Ralph P. Forsyth

Contribution of Kinins to Endotoxin Shock in Unanesthetized Rhesus Monkeys

The effects of endotoxin (Escherichia coli and Pseudomonas pseudomallei) were studied in 18 unanesthetized rhesus monkeys restrained in primate chairs. Indwelling arterial and venous catheters were used for hemodynamic measurements and blood sampling. Whole blood kinin, plasma kininogen, lysosomal enzymes, complete blood counts, and blood gas tensions were measured. Within an hour of beginning the infusion of the endotoxin, the mean arterial pressure and systemic peripheral resistance decreased significantly in the 18 experimental monkeys compared to 13 control monkeys. These early changes were associated with significant elevation in whole blood kinin concentration and a decrease in plasma kininogen. All of these early changes were most marked in the animals that died. Granulocytopenia occurred within 15 minutes, and the concentration of free lysosomal enzyme in the plasma rose 2 hours after endotoxin infusion. The preterminal phase of shock was characterized by a low peripheral vascular resistance and decreasing cardiac output without elevation of kinin levels. These findings support the hypothesis that kinins play a pathogenetic role in the early phase of endotoxin-induced shock and that the severity of the early phase may influence the animals survival. The relation of kinins to other vasoactive substances released after endotoxin-induced shock is unknown.

Lidocaine disposition kinetics in monkey and man; II. Effects of hemorrhage and sympathomimetic drug administration

Lidocaine disposition kinetics in normal and hemorrhaged rhesus monkeys was studied. During bleeding there was a reduction in distribution and clearance of lidocaine, along with an increase in half‐life, which was similar to that in human patients with congestive heart failure. In the monkey in shock there was impaired liver extraction of lidocaine. Sympathomimetic drugs, such as isoproterenol and norepinephrine, which influence hepatic blood flow, markedly altered clearance and steady‐state lidocaine concentrations in blood. A perfusion model that simulates blood and tissue levels during hemorrhage in monkey and man by using blood flow measurements during hemorrhagic shock is reported here. This perfusion model allowed a quantitative understanding of the interaction between lidocaine and sympathomimetic drugs and may be clinically useful in man simultaneously receiving a variety of cardioactive drugs ill suggesting appropriate ad;ustments of the dosages of the most critical drugs used.

Redistribution of Cardiac Output during Hemorrhage in the Unanesthetized Monkey

Regional flow measurements were made, using the Rudolph and Heymann microsphere technique, before and after 10, 30, and 50% of the previously measured blood volume was withdrawn from five unanesthetized rhesus monkeys restrained in horizontally tilted primate chairs. Measurements at similar time intervals were also made in seven control monkeys. Systemic arterial and central venous pressures, cardiac output, stroke volume, and hematocrit decreased progressively at each level of bleeding. Heart rate (until severe hemorrhage), respiratory rate, and blood levels of α-glucosidase rose; bradykinin levels in arterial blood were unchanged. The fraction of cardiac output was found to be progressively increased to brain, heart, adrenal gland, and hepatic artery vascular bed at the expense of skin, spleen, and pancreas. The hepatic artery vascular bed was the only one that showed significant vasodilatation at either 30 or 50% hemorrhage. During acute endotoxin shock in monkeys, we have previously found a similar fall in systemic arterial pressure due to a decrease in total peripheral resistance and a different pattern of regional blood flow changes. The lack of bradykinin production, the integrity of cardioregulatory mechanisms, and the fall of hematocrit levels found during hemorrhage may help account for some of the hemodynamic differences between these two types of shock.

Regional Blood-Flow Changes during 72-Hour Avoidance Schedules in the Monkey

Systemic and regional blood-flow measurements were made in five restrained monkeys before and during 72 hours of continuous work on an avoidance schedule. Systemic arterial pressures were elevated throughout the stress, initially owing to an increase in cardiac output, and after 72 hours owing to an increase in total peripheral resistance. Changes in the resistance in skeletal muscle blood vessels were closely related to these changes in total peripheral resistance.

Hemodynamic Effects of Angiotensin in Normal and Environmentally Stressed Monkeys

Simultaneous regional blood flow and resistance measurements were made in 21 organs in 11 supine unanesthetized rhesus monkeys before and during two different doses of intravenously infused angiotensin II or saline. Systemic arterial pressure and total peripheral resistance significantly increased at both infusion rates in the six experimental monkeys, compared with changes in five control monkeys; cardiac output decreased at the high dose level. Among major organs, the kidneys, skin, liver (hepatic artery), and mesentery had reductions in the fraction of cardiac output they received and, thus, the greatst increase in resistance and decrease in blood flow. No organ had a significant increase in its blood flow; however, skeletal muscle and bone were normally perfused due to increases in the fraction of cardiac output they received.Four other monkeys received continuous intravenous angiotensin infusions at initially subpressor rates for periods of 26 to 30 days. There were steady increases of systemic arterial blood pressure due to a rise in total peripheral resistance which reached a plateau in about 5 days. Avoidance schedules or other environmental stresses in these angiotensin-infused monkeys produced much more marked pressor episodes than those which occur in noninfused monkeys. These observations support the hypothesis that small amounts of angiotensin can potentiate sympathetic mediated vasomotor activity.

Endotoxin-Induced Regional Circulatory Changes in the Unanesthetized Monkey

Endotoxin in eight unanesthetized monkeys produced a small decrease in cardiac output, a marked fall in blood pressure, and a decrease in total peripheral vascular resistance. The distribution of cardiac output was measured by injecting nuclide-labeled radioactive microspheres (50μ in diameter) into the left ventricle, and blood flow and vascular resistance were calculated for each organ. All vascular beds except that of the spleen reacted with variable degrees of vasodilation, and the most pronounced decreases in resistance were observed in the coronary, gastrointestinal, and adrenal vasculature. Cerebral flow was reduced, but flow was maintained in the brain stem and cerebellum. In contrast to studies in other species, both the gastrointestinal tract and the kidneys showed vasodilation and no significant decrease in flow during the early phase of endotoxemia. There is some similar evidence in humans of decreased total systemic peripheral resistance without abnormal myocardial function or pooling of blood during the early phase of endotoxemia. The acute regional circulatory changes we have found appear to indicate that endotoxin either directly or through secondary biochemical reactions initiates and maintains a generalized (except for the spleen) vasodilation that reflex compensatory mechanisms cannot overcome. This vasodilation is particularly critical in preventing maintenance of adequate blood flow to the cerebral hemispheres.

Hypothalamic control of the distribution of cardiac output in the unanesthetized rhesus monkey.

Regional organ blood flow and resistance changes evoked after 10 minutes of electrical stimulation of pressor areas in the anterior hypothalamus were studied in six unanesthetized, restrained rhesus monkeys. Five other monkeys served as controls. The regional changes produced by stimulus intensities which did not affect systemic arterial pressure, central venous pressure, cardiac output, or pulse rate were similar to those produced by the stimulations at higher levels which significantly increased the levels of these variables. With both low and high levels of stimulation the fractions of cardiac output to skeletal muscle and chest wall were increased 51 and 146% at the expense of the output to the kidneys, skin, stomach, spleen, pancreas, mesentery, and thyroid which decreased 38 to 79%. In each of two monkeys tested, the marked rise in blood flow and vasodilatation of skeletal muscle was only slightly affected by atropine. Therefore, there is at least some hypothalamic control over skeletal muscular vasodilatation in the unanesthetized monkey that is not cholinergically mediated.

Cardiovascular and Metabolic Effects of Whole or Fractionated Gram-Negative Bacterial Endotoxin in the Unanesthetized Rhesus Monkey

Rhesus monkeys were infused with endotoxin lipopolysaccharide (LPS) (10 mg/kg [LPS10] or 2.5 mg/kg [LPS2.5]) or with fractions of LPS containing 6.3% lipid (PS1) or 0.5% lipid (PS2) (2.5 mg/kg). Systemic and regional hemodynamics, leukocyte counts, blood gases, pH, and plasma bradykinin concentration were measured. Monkeys receiving LPS10, LPS2.5, or PS1 became hypotensive (mean blood pressure −37 ± 10 mm Hg) and had decreased peripheral vascular resistance (−10% to −24% of the base line), compensated metabolic acidosis, and elevated plasma bradykinin concentrations (14 ± 6 ng/ml) 2 hours after infusion. Vasodilation occurred in coronary, hepatic, and splanchnic vasculature; vasoconstriction occurred in the spleen. Cardiac output was diverted from muscle to viscera. Monkeys receiving PS2 were normotensive with elevated peripheral vascular resistance (+46%) and no measurable plasma bradykinin concentration. By 6 hours, marked elevation of peripheral vascular resistance developed in monkeys given LPS10 (+113%) and LPS2.5 (+57%). Monkeys receiving PS1 returned to base-line values, but monkeys receiving PS2 remained unchanged. Leukopenia (−50% to −65%) was persistent only in monkeys receiving LPS or PS1. Toxicity of LPS apparently depends on the lipid portions of the molecule. Vasodilation and bradykinin generation are correlated with persistent granulocytopenia. Late toxicity may be independent of early cardiovascular events.

Hemodynamic changes during complete heart block in the unanesthetized monkey

Abstract After surgically produced complete heart block, the hearts of six monkeys were paced electrically for five to eight days at their preoperative heart rates. Simultaneous measurements of regional blood flow and other hemodynamic variables were then obtained before and 15 minutes, two hours, and six hours after stopping electrical pacing and 30 minutes after restarting pacing. Fifteen minutes after stopping pacing heart rate, cardiac output, and systemic mean and diastolic pressures decreased and stroke volume increased. This pattern persisted throughout the six-hour period of idioventricular rhythm except that left ventricular end-diastolic and central venous pressures were increased only at 15 minutes and cardiac output was not significantly decreased at the six-hour period. During heart block the fraction of cardiac output received by the heart (except at six hours), brain, liver (hepatic artery), skull, spine, and adrenals was increased at the expense of skin, kidneys (initially), skeletal muscle, spleen, and pancreas. This pattern of regional redistribution of blood flow is similar to that found during hemorrhage and other conditions in which the sympathetic nervous system is stimulated. After pacing was restarted all the systemic variables measured returned to base-line levels, and the regional blood flows measured did not differ from those observed before the heart block.

Bone Marrow Blood Flow After Marrow Removal or Nutrient Vessel Ligation

Summary Studies were made of the changes in blood flow in rabbits after localized depletion of femoral marrow or nutrient vessel ligation. Our findings confirm that the nutrient artery is the principal source of flow to medullary tissue in the diaphysis of long bones. They indicate further that (i) there is a highly effective collateral circulation to the medullary cavity, (ii) marrow regeneration is associated with an increased blood flow, and (iii) normal blood flow is restored at a time when the regenerated marrow after a localized depletion is indistinguishable from normal marrow.