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PubMed1978

Accumulation of lysophosphoglycerides with arrhythmogenic properties in ischemic myocardium.

Lysophosphoglycerides, products of membrane phospholipid catabolism known to influence membrane function in several systems, appeared in the effluents of anoxic isolated rabbit hearts perfused at low flow and accumulated in perfused hearts and myocardium rendered ischemic in situ. Comparable concentrations of lysophosphoglycerides bound to albumin markedly and reversibly altered action potentials of isolated canine Purkinje fibers in vitro. Changes induced included diminution of the maximum diastolic potential, peak dV/dt of phase zero, amplitude, and action potential duration--alterations resembling those seen in ischemic myocardium in vivo. These electrophysiological alterations are compatible with changes implicated in predisposing to dysrhythmia dependent on reentry, a phenomenon potentiated by the presence of zones of decreased conduction. Thus, accumulation of lysophosphoglycerides induced by ischemia may contribute to the genesis of malignant dysrhythmia early after its onset.

Action Potentials↗

PubMed2001

Right ventricular distension alters monophasic action potential duration during pulmonary arterial occlusion in anaesthetised lambs: evidence for arrhythmogenic right ventricular mechanoelectrical feedback.

Abnormal loading and distension of the right ventricle may induce arrhythmia through the process of mechanoelectrical feedback. Nonetheless, the electrophysiological effects of right ventricular distension are ill-defined and the mechanisms which underpin mechanoelectrical feedback in the right ventricle are unknown. We examined the effects of changes in right ventricular load (complete occlusion of both caval veins or the main pulmonary artery) in 14 anaesthetised lambs, instrumented with right ventricular surface electrodes and strain gauges for recording monophasic action potential and segment length, and an integrated conductance and micromanometer-tipped catheter for measurement of right ventricular pressure and volume. Caval occlusion did not alter right ventricular segment length and monophasic action potential duration. By contrast, pulmonary arterial occlusion increased the segment length and decreased the monophasic action potential duration at 25, 50 and 70% repolarisation by 29 +/- 6, 22 +/- 4 and 17 +/- 3 ms, respectively (all P < 0.01). Of the 42 pulmonary arterial occlusions, 38 were associated with early afterdepolarisations (EADs) which increased progressively in magnitude as the occlusion was maintained until, in 32, overt arrhythmia was observed. By contrast, none of the four occlusions in which EADs were not observed resulted in arrhythmia. As a result, the proportion of occlusions which resulted in arrhythmia were greater in those associated with EADs than in those which were not (P = 0.002). Right ventricular distension alters the pattern of repolarisation, precipitates early afterdepolarisations and results in a variety of ventricular arrhythmia, including ventricular tachycardia.

Action Potentials↗

PubMed1997

Telomerase RNA mutations in Saccharomyces cerevisiae alter telomerase action and reveal nonprocessivity in vivo and in vitro.

The ribonucleoprotein enzyme telomerase adds telomeric DNA to chromosomal ends. In most eukaryotes the telomeric repeat units are repeated precisely, consistent with the action of a telomerase that faithfully copies its RNA template. In contrast, Saccharomyces cerevisiae telomeric repeats are degenerate, suggesting that its telomerase has unusual mechanistic properties. We mutated the S. cerevisiae telomerase RNA (TLC1) with a series of 3-base (GUG) substitutions in and next to the 17-nucleotide templating domain. All mutant telomerases were active in TLC1/tlc1 diploids and synthesized patterns of mixed wild-type and mutant telomeric repeats into telomeric DNA, consistent with nonprocessive action. Telomerase isolated from cells containing each mutated tlc1 allele by itself had altered reaction properties in vitro. One mutant template enzyme, 476GUG, was active in vivo and in vitro in the presence of wild-type TLC1 RNA but lacked detectable activity in its absence. Haploid tlc1-476GUG cells containing only this mutant tlc1 allele underwent senescence. Other tlc1 template region mutations allowed maintenance of shortened telomeres in vivo but altered specific enzymatic properties of telomerase in vitro, including induction of primer-template slippage (472GUG) or alteration of the 5' boundary of the template (467GUG). These data demonstrate that telomerase RNA bases influence enzyme activity profoundly, suggesting that their roles are not confined to serving simply as the template for this specialized reverse transcriptase.

Base Sequence↗

PubMed1997

Rat amylin-(8-37) enhances insulin action and alters lipid metabolism in normal and insulin-resistant rats.

To clarify roles of amylin, we investigated metabolic responses to rat amylin-(8-37), a specific amylin antagonist, in normal and insulin-resistant, human growth hormone (hGH)-infused rats. Fasting conscious rats were infused with saline or hGH, each with and without amylin-(8-37) (0.125 mumol/h), over 5.75 h. At 3.75 h, a hyperinsulinemic (100 mU/l) clamp with bolus 2-deoxy-D-[3H]glucose and [14C]glucose was started. hGH infusion led to prompt (2- to 3-fold) basal hyperamylinemia (P < 0.02) and hyperinsulinemia. Amylin-(8-37) reduced plasma insulin (P < 0.001) and enhanced several measures of whole body and muscle insulin sensitivity (P < 0.05) in both saline- and hGH-infused rats. Amylin-(8-37) corrected hGH-induced liver insulin resistance, increased basal plasma triglycerides and lowered plasma nonesterified fatty acids in both groups, and reduced muscle triglyceride and total long-chain acyl-CoA content in saline-treated rats (P < 0.05). In isolated soleus muscle, amylin-(8-37) blocked amylin-induced inhibition of glycogen synthesis but had no effect in the absence of amylin. Thus 1) hyperamylinemia accompanies insulin resistance induced by hGH infusion; 2) amylin-(8-37) increases whole body and muscle insulin sensitivity and consistently reduces basal insulin levels in normal and hGH-induced insulin resistant rats; and 3) amylin-(8-37) elicits a significant alteration of in vivo lipid metabolism. These findings support a role of amylin in modulating insulin action and suggest that this could be mediated by effects on lipid metabolism.

Acyl Coenzyme A↗

PubMed2026

The genomic landscape of HER2 negative metastatic breast cancer with loss of estrogen and progesterone receptors.

INTRODUCTION: Loss of estrogen receptor (ER) and/or progesterone receptor (PR) might occur during the metastatic progression of ER positive and HER2 negative (ER+/HER2-) breast cancer (BC), but the underpinning molecular alterations remain elusive. We explored the genomic context of HER2- tumors with ER and/or PR loss to investigate potential drivers and actionable alterations that might help personalize treatment of ER+/HER2- BC. METHODS: We accessed data from metastatic HER2- BC included in the MSK-2018 dataset to compare outcome, tumor characteristics and genomic alterations of BC with loss of ER (ER+/-, n = 66) to those maintaining ER positivity (ER+/+, n = 364) or ER negativity (ER-/-, n = 50). We also compared metastatic ER+/+ BC with loss of PR (PR+/-, n = 111) to those maintaining PR positivity (PR+/+, n = 192) or PR negativity (PR-/-, n = 41). RESULTS: In line with previous reports, ER+/- BC was associated with aggressive clinico-pathological characteristics and poor outcome. ER+/- BC showed significantly higher frequency of TP53 and RB1 mutations and lower frequency of PIK3CA and GATA3 mutations compared to ER+/+. ER+/- or PR+/- status was mutually exclusive with ESR1 mutations and was associated with a significantly higher tumor mutational burden. Moreover, ER+/- BC were enriched in driver alterations in the genes of the Notch and Retinoblastoma pathways and showed a significantly lower frequency of level 1 actionable alterations according to OncoKB. CONCLUSIONS: Loss of ER and/or PR may identify a distinct evolutionary trajectory of ER+/HER2- metastatic progression, largely non-overlapping with ESR1-mutant endocrine resistance. Further studies on matched primary and metastatic samples are warranted.

Humans↗

PubMed1982

Further studies on the mechanism by which chlorpropamide alters the action of vasopressin.

The injection of chlorpropamide into Brattleboro homozygous rats (di/di) has previously been shown to result in enhanced activation of renal medullary adenylate cyclase activity and increased renal medullary content of cAMP in response to 1-desamino-8-D-arginine vasopressin (dDAVP). In contrast, in vivo chlorpropamide did not alter GTP, guanylylimidodiphosphate, or fluoride-stimulated adenylate cyclase activities in these renal membranes. We have now found that the effect of in vivo chlorpropamide in enhancing dDVAP-stimulated adenylate cyclase activity involves lowering the Km for ATP. We have also found that dDAVP increases urinary prostaglandin E2 (PGE2) excretion, and treatment with chlorpropamide causes an even greater PGE2 response to dDAVP. In contrast, in vivo chlorpropamide treatment did not increase vascular responses to arginine vasopressin (AVP) in the perfused kidney preparation and, in fact, inhibited the AVP-induced decrease in the glomerular filtration rate. Chlorpropamide, therefore, enhances the renal responses to dDAVP in terms of the cAMP and PG systems, while not increasing responses to postreceptor stimuli of the adenylate cyclase system or vascular responses to AVP. These observations support the concept that in vivo chlorpropamide acts at the receptor of the vasopressin-sensitive part of the tubule to augment responsiveness to vasopressin. In addition, in vivo chlorpropamide may inhibit certain vascular responses to AVP.

Adenylyl Cyclases↗

PubMed2004

Sustained reduction in plasma free fatty acid concentration improves insulin action without altering plasma adipocytokine levels in subjects with strong family history of type 2 diabetes.

To investigate the effect of a sustained (7-d) decrease in plasma free fatty acid (FFA) concentration in individuals genetically predisposed to develop type 2 diabetes mellitus (T2DM), we studied the effect of acipimox, a potent inhibitor of lipolysis, on insulin action and adipocytokine concentrations in eight normal glucose-tolerant subjects (aged 40 +/- 4 yr, body mass index 26.5 +/- 0.8 kg/m(2)) with at least two first-degree relatives with T2DM. Subjects received an oral glucose tolerance test (OGTT) and 120 min euglycemic insulin clamp (80 mU/m(2).min) with 3-[(3)H] glucose to quantitate rates of insulin-mediated whole-body glucose disposal (Rd) and endogenous (primarily hepatic) glucose production (EGP) before and after acipimox, 250 mg every 6 h for 7 d. Acipimox significantly reduced fasting plasma FFA (515 +/- 64 to 285 +/- 58 microm, P < 0.05) and mean plasma FFA during the OGTT (263 +/- 32 to 151 +/- 25 microm, P < 0.05); insulin-mediated suppression of plasma FFA concentration during the insulin clamp also was enhanced (162 +/- 18 to 120 +/- 15 microm, P < 0.10). Following acipimox, fasting plasma glucose (5.1 +/- 0.1 vs. 5.2 +/- 0.1 mm) did not change, whereas mean plasma glucose during the OGTT decreased (7.6 +/- 0.5 to 6.9 +/- 0.5 mm, P < 0.01) without change in mean plasma insulin concentration (402 +/- 90 to 444 +/- 102 pmol/liter). After acipimox Rd increased from 5.6 +/- 0.5 to 6.8 +/- 0.5 mg/kg.min (P < 0.01) due to an increase in insulin-stimulated nonoxidative glucose disposal (2.5 +/- 0.4 to 3.5 +/- 0.4 mg/kg.min, P < 0.05). The increment in Rd correlated closely with the decrement in fasting plasma FFA concentration (r = -0.80, P < 0.02). Basal EGP did not change after acipimox (1.9 +/- 0.1 vs. 2.0 +/- 0.1 mg/kg.min), but insulin-mediated suppression of EGP improved (0.22 +/- 0.09 to 0.01 +/- 0.01 mg/kg.min, P < 0.05). EGP during the insulin clamp correlated positively with the fasting plasma FFA concentration (r = 0.49, P = 0.06) and the mean plasma FFA concentration during the insulin clamp (r = 0.52, P < 0.05). Plasma adiponectin (7.1 +/- 1.0 to 7.2 +/- 1.1 microg/ml), resistin (4.0 +/- 0.3 to 3.8 +/- 0.3 ng/ml), IL-6 (1.4 +/- 0.3 to 1.6 +/- 0.4 pg/ml), and TNFalpha (2.3 +/- 0.3 to 2.4 +/- 0.3 pg/ml) did not change after acipimox treatment. We concluded that sustained reduction in plasma FFA concentration in subjects with a strong family history of T2DM increases peripheral (muscle) and hepatic insulin sensitivity without increasing adiponectin levels or altering the secretion of other adipocytokines by the adipocyte. These results suggest that lipotoxicity already is well established in individuals who are genetically predisposed to develop T2DM and that drugs that cause a sustained reduction in the elevated plasma FFA concentration may represent an effective modality for the prevention of T2DM in high-risk, genetically predisposed, normal glucose-tolerant individuals despite the lack of an effect on adipocytokine concentrations.

Adiponectin↗

PubMed1988

Pharmacodynamic basis for altered drug action in the elderly.

The elderly have the highest incidence of medical and psychiatric disorders. These conditions frequently occur simultaneously and are often chronic, lasting the lifetime of the individual. Consequently, the elderly require more medications than do younger patients. Consumption of over-the-counter drugs is considerable among the aged. There is considerable evidence that the elderly patient in most cases responds differently to drugs than do young adults. Many factors contribute to these differences. Among them are reduced protein binding, reduced biotransformation, diminished renal elimination, changes in receptor density or affinity, or both, diminished receptor adaptability, changes in the coupling between receptors and effector systems, impairment of responding organs resulting from the pathologic state, reduction in the reactivity of homeostatic mechanisms, and the aging process itself. These components may have different weight, depending on the drug and the individual considered. Because of the physiologic age-related changes in the distribution and elimination of drugs and in the sensitivity to medications, adverse side effects develop frequently in the elderly. Accordingly, dosages and dosage intervals must be adjusted carefully. In addition, since the elderly often take multiple medications, they frequently experience ADRs. Psychotropic drugs are often involved in such interactions and cause twice the incidence of side effects in elderly patients as they do in younger patients. Drug-nutrient and drug-drug interactions, programs to enhance patient compliance, and sociogenic factors should be taken into account in any well-designed dose regimen for the elderly. Physician awareness of problems that exist in the elderly population's use of drugs is essential if rational drug therapy for the aged is to evolve. The proper use of drugs in the elderly largely depends on taking into account both the pharmacokinetic and the pharmacodynamic properties of the drug and how these parameters are altered with age; such information can be obtained only by investigating drug action in older people.

Aged↗

PubMedDate not supplied

The effects of doxazosin on plasma lipid and lipoprotein levels in hypertensive patients.

Plasma lipid and lipoprotein levels were evaluated in 27 adults with essential hypertension at four different periods during a 12-month treatment with doxazosin. Mean plasma total cholesterol (TC), low-density lipoprotein-cholesterol (LDLC), triglyceride (TG), very low density lipoprotein-cholesterol (VLDLC) and the LDLC/HDLC ratio were significantly reduced following doxazosin therapy. The HDLC/C ratio was found to be increased, while mean high density lipoprotein cholesterol (HDLC) level remained unchanged at 3, 6, 9 and 12 months of measurement after doxazosin treatment. Our data showed that the duration of doxazosin treatment did not influence the observed favourable lipid changes; but TC and LDLC appear to be the lipid fractions most affected by doxazosin in all the patients. In order to determine the possible factors responsible for the lipid-altering actions of doxazosin treatment, we observed beneficial lipid and lipoprotein changes in both the male and female subpopulations of patients with a slightly higher magnitude in the females. The dosage of doxazosin was, however, found to have no influence on the lipid-altering actions; a further study was therefore recommended.

Adult↗

PubMed2006

Delayed satiety-like actions and altered feeding microstructure by a selective type 2 corticotropin-releasing factor agonist in rats: intra-hypothalamic urocortin 3 administration reduces food intake by prolonging the post-meal interval.

Brain corticotropin-releasing factor/urocortin (CRF/Ucn) systems are hypothesized to control feeding, with central administration of 'type 2' urocortins producing delayed anorexia. The present study sought to identify the receptor subtype, brain site, and behavioral mode of action through which Ucn 3 reduces nocturnal food intake in rats. Non-food-deprived male Wistar rats (n=176) were administered Ucn 3 into the lateral (LV) or fourth ventricle, or into the ventromedial or paraventricular nuclei of the hypothalamus (VMN, PVN) or the medial amygdala (MeA), regions in which Ucn 3 is expressed in proximity to CRF(2) receptors. LV Ucn 3 suppressed ingestion during the third-fourth post-injection hours. LV Ucn 3 anorexia was reversed by cotreatment with astressin(2)-B, a selective CRF(2) antagonist and not observed following equimole subcutaneous or fourth ventricle administration. Bilateral intra-VMN and intra-PVN infusion, more potently than LV infusion, reduced the quantity (57-73%) and duration of ingestion (32-68%) during the third-fourth post-infusion hours. LV, intra-PVN and intra-VMN infusion of Ucn 3 slowed the eating rate and reduced intake by prolonging the post-meal interval. Intra-VMN Ucn 3 reduced feeding bout size, and intra-PVN Ucn 3 reduced the regularity of eating from pellet to pellet. Ucn 3 effects were behaviorally specific, because minimal effective anorectic Ucn 3 doses did not alter drinking rate or promote a conditioned taste aversion, and site-specific, because intra-MeA Ucn 3 produced a nibbling pattern of more, but smaller meals without altering total intake. The results implicate the VMN and PVN of the hypothalamus as sites for Ucn 3-CRF(2) control of food intake.

Amygdala↗

PubMed1983

[Damaging action of dithizone on insulin-releasing cells].

Alterative action of dithizone was investigated in the experiments on various species of animals (fish, frogs, pigeons, mice, guinea pigs, golden hamsters, rats, rabbits, cats and dogs). The data received support the previously advanced suggestion that unsaturated (electrophilic) zinc complex formation is the basic mechanism of the alterative chelant's action.

Animals↗

PubMed2001

Alterations in action potential profile enhance excitation-contraction coupling in rat cardiac myocytes.

Action potential (AP) prolongation typically occurs in heart disease due to reductions in transient outward potassium currents (Ito), and is associated with increased Ca2+ transients. We investigated the underlying mechanisms responsible for enhanced Ca2+ transients in normal isolated rat ventricular myocytes in response to the AP changes that occur following myocardial infarction. Normal myocytes stimulated with a train of long post-myocardial infarction (MI) APs showed a 2.2-fold elevation of the peak Ca2+ transient and a 2.7-fold augmentation of fractional cell shortening, relative to myocytes stimulated with a short control AP. The steady-state Ca2+ load of the sarcoplasmic reticulum (SR) was increased 2.0-fold when myocytes were stimulated with trains of long post-MI APs (111 +/- 21.6 micromol l(-1)) compared with short control APs (56 +/- 7.2 micromol l(-1)). Under conditions of equal SR Ca2+ load, long post-MI APs still resulted in a 1.7-fold increase in peak [Ca2+]i and a 3.8-fold increase in fractional cell shortening relative to short control APs, establishing that changes in the triggering of SR Ca2+ release are largely responsible for elevated Ca2+ transients following AP prolongation. Fractional SR Ca2+ release calculated from the measured SR Ca2+ load and the integrated SR Ca2+ fluxes was 24 +/- 3 and 11 +/- 2 % following post-MI and control APs, respectively. The fractional release (FR) of Ca2+ from the SR divided by the integrated L-type Ca2+ flux (FR/[integral]FCa,L) was increased 1.2-fold by post-MI APs compared with control APs. Similar increases in excitation-contraction (E-C) coupling gains were observed establishing enhanced E-C coupling efficiency. Our findings demonstrate that AP prolongation alone can markedly enhance E-C coupling in normal myocytes through increases in the L-type Ca2+ current (ICa,L) trigger combined with modest enhancements in Ca2+ release efficiency. We propose that such changes in AP profile in diseased myocardium may contribute significantly to alterations in E-C coupling independent of other biochemical or genetic changes.

Action Potentials↗

PubMed2006

Sphingosine-1-phosphate effects on guinea pig atrial myocytes: Alterations in action potentials and K+ currents.

OBJECTIVE: Sphingosine-1-phosphate (S-1-P), a potent lysophospholipid mediator which is released from platelets during clotting, activates a G-protein-gated inwardly rectifying K+ current (GIRK) in atrial and sino-atrial node myocytes. We denote this current I(K(S-1-P).) A similar GIRK, which is activated by acetylcholine (ACh) and denoted I(K(ACh)), is expressed in atrium. It shortens the action potential duration (APD) and reduces the effective refractory period (ERP). We have examined the effect of S-1-P on APD in guinea pig atrial myocytes by characterizing the rectification properties of I(K(S-1-P)) and evaluating whether I(K(S-1-P)) and I(K(ACh)) exhibit convergence/occlusion. METHODS: Membrane potential and K+ currents were recorded from guinea pig atrial myocytes. Inwardly rectifying K+ currents were recorded using a ramp voltage clamp waveform between +30 to -130 mV from a holding potential of -7 mV. Agonist-induced current changes were obtained by subtracting the control current. RESULTS: S-1-P (1 and 10 nM) altered both passive and active properties of atrial myocytes. S-1-P increased the threshold current for excitation and decreased the time constant of the subthreshold electrotonic potentials. In addition, both APD50 and APD90 were decreased substantially. Voltage clamp analysis showed that the outward conductance of I(K(IR)) (G(K(IR)out)) was 134.8+/-11.3 pS pF(-1) (n = 19) in S-1-P (100 nM), and 207.0+/-19.6 pS pF(-1) (n = 18) in ACh (10 microM). The ratio of G(K(IR)out):G(K(IR)in) was about 0.7 for both S-1-P and ACh. The EC50 values for the activation of G(K(IR)out) and G(K(IR)in) by S-1-P were 1.6 and 1.3 nM, respectively. Addition of S-1-P (100 nM) after the effect of ACh (10 microM) had developed fully caused very little additional change. CONCLUSION: I(K(S-1-P)) is carried by weakly inwardly-rectifying K+ channels that are the same as those activated by ACh. This K+ current can markedly shorten APD in guinea pig atrial myocytes. This effect would be expected to increase the incidence of atrial rhythm disturbances.

Acetylcholine↗

PubMed1990

Levonorgestrel and norethindrone alter insulin action on skeletal muscle of the female rat.

Prospective studies of women receiving oral contraceptives suggest that the progestin component may induce insulin resistance and variable deterioration of glucose tolerance. Because the tissue sites and nature of this insulin antagonism are not well-defined, we studied the effects of two parenterally administered progestins, levonorgestrel (NG) and norethindrone (NE), on insulin-regulated glucose uptake and phenylalanine release by the perfused rat hindquarter. Female rats were injected sc for 14 days with NG or NE (10 or 30 micrograms/kg/day). Low-dose NG and high-dose NE approximate the per kg dose received by women taking a high-dose progestin oral contraceptive. Phenylalanine release and glucose uptake (nmole/min/g) by the perfused hindquarters were calculated from the A-V difference for each. Progestin treatment (30 micrograms/kg/d) significantly reduced phenylalanine release from hindquarters perfused without exogenous insulin. Hindquarters from the high dose NG and low and high dose NE rats perfused with insulin (100 microU/ml) released 22% less phenylalanine than control rats perfused with the same insulin concentration (P less than 0.01) but the net suppression below baseline was similar in the control and steroid-treated groups. High-dose progestin treatment did not alter glucose uptake by hindquarters perfused without exogenous insulin. Insulin (100 microU/ml) increased glucose uptake by hindquarters of control and progestin-treated rats as compared to animals in the same treatment group perfused without exogenous insulin (P less than 0.01). High dose NE impaired insulin-stimulated glucose uptake 24% below values of the control group (P less than 0.01). The other NE and NG doses had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Premedication with oral dexmedetomidine alters hemodynamic actions of intravenous anesthetic agents in chronically instrumented dogs.

Dexmedetomidine (the D-stereoisomer of medetomidine), a highly selective alpha 2-adrenoceptor agonist, has been demonstrated to produce analgesia and sedation and attenuate hemodynamic responses to emergence from inhalational anesthetics, which suggests a potential use for this drug as a premedicant for general anesthesia. The authors examined hemodynamic interactions between dexmedetomidine and three commonly used intravenous anesthetic agents with markedly different hemodynamic effects. Conscious, chronically instrumented dogs received intravenous induction doses of ketamine, propofol, or etomidate, followed by continuous infusions of each drug at four different doses for 15-min intervals on different days. Studies in six separate groups (range, 9-12 dogs/group) with and without pretreatment with oral dexmedetomidine (20 micrograms/kg) were completed. Heart rate, arterial pressure, left ventricular pressure, rate of increase of left ventricular pressure at 50 mmHg (dP/dt50), and cardiac output were continuously recorded. Dexmedetomidine administration caused a significant (P less than 0.05) decrease in heart rate, rate-pressure product, left ventricular dP/dt50, and cardiac output. Dexmedetomidine abolished or attenuated the increase in heart rate, rate-pressure product, cardiac output, and arterial pressure produced during induction of anesthesia with ketamine. After the dexmedetomidine pretreatment, continuous infusion of ketamine caused no increase in heart rate or rate-pressure product. However, ketamine significantly reduced left ventricular dP/dt50 compared to control in dogs premedicated with dexmedetomidine. Except for a significant reduction in systemic vascular resistance, dexmedetomidine did not significantly affect the hemodynamic response to induction of anesthesia with propofol. Similarly, dexmedetomidine did little to alter the hemodynamic response to induction of anesthesia with etomidate.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed2000

Influence of baseline values on lipids, lipoproteins and fibrinolytic parameters during treatment of hypertension with cilnidipine.

Sixteen adult hypertensive patients of both sexes, classified as having 'medium' (total lipid profile 240-300 mg dl(-1)), and 'high' (total lipid profile >300 mg dl(-1)) baseline values, underwent serum lipids, lipoproteins and plasma fibrinolytic parameters evaluations after 3 months of cilnidipine treatment. Patients with 'medium baseline values' did not have any change in lipids, lipoproteins and fibrinolytic parameters while patients with 'high baseline values' had beneficial lipid and lipoprotein changes [decreases in total cholesterol (TC), triglycerides (TG), very low density lipoprotein-cholesterol (VLDLC) and increases in high density lipoprotein-cholesterol (HDLC), and HDLC/TC ratio] after cilnidipine treatment. Changes in lipids were negatively associated with fibrinolysis for the patients with 'medium baseline values' and positively associated in patients with 'high baseline values' after cilnidipine treatment. Reduction in blood pressure was related to fibrinolysis and reduced risk of coronary heart disease in the patients with 'high baseline values' after cilnidipine therapy. These results show that during cilnidipine treatment, the baseline lipid profile levels of the patients may influence the lipid altering actions as well as the interaction between lipids and fibrinolysis.

Aged↗

PubMed1991

[Effects of lipoic acid on reperfusion induced arrhythmias and myocardiac action potential alterations induced by free radical generating system].

By means of Langendorff method the isolated rat heart was perfused with Krebs Henseleit solution. Following ligation of the left descending coronary artery for 10 min the heart was reperfused for 3 min. The incidence of ventricular fibrillation in the reperfusion period was 100%, and the normal sinus rhythm time was shortened to 29 s within 3 min of reperfusion. Administration of lipoic acid (6.8 X 10(-6)-1.7 X 10(-4) mol/L) to the perfusate significantly reduced the incidence of ventricular fibrillation to 33-50% and prolonged the normal sinus rhythm time to 97-107 s. APA, RP, and Vmax recorded from the guinea pig papillary muscle were depressed due to the deleterious effect of xanthine oxidase and hypoxanthine free radical generating system. Under the treatment of lipoic acid (3.5 X 10(-5) mol/L), the depression of APA, RP, and Vmax were significantly relieved. This confirms that lipoic acid treatment, owing to its free radical scavenger effect, is able to protect myocardium from free radical induced electrophysiological abnormalities, and consequently decrease the incidence of malignant arrhythmias.

Action Potentials↗

PubMed1997

Effects of hepatic glycogen content on hepatic insulin action in humans: alteration in the relative contributions of glycogenolysis and gluconeogenesis to endogenous glucose production.

Hepatic glycogen content varies by almost 2-fold during the day, generally increasing from a nadir before breakfast to a peak 4-5 h after supper. To determine whether differences in hepatic glycogen content of this magnitude alter hepatic insulin action, nine subjects were studied on two occasions. On one occasion saline was infused, whereas on the other occasion an infusion of glucose [16.4 micromol/kg lean body mass (-lbm) x min] was started immediately after supper and continued throughout the night so as to spare hepatic glycogen. The nocturnal glucose infusion resulted in higher (P < 0.05) plasma glucose (6.0 +/- 0.1 vs. 5.1 +/- 0.1 mmol/L) and insulin (127 +/- 38 vs. 49 +/- 9 pmol/L) concentrations, and lower (P < 0.05) plasma glucagon concentrations (74 +/- 11 vs. 97 +/- 20 pg/mL) than did saline infusion. As anticipated, endogenous glucose production (EGP) was substantially lower (P < 0.001) during the glucose than during the saline infusion (7.0 +/- 0.9 vs. 19.4 +/- 1.3 micromol/kg-lbm x min). After discontinuation of the glucose infusion, glucose and insulin concentrations fell to levels that no longer differed from those observed during the saline infusion. In contrast, EGP increased to rates that were higher (P < 0.05) than those observed over the same interval after overnight saline infusion (19.2 +/- 1.2 vs. 16.5 +/- 0.7 micromol/kg-lbm x min). Despite higher EGP, the rate of incorporation of 14CO2 into glucose was lower (P < 0.001) after glucose than that after saline infusion (9.8 +/- 1.2% vs. 24.4 +/- 3.0%), implying a reciprocal relationship between hepatic glycogen content and gluconeogenesis. On the other hand, when differences in basal rates were taken into account, insulin-induced suppression of both EGP and incorporation of 14CO2 into glucose did not differ on the two occasions. Thus, whereas hepatic glycogen content influences both the absolute rate of EGP and the percent contribution of gluconeogenesis to EGP, it does not alter hepatic insulin action.

Blood Glucose↗