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Biomedical subjects

G Feuerstein

Publications and source records attributed to G Feuerstein.

At least 181 records · Page 10Linked to original sources

The use of antiserotonergic agents for the treatment of acute hemorrhagic shock of cats.

In cats anesthetized with pentobarbitone sodium the effect of two types of antiserotonergic agents on cardiovascular recuperation after acute hemorrhage was examined. Methysergide, a competitive inhibitor for 5-HT receptors and p-chlorophenylalanine (PCPA), an inhibitor of tryptophan-5-hydroxylase, improved blood pressure recovery after bleeding. After extensive hemorrhage (40 ml/kg blood), treatment with methysergide improved survival. It is proposed that serotonin participates in the depressor response and survival of acute hypovolemic hypotension.

Animals↗

Motilin effects on the heart and blood vessels of the pithed rat.

Motilin, a 22 amino acid polypeptide was shown to affect smooth muscle tone in the gastrointestinal tract. However, its widespread distribution in peripheral and central components of the autonomic nervous system suggest a role in other functions such as regulation of vascular tone and hemodynamic variables. Therefore, the effect of motilin on vascular tone, cardiac rhythm and blood vessel response to pressor stimuli was studied in the pithed rat. It is shown that motilin produces a prolonged depressor effect. The depressor responses were dose dependent at the range of 30 - 300 nmol/kg (max. decrease: -22 +/- 4 mmHg). In addition, motilin attenuated pressor responses to vasopressin, leukotriene D4, and the pressor effect evoked by complete spinal cord stimulation. Motilin did not affect the basal heart rate nor did it alter sympathetically induced heart rate acceleration. Motilin did not affect the circulatory level of norepinephrine or epinephrine at resting state or of norepinephrine released by spinal cord stimulation; motilin significantly suppressed epinephrine released by spinal cord stimulation. These data suggest a role for motilin in regulation of blood vessel tone by direct action on the vascular smooth muscle. In addition, motilin might play a role in regulation of epinephrine release from the adrenal medulla.

Animals↗

Cardiovascular effects of centrally administered vasopressin in conscious and anesthetized rats.

Intracerebroventricular (ICV) injections of arginine vasopressin (AVP) in doses of 0.015 nmoles and 0.15 nmoles produced a fall in mean actual pressure heart rate and respiration in pentobarbital anesthetized rats. The changes in mean arterial pressure and respiration after the higher dose were significantly different from saline injection. In contrast, the same doses of AVP given to conscious animals increased both blood pressure and heart rate. Following the 0.15 nmole dose, there was a marked and significant rise in plasma norepinephrine and epinephrine, indicating that activation of the sympathetic nervous system was, at least in part, responsible for the rise in blood pressure. Plasma vasopressin increased by less than 10 pg/ml following injection. Similar doses of a vasopressin pressor antagonist had no significant effect on mean arterial pressure or heart rate. These results indicate that ICV injection of vasopressin has different effects on blood pressure, depending on the presence or absence of anesthesia: depressor responses in the anesthetized animal and pressor responses in the unanesthetized animal.

Anesthesia↗

Central effects of mu, delta, and kappa receptor agonists in hemorrhagic shock.

We have recently shown that selective mu-opiate receptor agonists increase blood pressure and heart rate when injected into the anteroventral hypothalamus (AV3V) of the conscious rat, and that lesions of this area may worsen the effects of hypovolemia. These experiments suggested the possibility that mu-agonists might enhance cardiovascular recuperation following acute hemorrhagic shock. Sprague-Dawley rats (250-300 g) were prepared with indwelling polyethylene catheters (under halothane anesthesia) in both femoral arteries, and a guide cannula to allow intrahypothalamic injections. Twenty-four hours after surgery, animals were made hypovolemic by withdrawing arterial blood (8.5 ml/300 g) over a 5 min period. After the bleeding, 0.9% NaCl or D-Ala2-D-Leu5-enkephalin (DADL; delta-agonist), D-Ala2-MePhe4-Gly-ol-enkephalin (DAGO; mu-agonist) and U-50488H (trans(+)-dichloro-N-methyl-N-(2-[1-pryodynyl])-benzene-acetami ne, methane-sulfate hydrate) (kappa-agonist) were injected in 1 microliter volume into the AV3V. Hemodynamic parameters were followed for 2 hr. Neither DADL nor U-50488H affected the blood pressure and heart rate responses to hemorrhage. In contrast, the mu-opiate receptor agonist, DAGO, enhanced the recovery of blood pressure and stimulated the heart rate. These data suggest that specific mu-opiate receptor agonists might possess beneficial effects in shock and trauma by enhancing cardiovascular recuperation through centrally-mediated mechanisms.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

Bombesin and substance P modulate peripheral sympathetic and cardiovascular activity.

The vascular and cardiac effects of bombesin and substance P were evaluated in a "pithed rat preparation" in order to study the cardiovascular effects of these neuropeptides in the absence of the central nervous system control mechanisms. Bombesin (0.7, 7.0 and 70 nmol/kg) produced dose-dependent increases in mean arterial blood pressure (MAP): +6 +/- 1, +11 +/- 2 (p less than 0.05) and +22 +/- 2 mm Hg (p less than 0.01), respectively, when injected IV into the pithed rat. Heart rate (HR) responses to bombesin (0.7-70 nmol/kg) were also increased in a dose-dependent manner: +14 +/- 6, +28 +/- 5 (p less than 0.05) and +45 +/- 3 (p less than 0.05) beats/min (bpm), respectively. The blood pressure (BP) and HR responses to bombesin were diminished but not completely abolished by pretreatment with 1 mg/kg of either the beta-adrenergic receptor blocker propranolol or the H1-histamine receptor antagonist pyrilamine. Substance P similarly caused a dose-dependent increase in MAP: +7 +/- 1 and +38 +/- 7 mm Hg (p less than 0.001), by 0.7 and 700 nmol/kg, respectively, without altering HR. BP responses to sympathetic stimulation were also examined in the pithed rat utilizing electrical stimulation of the spinal cord (1 Hz, 50 V, 1 msec duration for 30 sec). These responses were potentiated by the low doses (0.7 and 7.0 nmol/kg) of bombesin (p less than 0.01) but tended to be suppressed by the highest dose. The HR response to stimulation was significantly reduced: -25 +/- 8 bpm (p less than 0.05) by the highest dose of bombesin (70 nmol/kg) but not with lower doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

The opioid system and central cardiovascular control: analysis of controversies.

Opiates, like morphine, were long known to produce changes in blood pressure and cardiac functions. However, the nature of these changes are a subject of continuous controversy. The substantial differences in the opiate effects on the cardiovascular system is also apparent in more recent studies using enkephalins, beta-endorphin and dynorphins. The present review is aimed to indicate the source of the variations in the experimental data and analyze the relative contribution of different experimental factors to the observed effects of opiates and opioid peptides on the cardiovascular system. The major factors which contribute to the nature of the opioid effect on the cardiovascular system are: anesthesia, species, dose, site of action in the brain, respiratory changes and receptor specificity. However, the cardiovascular status per se is an important determinant of the opiates and opioid peptide effects on hemodynamic functions as indicated in states of hypertension and shock. A newly described factor is the plasticity of the opioid receptor system which changes its level and distribution pattern in different physiological and pathophysiological states. This review emphasizes the importance of utilization of highly specific ligands to opiate receptors administered to discrete brain areas in the conscious animal.

Anesthesia, General↗

Substance K: vascular and cardiac effects in rat and pig.

The effects of substance K (SK), a newly discovered tachykinin, on the cardiovascular and sympathetic system were evaluated in the pithed rat preparation and in the in situ domestic pig heart. In pithed rats, SK (10 nmol/kg, IV) produced a triphasic mean blood pressure (MAP) response: short depressor, short pressor (+11 +/- 1 mmHg), and prolonged depressor phase (-9 +/- 1 mmHg, n = 9-24, p less than 0.001). Neither effect was significantly affected by pretreatment with propranolol (2 mg/kg) or phentolamine (1 mg/kg). The pressor response was accompanied by increased heart rate (HR): 41 +/- 4 beats/min, while lower doses produced a decrease: -8 +/- 2 beats/min (p less than 0.01). Propranolol abolished the increase in HR. SK inhibited the pressor response evoked by electrical stimulation of the spinal cord (SCS) and by Arg8-vasopressin (AVP). SK increased circulating levels of epinephrine and norepinephrine but did not change release of catecholamines evoked by SCS. Direct intracoronary injections of SK (0.3-100 nmol, intact pig heart) increased coronary blood flow; higher doses decreased MAP and increased HR. These results indicate that: SK can produce pressor and depressor effects in the rat and is a potent coronary dilator in the pig. In the pithed rat SK causes catecholamine release which mediates its cardiac accelerator effect and it antagonizes adrenergic and non-adrenergic pressor stimuli.

Animals↗

Differential hemodynamic effects of leukotriene D4 in anesthetized rats: evaluation by directional pulsed Doppler technique.

Leukotriene D4 (LTD4) is the major constituent of slow-reacting substance of anaphylaxis (SRS-A). Cardiovascular depression and hypotensive shock represent the major manifestations that attend systemic anaphylaxis. To further evaluate the hemodynamic effects of LTD4, we measured blood pressure (BP), heart rate (HR) and blood flow (BF) (directional pulsed Doppler flowmeter) to different vascular beds (hindquarter, mesenteric and renal) of the urethane-anesthetized rat. LTD4 (3, 10 and 30 micrograms/kg, i.v.) caused a dose-dependent increase in BP: 15 +/- 3, 20 +/- 4 and 24 +/- 2 mm Hg, respectively, which was maximum after 2 min and returned to control level at 10 min; HR was not significantly altered. BF to different vascular beds was differentially altered: mesenteric (-59%) greater than hindquarter (-38%) greater than renal (-10%). Vascular resistance (VR) increased by 195, 85 and 40% in mesenteric, hindquarter and renal beds, respectively. Thyrotropin-releasing hormone (TRH) (2-5 mg/kg, i.v.) injected after LTD4 increased BP, reversed the decrease in BF and the increase in VR in the mesenteric and hindquarter vascular beds. These data suggest that LTD4 receptors are unevenly distributed in various vascular beds and that the splanchnic area is particularly vulnerable to anaphylaxis-induced ischemia. Furthermore, Thyrotropin Releasing Hormone (TRH) might be useful to antagonize the hemodynamic consequences mediated by SRS-A or leukotriene.

Animals↗

Hemorrhagic shock and the central vasopressin and opioid peptide system of rats.

The effect of hemorrhagic shock (40% of blood vol) on the distribution of immunoreactive dynorphin A (Dyn A-IR), [Arg8]vasopressin (AVP-IR), and [Leu5]enkephalin (LE-IR) in the pituitary and brain nuclei was studied in the conscious rat. At 24 h after hemorrhage, the neurointermediate lobe (NIL) showed a reduction in Dyn A-IR (52%) and AVP-IR (32%) and an increase in LE-IR (72%); at this time, the anterior lobe also showed decreased Dyn A-IR (50%) and increased LE-IR (210%). Dyn A-IR, but not LE-IR, was also significantly depleted in some forebrain nuclei in all experimental groups as compared with intact controls, whereas Dyn A-IR in the hypothalamic ventromedial nucleus was elevated only in the sham-control rats. AVP-IR was elevated in the supraoptic nucleus and median eminence (200 and 31%, respectively) 2 and 24 h after bleeding, although plasma AVP returned to normal levels. These data indicate that stress and hypovolemic hypotension produce site and time-dependent change in distribution of dynorphins, AVP, and LE in the central nervous system.

Animals↗

Unique coronary vasodilator induction by leukotriene D4.

Coronary blood flow (CBF) and myocardial contractility decrease markedly in response to intracoronary administration of leukotriene D4 (LTD4). With steady infusion, however, both CBF and contractility escape, approaching preinfusion values despite ongoing LTD4 administration. To clarify the mechanism of this escape, we reinfused plasma from the coronary vein draining the myocardial area receiving LTD4. Introducing this plasma into a coronary artery caused a marked rise in coronary flow for the duration of the plasma infusion. Coronary flow reduction with vasopressin or mechanical occlusion matching that caused by LTD4 failed to elicit vasodilator production. Thus a unique coronary vasodilator factor is induced by LTD4. Whole blood or platelet-rich plasma incubated with LTD4 in vitro produced the same pattern of coronary dilation on intracoronary infusion; LTD4 incubation with platelet-poor plasma failed to elicit a vasodilation. The vasodilator factor is stable and is not potassium, a prostaglandin, catecholamine, histamine, serotonin, adenosine, adenosine diphosphate, or platelet-activating factor. Production of this leukotriene-induced vasodilator factor may account for the escape from LTD4-induced coronary constriction.

Adenosine↗

Monoclonal antibodies to T-2 toxin. In vitro neutralization of protein synthesis inhibition and protection of rats against lethal toxemia.

A murine monoclonal antibody (15H6) against the trichothecene mycotoxin T-2 was capable of neutralizing the in vitro protein synthesis inhibitory effect of T-2 toxin in human B lymphoblastoid cultures. It was further shown that 15H6 given to rats (250 mg/kg) 30 min before or 15 min after a lethal dose (1 mg/kg) of T-2 toxin conferred 100% survival. A lower dose of 15H6 (125 mg/kg), given 15 min after the lethal dose of T-2 toxin, protected 25% of the rats. An increased time to death and 45% survival was seen in rats given the full dose of 15H6 antibody 60 min after lethal toxin. These data are the first demonstration of effective prophylaxis and therapy for T-2 toxemia.

Animals↗

The adrenergic system and the cardiovascular effects of platelet activating factor (1-0-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine) in SHR and WKY rats.

1-0-Hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (1-hexadecyl-2-acetyl-GPC, platelet activating factor, PAF) was previously shown to produce profound hypotension and sympathetic activation in conscious rats. To determine the role of the sympatho-adrenomedullary system in the cardiovascular responses elicited by 1-hexadecyl-2-acetyl-GPC, the vasoactive phospholipid was administered (1 nmol per 300 g) to a) intact, b) bilaterally demedullated, and c) propranolol- (a beta-adrenoceptor blocker) treated SHR and WKY rats. The hypotensive response to 1-hexadecyl-2-acetyl-GPC was prolonged in demedullated or propranolol-pretreated WKY rats and in propranolol-treated SHR rats. The extreme tachycardia produced by 1-hexadecyl-2-acetyl-GPC in both the WKY and SHR rats was abolished by propranolol pretreatment. Pressor responses to norepinephrine during the 1-hexadecyl-2-acetyl-GPC-induced hypotension in propranolol-pretreated rats were suppressed in both the normotensive and SHR rats. Plasma acetylhydrolase activity, which inactivates PAF, was higher in hypertensive (SHR) rats or demedullated WKY rats than in the normotensive (WKY) rats. These results show that the tachycardia evoked by 1-hexadecyl-2-acetyl-GPC is mediated solely by sympathetic activation and the beta-adrenergic receptors and further indicate the major role of the sympathetic system and beta-adrenoceptors in recuperation from 1-hexadecyl-2-acetyl-GPC-induced shock. The data also suggest that acetylhydrolase in serum is an important regulatory enzyme for controlling PAF levels in the vascular compartment.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

Effects of nafazatrom on cardiovascular, sympathetic, and endocrine responses to hemorrhagic shock in conscious rats.

Nafazatrom is an antithrombic drug that has been shown to have beneficial effects in traumatic shock and organ ischemia. This study evaluated the effect of nafazatrom on cardiovascular, sympathetic, and endocrine consequences to moderate or severe hemorrhagic shock in the conscious rat. Nafazatrom (2 mg/kg, i.v.) had no effect on the blood pressure, heart rate, and circulatory norepinephrine, vasopressin, and leukotriene C4 responses to bleeding. Nafazatrom significantly reduced plasma TXB2 and 6-keto-PGF1 alpha and blocked the increment in these cyclooxygenase metabolites in response to hemorrhage. It is concluded that nafazatrom does not increase survival after moderate hypovolemic hypotension and decreases survival to severe hemorrhage. Nafazatrom does not modify the cardiovascular, sympathetic, and neuroendocrine responses to hypovolemic hypotension.

6-Ketoprostaglandin F1 alpha↗

Cardiorespiratory, sympathetic and biochemical responses to T-2 toxin in the guinea pig and rat.

The cardiorespiratory, sympathetic and biochemical effects of T-2 toxin were examined in conscious rats and guinea pigs. The pithed rat preparation was also used to evaluate possible direct effects of T-2 on the heart and vasculature. Injection of T-2 (0.5-2.0 mg/kg i.v.) into conscious rats produced prolonged (6-8 hr) hypertension and tachycardia, followed by hypotension. Total peripheral resistance was increased and cardiac output decreased. In guinea pigs, a steady decrease in pressure and rate occurred. Intravenous administration of T-2 to pithed rats did not alter blood pressure or heart rate at a time when, in conscious rats, both blood pressure and heart rate were increased. Significant elevations of arterial plasma norepinephrine, epinephrine and dopamine occurred after T-2, with metabolic acidosis, hypocarbia and hyperoxemia in both conscious rats and guinea pigs. In the rat, increase in plasma vasopressin and prostacyclin were elevated, but thromboxane and leukotriene C4-immunoreactivity were not changed. In pithed rats, T-2 did not increase basal or stimulated plasma catecholamines but produced the same changes in blood gases, pH and lactate. The LD50 values for i.v. T-2 in the rat and guinea pig were 0.74 and 1.30 mg/kg, respectively. The data are consistent with the hypothesis that T-2 toxin disrupts cellular aerobic metabolism, resulting in lactic acidosis, sympathoadrenomedullary activation, variable initial circulatory responses and eventual cardiovascular collapse.

Animals↗