Effects of naloxone and an enkephalin analog on serum prolactin, cortisol, and gonadotropins in the chimpanzee.

To assess a possible regulatory influence of opioids upon anterior pituitary function in the chimpanzee, we evaluated the effects of the specific opiate receptor antagonist naloxone and the agonistic enkephalin analog [D-Ala2, MePhe4,Met(o)-ol]enkephalin (FK 33-824; Sandoz) on serum levels of PRL, cortisol, FSH, and LH. Under ketamine anesthesia, the following were administered by iv injection during the early follicular phase of successive menstrual cycles in nine female chimpanzees: naloxone (10 mg; n = 7) or saline vehicle (n = 7) randomly assigned in the first two cycles, FK 33-824 0.25 mg (n = 3) in the third cycle, FK 33-824 0.50 mg (n = 4) in the fourth cycle, and FK 33-824 (0.50 mg) immediately preceded by naloxone (10 mg; n = 4) in the last cycle. Five pretreatment and 12 posttreatment serum samples were obtained at 10- to 15-min intervals for subsequent RIA. Naloxone caused a significant reduction in PRL levels from a pretreatment mean of 29.3 ng/ml to a mean of 11.1 ng/ml at 180 min. Values from 60-180 min were significantly below the saline control group at comparable times. A dose-related increment in PRL levels was seen after FK 33-824 administration, with mean peak values at 30 min of 61.0 and 92.3 ng/ml after the low and high doses, respectively. Naloxone pretreatment markedly attenuated the response to high dose FK 33-824. Cortisol levels rose in all groups throughout the study period, a presumed effect of the ketamine anesthesia. Compared to the saline group, no effects of FK 33-824 were observed. Naloxone, given alone or with FK 33-824, had a small, but significant, stimulatory effect on cortisol from 60-120 min posttreatment compared to the control group. Naloxone caused a significant increment in LH levels from a pretreatment mean of 11.7 micrograms/dl to a peak of 19.1 micrograms/dl at 30 min and in FSH level from 33.2 micrograms/dl before therapy to 40.0 micrograms/dl at 45 min. There was no influence of FK 33-824 on gonadotropin levels, although the high dose did blunt the response to naloxone. Taken together, these effects suggest that opiate agonists and endogenous opioid pathways may modulate anterior pituitary function in the chimpanzee, as in man.

Capillary permeability in the isolated rabbit heart as measured by local tissue clearance.

The relatively simple method of local tissue clearance was used to measure capillary permeability-surface area products (PS) in the isolated, Ringer-perfused rabbit heart. Ten microliters of a mixture of [3H]inulin and [14C]sucrose was injected at a depth of 2 mm into the left ventricular myocardium and clearance rate constants (k in min-1) were determined by analyzing the draining perfusion fluid. PS (ml/min per 100 ml) for each solute was calculated by the following equation: PS = -F ln(1 - lambda k/F), where F is perfusate flow (ml/min per 100 ml) and lambda is the equilibrium tissue/Ringer partition coefficient. At a perfusion pressure of 40 mm Hg, F = 133 +/- 9.7 (mean +/- SEM), PSsucrose = 77 +/- 8.0, and PSinulin = 13.9 +/- 0.7. These PS products are within the range of values previously reported by others using several different techniques. The mean inulin/sucrose permeability ratio was 0.189 +/- 0.018 which is significantly less than the separately measured free diffusion coefficient ratio (= 0.41 +/- 0.005), thus indicating that sucrose and inulin crossed myocardial capillary walls by restricted diffusion. The reasons why some investigators did not find similar evidence of restricted diffusion are discussed.

Mechanism of L-glucose, raffinose, and inulin transport across intact blood-brain barriers.

Brain capillary permeability-surface area products (PS) of hydrophilic solutes were evaluated in terms of a conventional two-compartment model. In rats whose blood-brain barrier (BBB) was presumed to be intact, metabolically inert carbohydrates with different molecular weights were injected in pairs to elucidate whether their transfer into the brain proceeds by diffusion through water- or lipid-filled channels or by vesicular transport. The distribution volume of 70 kDa dextran 10 min after intravenous injection was used as a measure of the residual volume of plasma in brain tissue after death. The two-compartment model yielded larger PS values for inulin and raffinose than for L-glucose, and the PS values of inulin and L-glucose were found to decrease as the labeling time was lengthened (10, 30, and 60 min). These observations were interpreted to mean that a rapidly equilibrating compartment was present between blood and brain, rendering the two-compartment model inadequate for computing true transfer rate constants. When multiple-time uptake data were reanalyzed using the three-compartment graphical analysis of Patlak, Blasberg, and Fenstermacher (J. Cereb. Blood Flow Metab. 3: 1-7, 1983), solutes of differing molecular size were found to enter the brain at approximately equal rates. This observation suggested that the predominant transport mechanism across an intact BBB is vesicular. Specifically, unidirectional transport is likely to be initiated by solute binding to the glycocalyx on the luminal surface of brain capillary endothelium. Apparently more inulin than L-glucose is absorbed, which may account for its slightly faster transfer across the BBB. We suggest that this adsorptive surface is the location of the rapidly equilibrating compartment on the plasma side of the BBB.

Venous waterfalls in coronary circulation.

Several studies of flow through collapsible tubing deformed by external pressures have led to a concept known as the "vascular waterfall". One hallmark of this state is a positive zero-flow pressure intercept (Pe) in flow-pressure curves. This intercept is commonly observed in the coronary circulation, but in blood-perfused beating hearts a vascular waterfall is not the only putative cause. To restrict the possibilities, we have measured flow-pressure curves in excised non-beating rabbit hearts in which the coronary arteries were perfused in a non-pulsatile way with a newtonian fluid (Ringers solution) containing potent vasodilator drugs. Under these circumstances, vascular waterfalls are believed to be the only tenable explanation for Pe. In physical terms the waterfall is a region where the vessel is in a state of partial collapse with a stabilized intraluminal fluid pressure (Pw). It is argued that the most probable site of this collapse was the intramural veins just before they reached the epicardial surface. In accord with the waterfall hypothesis, Pe increased as the heart became more edematous, but flow-pressure curves also became flatter, implying multiple waterfalls with differing Pws, leading to complete collapse of some of the venous channels. The principal compressive force is believed to have been the interstitial fluid pressure as registered through a needle (Pn) implanted in the left ventricular wall, but a small additional force (Ps) was probably due to swelling of interstitial gels. A method is presented for estimating Ps and Pw. Unlike rubber tubing, blood vessels are both collapsible and porous. Apparently because of increased capillary filtration, Pn was found to increase linearly with the perfusion pressure. Thus, Pw was not the same at all points on the flow-pressure curve. This finding has interesting implications with respect to the concept of coronary resistance.

Hydrogen sulfide poisoning.

Poisoning by hydrogen sulfide has been recognized as an occupational hazard for at least two centuries. The development of alternative sources of energy in North America may increase the incidence of this medical emergency in the future. Until recently, no specific antidote to sulfide was recognized. We have compared sulfide poisoning to cyanide poisoning and documented recent findings that indicate many similarities between the two. The therapeutic induction of methemoglobinemia, as by the intravenous administration of sodium nitrite, has both protective and antidotal effects against sulfide as well as against cyanide in laboratory animals. This procedure has been used successfully in at least one severe human case of sulfide poisoning. Industries at risk should be prepared to initiate this form of therapy in addition to the usual measures for cardiopulmonary resuscitation. No evidence exists to suggest that sulfide poisoning results in an impairment of the oxygen transport capability of blood. On the other hand, some victims of hydrogen sulfide poisoning exhibit frank cyanosis, suggesting that the respiratory tract obstruction is more common in this condition than is generally recognized. Suction of the upper tract and the administration of oxygen may be important ancillary procedures to the administration of sodium nitrite.

Computer-derived exposure lights for common contact dermatitis antigens.

An established computer file was searched for lists of products containing 45 antigens recognized as causes of allergic contact dermatitis. The final lists included over 8000 products. The problem, ptoential and limitations of such lists are discussed.

The failure of serum albumin to affect capillary permeability in the isolated rabbit heart.

The method of local tissue clearance was used to measure capillary permeability-surface area products (PS) for [3H]inulin and [14C]sucrose in the left ventricular wall of the isolated rabbit heart. As soon as a heart was excised, its coronary arteries were perfused with Ringer solution at 37 degrees for at least 30 min before clearance trials were begun. In paired trials, Ringer perfusion fluid containing 1% bovine serum albumin (Sigma) was compared with protein-free Ringer solution in terms of sucrose PS (PSs), inulin PS (PSi), and the PS ratio (Pi/Ps). With or without protein, the mean Pi/Ps was significantly less than the ratio of the free diffusion coefficients. With the untreated albumin, flow resistance rose markedly, and the PSs of both solutes fell but not Pi/Ps. To remove the unidentified vasoactive contaminant (which apparently resisted dialysis), the albumin was "defatted" by the procedure of R. F. Chen (1967, J. Biol. Chem. 242, 173-181). Defatted albumin (1% in the perfusion fluid) did not affect the volume of distribution (lambda) of sucrose or inulin in the myocardium, the heart rate, coronary flow, flow resistance, PSs, PSi, or Pi/Ps. Apparently bovine serum albumin does not influence capillary permeability in the rabbit heart. A protein effect on permeability, however, could have been missed if it has a long latent period (more than 15 min) or a long persistence (more than 30 min).

Transcapillary transport of solutes in the myocardium: effects of nitroglycerin, isoproterenol and histamine on permeability-surface area products of inulin and sucrose.

Three vasoactive drugs (nitroglycerin, isoproterenol and histamine) were examined for their effects on microsolute transport across capillary walls in the myocardium. Coronary arteries of the isolated rabbit heart were perfused at constant pressure with Tris-buffered Ringer's solution (pH = 7.4, 37 degrees C) with and without drug present in the perfusion fluid. A mixture of [3H]inulin and [14C]sucrose was injected into the left ventricular wall. From measured clearance rates, capillary permeability-surface area products (PS) (in milliliters per minute per 100 g) were computed for both solutes by the method of Gosselin and Stibitz (Pflügers Arch. 318: 85-98, 1970). Mean control PS values were 60.7 and 14.1 for sucrose and inulin, respectively. This computation required experimental determination of the myocardial volume of distribution (in milliliters per gram) for each reference solute. Values of myocardial volume of distribution obtained in the presence of nitroglycerin, isoproterenol and histamine did not differ significantly from controls. In paired clearance trials, isoproterenol and nitroglycerin significantly increased coronary flow, but neither drug influenced PS-inulin, PS-sucrose or the ratio PS inulin/PS sucrose. In contrast, histamine caused an apparently irreversible decrease in flow. Furthermore, in the presence of histamine, PS inulin/PS sucrose increased from 0.28 +/- 0.03 to 0.40 +/- 0.05 (P less than 0.003). This rise is consonant with a widening of diffusion channels between neighboring endothelial cells in the capillary wall. Thus, histamine (and presumably substances capable of histamine release) appears to increase myocardial permeability to microsolutes, in addition to its well known ability to enhance protein transport across postcapillary venules.