Isradipine prevents global and regional cocaine-induced changes in brain blood flow: a preliminary study.

The L-type calcium channel antagonist, isradipine, reduces brain ischemia in animal models of ischemic stroke. These effects of isradipine appear more pronounced in dopamine (DA) rich brain regions. These same DA-rich brain regions have also been shown to be the areas most affected by cocaine-induced ischemic changes. Using a novel quantified approach to single photon emission computerized tomography, we demonstrated that isradipine pre-treatment prevented cocaine-induced ischemic changes, especially in these DA-rich brain regions. This is the first demonstration that any medication, including isradipine, can prevent the ischemic effects of cocaine on brain blood flow. Isradipine may, therefore, be a useful therapeutic agent for the prevention of brain ischemia in cocaine addicts.

Demonstration of dose-dependent global and regional cocaine-induced reductions in brain blood flow using a novel approach to quantitative single photon emission computerized tomography.

Ischemic stroke is a common cause of morbidity and mortality in cocaine addicts. Because the previous semiquantitative single photon emission computerized tomography (SPECT) method for measuring brain blood flow does not quantify blood flow, the magnitude and specificity of cocaine's effects during drug taking has not been well established. Here, using a novel quantitative approach to SPECT, we established that intravenous cocaine administration to nine recently abstinent cocaine-dependent subjects was associated with significant decreases in global and regional brain blood flow to dopamine-rich areas such as the prefrontal, frontal temporal, and subcortical gray matter. Establishing the utility of this relatively new quantitative SPECT technique provides an important tool for the management of vascular disorders of the brain. Additionally, identifying the site-specific effects of cocaine provides targets for the development of putative therapeutic medications to attenuate or minimize ischemic stroke in cocaine addicts.

Effects of acute intravenous cocaine on cardiovascular function, human learning, and performance in cocaine addicts.

Continuous non-invasive cardiovascular monitoring in eight healthy cocaine addicts receiving intravenous cocaine (0.325 mg/kg or 0.650 mg/kg) or placebo in double-blind, randomized, cross-over fashion demonstrated significant dose-dependent increases in pulse and mean arterial pressure following cocaine. Pulse and mean arterial pressure peaked 5 min post-cocaine injection and maximal response was sustained for a further 15 min and 35 min afterwards, respectively. Cocaine administration had no significant effect on peripheral oxygen saturation, and no clinically significant abnormalities of rhythm or conduction were seen on the electrocardiogram. These doses and method of single-dose intravenous cocaine administration, and our procedures for cardiovascular monitoring, appear relatively safe for laboratory studies of healthy cocaine addicts with no pre-existing cardiovascular disease. In addition, cocaine-taking (0.325 mg/kg i.v. and 0.650 mg/kg i.v.) was associated with enhanced attention (i.e. increased numbers of correct responses on the Rapid Visual Information Processing Task), but the trend towards reduced reaction time did not achieve statistical significance. Cocaine-taking resulted in a small but statistically insignificant improvement in learning on the Digit Symbol Substitution Task. These results suggest that cocaine-taking in rested subjects is associated with some cognitive enhancement.

Protein osmotic pressure gradients and microvascular reflection coefficients.

Microvascular membranes are heteroporous, so the mean osmotic reflection coefficient for a microvascular membrane (sigma d) is a function of the reflection coefficient for each pore. Investigators have derived equations for sigma d based on the assumption that the protein osmotic pressure gradient across the membrane (delta II) does not vary from pore to pore. However, for most microvascular membranes, delta II probably does vary from pore to pore. In this study, we derived a new equation for sigma d. According to our equation, pore-to-pore differences in delta II increase the effect of small pores and decrease the effect of large pores on the overall membrane osmotic reflection coefficient. Thus sigma d for a heteroporous membrane may be much higher than previously derived equations indicate. Furthermore, pore-to-pore delta II differences increase the effect of plasma protein osmotic pressure to oppose microvascular fluid filtration.

Lymph flow in sheep with rapid cardiac ventricular pacing.

Increases in systemic venous pressure (Pv) associated with heart failure cause an increase in microvascular fluid filtration into the tissue spaces. By removing this excess filtrate from the tissues, lymphatic vessels help to prevent edema. However, the lymphatics drain into systemic veins and an increase in Pv may interfere with lymphatic flow. To test this, we cannulated caudal mediastinal node efferent lymphatics in sheep. We used rapid cardiac ventricular pacing (240-275 beats/min) to cause heart failure for 4-7 days. Each day we determined the lymph flow rate two ways. First, we adjusted the lymph cannula height so that the pressure at the outflow end of the lymphatic was zero. After we determined the lymph flow with zero outflow pressure, we raised the cannula so that outflow pressure was equal to the actual venous pressure. We quantitated the effect of venous pressure on lymph flow rate by comparing the flow rate with outflow pressure = Pv to the flow rate with zero out low pressure. At baseline, Pv = 5.0 +/- 2.5 (SD) cmH2O and we found no difference in the two lymph flow rates. Pacing caused Pv and both lymph flow rates to increase significantly. However for Pv < 15 cmH2O, we found little difference in the two lymph flow rates. Thus increases in Pv to 15 cmH2O at the outflow to the lymphatics had little effect on lymph flow. By comparison, Pv > 15 cmH2O slowed lymph flow by 55 +/- 29% relative to the lymph flow rate with zero outflow pressure. Thus Pv values > 15 cmH2O interfere with lymph flow from the sheep caudal mediastinal lymph node.

Pulmonary microvascular reflection coefficients estimated with modified lymphatic washdown technique.

Many investigators have used the lymphatic protein washdown technique to estimate the pulmonary microvascular membrane reflection coefficient to protein (sigma d). With that technique, the investigator causes a high microvascular filtration rate then estimates sigma d from the lymph and plasma protein concentrations. However the lymph may contain protein washed from the lung tissue, and the tissue protein may cause investigators to underestimate sigma d. Plasma protein osmotic pressure (IIc) may cause investigators to underestimate sigma d because IIc opposes fluid filtration. To minimize the effect of IIc, we decreased IIc to 5.6 +/- 1.1 mmHg in five anesthetized sheep. We increased the microvascular filtration rate by increasing pulmonary microvascular pressure to 22 +/- 3 mmHg. Then we tagged plasma protein with Evans blue dye and estimated sigma d from the lymph and plasma dye concentrations. Because tissue protein was not tagged, it did not interfere with our sigma d estimate. Our sigma d estimate (0.79 +/- 0.08) was much higher than previous estimates in anesthetized animals.

Tissue protein washout in sheep lung lymph.

At high microvascular filtration rates, the lung lymph protein concentration (C1) may be higher than the filtrate protein concentration due to protein washed into the lymph from the lung tissue space. To test that hypothesis, we increased the microvascular filtration rate in 5 anesthetized sheep and determined the relationship between C1, and the plasma protein concentration (Cp). Then we extrapolated the data to estimate C1 at Cp = 0. Because the filtrate protein concentration should be zero at Cp = 0, we recorded the extrapolated C1, as the concentration of tissue protein in the lymph (C1). Our C1 estimate (0.92 +/- 0.38g/dl) was significantly greater than zero (P < 0.05). This result is important because tissue protein in lymph may cause errors when investigators use lung lymph to study microvascular permeability. However, our technique to estimate Ct may allow investigators to correct for the tissue protein problem.

Lymphatic pump function curves in awake sheep.

We determined the relationship between flow rate and inflow pressure for intestinal lymphatic vessels in six sheep. First we anesthetized the sheep and cannulated both ends of a 6- to 10-cm-long segment of intestinal lymphatic. We allowed the sheep to recover from the anesthesia for 2-24 h. To determine the flow rate-inflow pressure relationship, we recorded the inflow pressure and infused Ringer solution into the lymphatic at rates from 34 to 510 microliters/min. The flow rate-pressure relationship was not linear and it had two regions. For flow rates less than approximately 150 microliters/min, inflow pressure was greater than outflow pressure. Thus the lymphatic pumped fluid against a pressure gradient. For flow rates > 150 microliters/min, inflow pressure was greater than outflow pressure, and we attributed most of the flow to the favorable inflow-outflow pressure gradient (passive flow). When we used verapamil to inhibit lymphatic pumping, we found no flow for inflow pressure less than outflow pressure, and flow increased linearly for inflow pressure greater than outflow pressure. Our data for actively pumping lymphatic vessels are consistent with the flow vs. pressure relationships derived from mathematical models of the lymphatic pump. Furthermore, our data with verapamil confirm that active lymphatic pumping was responsible for the nonlinear flow vs. pressure relationship for the lymphatic vessels.

Increased abdominal lymph flow increases lung lymphatic outflow pressure in sheep.

We tested the hypothesis that increased lymph flow from the abdominal organs would increase the pressure within the thoracic duct at the thoracic duct-lung lymphatic junction. Cannulas were placed into the thoracic duct via the caudal mediastinal (lung) node efferent lymphatics in 4 sheep. After the sheep recovered from the surgery, we monitored the thoracic duct pressure with pressure transducers. To increase lymph flow from the lower body, we infused Ringers solution (59 +/- 19 [mean +/- SD] ml/kg body weight in 30 min.) intravenously into the sheep and we inflated a balloon in the inferior vena cava. This technique causes substantial increases in lymph flow from the lower body (mainly from the liver and intestines) through the thoracic duct. During the infusions, the thoracic duct pressure increased significantly from 4.1 +/- 2.9 cm H2O (baseline) to 6.8 +/- 1.7 cm H2O. The neck vein pressure (pressure at the outflow of the thoracic duct) did not increase from baseline (3.0 +/- 2.6 cm H2O). Thus our results support the hypotheses that increased flow through the thoracic duct causes increased thoracic duct pressure.

Increased lymphatic pressure without increased neck vein pressure during intravenous infusions.

Postnodal intestinal lymphatic pressure increases during rapid intravenous infusions with Ringer solution in sheep. Part of the lymphatic pressure increase is due to increased venous pressure at the lymphatic outflow (the neck veins). We tested the hypothesis that other factors besides increased neck vein pressure may cause increased lymphatic pressure during intravenous infusions. We placed cannulas into postnodal lymphatic vessels in eight sheep. After the sheep recovered from the surgery, we infused Ringer solution [46 +/- 21 (SD) ml/kg body wt in 30 min] intravenously into the sheep and inflated a balloon in the inferior vena cava. We adjusted the balloon inflation to prevent any increase in neck vein pressure during the infusions. At baseline, the intestinal lymphatic pressure was 15.5 +/- 2.5 cmH2O. During the infusions, lymphatic pressure increased significantly, and for the last 10 min of the infusion period, intestinal lymphatic pressure was 24.0 +/- 6.1 cmH2O. These results are consistent with the hypothesis that factors in addition to increased neck vein pressure may cause increased intestinal lymphatic pressure during rapid intravenous infusions.