Lung protection against paraquat is calcium dependent.

Isolated, perfused, and ventilated rat lungs were challenged by paraquat (0.01 M) in the presence of 2.5 mM Ca2+, 2.5 mM Ca2+ with trifluoperazine (100 microM), 0.025 mM Ca2+, or 0.025 mM Ca2+ with sodium metavanadate (10 microM) to establish the effect of varying calcium concentration or calcium-dependent enzyme activities on injury induced by paraquat. Segmental vascular resistances, microvascular permeability (as assessed by the capillary filtration coefficient), lung tissue oxidized glutathione, and lung paraquat accumulation were measured. Exposure to paraquat for 2.5 h did not increase microvascular permeability or pulmonary vascular resistance in the presence of either normal extracellular calcium or low extracellular calcium and sodium metavanadate. Lungs exposed to paraquat were injured (as assessed by increased filtration coefficient) only in the presence of low extracellular calcium or after trifluoperazine was added. This injury was associated with decreased levels of oxidized glutathione and increased paraquat accumulation, suggesting that calcium's protective effect was both by inhibition of paraquat accumulation and maintenance of NADPH. Pulmonary vascular resistance was not increased with paraquat challenge.

Villous motility and unstirred water layers in canine intestine.

The possibility that villous motility reduces the mucosal unstirred water layer by mechanical stirring was examined. The frequency of contraction of villi was measured by using videomicroscopic techniques while a segment of anesthetized canine jejunum or ileum with its nerve and blood supply intact was maintained in a sealed chamber through which Tyrode solution was perfused. Radioisotopically labeled inulin, H2O, and butyric and lauric acid were used to measure net and/or unidirectional fluxes from the chamber. The unidirectional absorptive transport of H2O and butyric acid but not lauric acid by jejunal segments was significantly correlated with flow through the chamber. Plasma volume expansion increased villous motility but decreased the absorption of H2O and lauric acid. Absorption of butyric acid from the ileum was little different than from the jejunum although the degree of villous motility was less and net water absorption was greater from the ileum. Absorption of butyric acid into dead tissue indicated that passive diffusion into the tissue accounted for between 7 and 25%, depending on flow rate, of the absorption in intact tissue and that nonspecific binding was low. It was concluded that villous motility did not stir the unstirred water layers and was not directly associated with altered transport.

Neurohumoral control of villous motility.

A quantitative videomicroscopic method was used to examine neurohumoral control of villous motility. Intraduodenal instillation of saline, 0.4% hydrochloric acid, or acidified predigested food did not cause a significant change in villous contraction frequency in an isolated segment of jejunum. Villous motility in the jejunum of fed dogs, from which the chyme had been removed, was not greater than that in fasted dogs (2.9 +/- 0.3 vs. 3.4 +/- 0.5 contractions/min). Furthermore, acid extracts of the duodenal mucosa did not produce an increase in jejunal villous motility when injected intravenously. These data argue against the existence of a humoral stimulant of villous motility (villikinin). Vagotomy caused only a small (20%) and transient (10 min) decline in villous motility. Vagal stimulation at 5, 10, and 20 Hz caused villous motility to increase by 24 +/- 7, 23 +/- 9, and 32 +/- 10%, respectively. Atropine blocked the effects of vagal stimulation. Section of the periarterial (sympathetic) nerves did not alter villous contractile activity. Stimulation of the periarterial nerves at 5, 10, and 20 Hz caused villous contraction frequency to decline by 41 +/- 5, 45 +/- 5, and 38 +/- 10%, respectively. This inhibition appears to involve both alpha- and beta-adrenergic receptors and a reduction in blood flow. Neither atropine, alpha-blockade, nor beta-blockade produced a sustained alteration in basal contraction frequency.

Villous motility: relationship to lymph flow and blood flow in the dog jejunum.

Villous contraction frequency, lymph flow, blood flow, and arteriovenous oxygen difference were measured in dog jejunum. Venous pressure elevation and plasma dilution were used to increase capillary fluid filtration. Both perturbations produced concomitant increases in villous contraction frequency and lymph flow. A highly significant correlation (r = 0.83, p less than 0.001) was obtained between villous contraction frequency and lymph flow. This finding, coupled with the observation that stimulation of net fluid absorption increases villous contraction frequency, suggests that villous motility is increased by a myogenic response elicited by increments in interstitial fluid pressure. In another series of experiments local arterial pressure was reduced in 20-mmHg steps from 120 to 20 mmHg. Although blood flow fell proportionately to arterial pressure, villous contraction frequency and oxygen uptake were maintained at a normal level when arterial pressure was between 120 and 60 mmHg. Villous motility and oxygen consumption fell progressively as arterial pressure was reduced below 60 mmHg. This observation indicates that ischemia does not alter villous contraction frequency unless blood flow is reduced below the level necessary to maintain normal tissue oxygenation.

Importance of collateral circulation in the vascularly occluded feline intestine.

The aim of this study was to assess the extent of collateral blood flow provided by the celiac and inferior mesenteric arteries to the intestines during total occlusion of the superior mesenteric artery (SMA). In anesthetized cats, blood flow to the pancreas, duodenum, jejunum, ileum, and colon was measured with radioactive micropheres (15 microns in diameter) before and during occlusion of the SMA. Superior mesenteric artery occlusion significantly decreased (by 63%) blood flow to the head of the pancreas. Flow to the neck and tail of the pancreas was not altered. Blood flow to the proximal and distal duodenum was significantly reduced by 35% and 61%, respectively. Along the entire jejunum and ileum, SMA occlusion markedly decreased blood flow by an average of 71%. In the proximal colon, blood flow decreased by 63%, whereas flow to the middle and distal colon was not affected by SMA occlusion. Reduction in total wall blood flow to the small and large intestines was largely due to a marked reduction in mucosa/submucosa blood flow; muscularis/serosa flow was not affected. The results of this study suggest that total occlusion of the SMA does not compromise blood flow to the neck and tail of the pancreas and middle and distal colon (tissues that are normally perfused with blood from either the celiac or inferior mesenteric arteries). Perfusion through collaterals maintains flow to the head of the pancreas and gut (from duodenum to proximal colon) to within 30%-65% of control (preocclusion) flow. An important new observation of this study is that collateral blood vessels are much more effective in preventing ischemia in the muscularis/serosa than in the mucosa/submucosa after SMA occlusion.

Quantitative assessment of villous motility.

A videomicroscopic method was used to quantitatively analyze villous motility in the dog small intestine. The frequency and duration of villous contractions (retractions) were measured in the duodenum, midjejunum, and distal ileum under controlled conditions. A pronounced gradient of villous motility was evident along the bowel. The duodenum exhibited the highest frequency (7.3 +/- 0.1/min) and longest duration (2.6 +/- 0.1 s) of contraction; the jejunum exhibited an intermediate frequency and duration of contraction (4.0 +/- 0.1/min, 2.1 +/- 0.1 s), and the lowest values were measured in the ileum (2.0 +/- 0.1/min and 1.8 +/- 0.1 s). In contrast to the retraction movements, the frequency of pendular villous movements (whipping, swaying movements without shortening) was highest in the jejunum and lowest in the duodenum. The frequency and duration of villous contractions (retractions) remained relatively constant over a 2-h observation period. Reducing mucosal surface temperature from 38 to 30 degrees C caused the frequency of contraction to fall by 33% and the duration to increase by 106%. Varying the suffusate pH within the physiological range of 5.0-7.4 produced no significant effects on jejunal villous motility. Suffusion with glucose (140 and 280 mM) failed to alter villous motility. However, amino acid (15 and 30 mM) and fatty acid (10 mM) solutions significantly increased contraction frequency by 30-50% and 90%, respectively. The videomicroscopic method provides useful quantitative information, which should extend current knowledge regarding the regulation and physiological importance of villous motility.

Collateral blood flow in segmental intestinal ischemia: effects of vasoactive agents.

We evaluated the effects of common vasoactive agents on collateral blood flow to an ischemic segment of small intestine and on the hemodynamic determinants of that flow. Two adjacent canine jejunal segments were isolated together, and the artery to each was cannulated for autoperfusion from a femoral and a carotid artery, respectively. Arterial pressure, arterial blood flow into, and venous outflow from each segment was measured separately. Venous pressure was zero. Vascular resistances were calculated. After clamping the arterial circuit to one segment, designated "ischemic," its steady-state venous outflow was taken as the collateral blood flow from the nonischemic into the ischemic segment. Without drugs, collateral blood flow was equal to 29 +/- 4 ml/min X 100 gm or, 56% +/- 8% of normal, well above the level needed to sustain oxygen consumption and thereby prevent ischemic injury. Local intra-arterial infusion of the vasodilators isoproterenol and papaverine not only failed to increase collateral flow but actually caused a small but (with isoproterenol) significant reduction, caused by vasodilation in the nonischemic bed, and a resulting drop in arterial pressure distal to the occlusion in the ischemic segment (i.e., a steal phenomenon). The vasoconstrictors levarterenol and vasopressin also reduced collateral flow but by direct and preferential vasoconstriction of the dilated ischemic bed. These findings suggest that collateral blood flow may be optimal without drugs and is decreased only by vasoactive agents, including vasodilators. This contradicts the rationale for vasodilator therapy for the direct augmentation of collateral blood flow in acute occlusive intestinal ischemia.

Chronic portal hypertension: effects on gastrointestinal blood flow distribution.

The intramural distribution of blood flow in the gastrointestinal tract was measured in shamoperated control and portal vein-stenosed rats. Total organ blood flow, measured via the radioactive microsphere technique, was elevated in the esophagus (66%), stomach (102%), duodenum (42%), jejunum (52%), ileum (54%), and colon (79%) of portal-hypertensive rats. Histological evaluation of carbonized nonradioactive 15-microns microspheres allowed for fractionation of blood flow within the wall (mucosa, submucosa, and muscularis externa) of each organ. The microsphere distribution pattern indicates that intramural blood flow distribution in all organs was not dramatically affected by chronic portal hypertension. These findings further define the characteristics of the factors responsible for the gastrointestinal hyperemia produced by chronic portal hypertension.

"Forward" and "backward" flow mechanisms of portal hypertension. Relative contributions in the rat model of portal vein stenosis.

The contribution of "forward" and "backward" flow mechanisms to the increased portal pressure observed in the rat model of portal vein stenosis was evaluated using experimental and theoretical data. The experimental data indicate that portal venous inflow, portasystemic shunting, and portal venous pressure are increased after 10 days of portal vein stenosis when compared with sham-operated controls. Furthermore, portal vascular resistance was 40% higher in portal hypertensive animals than in control animals. The elevated portal vascular resistance in the rat with portal vein stenosis was attributed to the high resistance of the portal venous collaterals. Incorporation of the experimental data into a mathematical model that simulated the changes induced by chronic portal vein stenosis allowed for fractionation of the "forward" and "backward" flow components involved in the pathogenesis of portal hypertension. Model predictions indicate that the "forward" and "backward" flow mechanisms account for 40% and 60% of the increase in portal pressure, respectively.

Characterization of segmental collateral blood flow in the small intestine.

Collateral blood flow and the pressures and resistances determining that flow were measured between two adjacent segments of canine jejunum following acute occlusion of the arterial branch perfusing one of the segments (the "recipient" segment). Collateral flow was approximately 55% of control flow in the recipient segment. This flow was provided by an equal increment in arterial flow to the nonischemic ("donor") segment, such that pressures, resistances, and flows in the donor segment were not affected. Virtually all of the total collateral flow was derived from precapillary channels and was therefore available to the capillary bed of the recipient segment. Collateral flow was adequate to maintain the recipient segment in a nonischemic state, as indicated by the absence of a reactive hyperemia following release of the arterial occlusion. Selective occlusions of intramural or extramural collateral channels indicate that about two-thirds of the total collateral flow is derived from the extramural (marginal) vessels, while the remainder is supplied by intramural collaterals. For the most part collateral flow between adjacent segments is determined simply by the pressure gradient between connecting collateral channels.