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Biomedical subjects

E D Jacobson

Publications and source records attributed to E D Jacobson.

At least 19 recordsLinked to original sources
PubMed1992

Circulatory mechanisms of gastric mucosal damage and protection.

The history of exploring the circulatory mechanisms underlying chemical injury of the gastric mucosa and protection against such damage is reviewed. Special emphasis is placed on recent findings in the areas of inflammatory mediators and the role of local neuropeptides. Attention is also given to the methods used to assess mucosal blood flow and structural injury in the tissue. After weighing the evidence for and against vascular mechanisms in damage and cytoprotection, it is concluded that the local circulation is involved in both processes, but simple changes in mucosal blood flow or microvascular permeability do not adequately explain the early pathophysiology of injury and protection against damage.

Animals↗
PubMed1992

Peptidergic nerves mediate post-nerve stimulation hyperemia in rat gut.

Cessation of perivascular nerve stimulation (NS) elicits a transient increase in intestinal blood flow above the prestimulatory value. This enhancement of blood flow constitutes the phenomenon of post-nerve stimulation hyperemia (PSH). We investigated the involvement of peptidergic sensory nerves in intestinal PSH. In anesthetized rats the velocity of blood flowing through the anterior mesenteric artery (VBF) was measured with a pulsed Doppler velocimeter. PSH was induced by 4 min of postganglionic electrical NS (5 Hz). PSH was abolished by distal periarterial application of tetrodotoxin and intra-arterial lidocaine, which suggests a peripheral sensory nervous mechanism for PSH. The increase in conductance at peak PSH was blocked by pretreatment with the selective, primary afferent neurotoxin capsaicin administered as 1) subcutaneous injection in neonatal life, 2) topical application to periarterial nerves, or 3) injection into the jejunal lumen. In rats pretreated with reserpine, NS evoked a hyperemic response, which was blocked by capsaicin. Treatment with adenosine deaminase inhibited PSH considerably less than capsaicin, suggesting a lesser role for adenosine in PSH. Our findings support the hypothesis that postganglionic NS activates both adrenergic and peptidergic nerves and that the latter release vasodilator peptides in the gut during PSH.

Adenosine Deaminase↗
PubMed1992

Capsaicin-sensitive nerves modulate reactive hyperemia in rat gut.

Reactive hyperemia (RH) is a local, vascular response that occurs following release from mechanical occlusion of an artery, with restoration of intra-arterial pressure. The mechanism of this postocclusion hyperemia in the gut has not been identified, although metabolic, myogenic, and neurogenic mediators of this response have been proposed. The present study was conducted to evaluate a possible modulatory role for sensory innervation of the intestinal vasculature in RH, using acute and chronic treatment with capsaicin applied in different ways. In anesthetized rats, the velocity of flowing blood in the gut was determined continuously with a pulsed Doppler velocimeter, and arterial pressure was determined with a transducer. The increase in calculated intestinal vascular conductance at the height of RH (Ch), the excess volume of blood accumulating during RH, and the duration of the hyperemia were also used to quantify RH after occluding the anterior mesenteric artery for 30, 60, and 120 sec. In the initial control group of rats, the maximal increases in the velocity of flowing blood during RH were 61 +/- 4%, 90 +/- 7%, and 129 +/- 10% of control, conductances were increased to 192 +/- 5%, 222 +/- 12%, and 267 +/- 15% of control, volumes were 3.5 +/- 0.6 ml, 7.2 +/- 0.4 ml, and 16.2 +/- 1.8 ml, and durations of hyperemia were 78 +/- 5 sec, 93 +/- 6 sec, and 178 +/- 7 sec, respectively, after each elapsed period of occlusion. Acute treatment with periarterial capsaicin significantly decreased peak conductances in RH by 15-35% for all occlusions tested and reduced both volume and duration values. Rats treated with capsaicin in neonatal life exhibited reduced Ch values, as did adult rats treated chronically with capsaicin. Both periarterial and intrajejunal treatment with capsaicin decreased the duration of RH. Hexamethonium increased both Ch and the duration of RH and tended to reverse reductions in these parameters caused by capsaicin. These results suggest that sensory innervation of the intestinal vasculature exerts a modulatory influence in the regulation of intestinal RH.

Animals↗
PubMed1992

Adenosine mediation of mesenteric blood flow.

The mesenteric circulation is regulated by multiple mechanisms, there is sufficient reason to support the suspicion that local metabolic factors are especially important in the control of intestinal vasculature. Of these, adenosine, a purine nucleoside and mesenteric vasodilator, may be the messenger of the intestinal tissue to signal appropriate responses of the intestinal vessels. The evidence supporting the candidacy of the nucleoside as a local regular of mesenteric circulation may be summarized, as follows: Adenoside is present in the tissue of the gut in measurable quantities. Exogenous adenosine is a powerful dilator of mesenteric resistance vessels. Blockade of adenosine receptors in the mesenteric circulation interferes significantly with three autoregulatory phenomena, i.e., postprandial hyperemia, pressure-flow autoregulation, and reactive hyperemia. The evidence which weakens the role of adenosine as mesenteric vasoregulator includes: Findings in several reports that adenosine depressed intestinal oxygen consumption. The failure of adenosine receptors to inhibit some autoregulatory hyperemias of the gut and the rather limited amount of evidence regarding tissue adenosine release in autoregulatory responses of the gut's vasculature.

Adenosine↗
PubMed1991

Capsaicin-sensitive nerves modulate resting blood flow and vascular tone in rat gut.

Acute and chronic treatments with capsaicin were used to evaluate the role of afferent neurons in the regulation of intestinal blood flow. Experiments were performed on anesthetized rats, in which mean intestinal blood flow was determined with a pulsed Doppler flowmeter, mean systemic arterial pressure was determined with a transducer, and intestinal vascular conductance (C) was calculated from these measurements. Acute administration of periarterial capsaicin (0.5 mg) induced biphasic intestinal vascular responses. An early hyperemic response occurred with a maximal increase in blood flow of 31% at 5 min, followed by a decrease in blood flow of 17% at 30 min. Arterial pressure was decreased by the application of capsaicin, initially by 10%. There was an early increase of 49% in conductance, followed by a 15% decrease, compared with control values. When 1 or 4 mg capsaicin was instilled into the lumen of the jejunum there was a response pattern similar to that observed after periarterial application of capsaicin. Intrajejunal capsaicin (4 mg) increased blood flow by 51%, followed by a decrease of 16%. Mean mesenteric artery conductance was increased by 32% initially and subsequently was decreased by 21%, in response to acute intrajejunal administration of capsaicin. Both mean blood flow and conductance were increased (44% and 76%, respectively) in adult rats chronically pretreated with capsaicin (170 mg total dose) when compared with vehicle-treated controls. However, in rats pretreated neonatally with capsaicin (50 mg/kg) and allowed to mature, basal flood flow was lower than in control animals but C was not different from control littermates.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Adrenergic modulation of reactive hyperemia in rat gut.

The hypothesis was tested that peripheral, adrenergic nerves modulate reactive hyperemia (RH) in the intestinal circulation. In anesthetized rats, anterior mesenteric arterial occlusion for 30-120 s elicited subsequent RH responses, including 63-118% increases in the velocity of arterial blood flow, even greater increases in conductance, and durations of 64-139 s. The longer the period of arterial occlusion, the greater the magnitude of RH. Electrical stimulation of postganglionic, sympathetic nerves reduced RH responses in a frequency-dependent manner. RH responses were enhanced by pretreatment with hexamethonium and phenoxybenzamine and were diminished by pretreatment with propranolol. Propranolol also prevented the enhanced RH responses caused by hexamethonium and phenoxybenzamine. Reserpine prevented the enhanced RH responses to hexamethonium, but bilateral adrenalectomy did not. These findings support the hypothesis that peripheral sympathetic nerves modulate RH in rat gut, with alpha-adrenergic receptors restricting and beta-adrenergic receptors enhancing the hyperemia.

Adrenalectomy↗
PubMed1991

[Role of adenosine in functional and reactive intestinal hyperemia].

This study was designed to evaluate the role of adenosine and adenosine receptors in the reactive (RH) and functional hyperemia (FH) in rat gut. Experiments were performed on anesthetized rats. Mesenteric blood flow was measured with a pulsed Doppler flowmeter. We also determined the duration of reactive hyperemia, excess volume of blood flow above control value and maximal increase in mesenteric vascular conductance during both hyperemic responses. Data were collected following release from occlusions lasting 30, 60 and 120 sec. Functional hyperemia was induced by perfusion of the gut with a solution. Studied parameters were obtain before and after adenosine deaminase (ADA) and two adenosine receptor antagonists: 8-phenyltheophylline (8-PT) and 1.3-dipropyl-7-methyl-xanthine (DPMX). In fasted rats ADA and 8-PT reduced of RH after each period of occlusion and DPMX was ineffective in reducing any parameter of RH. In fed rats control mesenteric blood flow was increased. ADA, 8-PT, and DPMX were more effective inhibitors of RH and FH. Above findings suggest that adenosine play a role in the modulation of RH and FH acting on A2 subtype receptors.

Adenosine↗
PubMed1990

Sensory nerves mediate neurogenic escape in rat gut.

We investigated the involvement of primary sensory nerves in intestinal autoregulatory escape induced by postganglionic nerve stimulation (NS) in anesthetized rats. Anterior mesenteric artery (AMA) blood flow velocity (BF) was measured with a pulsed Doppler flowmeter. Periarterial NS elicited an abrupt fall in BF, which was followed by a recovery in BF toward the basal value, despite sustained NS. This recovery from NS constituted the neurogenic escape phenomenon. Vasoconstrictor responses to NS were abolished by periarterial application of tetrodotoxin. Acute, surgical interruption of proximal periarterial nerves had no effect on BF responses to distal NS, suggesting a peripheral rather than a central nervous mechanism for the escape phenomenon. Escape from NS-induced vasoconstriction was significantly inhibited by prior administration of the selective sensory neurotoxin capsaicin as either subcutaneous injection in neonatal life, acute application to periarterial nerves, or acute injection into the jejunal lumen. In rats pretreated 24 h with reserpine, NS provoked a vasodilator response that was inhibited by intrajejunal capsaicin. Increases in arterial blood pressure (BP) and heart rate observed during NS were blocked by periarterial (but not intrajejunal) application of capsaicin. Transmural electrical field stimulation elicited significantly greater nerve-induced contractions in AMA rings from control rats. Our findings support the hypothesis that postganglionic NS activates both vasoconstrictor sympathetic nerve branches and vasodilator afferent C-fibers. The latter nerves release vasodilator peptides in the periphery during continuous low frequency NS that appear to be essential for autoregulatory escaped in our model.

Animals↗
PubMed1990

Vascular mediation of gastric mucosal damage and cytoprotection.

This review addresses questions surrounding the role of the mucosal circulation in damage and protection against chemical injury to the stomach. The modern history of the topic is briefly summarized, and widely used methods are appraised critically. The role of the circulation is examined in mucosal injury and in cytoprotection, and a new conceptual model is described which involves the vasculature and inflammatory mediators.

Animals↗
PubMed1989

Capsaicin-sensitive nerves are involved in bile-oleate-induced intestinal hyperemia.

The purpose of the present study is to assess the role of capsaicin-sensitive afferent nerves of the gut in bile-oleate-induced intestinal hyperemia. In anesthetized rats, intestinal blood flow (BF) was determined with a pulsed Doppler flowmeter. Systemic arterial blood pressure and heart rate were also measured. Test solutions containing either 40 or 80 mM oleic acid, combined with 10% natural bile, were introduced into the jejunum and produced abrupt increases in BF (64 +/- 12 and 118 +/- 14% of control, respectively). The vasodilator response was abolished by pretreatment with systemic capsaicin in neonatal life and by topical application of either capsaicin or lidocaine to the mucosa in adult animals. The response was inhibited 69 +/- 6% by an antiserum to vasoactive intestinal peptide. We found no significant inhibition of the vasodilator response by pretreating animals with antisera to cholecystokinin octapeptide or substance P, nor with hexamethonium, atropine, or reserpine. It appears that bile-oleate-induced intestinal vasodilation involves primary afferent nerve fibers of gut that release vasoactive intestinal peptide.

Animals↗
PubMed1988

Substance P mediates a gastrointestinal thermoreflex in rats.

We have characterized a viscerocirculatory thermoreflex, quantified its responses, and identified the major neurotransmitter. Application of fluid at 45 degrees C to mucosas or serosas of the stomach, jejunum, or ileum of anesthetized rats promptly evoked consistent cardiovascular responses, namely arterial hypotension, tachycardia, and a diminished intestinal blood flow (latency less than or equal to 5 s with a duration of 2-4 min). Thus, for example, warming of the stomach caused blood pressure to decrease 40%, heart rate to increase 15%, and mesenteric blood flow to decline 50%. These responses were inhibited totally or mostly by capsaicin, administered neonatally, topically, or perineurally, by topical lidocaine, and by parenteral administration of substance P antiserum, somatostatin, or hexamethonium. Epidural anesthesia also inhibited the cardiovascular responses to visceral warming. Pretreatment with reserpine or splanchnic ganglionectomy converted the thermally induced decline in mesenteric blood flow into a vasodilator response, which could then be blocked by an antiserum to substance P. Visceral warming also stimulated afferent, preganglionic sympathetic neural activity. Our conclusions are (a) application of fluid at 45 degrees C to gastrointestinal organs of anesthetized rats initiates a viscerocirculatory reflex that involves primary sensory, afferent C fibers; (b) the major neurotransmitter of this reflex appears to be substance P; and (c) visceral afferent C fibers have central and peripheral vasomotor functions.

Animals↗
PubMed1987

Prostaglandin deficiency by itself is not the cause of mepirizole-induced duodenal ulcers in rats.

The purpose of these studies was to determine the role played by endogenous prostaglandins in the development of gastric ulcers produced by indomethacin, and of duodenal ulcers produced by mepirizole in rats. Indomethacin (10 mg/kg subcutaneously) produced gastric ulcers, whereas mepirizole (100 mg/kg subcutaneously) produced exclusively duodenal ulcers. Both drugs, given at ulcerogenic doses, reduced the gastric and duodenal generation of PGE2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane B2. In this regard, the extent of reduction was more pronounced after indomethacin than after mepirizole. Despite this greater inhibition of prostaglandin synthesis by indomethacin, this drug did not produce duodenal ulcers, whereas mepirizole was duodenoulcerogenic. In addition, mepirizole increased gastric acid secretion by 74%, whereas indomethacin had no effect on acid secretion. Oral administration of 16,16-dimethyl PGE2, given at nonantisecretory doses (0.5-5 micrograms/kg), prevented formation of indomethacin-induced gastric ulcers, whereas antisecretory doses were required to prevent formation of mepirizole-induced duodenal ulcers. We conclude that a reduction of prostaglandin formation in the duodenal mucosa is not by itself sufficient to induce duodenal ulcers. We hypothesize that three changes, produced by mepirizole, must be present for duodenal ulcers to develop: increased gastric acid secretion, decreased duodenal bicarbonate secretion (as demonstrated earlier), and decreased duodenal content of prostaglandins. The decreased prostaglandin formation, although not causing duodenal ulcers, may lower the resistance of duodenal mucosa to the hyperacidity induced by mepirizole. On the other hand, in the case of gastric ulcers following administration of indomethacin, a decrease in gastric mucosal levels of prostaglandins may play a more important role than changes in gastric acidity.

16,16-Dimethylprostaglandin E2↗
PubMed1986

Direct and adaptive cytoprotection.

Cytoprotection confers increased cellular resistance to various damaging challenges. For example, the administration of certain prostaglandins (PG) prevents injury or facilitates recovery from injury in tissues exposed to noxious substances, such as ethanol, aspirin, and indomethacin. In addition, naturally occurring PG (E and I types) may play a physiological role in protecting the gastroduodenal mucosa against corrosion by gastric juice. Within a responsive tissue, not all cells may be protected by PG against severe damage. Thus, while PG will not prevent necrosis of the gastric epithelial monolayer during exposure to 100% ethanol, it does protect the deeper gastric cells of the mucosa from destruction. Cytoprotection of the gastroduodenal mucosa is independent of the antisecretory activity of PG. The ED100 cytoprotective dose of a prostaglandin may be less than 1% of the ED50 antisecretory dose of the same agent, and some cytoprotective prostaglandins are not antisecretory in some animal models. The best of the proposed mechanisms to account for cytoprotection include stimulation of mucus or HCO3 secretion, and mucosal vasodilation. However, there are no definitive data to substantiate these hypotheses and, in fact, evidence does exist to disprove each theory. Gastric mucosal exposure to mildly damaging concentrations of an agent will increase mucosal resistance to subsequent exposure to a much greater and more damaging concentration of the same agent. This "adaptive cytoprotection" can be abolished by indomethacin, an inhibitor of endogenous prostaglandin synthesis.

Adaptation, Physiological↗
PubMed1986

Effects of micellar oleic acid on canine jejunal blood flow and neurotensin release.

The purpose of this study was to evaluate the role of neurotensin in the local regulation of the lipid-induced jejunal hyperemia. Total blood flow and the arteriovenous hormone concentration difference were measured in isolated jejunal loops of anesthetized dogs with either saline, bile (10% in normal saline), oleic acid (40 mM in normal saline), or oleic acid and bile in the lumen. The bile-oleic acid mixture produced a sustained increase (+25 +/- 3%) in jejunal blood flow, whereas neurotensin release reached a maximum (1.14 +/- 0.34 pmol X min-1 X 100 g-1) 2 min after initiation of the response and then returned to control. Venous neurotensin concentrations also reached a maximum (51 +/- 17 pmol/l) at 2 min. There were no significant changes in either blood flow or neurotensin release in response to the other test solutions. Intra-arterial infusion of neurotensin did not significantly decrease jejunal vascular resistance (-12 +/- 3%) until venous concentrations of 478 +/- 101 pmol/l were attained. It seems unlikely, then, that neurotensin plays any role in the regulation of the lipid-induced jejunal hyperemia.

Animals↗
PubMed1985

Gastric blood flow and the gastric mucosal barrier.

The basic mechanisms underlying cytoprotection of gastrointestinal mucosae against damage are not understood. One hypothesis is that the initial and primary system affected by a cytoprotective agent is the local circulation of the tissue that is being protected. According to this circulatory hypothesis, a cytoprotective prostaglandin would increase gastric mucosal blood flow, thereby ameliorating the effect of topical damaging agents, such as ethanol, aspirin or bile salts. Four questions need to be considered in order to evaluate the circulatory hypothesis: (i) What degree of ischemia is necessary to break the gastric mucosal barrier? (ii) Is peptic ulcer disease due to local ischemia of the mucosa? (iii) Do mucosal damaging agents invariably reduce gastric blood flow? (iv) Do cytoprotective agents invariably increase gastric blood flow? A survey of available literature concerning blood flow and damage to the gastric mucosa suggests that: (i) severe degrees of gastric ischemia are necessary to impair vital functions of the epithelial cells of the stomach; (ii) peptic ulcer disease is not a manifestation of isolated gastric ischemia; (iii) mucosal damaging agents do not invariably reduce gastric blood flow; and (iv) cytoprotective drugs do not invariably increase gastric mucosal blood flow. The weight of available evidence does not support the circulatory hypothesis about the mechanism of cytoprotection.

Animals↗
PubMed1985

Vasoactive intestinal polypeptide, cholecystokinin, glucagon, and bile-oleate-induced jejunal hyperemia.

The purpose of this study was to evaluate the roles of vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK), and glucagon in the local regulation of the lipid-induced intestinal hyperemia. Total blood flow and the arteriovenous hormone concentration gradient were measured in isolated jejunal loops of anesthetized dogs with either saline, bile (10% in normal saline), oleic acid (40 mM in normal saline), or oleic acid and bile in the lumen. The bile-oleic acid mixture increased both blood flow (+21 +/- 7%) and VIP release (+118 +/- 7%), while CCK release was considerably less. There was a transient rise in glucagonlike immunoreactivity but no change in pancreatic glucagon release. Neither bile nor oleic acid alone altered either local blood flow or hormone release. Infusion of VIP into the arterial circulation of the jejunum significantly reduced vascular resistance (-11 +/- 4%) but at a dose (150 ng . min-1 X 100 g-1) 10 times that released in response to the bile-oleic acid mixture. This study indicates that oleic acid increases both blood flow and intestinal hormone production only when present in the lumen in micellar form and suggests that VIP could play a role in the jejunal vascular response to fat.

Animals↗