormal vascular tone. Some degree of myocardial depression was a common feature of all forms of bacterial or fungal septicemia. Heart rate was the cardiac variable producing the increased cardiac output in this setting. The exact pathogenesis of the septic response remains undetermined. However, the response appears to be host determined and not peculiar to a specific pathogenic microorganism.

Abnormal vascular tone, defective oxygen transport and myocardial failure in human septic shock

Abnormal vascular tone, defective oxygen transport and myocardial failure in human septic shock