Biomedical subjects

I K Anderson

Publications and source records attributed to I K Anderson.

8 recordsLinked to original sources

PubMed2000

Oxidative neuropathology and putative chemical entities for Alzheimer's disease: neuroprotective effects of salen-manganese catalytic anti-oxidants.

Considerable evidence exists that the brains of individuals with Alzheimer's disease are subject to elevated levels of oxidative stress, particularly in regions exhibiting pathological damage. A major contributor to this oxidative stress appears to be the inflammatory process. Activation of rodent microglial cells by LPS or beta-amyloid peptide results in a marked up-regulation of inducible nitric oxide synthase (iNOS) and corresponding nitric oxide (NO) production. Elevated levels of iNOS are also observed in the brains of Alzheimer patients. The reaction of NO with superoxide leads to the generation of the highly reactive and damaging peroxynitrite free radical species. Peroxynitrite appears to play a key role in the generation of an oxidative stress in the Alzheimer brain as evidenced by widespread nitrotyrosine immunoreactivity. We have employed SIN-1 as a peroxynitrite generating system in cell cultures in order to characterize the effects of this free radical on neurons. SIN-1 treatment of primary rat hippocampal neurons in culture results in neurotoxicity by a necrosis mechanism according to electron microscopic criteria. One approach to limiting peroxynitrite mediated damage is to limit superoxide production. An approach we have evaluated is treatment with salen manganese compounds, a class of catalytic antioxidant compounds which behave as superoxide dismutase (SOD)/catalase mimetics to detoxify superoxide. A number of such salen manganese compounds, including EUK-8 and EUK-134, can markedly protect primary rat cortical neurons from hydrogen peroxide mediated oxidative stress. Such salen manganese compounds can similarly afford marked neuroprotection to an oxidative stress imposed by SIN-1, potentially attributable at least in part to their inherent SOD activity. The salen manganese SOD/catalase mimetics represent a promising class of catalytic antioxidant for attenuating oxidative stress.

Journal Article↗

PubMed1998

The antihypertensive profile of the angiotensin AT1 receptor antagonist, GR138950, and the influence of potential homeostatic compensatory mechanisms in renal hypertensive rats.

The cardiovascular profile of the angiotensin AT1 receptor antagonist, GR138950, and the influence of potential compensatory homeostatic mechanisms on this profile, were investigated in renal artery ligated hypertensive (RALH) rats. GR138950 caused a marked reduction in blood pressure associated with immediate tachycardia in conscious RALH rats. The antihypertensive action of GR138950 appeared biphasic; an immediate fall in blood pressure, which plateaued within 1 h, and which was followed by a further slow decline that reached maximum between 5-7 h after administration. The tachycardia caused by GR138950 was attenuated by atenolol and was abolished by combined pretreatment with atenolol and atropine methyl nitrate. However, the antihypertensive profile of GR138950 was unchanged by these pretreatments. The resting blood pressure and the antihypertensive effect of GR138950, in RALH rats, were unaffected by the vasopressin V1 receptor antagonist, [beta-mercapto-beta,beta-cyclopentamethylene propionyl(1)-O-Me-Tyr2,Arg8]-vasopressin. Thus, vasopressinergic mechanisms are not involved in either maintaining blood pressure in RALH rats, or in compensating for the fall in blood pressure caused by GR138950. In anaesthetized RALH rats, GR138950 caused a marked fall in blood pressure that was accompanied by an increase in heart rate along with sustained increases in renal and splanchnic sympathetic nerve activity. In summary, the biphasic fall in blood pressure evoked by GR138950 in RALH rats can not be explained on the basis of changes in autonomic control of the heart, alteration of vasopressin-mediated vasoconstrictor mechanisms or overall suppression of central sympathetic outflow. Rather, increased vasoconstrictor tone might serve to oppose the initial fall in blood pressure.

Angiotensin Receptor Antagonists↗

PubMed1997

Investigation of the inhibitory effect of N(G)-nitro-L-arginine methyl ester on the antihypertensive effect of the angiotensin AT1 receptor antagonist, GR138950.

1. The effect of systemic administration of the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) on the antihypertensive effects of the angiotensin AT1 receptor antagonist, GR138950, the angiotensin-converting enzyme (ACE) inhibitor, enalapril, or hydralazine has been evaluated in unrestrained, conscious renal artery ligated hypertensive (RALH) rats. The effect of the phosphodiesterase type V inhibitor, zaprinast on the antihypertensive effect of GR138950 in RALH rats was also examined. The effect of GR138950 on blood pressure, and plasma and urine cyclic GMP levels was compared to that of zaprinast in conscious RALH rats. 2. GR138950, enalapril or hydralazine caused marked reductions in blood pressure associated with immediate tachycardia in conscious RALH rats. L-NAME pretreatment attenuated the antihypertensive effects of GR138950 or enalapril but not that of hydralazine in conscious RALH rats. The initial tachycardia caused by GR138950 or enalapril but not hydralazine was attenuated by L-NAME pretreatment. L-NAME alone caused a transient (20 min) pressor response and a prolonged (6 h) bradycardia in conscious RALH rats. 3. Pretreatment with indomethacin did not affect the cardiovascular effect of GR138950 in conscious RALH rats. Indomethacin alone did not significantly change basal blood pressure or heart rate in RALH rats. 4. Zaprinast pretreatment did not affect the antihypertensive effect of GR138950 in conscious RALH rats but potentiated the depressor response to sodium nitroprusside. Zaprinast alone caused a small reduction in basal blood pressure but did not change basal heart rate in RALH rats. 5. The antihypertensive effect of GR138950 was not associated with an increase in plasma or urine cyclic GMP levels in conscious RALH rats, whereas zaprinast caused a small fall in blood pressure associated with increases in plasma and urine cyclic GMP. 6. The ability of L-NAME to inhibit the antihypertensive action of GR138950 or enalapril suggests that these agents release nitric oxide (NO) and/or enhance the cardiovascular effects of NO as part of their mechanism of action. However, the inability of zaprinast to potentiate the antihypertensive effects of GR138950 and the finding that GR138950 did not increase urine and plasma cyclic GMP levels are not consistent with this view. Attenuation of the response to GR138950 or enalapril, but not hydralazine, suggests a selective interaction between L-NAME and inhibitors of the renin-angiotensin system, although the nature of this interaction is unknown.

Animals↗

PubMed1996

Cardiovascular effects of serotonin and DP-5-CT in conscious Long-Evans and Brattleboro rats.

The regional hemodynamic changes caused by intracerebroventricular 5-hydroxytryptamine (5-HT) were investigated in conscious Long-Evans and Brattleboro rats with chronically implanted Doppler flow probes. In both strains, a low dose of 5-HT (4 nmol/kg) caused a pressor response associated with tachycardia, mesenteric vasoconstriction, and a transient hindquarters vasodilatation. In Long-Evans rats, higher doses of 5-HT (40 and 120 nmol/kg) caused a pressor response, a bradycardia, mesenteric vasoconstriction, and maintained hindquarters dilatation. The bradycardia and mesenteric vasoconstriction caused by 40 nmol/kg of 5-HT in Long-Evans rats were attenuated by d(CH2)5Tyr(Me)arginine vasopressin, a V1-receptor antagonist. In Brattleboro rats the high doses of 5-HT failed to cause a pressor response but caused a delayed depressor response, a transient tachycardia, less mesenteric vasoconstriction, and a larger initial hindquarters dilatation compared with Long-Evans rats. The initial part of the hindquarters vasodilator response caused by 120 nmol/kg of 5-HT in Brattleboro rats was attenuated by the beta 2-adrenoceptor antagonist ICI-118551. In Long-Evans rats, N,N-di-n-propyl-5-carboxamidotryptamine maleate (DP-5-CT; 3, 30, and 100 nmol/kg icv), a 5-HT1A receptor agonist, caused a tachycardia associated with a marked hindquarters vasodilatation. These changes were accompanied by a weak mesenteric vasoconstriction and, for the highest dose of DP-5-CT, a pressor response. These data overall are consistent with the hemodynamic effects of intracerebroventricular 5-HT contingent on vasopressin release and, along with DP-5-CT, sympathoadrenal excitation; however, additional mechanisms are indicated.

Adrenergic beta-Antagonists↗

PubMed1995

Evidence that activation of 5-HT2 receptors in the forebrain of anaesthetized cats causes sympathoexcitation.

1. The aim of the present experiments was to determine whether the effects of lateral ventricular application of 5-HT on cardiovascular and respiratory variables in anaesthetized cats are mediated by forebrain 5-HT2 receptors. This was carried out by determining whether the effects of 5-HT are blocked by the 5-HT2 antagonist, cinanserin and if they are mimicked by the selective 5-HT2 agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). 2. Cats were anaesthetized with a mixture of alpha-chloralose and pentobarbitone sodium, neuromuscularly blocked and artifically ventilated. The following cardiovascular and respiratory variables were recorded: renal, splanchnic and cardiac sympathetic nerve activities, phrenic nerve activity, heart rate, arterial blood pressure, femoral arterial conductance and tracheal pressure. All drugs were administered via the lateral ventricle and the action of these agonists was restricted to forebrain sites by a cannula placed in the Aqueduct of Sylvius. 3. Cumulative doses of 5-HT (10-160 nmol kg-1) and DOI (80-320 nmol kg-1) injected into the lateral ventricle caused significant increases in blood pressure, heart rate, cardiac and splanchnic sympathetic nerve activity and a decrease in femoral arterial conductance. DOI and 5-HT caused a greater increase in cardiac compared with splanchnic nerve activity and failed to change renal nerve activity. 5-HT but not DOI significantly increased the magnitude and the number of phrenic bursts as well as significantly increasing tracheal pressure. The effects of 5-HT also differed from DOI in that 5-HT evoked maximal pressor and near maximal sympathoexcitatory effects after the first dose, whereas the pressor and sympathoexcitatory effects of DOI were graded over the complete dose-range.4 The 5-HT2 antagonist, cinanserin (265 nmol kg-1, i.c.v.) caused significant falls in blood pressure,heart rate and cardiac nerve activity and an increase in femoral arterial conductance. Splanchnic andrenal sympathetic nerve activity, phrenic nerve activity and tracheal pressure were unaffected by cinanserin. After pretreatment with cinanserin all cardiovascular and respiratory effects of 5-HT were significantly attenuated.5 It is concluded that in the cat, as DOI and 5-HT have similar effects on the cardiovascular variables recorded and as the effects of 5-HT are blocked by cinanserin, 5-HT can act on 5-HT2 receptors located in the forebrain to cause differential sympathoexcitation and a rise in arterial blood pressure. Further,the sympathoexcitatory effects mediated by 5-HT2 receptors located in the forebrain differ from those located in the hindbrain in that they mediate increases in cardiac nerve activity and heart rate and also have no effect on renal nerve activity.

Anesthesia↗

PubMed1992

Central administration of 5-HT activates 5-HT1A receptors to cause sympathoexcitation and 5-HT2/5-HT1C receptors to release vasopressin in anaesthetized rats.

1. The effects of intracerebroventricular injections to the right lateral ventricle (i.c.v.) of 5-hydroxytryptamine (5-HT, 40 and 120 nmol kg-1), N,N-di-n-propyl-5-carboxamidotryptamine (DP-5-CT; 3 nmol kg-1), 5-carboxamidotryptamine (5-CT; 3 nmol kg-1), 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT; 3, 40 and 120 nmol kg-1) and 1-(2,5-di-methoxy-4-iodophenyl)-2-aminopropane (DOI; 40 and 120 nmol kg-1) on renal sympathetic nerve activity, blood pressure, heart rate and phrenic nerve activity were investigated in normotensive rats anaesthetized with alpha-chloralose. 2. 5-HT caused a long lasting pressor response which was associated with an initial bradycardia and renal sympathoinhibition followed by a tachycardia and renal sympathoexcitation. Pretreatment with the 5-HT2/5-HT1C receptor antagonists, cinanserin (300 nmol kg-1, i.c.v.) or LY 53857 (300 nmol kg-1, i.c.v.) reversed the initial bradycardia and sympathoinhibition to tachycardia and sympathoexcitation. Combined pretreatment with LY 53857 (300 nmol kg-1, i.c.v.) and the 5-HT1A antagonist, spiroxatrine (300 nmol kg-1, i.c.v.), blocked the effects of 5-HT on all the above variables. 3. Pretreatment with the vasopressin V1-receptor antagonist, beta-mercapto-beta,beta-cyclopentamethylene-propionyl1, O-Me-Tyr2, Arg8-vasopressin [(d(CH2)5Tyr(Me)AVP, 10 micrograms kg-1, i.v.] did not affect the magnitude but reduced the duration of the pressor response produced by i.c.v. 5-HT and reversed the initial bradycardia and renal sympathoinhibition to tachycardia and sympathoexcitation. 4. 1-(2,5-Di-methoxy-4-iodophenyl)-2-aminopropane (DOI) caused a pressor effect which was associated with a bradycardia and sympathoinhibition. These effects were blocked by pretreatment with BWSOlC67 (0.1 mg kg-', i.v.), a peripherally acting 5-HT2/5-HTc receptor antagonist. However,BWSOlC67 (0.1 mg kg-', i.v.) failed to block the effects of i.c.v. 5-HT.5. DP-5-CT, 5-CT and 8-OH-DPAT (3 nmol kg-', i.c.v.) caused sympathoexcitation, tachycardia and a rise in blood pressure. Pretreatment with methiothepin (1 mg kg-', i.v.) or spiroxatrine (300 nmol kg-',i.c.v.) attenuated the response to i.c.v. DP-5-CT.6. It is concluded that i.c.v. administration of 5-HT activates 5-HTlA receptors to cause sympathoexcitation and 5-HT2 or 5-HT1c receptors to cause the release of vasopressin.

Animals↗

PubMed1992

Helicopters.

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Aircraft↗

PubMed1977

Physical characteristics and ventilatory function of 404 commercial divers working in the North Sea.

The physical characteristics and simple lung ventilatory indices (FVC, FEV 1, FEV 1/FVC) of 404 commercial divers employed by companies operating in the North Sea were analysed. These findings were correlated with the diving experience and maximum operating depth of each diver. All the divers were men of average height 176-9 cm, and weight 77-1 kg which is greater than average for active Western males, but only 6% were more than 120% of their predicted weight. The average duration of commercial diving was 7-1 years, 11% of divers having less than one year's experience. Sixty-seven per cent had worked at a maximum depth of 200 ft (61 m) and only 6% had worked deeper than 500 ft (153 m). The mean forced vital capacity (FVC) was 120-4% of the predicted value which indicated that they could voluntarily move large amounts of gas in and out of their lungs. This was greatest in the divers who when deepest. The mean forced expired volume in one second (FEV 1) was 117% of the predicted value showing that expiratory airflow capacity was also increased, but to a lesser extent than the FVC. Thper and activated by zinc. Plasma protein protected the enzyme from both inhibition and activation. ALAD activity was found to be an indicator of the total metal ion concentration in the blood and was therfore considered to be of doubtful value in screening large population for increased lead absorption.

Adolescent↗