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Biomedical subjects

G Feuerstein

Publications and source records attributed to G Feuerstein.

At least 145 records · Page 8Linked to original sources
PubMed1989

Effect of morphine on the hemodynamic and neuroendocrine responses to hemorrhage in conscious rats.

We have previously reported that analgesic doses of morphine accelerate mortality of rats exposed to hemorrhage (Feuerstein and Sirén: Circ Shock 19:293-300, 1986). To study the potential mechanisms involved in this phenomenon, rats were chronically implanted with catheters in the femoral vessels and morphine (1.5 or 5 mg/kg) was administered 30 min or 24 hr after bleeding (8.5 ml/300 g over 5 min) while arterial blood pressure and heart rate were continuously monitored. Furthermore, the effect of morphine (5 mg/kg) on cardiac output (CO) response to hemorrhage was studied in rats chronically equipped with a minithermistor for CO monitoring by a thermodilution technique. In addition, plasma catecholamines (HPLC), plasma renin activity (PRA, RIA), vasopressin (RIA), pH, and blood gases were also determined. Morphine administration 30 min after hemorrhage produced a pressor response and tachycardia which were in marked contrast to its depressor effect in intact rats. Morphine elevated PRA and epinephrine but not vasopressin, while blood pH and gases showed no consistent change as compared to saline-treated hemorrhaged rats. Morphine given after the bleeding resulted in enhanced cardiac depression in response to a second bleed of 2 ml/300 g. Our data suggest that activation of pressor mechanisms by morphine during hypovolemic hypotension might enhance vasoconstriction in essential organs, depress cardiac function, and further reduce effective tissue perfusion.

Animals↗
PubMed1988

Interaction of thyrotropin-releasing hormone (TRH) and serotonin in cardiovascular control.

Intravenous injection of the synthetic TRH analog, MK-771, to anesthetised cats raised the blood pressure by a central mechanism, i.e. by activating the outflow of sympathetic stimuli from the CNS to the periphery and raising the plasma concentration of adrenaline and noradrenaline. In contrast, noradrenaline in the CSF was lowered by intravenously injected MK-771. The concentration of 5-HT in the CSF was increased and the pressor action of the peptide was correspondingly enhanced by 5-HT antagonists. These findings suggest that the release of 5-HT into the CSF lowers blood pressure and thus reduces the hypertensive effect of MK-771. Methysergide acts synergistically with MK-771 to combat the sudden fall in pressure induced by acute hemorrhage in the anesthetised cat. Combination of the two drugs enhanced and accelerated recovery from this hypotensive state.

Animals↗
PubMed1988

Mesenteric vascular responses to i.v. administration of lipoxin A4 and lipoxin B4 in the conscious rat.

Lipoxin A4 and lipoxin B4 are newly discovered lipoxygenase-interacting products of leukocytes which might have a role in cardiovascular events associated with anaphylaxis. We have tested this possibility by systemic administration of both LXA4 and LXB4 to the conscious rat while monitoring systemic and regional hemodynamic changes. LXA4 and LXB4 (1-100 micrograms/kg) produced dose-dependent constriction of the mesenteric vessels, up to +123 +/- 23% and +50 +/- 9% for LXA4/B4, respectively. Dose-related changes were not observed in arterial blood pressure, heart rate, renal (LXB4) and hindquarter blood flow. We suggest that LXA4 and LXB4 might affect selective vascular beds, such as the mesenteric vessels, and contribute to variations in blood flow in specific pathophysiological states.

Animals↗
PubMed1988

N-acetyl-leukotriene E4 is a potent constrictor of rat mesenteric vessels.

N-Acetyl-leukotriene E4 administered to conscious freely moving rats produced a dose-dependent vasoconstriction in the mesenteric vessels which led to profound reduction of blood flow to the gut. Renal and hindquarter blood flow and vascular resistance were not affected even by high doses of N-Acetyl-leukotriene E4. N-Acetyl-leukotriene E4 was 10-fold more potent than the thromboxane analog U-46619 and 1000-fold more potent than prostaglandin F2 alpha but 2-5-fold less potent than leukotriene D4/E4 to induce mesenteric vasoconstriction. These data indicate that N-acetyl-leukotriene E4 is a biologically active metabolite of peptide leukotrienes, and might play a role in cardiovascular derangements mediated by leukotrienes.

Animals↗
PubMed1988

Antagonism of dermorphin-induced catalepsy with naloxone, TRH-analog CG3703 and the benzodiazepine antagonist, Ro 15-1788.

Intracerebroventricular (i.c.v.) administration of the highly selective opiate mu-receptor agonist, dermorphin, produced dose-dependent catalepsy in conscious rats. The cataleptic effect of dermorphin was abolished by pretreatment (intraperitoneal, i.p.) with the opiate-antagonist naloxone (5 mg/kg), thyrotropin-releasing hormone analog CG3703 (1 mg/kg) or the benzodiazepine-antagonist Ro 15-1788 (5 mg/kg) whereas pretreatment with the benzodiazepine alprazolam (1 mg/kg) potentiated the cataleptic effect of dermorphin. When given to cataleptic rats, naloxone and CG3703, but not Ro 15-1788, reversed the dermorphin-induced catalepsy. The data suggest an involvement of benzodiazepine receptors in the induction of catalepsy mediated by opioid mu-receptors. Other opioid-modulating neuronal systems, antagonized by CG3703, may be involved in maintaining the dermorphin-induced cataleptic state.

Alprazolam↗
PubMed1988

Hypothalamic mu-opioid receptors in cardiovascular control: a review.

The endogenous opioid system includes three major families of peptides [22]: dynorphins (derived from pre-proenkephalin B); endorphins (derived from pre-proopiomelanocortin) and enkephalins (derived from pre-proenkephalin A). Multiple species of opioid peptides are derived from these major precursors and many of them possess potent cardiovascular properties. Multiple forms of opioid receptors have been defined in the central nervous system. Although the relationship of these receptors to the multiple actions of the opioid systems is not well understood, some predications can be made: in vitro the dynorphin-related peptides bind preferentially to kappa-opioid receptors; the enkephalins bind preferentially to delta and mu-opioid receptors and while beta-endorphin binds to mu- and delta-, but not to kappa-opioid receptors. While little is known on the role of the opioid system in normal cardiovascular regulation, it has become clear that cardiovascular stress situations substantially modify the activity of the endogenous opioid system. This review focuses on the mu-opioid system in the hypothalamus with special emphasis on its potential role in cardiovascular control of both normal and pathophysiologic states.

Animals↗
PubMed1988

Hemodynamic and neural mechanisms of action of thyrotropin-releasing hormone in the rat.

The mechanisms mediating the effects of thyrotropin-releasing hormone (TRH) on the cardiovascular system were studied in the conscious rat. Intracerebroventricular (i.c.v.) injection of TRH (8 pmol-80 nmol/kg) induced dose-dependent increases in mean arterial pressure, heart rate, and cardiac index. Hindquarter blood flow increased due to vasodilation, while an increase in renal and mesenteric vascular resistance caused a decrease in blood flow in the respective organs. The plasma levels of norepinephrine and epinephrine were increased by TRH, while there was no change in plasma renin activity or vasopressin. The cardiovascular actions of i.c.v. TRH were not influenced by blockade of the renin-angiotensin system or vasopressin receptors. The ganglion blocker chlorisondamine and the alpha 1- and alpha 2-adrenoreceptor antagonist phentolamine (2 mg/kg i.v.) abolished the increase in blood pressure and mesenteric vasoconstriction after i.c.v. TRH. Propranolol (2 mg/kg i.v.) blocked the TRH-induced increase in cardiac index, heart rate, and hindquarter blood flow. The hindquarter vasodilation induced by TRH was also blocked by the selective beta 2-adrenoceptor antagonist ICI 188,551 (1 or 2 mg/kg i.v.), while the beta 1-adrenoceptor blocker practolol (10 mg/kg i.v.) had no effect on the hindquarter vasodilation produced by TRH but totally blocked the increase in cardiac index. In adrenal demedullated rats, the systemic hemodynamic effects of i.c.v. TRH were diminished along with the decrease in renal blood flow and increase in renal vascular resistance; however, the increase in hindquarter blood flow was attenuated only in adrenal demedullated rats pretreated with the sympathetic blocker bretylium. The renal vasoconstriction induced by i.c.v. TRH was not abolished by renal denervation. In sinoaortic debuffered rats, the pressor, tachycardic, and mesenteric vasoconstrictor responses to centrally administered TRH were significantly potentiated. Taken together, these data suggest that the putative neurotransmitter TRH may play a role in central regulation of cardiac functions and organ blood flow distribution through both the sympathetic nerves and the adrenal medulla. A pivotal role for beta 2-adrenoceptors in mediation of hindquarter vasodilation is also demonstrated.

Adrenalectomy↗
PubMed1988

Stroke risk factors prepare rat brainstem tissues for modified local Shwartzman reaction.

Stroke risk factors such as hypertension, diabetes, advanced age, and genetic predisposition to stroke were demonstrated to prepare rat brainstem tissues for a modified local Shwartzman reaction. A single intracisternal injection of endotoxin provoked the reaction, and affected rats manifested neurologic deficits accompanied by pathologic lesions. Brainstem infarcts developed in only a small proportion of rats without recognized risk factors after intracisternal injection of endotoxin. Thus, stroke risk factors, which are ordinarily regarded as operating through acceleration of atherosclerosis, may predispose to brain ischemia by local effects on brain microcirculation such as those thought to underlie preparation of a tissue for the local Shwartzman reaction.

Animals↗
PubMed1988

Cardiovascular effects of rat calcitonin gene-related peptide in the conscious rat.

The role of rat calcitonin gene-related peptide (CGRP), a recently characterized vasoactive neuropeptide, in cardiovascular regulation was studied in the conscious rat. Mean arterial pressure (MAP), heart rate, cardiac output (thermodilution technique) and regional blood flow (directional pulsed Doppler velocimetry) were monitored after i.v. or i.c.v. administration of CGRP. Systemic administration of CGRP (0.1-10 nmol/kg i.v.) decreased MAP and increased heart rate in a dose-related manner. Cardiac output increased (+95 +/- 16 ml/min/kg, P less than .01) after the 1-nmol/kg dose. At the lower or higher doses, CGRP produced no consistent changes in cardiac output. Total peripheral resistance was decreased significantly at the doses of 1 and 10 nmol/kg of CGRP. The CGRP i.v. doses of 1 and 10 nmol/kg increased mesenteric and hindquarter blood flow to a maximum of +23 +/- 7 and +30 +/- 6%, respectively (P less than .01). An increase in renal blood flow (+19 +/- 6%, P less than .05) and a decrease in renal resistance (-15 +/- 4%, P less than .05) were produced by the 0.1-nmol/kg dose of CGRP which had no effect on MAP; higher doses of CGRP tended to decrease renal blood flow. The resistance in all vascular beds was decreased by the CGRP doses of 1 and 10 nmol/kg. The maximum decreases in mesenteric, renal and hindquarter vascular resistance after the 10-nmol/kg dose were -53 +/- 3, -42 +/- 5 and -48 +/- 4%, respectively (P less than .01). The hypotensive and vasodilator responses to CGRP i.v. were significantly magnified, and the tachycardia produced by CGRP was attenuated in the sinoaortic denervated rats. Atropine (muscarinic blockers), propranolol (beta adrenoceptor blocker), cimetidine and pyrilamine (histamine H1 and H2 blockers), indomethacin (prostaglandin synthesis inhibitor), BN52021 (platelet activating factor antagonist) or a substance P antagonist had no effect on the cardiovascular responses elicited by systemic CGRP. CGRP, i.c.v. (0.1-10 nmol/kg), induced a modest tachycardia in both intact and sinoaortic denervated rats, but was devoid of any other cardiovascular effects. The results indicate that CGRP is a potent vasodilator of mesenteric, renal and hindquarter skeletal muscle blood vessels in the conscious rat. The hypotensive and vasodilator actions of circulating CGRP are likely to be mediated by direct peripheral interaction with CGRP receptors on vascular smooth muscle, whereas its tachycardic effect seems to involve reflex activation of the sympathetic nervous system.

Animals↗
PubMed1988

Platelet-activating factor and shock.

The aim of this chapter was to highlight the major components of PAF actions which lead to a state of shock, i.e. inadequate perfusion of essential organs which if sustained over a critical period of time, leads to irreversible damage in essential organs and eventually death. The heart, the pulmonary vessels and the microcirculation seem to be the primary target organs to PAF-induced hypotension. The effects of PAF on the pulmonary airways in some species (bronchoconstriction) might lead to hypoxemia and further exacerbate organ function. Thrombocytopenia, leukopenia and activation of the complement system are also important in PAF-induced shock by promoting thrombi formation and generation of multiple secondary mediators (e.g. histamine kinins, TXA2, leukotrienes, oxygen radicals). Identification of PAF production during specific or generalized pathophysiological processes is a critical step to implicate this vasoactive lipid in disease processes. So far, only limited information has been derived from studies involving immune responses (anaphylaxis) or bacterial endotoxins. Yet, the growing number of selective and potent PAF antagonists provide important information on the potential role of PAF in shock states. Such evidence, summarized in table I, is of great importance in designing new therapeutic strategies to a highly complex and lethal disease such as septicemia. However, the data summarized in table I clearly show that little is known on the mechanism of action of the various PAF antagonists. It is also important to note that PAF-induced shock and death can be prevented by drugs which are not necessarily PAF antagonists. For example, dexamethasone is extremely efficient in preventing PAF-induced shock and death in the mouse [24, 39] and thyrotropin releasing hormone in the guinea pig [15]. Therefore, it is conceivable that pathological conditions in which PAF might play a fundamental role might be reversed by pharmacological interventions which activate physiological mechanisms which can overcome and reverse the pathological processes activated by PAF. In conclusion, PAF is a powerful vasoactive lipid which can produce severe derangements in essential biological functions which can lead to death. The role of PAF in pathological processes in vivo is well supported in conditions such as anaphylaxis and endotoxemia. Yet, direct proof for PAF production in other shock states, such as multiple trauma, ischemia, inflammation and hemorrhage, is still missing. Furthermore, it is important to keep in mind that in shock, trauma or inflammation, multiple mediators in addition to PAF are formed.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Calcitonin gene-related peptide: a potent modulator of coronary flow.

Calcitonin gene-related peptide (CGRP) has been identified in nerve fibers innervating cardiovascular elements and particularly in coronary arteries (CA). To investigate its potential role in modulating coronary blood flow, we injected rat-CGRP into the CA of pentobarbital anesthetized, open chest pigs. Significant dose-related increments in coronary flow were observed. The rise in coronary flow was characterized by unusually, slow onset, late peak and prolonged duration. Arterial pressure, heart rate (HR) and myocardial contractility were unchanged, except at the highest dose (3.0 nmol), which produced mild systemic hypotension and sinus tachycardia. Coronary levels of catecholamines and 6-keto-PGF1 alpha were unchanged by CGRP. The direct, sustained, and potent dilatory activity of CGRP, in coronary arteries of the pig together with anatomical CGRP localization in this site suggest a role for this neuropeptide in hemodynamic regulation.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Cardiac and coronary consequences of intracoronary platelet activating factor infusion in the domestic pig.

In previous studies we have shown that platelet-activating factor (PAF) is a potent vasoactive substance with deleterious effects on coronary blood flow (CBF) and myocardial performance. The present study further investigates the effects of PAF during its sustained intracoronary infusion in the blood-perfused domestic pig (n = 16). PAF infusion (1-9 nmol/min) produced triphasic changes in CBF (n = 7): an initial brief phase of coronary dilation (14 +/- 2% above baseline), followed by severe reduction in CBF due to increase in coronary vascular resistance and a third phase of escape that was characterized by return of CBF towards baseline in spite of continuing PAF infusion. In 9 remaining pigs PAF infusion had a biphasic response: the first phase of coronary dilation rapidly turned into severe coronary constriction accompanied by severe systemic hypotension and death within a few min. PAF infusion caused a profound rise in systemic arterial and coronary venous thromboxane B2 levels, while 6-keto-PGF1 alpha and leukotriene C4-immunoreactivity levels were not changed. Indomethacin completely blocked the rise in thromboxane level during PAF infusion and abolished the constrictor effect of PAF on the coronary vessels. These data suggest that PAF might play a detrimental role on the coronary circulation and cardiac function, primarily through thromboxane A2 mediated mechanism.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Dissociation of the cardiovascular and prolactin-releasing activities of norvaline2-TRH.

The effects of thyrotropin-releasing hormone (TRH) and norvaline2-TRH (Nva2-TRH) on blood pressure, heart rate and plasma prolactin levels in conscious rats have been compared. Systemic injection of TRH or Nva2-TRH (1 mg/kg or 5 mg/kg) produced equipotent increases in plasma prolactin. On the other hand, while TRH significantly increases blood pressure and heart rate, Nva2-TRH was essentially inactive. Thus, two contrasting analogues are now available: 4-NO2-Im-TRH (Neuropeptides, 8, 63, 1986) has full cardiovascular activity and no PRL-releasing activity, while Nva2-TRH has no cardiovascular activity and full PRL-releasing activity of TRH.

Animals↗
PubMed1987

Increased thromboxane A2 and 5-HETE production following spinal cord ischemia in the rabbit.

Ischemia was induced for 25 min in the spinal cord of rabbits followed by a long term period of recirculation. At various time points of recirculation (5, 30 min, 4, 18 hr and 1 wk) slices were taken from the ischemic region and incubated for 45 min in Krebs-Ringer solution. The levels of the eicosanoids, PGE2, PGD2, PGF2 alpha, TXB2, 6-keto-PGF1 alpha and 5-HETE accumulated in the incubation medium were measured by radioimmunoassay. TXB2, release was found to be increased at an early (5 min) and late (1 wk) period of reperfusion. A seven-fold increase in the release of 5-HETE was found 5 min after reperfusion that tended to stay elevated at 18 hr and 1 week of recirculation. PGI2 synthetase activity decreased by 40% at 30 min, with return to normal at later time points. The ratio of TXA2/PGI2 was significantly higher than control at 30 min and 1 wk. The synthesis of PGE2, PGD2 and PGF2 alpha was maintained at normal levels throughout the complete course of reperfusion. No changes in eicosanoid synthesis were noted in remote spinal cord regions. The significant increase of TXA2 synthesis at 5 min and 1 wk of reperfusion may point to a role of this arachidonate metabolite in the acute events and in the later stages of neurological dysfunction. The enhanced release of 5-HETE, a metabolite of 5-HETE, suggest an enhanced formation of leukotriene B4 and peptide leukotrienes and a potential role for these 5-lipoxygerase metabolites of arachidonate in ischemia injury to the brain and the spinal cord.

Animals↗
PubMed1987

Protective effect of a PAF-acether antagonist, BN 52021, in trichothecene toxicosis.

Trichothecenes are mycotoxins which produce lethal toxicosis in humans and animals, yet no adequate therapeutic regimen has been developed. This study provides evidence that the selective platelet activating factor (PAF) antagonist, BN 52021 (5-15 mg/kg i.v.) can prolong the survival of conscious rats exposed to a highly lethal T-2 toxicosis. These data also suggest that PAF is an important mediator of this unique toxicosis.

Animals↗
PubMed1987

Therapeutic effect of dexamethasone in T-2 toxicosis.

T-2 Toxin is a mycotoxin that induces toxemia characterized by numerous hematological and biochemical changes. We have previously shown that prostaglandin (PG) production in brain tissue is increased following T-2 toxin. The present study was designed in order to test the effect of dexamethasone on brain prostaglandins and survival of rats subjected to T-2 toxin. Furthermore, the effect of BW 755c, a dual inhibitor of the cyclooxygenase and lipoxygenase pathways of arachidonate metabolism, on the survival of rats exposed to T-2 toxin was also examined. The present study demonstrated that dexamethasone increases the survival of rats exposed to a highly lethal T-2 toxicosis. This effect was demonstrated at low as well as high doses and at different times after T-2 administration. Dexamethasone depressed PGE2 levels in the brain cortex 6 hr after T-2 toxin but abolished the reduction of PGE2 in brain cortex seen 24 hr after T-2. BW 755c had no consistent effect on the survival of rats in T-2 toxicosis. It is suggested that dexamethasone might be a useful therapeutic agent in T-2 toxicosis in animals and humans, but its mechanism of action remains obscure.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1987

Adenosine triphosphate stimulates inositol phospholipid metabolism and prostacyclin formation in adrenal medullary endothelial cells by means of P2-purinergic receptors.

In the adrenal medulla, chromaffin cells secrete high concentrations of catecholamines, ATP, peptides and other factors that must pass through an endothelial cell barrier to enter the bloodstream. We have measured the effect of several of these chromaffin cell secretory products on cultured bovine adrenal medullary endothelial cells and have found that only ATP stimulates prostacyclin formation. The stimulation of prostacyclin formation by ATP coincides with the metabolism of inositol phospholipids and the accumulation of the putative second messenger inositol trisphosphate. The time course, concentration dependence, and P2-purinergic receptor specificity were similar for ATP-stimulated prostacyclin formation and ATP-stimulated inositol phospholipid metabolism. Thus, the increase in prostacyclin formation may be secondary to mobilization of intracellular Ca2+ by inositol trisphosphate, leading to activation of phospholipase A2, liberation of arachidonic acid, and the conversion of arachidonic acid to prostacyclin. We propose that the function of ATP, which is often colocalized with cell-specific hormones in secretory cells, may be to regulate blood flow in the adrenal medulla and other endocrine tissues by interacting with adjacent endothelial cells.

6-Ketoprostaglandin F1 alpha↗