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Biomedical subjects

G Feuerstein

Publications and source records attributed to G Feuerstein.

At least 271 records · Page 15Linked to original sources
PubMed1971

Preferential secretion of adrenaline or noradrenaline by the cat adrenal in vivo in response to different stimuli.

1. The concentrations of adrenaline and noradrenaline in the adrenal vein and the adrenal gland of the cat were studied in response to different stimuli leading to increased catecholamine (CA) secretion.2. Haemorrhage and hypoglycaemia, but not acute exposure to cold or intravenous administration of cocaine, induced considerable increases in total catecholamine secretion.3. The ratio of the concentration of adrenaline to noradrenaline in adrenal vein plasma during the control period was higher than the ratio in the adrenal gland itself.4. Haemorrhage increased noradrenaline secretion considerably more than adrenaline secretion so that the ratio of the concentration of adrenaline to noradrenaline in adrenal vein plasma was significantly lower than in the adrenal gland itself.5. Hypoglycaemia induced by insulin increased catecholamine secretion, with the adrenaline to noradrenaline ratio significantly higher than in the adrenal gland itself.6. Hypothermia resulted in a fall of the initial high ratio of adrenaline to noradrenaline, to a value similar to that in the adrenal gland.7. Neither cocaine nor changes in adrenal plasma flow affected the adrenaline to noradrenaline ratio in adrenal vein blood.8. It is concluded that preferential release from the adrenal gland of either adrenaline or noradrenaline is possible in vivo in response to different stimuli.

Adrenal Glands↗
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Differential cardiovascular effects of mu, delta and kappa opiate agonists at discrete hypothalamic sites in the anesthetized rat.

Cardiovascular and respiratory activity of mu, delta and kappa opioid agonists were investigated utilizing microinjections into the n. preopticus medialis (POM) and periventricularis hypothalami (HPV) of anesthetized rats. Injections of the relative mu agonists Morphine and Morphiceptin the delta agonist D-Ala2, D-Leu5-Enkephalin (DADL) or the putative kappa agonist Dynorphin 1-13 into the HPV caused hypotension and bradypnea; Morphine produced tachycardia while DADL and Dynorphin bradycardia. In the POM, injections of Morphine or DADL increased blood pressure and heart rate whereas Dynorphin caused hypotension and bradycardia. At this site, the mu agonist D-Ala2-MePhe4-Gly5-ol-Enkephalin (DAGO) produced hypotension, tachycardia and bradypnea, DAGO and DADL but not Morphine or Dynorphin also caused bradypnea in this region. These data show that the central cardiovascular and respiratory effects of opioids vary according to injection site and opioid subtype and may differ from findings obtained using cerebroventricular injections.

Animals↗
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The effect of mu, delta, kappa and epsilon opioid receptor agonists on heart rate and blood pressure of the pithed rat.

Opioid peptides and opioid receptors are found in the hearts of various species. Opioid peptides were also shown to modulate norepinephrine inducing changes in atrial rate, in vitro. Since we have recently shown a predominance of kappa and delta receptors in the rat atria, we found it of interest to study the role of highly selective opioid agonists on spontaneous and sympathetically stimulated heart rate. The pithed, artificially ventillated rat was used in these studies. D-Ala2-D-Leu5-enkephalin (DADL), was used as an delta-agonist, D-Ala2-MePhe4-Gly-ol5-enkephalin (DAGO) as a highly selective mu-agonist; Dynorphin A (1-17) as a kappa-agonist and beta-endorphin (beta-END) as a mixed epsilon-delta-mu agonist. Naloxone was used as an opiate antagonist. None of the above opioid peptides changed the basal blood pressure and heart rate at 1-100 nmol/kg except Dyn A-(1-17) which produced a brief depressor response (-15 +/- 2 mmHg, p less than 0.01). Stimulation of the spinal cord (50 v, 1 msec, 1 Hz, 30 sec) produced consistant pressor and cardiac accelerating responses. None of the opioid peptides studied blocked or enhanced the increase in blood pressure or heart rate produced by spinal cord stimulation. The depressor effect of the high dose of Dyn A-(1-17) was not blocked by naloxone. These results suggest that mu, delta or kappa opioid receptors in the rat heart have no role in the regulation of basal or sympathetically driven heart rate. Our data also suggest no role for these opioid receptors in modulation of basal arterial tone or norepinephrine-induced arteriolar constriction.

Animals↗
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Effect of dermorphin and morphine on the sympathetic and cardiovascular system of the pithed rat.

Dermorphin is a recently discovered opioid peptide which is unique in having a D-amino acid in its sequence. Dermorphin binding sites have been shown in central and peripheral organs and central administered dermorphin produces profound autonomic responses. The purpose of this study was to examine the effect of intravenous dermorphin on heart rate and blood pressure of the pithed rat in basal condition and in response to controlled sympathetic stimulation. Also, since dermorphin is a selective mu-receptor agonist, its effects were compared to morphine, an opiate selective for mu receptors. Dermorphin (0.0001-10 mumol/kg, i.v) or morphine (1-10 mg/kg) had no effect on basal heart rate or blood pressure and failed to modify sympatho-adreno-medullary evoked pressor and tachycardic responses. Furthermore, dermorphin or morphine did not affect the increase in plasma norepinephrine and epinephrine in response to spinal cord stimulation. It is concluded that the dermorphin and morphine have no direct peripheral effects on heart rate or blood vessel tone nor do these mu-receptor agonists have any effect on norepinephrine and epinephrine release from the sympathetic nerves and the adrenal medulla in the rat.

Animals↗
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Hemodynamic effects of endothelin after systemic and central nervous system administration in the conscious rat.

The effects of endothelin-1 (ET-1) administered i.v. or intracerebroventricularly (i.c.v.) on arterial pressure (MAP), heart rate and cardiac output were studied in the conscious rat. Systemic injection of ET-1 (0.1 to 1 nmol/kg i.v.) increased dose-dependently MAP and decreased heart rate. The doses of 0.3 and 1 nmol/kg produced initially transient hypotension and tachycardia which were accompanied by a decrease in total peripheral resistance index (TPRI). Cardiac output was significantly reduced and TPRI increased during the pressor response to 0.3 and 1 nmol/kg ET-1. ET-1 i.c.v. (30 pmol/kg) produced a profound pressor and vasoconstrictor response which was followed by cardiovascular collapse and death within 20 min after i.c.v. injection. Low doses (1 to 10 pmol/kg) of ET-1 i.c.v. had no effect on the cardiovascular system. The present data are in accordance with the studies demonstrating biphasic blood pressure and heart rate responses to i.v. ET-1 in the rat. Profound cardiac depressor and peripheral vasoconstrictor responses were found to accompany the pressor phase. Our results also showed for the first time direct central pressor and vasoconstrictor effects of ET-1 insinuating that endothelin might be a neuropeptide participating in the central cardiovascular control.

Animals↗
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mu Receptors and opioid cardiovascular effects in the NTS of rat.

In order to assess the potential role of mu (mu) and delta (delta) opiate receptors in the central regulation of the cardiovascular and respiratory systems, the cardiovascular and respiratory effects of the relatively selective mu-opioid agonist D-Ala2, MePhe4, Gly-ol5 enkephalin (DAGO) and relatively selective delta-agonist D-Ala2-D-Leu5 enkephalin (DADL) were compared following microinjection of these compounds into the nucleus tractus solitarius of pentobarbital-anesthetized rats. Both opioid agonists produced dose dependent increases in systolic and diastolic blood pressure as well as heart rate; but DAGO was nearly ten times more potent in eliciting these changes. Respiratory rate was increased by DADL and by lower doses of DAGO, but was depressed by higher doses of DAGO. Tidal volume was depressed by both peptides. These data support the concept that the cardiovascular pressor responses and tachycardia as well as the respiratory effects of opioids in the rat NTS are mediated by mu receptors.

Animals↗
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Vasopressin: an essential pressor factor for blood pressure recovery following hemorrhage.

Two experimental approaches were used to evaluate the importance of the pressor effects of vasopressin in blood pressure recovery following hypotensive hemorrhage. Experiments using homozygous Brattleboro rats demonstrated that the hemodynamic recovery of these animals was subnormal, even though the activation and efficacy of the sympathetic nervous and renin-angiotensin systems were intact. Experiments using an antipressor vasopressin analogue in normal rats during hypotensive hemorrhage demonstrated significantly blunted blood pressure recovery in the presence of the analogue. Thus, both experiments indicate that the pressor effects of circulating vasopressin play an essential role in blood pressure recovery following hypovolemic hypotension induced by hemorrhage.

Angiotensin II↗
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TRH: cardiovascular and sympathetic modulation in brain nuclei of the rat.

The cardiovascular and sympathetic effects of TRH in discrete cardiovascular-related brain nuclei were studied. Microinjections of TRH were made into the nucleus preopticus medialis (POM) of conscious rats and the nucleus tractus solitarius (NTS) of pentobarbitone-anesthetized, artificially respired rats. POM injections (1 microliter, 0.8-80 nM) elicited dose dependent pressor and tachycardic responses which were accompanied by increased levels of norepinephrine (NE) and epinephrine (EPI) in the plasma. These pressor/tachycardic effects of TRH were also elicited in adrenal demedullated (ADM-x) rats, but completely abolished in ADM-x rats pretreated with bretylium (30 mg/kg, IA). NTS injections (0.1 microliter, 30 and 150 nM) had a short depressor effect on blood pressure (BP) and a delayed increase in heart rate (HR). From these findings we suggest that the POM, a central nucleus in the AV3V region, may be an important forebrain site for autonomic regulation by TRH, mediated through the sympathetic nervous system.

Adrenal Medulla↗
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Differential cardiovascular effects mediated by mu and kappa opiate receptors in hindbrain nuclei.

To further investigate the role of opioid peptides and specific opiate receptor subtypes in central cardiovascular regulation by hindbrain nuclei, mu (D-Ala2,MePhe4,Gly-ol5 enkephalin, DAGO), delta (D-Ala2,D-Leu5 enkephalin, DADL) or kappa (MRZ 2549) agonists were microinjected into hindbrain nuclei of spontaneously or artificially respired, pentobarbital-anesthetized rats. In the nucleus tractus solitarius (NTS), DAGO and DADL (0.3 nmol) elicited pressor responses and tachycardia. MRZ (3.0-16 nmol) depressed blood pressure in spontaneously breathing rats, but accelerated heart rate in artificially ventilated animals. Blood pressure and heart rate of spontaneously breathing animals were not altered following nucleus ambiguus (NA) injection of DAGO or DADL (0.3 nmol), but were elevated in artificially respired animals; MRZ (3.0-10 nmol) injected into the NA depressed blood pressure in both groups. These data suggest that in the absence of respiratory depression, NTS and NA mu receptors mediate pressor responses and tachycardia; kappa receptors in the NA mediate a decrease in blood pressure but cardioacceleration in the NTS.

Animals↗
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Central cardiovascular effects of mammalian neurohypophyseal peptides in conscious rats.

To confirm and extend the results of previous studies which demonstrated central cardiovascular effects of vasopressin in anesthetized rats, we determined blood pressure and heart rate changes for 30 minutes after intracerebroventricular injections of arginine vasopressin, arginine vasotocin and oxytocin in conscious rats. As compared to sham injections, significantly greater increases in either systolic or diastolic blood pressure were noted over the 30 minutes which followed the injection of 0.15, 1.0 or 10.0 nM of either vasopressin or vasotocin. In animals given vasopressin, plasma levels of the peptide were determined. There was a substantial increase in plasma vasopressin only after the highest dose. Overall blood pressure responses to doses of oxytocin as high as 100 nM were not significantly different than sham injections. Heart rate following both vasopressin and vasotocin was increased at 0.15 nM, was initially decreased then increased at 1.0 nM and was substantially decreased after the 10.0 nM dose. There was a significant increase in heart rate at the 10.0 nM and 100 nM doses of oxytocin. Dose response curves for systolic blood pressure and heart rate 20 minutes after injection were similar for vasopressin and vasotocin. We conclude that arginine vasopressin has significant central pressor and tachycardic effects in conscious rats, and it is related, at least in part, to the tail structure of the peptide, which is shared with arginine vasotocin.

Animals↗
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Dynorphins and Leu-enkephalin in brain nuclei and pituitary of WKY and SHR rats.

The distribution of dynorphin 1-13 (Dyn-1-13, Dyn-(1-8) and Leu5-enkephalin (LE) immunoreactivities (ir) were determined in discrete brain nuclei of normotensive (WKY) and hypertensive (SHR) rats. The concentration of ir-Dyn-(1-13) and ir-Dyn-(1-8) varied markedly among the various nuclei studies with a predominance of ir-Dyn-(1-13) over ir-Dyn-(1-8) in all the nuclei of both WKY and SHR rats. Ir-LE also showed large variations in different sites and no consistent relationships were found between the distribution of ir-Dyn-(1-8), Dyn-(1-13) and LE. SHR rats had lower levels of ir-Dyn-(1-13), Dyn-(1-8) and LE in the suprachiasmatic nucleus compared with WKY rats. In addition, SHR rats had lower levels of ir-Dyn-(1-8)- in the paraventricular and central amygdala, and higher ir-Dyn-(1-13) levels in the substantia nigra. The level of ir-Dyn-(1-13) in the neurointermediate lobe (NIL) of SHR rats was decreased substantially compared with that of WKY rats. The localization of these opioid peptides suggests that dynorphin-like peptides may serve a variety of hypothalamic and extrahypothalamic functions which might differ between SHR and WKY rats.

Animals↗
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Selective cardiorespiratory activity of an iodinated analog of thyrotropin-releasing hormone (TRH).

The biological activity of thyrotropin-releasing hormone (TRH) and its analogs 4(5)-I-Im-TRH and 2,4(5)-I2-Im-TRH was assessed by means of their effects on: 1) the mean arterial pressure (MAP), 2) heart rate (HR), 3) ventilation minute volume (MV), 4) contractility of the rat duodenum, and 5) concentrations of thyrotropin (TSH) or prolactin (PRL) in serum. Also their binding to TRH-receptors in brain homogenates was studied. In urethane-anesthetized rats TRH ICV increased MAP, HR and MV. 4(5)-I-Im-TRH was equally as active as TRH on HR and MV but a significant elevation in MAP was observed only at a dose 100-fold to that of TRH. However, the maximal responses of 4(5)-I-Im-TRH and TRH did not differ. In conscious rats, TRH 1A elevated MAP and HR but 4(5)-I-Im-TRH was active on MAP only. 2,4(5)-I2-Im-TRH was devoid of cardiorespiratory activity. TRH dose-dependently inhibited the contractions of the rat duodenum while the iodinated analogs lacked such an activity. To induce a significant release of TSH several hundred times more of 4(5)-I-Im-TRH and over 1000 times more of 2,4(5)-I2-Im-TRH were needed as compared to TRH. The iodoanalogs elevated PRL levels only at doses 2000-fold higher than those of TRH. The iodoanalogs displaced [3H][3-Me-His2]TRH [( 3H]MeTRH) from its binding sites at concentrations about 1000 times higher than those of TRH. Substitutions of the histidyl moiety of TRH in 4(5)-I-Im-TRH and 2,4(5)-I2-Im-TRH resulted in substantial loss of the endocrine activity. While the di-iodinated analog was practically devoid of any biological activity the monoiodinated analog exerted similar cardiorespiratory activity to that of TRH.

Animals↗
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CGRP stimulates the adhesion of leukocytes to vascular endothelial cells.

Calcitonin gene-related peptide (CGRP) stimulates the adhesiveness of human umbilical vein endothelial cells for U937 cells and human neutrophils in a dose- and time-dependent manner. The onset of CGRP-induced adhesives of HUVEC was rapid (30 min), independent of protein synthesis, and lasted over 24 h in the continuous presence of the peptide. The stimulatory effect of CGRP was completely blocked by the CGRP antagonist, CGRP(8-37). The present study provides evidence in support of the potential role of sensory nerve-derived neuropeptides in the modulation of leukocyte adhesion to vascular endothelial cells.

Calcitonin Gene-Related Peptide↗
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Novel mechanisms in the treatment of heart failure: inhibition of oxygen radicals and apoptosis by carvedilol.

Carvedilol is a novel cardiovascular drug of proven efficacy in the treatment of hypertension, angina, and heart failure. Several mechanisms may account for the beneficial effects of carvedilol in patients with heart failure. As with other beta-blockers, blockade of cardiac beta-adrenergic receptors (both beta1 and beta2), and hence reduction of cardiac work load and oxygen consumption, plays an important role in the actions of this agent. Additional benefit is provided by vasodilation (alphal-adrenergic blockage) at peripheral resistance vessels, which decreases preload and after-load, thereby further reducing cardiac work and wall tensions. In addition, potential advantages of carvedilol resulting from alpha1-adrenergic blockade are likely because alpha1-adrenergic receptors mediate cardiac remodeling by inducing hypertrophy. Finally, carvedilol is a potent antioxidant and is unique among beta-blockers in this respect. In recent years, evidence has accumulated in support of the role played by reactive oxygen radicals in chronic pathological states of the myocardium. In this article, the role of oxygen radicals in heart failure is discussed with special reference to apoptosis, a phenomenon believed to be involved in progressive cardiac myocyte loss in ischemic or myopathic heart diseases. The potential role of the antioxidant actions of carvedilol, especially in prevention of apoptotic cell death, is highlighted as a novel mechanism of action in heart failure.

Adrenergic beta-Antagonists↗
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Alteration of cardiovascular, neurogenic, and humoral responses to acute hypovolemic hypotension by administered prostacyclin.

Acute hypovolemia induced by bleeding (5 ml/300 g body weight) halothane-anesthetized (0.8% in oxygen) rats is attended by hypotension, bradycardia, and increases in plasma renin, vasopressin, and catecholamine levels. Infusion of prostacyclin (PGI2, O.03 microgram/kg.min) to acutely hemorrhaged rats enhanced recuperation of heart rate, and potentiated the sympathetic response and vasopressin release without altering blood pressure of plasma renin concentration (PRC). Bleeding of bilaterally adrenal demedullated, splanchnicectomized rats resulted in prolonged hypotension and increased plasma levels of vasopressin and renin; epinephrine in the plasma was not detectable, and plasma norepinephrine concentration was not increased after hemorrhage. Prostacyclin infusion to the demedullated, splanchnicectomized rats had no effect on heart rate but enhanced blood pressure recovery after hemorrhage; in this experimental group, PRC was markedly elevated but prostacyclin had no effect on plasma vasopressin or catecholamine concentrations. In rats exposed to severe bleeding, resulting in a nonreversible shock and high mortality, PGI2 infusion after the bleeding increased the survival rate without effect on blood pressure, heart rate, or circulating levels of vasopressin and catecholamines. This study suggests that prostacyclin, through stimulation of the sympathoadrenal axis, enhances heart rate recuperation and vasopressin release in response to acute hemorrhagic shock. Furthermore, prostacyclin may stimulate renin secretion in sufficient amount to compensate for the inadequate sympathetic response during hemorrhagic shock. It is also shown that prostacyclin improves the survival rate to severe hemorrhage without overt hemodynamic or sympathetic effects.

Angiotensin II↗
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Thyrotropin-releasing hormone blocks the hypotensive effects of platelet-activating factor in the unanesthetized guinea pig.

Platelet-activating factor (PAF) and leukotrienes, newly described classes of vasoactive lipids, may play a role in anaphylaxis. It has recently been suggested that the vasoconstrictor effects of PAF in isolated rat lung are related to release of leukotrienes C4 and D4. Thyrotropin-releasing hormone (TRH), a tripeptide, has potent antihypotensive activity in experimental shock, including that resulting from either leukotriene D4 administration or antigen-induced anaphylaxis. We utilized an unanesthetized guinea pig model to study the relationships among PAF, leukotrienes, and TRH and their potential interactions on the cardiovascular system. PAF (1 nmol/600 g body weight i.v.) produced profound hypotension which was completely blocked by TRH (2 mg/kg i.v.). Nafazatrom or FPL 55712, a presumed receptor antagonist of leukotrienes, was ineffective, whereas U-60257, a leukotriene synthesis inhibitor, displayed incomplete blockade. Moreover, leukotriene-like immunoreactivity in plasma did not increase following PAF administration. Thus, hypotension produced by PAF does not appear to result secondarily from release of cysteinyl leukotrienes. Moreover, the ability of TRH to block the hypotensive effects of PAF may partially account for its beneficial effects in experimental anaphylaxis and provides further rationale for the therapeutic evaluation of this peptide in anaphylactic shock.

Animals↗