Bias-dependent amino-acid-induced conductance changes in short semi-metallic carbon nanotubes.

We study the interaction between short semi-metallic carbon nanotubes and different amino acids using molecular dynamics and ab initio (density functional theory/non-equilibrium Green's function) simulations. We identify two different mechanisms of nanotube conductance change upon adsorption of amino acids: one due to the change of the coordinates of the nanotube arising from van der Waals forces of interaction with the adsorbed amino acid; and one due to electrostatic interactions, which appear only in the case of charged amino acids. We also find that the transport mechanism and the changes in the conductance of the tube upon amino acid adsorption are bias dependent.

Adenosine-mediated relaxation and activation of cyclic AMP-dependent protein kinase in coronary arterial smooth muscle.

Conflicting evidence exists regarding the participation of cyclic AMP (cAMP) in adenosine-induced relaxation of the coronary vasculature. Because the mechanism of action of cAMP is thought to involve activation of its dependent protein kinase, the purpose of this study was to determine if cytosolic cAMP protein kinase was activated in response to adenosine stimulation and to determine if such activation was correlated to the extent of relaxation in intact coronary arterial strips. Adenosine produced increases in cAMP protein kinase activity in both main trunk and branch circumflex bovine arterial strips. However, both the relaxant and kinase effects were greater in branch strips. Concentration and time-dependent increases in adenosine-induced relaxation of contracted branch strips were tightly coupled to concomitant increases in cAMP protein kinase activity (r = 0.93). Moreover, this increase in kinase activity was ascribable to the cAMP-dependent kinase, as the specific inhibitor of the cAMP protein kinase attenuated these increases. In contrast, relaxation produced by sodium nitroprusside was associated with an increase in a cAMP-independent kinase. In additional experiments, cumulative dose-response curves (10(-7) to 10(-3) M) for relaxation by adenosine and nine of its analogs showed that all agents were more effective in branch strips. Adenine-9-beta-D-arabinofuranoside, the least potent analog, did not produce relaxation or increase kinase activity. In contrast, 2-chloroadenosine, the most effective relaxant analog, also increased cAMP protein kinase activity. These findings suggest that adenosine-induced relaxation may involve cAMP and activation of cAMP protein kinase in coronary arterial smooth muscle.

Hemodynamic and metabolic changes during stimulation of ileal motility.

Hemodynamic and metabolic responses of the mesenteric circulation were studied during infusion of agents known to stimulate intestinal motility. Agents were infused intraarterially in graded doses and included acetylcholine, angiotensin II, prostaglandin D2, prostaglandin F2-alpha, methionine-enkephalin, and morphine. Measurements were made of blood flow to the ileal portion of the small intestine, arteriovenous oxygen content difference, fractional distribution of radiolabeled microspheres to the muscularis, and intraluminal pressure. The clearance of 86Rb was determined in some experiments. From these measurements we calculated oxygen consumption, fractional blood flow to the muscularis, permeability and surface area product (PS-product), and the mean motility index. All agents increased mean motility index to varying degrees. At comparable levels of increased mean motility index with each drug, there were variable degrees of increase or decrease or no change in the other parameters between drugs. Mesenteric hemodynamic and metabolic responses to these dissimilar stimuli of motor activity reflected mainly the vasoactive properties of each agent. This suggests that increased motor activity has little influence on the mesenteric circulation.

Effects of adenosine and its derivatives on the canine intestinal vasculature.

The effects of adenosine and two of its structural analogs on small intestinal blood flow, flow distribution, oxygen extraction, and uptake were studied in anesthetized dogs. Adenosine induced dose-dependent increases in intestinal blood flow and oxygen consumption but decreased oxygen extraction. These effects were significantly attenuated by theophylline, an adenosine antagonist. Propranolol did not influence the responses of the intestinal circulation to adenosine suggesting that beta-adrenergic receptors are not involved in the action of adenosine. 2-Chloroadenosine, one of the most potent adenosine analogs, produced changes very similar to adenosine but was about six times more potent on a molar basis. Effects of 2-chloroadenosine were attenuated by a 10-fold smaller dose of theophylline. Adenosine-9 beta-D-arabinofuranoside, another analog, was ineffective in the mesenteric circulation. Characteristic activity of both analogs and the antagonism of the effects of adenosine and 2-chloroadenosine by theophylline suggest the presence of adenosine-sensitive binding sites in precapillary resistance vessels of the intestinal circulation. The presence of adenosine receptors in intestinal vascular smooth muscle is further supported by our in vitro results in which all three agents induce patterns of response similar to those noted under in vivo conditions. However, concentrations necessary to obtain relaxation of isolated muscle strips were much greater than those sufficient to produce mesenteric vasodilation in vivo. It was also noted that strips obtained from branches of the superior mesenteric artery were more reactive to adenosine and its analogs than were strips prepared from the main trunk of the vessel.

Effect of met-enkephalin and morphine on gastric secretion and blood flow.

The effects of met-enkephalin and morphine on gastric acid and pepsin secretion and gastric mucosal and total blood flow were studied in anaesthetized dogs with an in vivo chambered secretion stomach preparation. It was found that both agents infused intraarterially caused an increase in histamine-induced acid and pepsin secretion and mucosal and total blood flow. The above responses were significantly blocked by naloxone and nalorphine. In the resting stomach both opiates did not induce secretory changes but they increased mucosal and total blood flow. Met-enkephalin and morphine were also effective after intravenous administration. Met-enkephalin but not morphine fails to stimulate acid secretion if given into the portal vein. The likely mechanism of action of opiates on gastric secretion is discussed and a hypothesis of existence of opiate receptors in the gastric wall is presented.

Relation between small intestinal motility and circulation.

Effects of muscular activity on local blood flow have been delineated in other muscular organs but are part of a complex relationship in the small intestine. Some of our inability to provide a clear picture of the circulatory events surrounding intestinal motility relates to the variety of imprecise techniques that have been used to explore the relationship. Distension of the gut impedes blood flow through the intestinal wall, especially in the mucosa. Stimulation of motility evokes more variable responses in the intestinal circulation, including increases in blood flow; however, the circulatory response reflects mostly the nature of the intervention used to activate motility. Many motor stimuli in the gut have intrinsic vasoactive properties. Spontaneous motor events seem to have only small effects on total blood flow to the small intestine. Reduction in blood flow to the gut evokes initial increases in motility followed by inhibition of motor activity. Products of metabolism in the intestine influence both motor and vascular reactivity. More sensitive methods need to be developed to separate the types of intestinal motor activity, to localize mechanical events in specific sites in the wall of the gut, to better record electrical correlates of motility, and to measure local tissue blood flow. These technical developments will permit delineation of the linkage between motor and vascular events and should identify the regulatory factors.

Mesenteric vascular reactivity to histamine receptor agonists and antagonists.

Response patterns of intestinal blood flow, oxygen extraction and consumption, blood flow distribution, and motility were assessed during intraarterial infusions of histamine, histamine after H1 or H2 blockade, dimaprit or dimaprit after H2 blockade. Histamine produced an initial peak response of blood flow with a slow decrease thereafter. Oxygen extraction was evenly depressed throughout the infusion, and oxygen consumption increased at the beginning. All initial responses were blocked by tripelennamine. Ranitidine, a new H2 antagonist, accelerated the decay of all responses. Dimaprit produced effects identical to those of histamine after tripelennamine. Distribution of blood flow was unchanged at the beginning of histamine infusion, but subsequently showed a shift to muscularis which was blocked by tripelennamine. Histamine usually stimulated intestinal contractions and this effect was abolished by tripelennamine. Thus, H1 stimulation, besides producing an initial vasodilation, increases oxygen uptake and redistributes flow to the muscularis.

Effects of calcium and its antagonists on the canine mesenteric circulation.

We studied circulatory and metabolic responses of the intestinal circulation to intraarterial infusions of solutions containing calcium chloride or calcium antagonists in anesthetized dogs. Measurements included blood flow to the terminal ileum, arteriovenous oxygen content difference, distribution of radiolabeled microspheres to the mucosal-submucosal compartment and intraluminal pressure. Calculated parameters included oxygen consumption and fractional mucosal-submucosal blood flow. Both calcium antagonists, nifedipine and diltiazem, increased intestinal blood flow, mainly to the mucosa-submucosa, depressed intestinal motility, and did not change oxygen consumption. Thus, both agents appear to act mainly on resistance vessels without increasing the nutrient circulation. Calcium chloride (1.0-500.0 microgram/kg per min) had a mild constrictor effect; at a dose of 1000.0 microgram/kg per min, calcium chloride became a dilator agent in the mesenteric circulation. The dilator effect of the highest dose of calcium was reversed by digoxin, suggesting the involvement of Na+,K+-ATPase. Nifedipine completely blocked calcium-induced constriction of the intestinal circulation and partly inhibited norepinephrine-induced constriction. Studies on isolated mesenteric arterial smooth muscle revealed that nifedipine relaxed KCl-contracted strips in the presence of external calcium and relaxed norepinephrine-contracted strips in both the presence and absence of external calcium. These in vitro findings suggest that calcium antagonists interfere with the release of calcium from intracellular sites as well as with the slow inward current of calcium.

Gastrointestinal secretory, motor, circulatory, and metabolic effects of prosomatostatin.

This study compares the gastrointestinal effects of somatostatin (SS) and its putative prohormone, prosomatostatin (Pro-SS), a 28-amino acid peptide isolated from the hypothalamus and the gut, in conscious dogs with chronic gastric and pancreatic fistulae. Pro-Ss suppressed the release of serum gastrin, insulin, and pancreatic polypeptide that occurs in response to feeding a meat meal in a manner similar to that seen with SS. However, in contrast to SS, which strongly reduced intestinal blood flow and oxygen consumption and stimulated intestinal motility, Pro-SS, at the doses tested, had no influence on mesenteric circulation, oxygen uptake, and intestinal motility. We conclude that Pro-SS mimics most of the gastrointestinal secretory actions of SS, but does not exhibit the intestinal circulatory, metabolic, and motor effects of SS.

Differential effects of prostaglandins and arachidonic acid on gastric circulation and oxygen consumption.

Experiments were carried out on anesthetized dogs to compare the effects of prostaglandin E2 (PGE2), prostacyclin (PGI2) and arachidonic acid (AA) administered intraarterially on gastric blood flow and oxygen consumption during constant arterial pressure perfusion and constant flow perfusion of the stomach. Both PGE2 and PGI2 increased total blood flow and oxygen consumption both in the resting stomach and following histamine stimulation although the effects of PGE2 on the oxygen consumption in stimulated stomach were not statistically significant. On the contrary, AA decreased both gastric blood flow and oxygen consumption in the histamine stimulated stomach. To determine if these compounds can influence gastric oxygen consumption independently of their effects on blood flow, the experiments with constant flow perfusion were performed. Both PGE2 and PGI2 decreased both the perfusion pressure and oxygen consumption in the resting as well as in the histamine-stimulated stomach whereas AA increased perfusion pressure and decreased oxygen consumption during histamine administration. Effects of AA were blocked by indomethacin suggesting that not AA itself but some of its metabolites, most likely thromboxanes were responsible for the hemodynamic and metabolic changes resulting from the contraction of gastric arterioles and precapillary sphincters. On the contrary, both PGE2 and PGI2 caused gastric hyperemia and an increase in oxygen consumption in the resting stomach, but decreased the latter parameter in the stimulated stomach, most probably as a result of secretory inhibition overcoming direct vascular effects of these compounds.

Effect of dibutyryl cyclic AMP on gastric secretion and mucosal blood flow.

The effects of dibutyryl cyclic AMP (db cAMP) on gastric secretion and blood flow were determined in studies on anesthetized and conscious dogs. In 6 experiments on animals under chloralose-urethane anesthesia, gastric secretion, gastric mucosal and left gastroepiploic artery blood flows were measured. In 8 experiments on 4 conscious dogs with gastric fistulas and Heidenhain pouches, gastric secretion and gastric mucosal blood flow were measured in both the stomach and pouch. Gastric secretion was stimulated with intravenous histamine at a dose of 80 microgram/kg-hr for 3 hours, in each of the above experiments. In the second hour db cAMP was infused intravenously at a dose of 0.5 mg/kg-min. In all experiments db cAMP increased gastric mucosal blood flow, but only in the first group of dogs was there an increase in gastric acid secretion. It is concluded that db cAMP at the dose employed, had a vasodilator effect on the gastric mucosa, which does not appear to depend upon the secretory response to the drug.

Direct inhibition of gastric secretion and mucosal blood flow by arachidonic acid.

1. Gastric acid and pepsin secretion stimulated almost maximally by i.v. infusion of histamine, the mucosal blood flow, and the immunoreactive prostaglandin E (PGE) content have been measured following arachidonic acid administration either intra-arterially or topically to the mucosa of the fundic portion of a stomach kept in a Lucite chamber. 2. Arachidonic acid administered directly to the stomach produced a marked and significant inhibition of histamine-induced gastric secretion accompanied by a reduction in mucosal microcirculation and a rise in the immunoreactive PGE content in the gastric juice. 3. These secretory and circulatory changes induced by arachidonic acid were prevented by pretreatment of the gastic mucosa with indomethacin, a potent inhibitor of the prostaglandin synthetase system. 4. Arachidonic acid infused intra-arterially in graded doses resulted in a dose-dependent reduction in gastric acid secretion, mucosal blood flow and cyclic AMP mucosal content. 5. These studies indicate that arachidonic acid applied directly to the stomach causes a marked gastric secretory inhibition, probably due at least in part to the enzymic transformation of arachidonic acid to prostaglandins and possibly other active lipids responsible for the changes in the gastric mucosal microcirculation and cyclic AMP mucosal content.