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PubMed2004

Pharmacology of GABAC receptors: responses to agonists and antagonists distinguish A- and B-subtypes of homomeric rho receptors expressed in Xenopus oocytes.

GABA(C) receptors, expressed predominantly in vertebrate retina, are thought to be formed mainly by GABA rho subunits. Five GABA rho subunits have been cloned from white perch retina, four of which form functional homooligomeric receptors when expressed in Xenopus oocytes. These rho subtypes, classified as rho1A, rho1B, rho2A and rho2B receptors based on amino acid sequence alignment, exhibit distinct temporal and pharmacological properties. To examine further the pharmacological properties associated with the various rho receptor subtypes, we investigated the effects of a selective GABA(C) receptor antagonist, TPMPA, on the GABA-mediated activity of receptors formed in Xenopus oocytes by the four GABA rho subunits. In addition, we recorded the activation profiles of beta-alanine, taurine, and glycine, three amino acids that modulate neuronal activity in various parts of the CNS and are purported to be rho receptor agonists. TPMPA effectively inhibited GABA-elicited responses on A-type receptors, whereas B-type receptors exhibited a relatively low sensitivity to the drug. A-type and B-type receptors also displayed distinctly different reactions to agonists. Both taurine and glycine-activated the B-type receptors, whereas these agents had no detectable effect on A-type receptors. Similarly, beta-alanine evoked large responses from B-type receptors, but was far less effective on A-type receptors. These results indicate that, in addition to the characteristic response properties identified previously, there is a pattern of pharmacological reactions that further distinguishes the A- and B-subtypes of GABA rho receptor.

Alanine↗
PubMed2004

Kinetic and pharmacological characterization of desensitizing and non-desensitizing glutamate-gated chloride channels in cockroach neurons.

Glutamate-gated chloride channels (GluCls) are found only in invertebrate nerve and muscle, where they mediate inhibitory synaptic transmission, and are important target sites of insecticides. Two GluCl subtypes have previously been distinguished in isolated cockroach CNS neurons based on differential pharmacology. The present study characterizes the kinetics and pharmacological properties of desensitizing and non-desensitizing GluCls. Both types of GluCls were sensitive to glutamate and ibotenic acid. The non-desensitizing GluCl subtype was elicited by glutamate with an EC(50) of 115.8 microM and a Hill coefficient of 2.6 and was also sensitive to the agonist ibotenic acid with an EC(50) of 42 microM and a Hill coefficient of 1.7. The desensitizing and non-desensitizing currents were carried by chloride ions, and occurred either separately or in combination in individual neurons. The GluCls were also found to coexist with and function independently of the GABA-activated chloride channels. The desensitizing and non-desensitizing GluCls exhibited different sensitivities to the ligand-gated channel blocker picrotoxinin. The desensitizing GluCls were blocked only 8% by 30 microM picrotoxinin, whereas the non-desensitizing GluCls were potently blocked by picrotoxinin with an IC(50) of 4.1 microM. The insecticides fipronil and dieldrin at 1 microM inhibited the desensitizing currents by 56 and 13%, respectively, and the non-desensitizing currents by 98 and 43%, respectively. It is concluded that the two types of GluCls found in cockroach neurons exhibit significantly different electrophysiological and pharmacological characteristics.

Animals↗
PubMed2005

The subunit composition and pharmacology of alpha-Conotoxin MII-binding nicotinic acetylcholine receptors studied by a novel membrane-binding assay.

The subunit composition and pharmacology of alpha-Conotoxin MII-binding (alpha-CtxMII) nicotinic acetylcholine receptors (nAChR) was studied by an improved [(125)I]-alpha-CtxMII membrane binding method. This binding method facilitates pharmacological studies that have been difficult to accomplish with [(125)I]-alpha-CtxMII autoradiography or alpha-CtxMII inhibition of [(125)I]-epibatidine binding. Binding densities and K(d)-values obtained by this [(125)I]-alpha-CtxMII membrane binding were similar to the values obtained by autoradiography or alpha-CtxMII inhibition of [(125)I]-epibatidine binding, verifying that each of these approaches measures the same nAChR population. Binding results with nAChR subunit-null mutant mice confirm and extend observations from earlier studies: [(125)I]-alpha-CtxMII binding measures two sets of alpha6beta2* nAChR (alpha4alpha6beta2beta3 or alpha6beta2beta3). Most nicotinic agonists and antagonists show monophasic inhibition of [(125)I]-alpha-CtxMII binding, indicating that alpha4alpha6beta2beta3 and alpha6beta2beta3 have similar binding properties. Comparison of the binding and activation profiles of alpha6beta2* nAChR to those of other nAChR subtypes (alpha4beta2* and beta4*) indicates that these receptors have distinctly different pharmacology indicating that it may be possible to target alpha6beta2* nAChR selectively to develop compounds that might be therapeutically useful.

Acetylcholine↗
PubMed2005

Use of an inverse agonist radioligand [3H]A-317920 reveals distinct pharmacological profiles of the rat histamine H3 receptor.

Selective radioligands for histamine H(3) receptors have been used to characterize H(3) receptor pharmacology by radioligand binding assays and to determine H(3) receptor distribution by tissue autoradiography. Here we report the synthesis and receptor binding characterization of [(3)H]A-317920 (furan-2-carboxylic acid(2-[4-[3-([3,5-(3)H]4-cyclopropanecarbonyl-phenoxy)-propyl]-piperazin-1-yl]-1-methyl-2-oxo-ethyl)-amide), a high affinity inverse agonist radioligand for the rat H(3) receptor. The binding of [(3)H]A-317920 to rat cortical and cloned H(3) receptors revealed fast on- and slower off-rate kinetics with calculated K(d) values in agreement with those determined in saturation binding assays (0.2 nM for both receptors). Further, we compared [(3)H]A-317920 with the agonist [(3)H](N)-alpha-methylhistamine ([(3)H]NalphaMH) as radioligand tools to study receptor pharmacology. Agonists and antagonists displaced [(3)H]NalphaMH with one-site binding characteristics and Hill slopes approached unity. In contrast, although antagonists exhibited one-site binding, [(3)H]A-317920 displacement by agonists was best fit by two-site binding models, and the potencies of the high affinity, GDP-sensitive sites correlated with the potencies defined in [(3)H]NalphaMH binding. Unlike [(125)I]iodoproxyfan, [(3)H]A-317920 exhibits potent and selective binding to rat H(3) receptors with low binding to non-H(3) sites, including cytochrome P450. These findings show that [(3)H]A-317920 is a potent rat H(3) receptor antagonist radioligand and has utility for studying H(3) receptor pharmacology.

Animals↗
PubMed2006

Neurorestorative treatment of stroke: cell and pharmacological approaches.

There is a compelling need to develop cell and pharmacological therapeutic approaches to be administered beyond the hyperacute phase of stroke. These therapies capitalize on the capacity of the brain for neuroregeneration and neuroplasticity and are designed to reduce neurological deficits after stroke. This review provides an update of bone marrow-derived mesenchymal stem cells (MSCs) and select pharmacological agents in clinical use for other indications that promote the recovery process in the subacute and chronic phases after stroke. Among these agents are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), erythropoietin (EPO), and phosphodiesterase type 5 (PDE-5) inhibitors and nitric oxide (NO) donors. Both the MSCs and the pharmacologic agents potentiate brain plasticity and neurobehavioral recovery after stroke.

Animals↗
PubMed2006

Zinc at pharmacologic concentrations affects cytokine expression and induces apoptosis of human peripheral blood mononuclear cells.

OBJECTIVE: The present study examined the effect of zinc at concentrations of the apoptotic signaling pathway and immune function of peripheral blood mononuclear cells (PBMCs). METHODS: PBMCs from healthy subjects were treated in vitro with various zinc concentrations to imitate different serum statuses of physiologic (2 to 15 microM) and pharmacologic (15 to 100 microM) concentrations to higher than 100 microM and analyzed their expressions of cytokines and apoptotically related factors. RESULTS: Although a normal physiologic concentration of zinc had no effect on immunologic function or apoptosis of PBMCs, a pharmacologic concentration (100 microM) or higher affected both functions. Zinc decreased cell proliferation at concentrations higher than 100 microM and stimulated cytokine expression at concentrations of at least 100 microM. Further, at concentrations of at least 100 microM, apoptosis was induced, and expressions of caspase-3 and proapoptotic genes, including Fas (FasL) and c-fos, which trigger apoptosis through receptor-mediated extrinsic and mitochondrion-mediated apoptotic pathways, respectively, were increased. At concentrations at least 300 microM, expressions of antiapoptotic factors nuclear factor-kappaB, Bcl-2, and Bcl-X(L) were markedly decreased. CONCLUSIONS: Zinc stimulates cytokine expression and induces apoptosis of PBMCs from healthy subjects only at concentrations equal to or greater than the serum pharmacologic range. Receptor-mediated extrinsic and mitochondrial-mediated intrinsic pathways are involved in this zinc-induced apoptosis.

Adult↗
PubMed2006

The pharmacology of nitroxyl (HNO) and its therapeutic potential: not just the Janus face of NO.

Nitroxyl (HNO), the 1-electron reduced and protonated congener of nitric oxide (NO), has received recent attention as a potential pharmacological agent for the treatment of heart failure and as a preconditioning agent for the mitigation of ischemia-reperfusion injury. Interest in the pharmacology and biology of HNO has prompted examination, or in some instances reexamination, of many of its chemical properties. Such studies have provided insight into the chemical basis for the biological effects of HNO, although the biochemical mechanisms for many of these effects remain to be established. In this review, a brief description of the biologically relevant chemistry of HNO is given, followed by a more detailed discussion of the pharmacology and potential toxicology of HNO.

Alcoholism↗
PubMed2006

The active components and the pharmacological multi-target principle of STW 5 (Iberogast).

The therapeutic equivalence of the multi-herbal drug combination STW 5 (Iberogast) with two synthetic standard drugs can be explained by an additive or overadditive pharmacological synergism. A review of the different chemical constituents contained in this fixed combination of nine herbal drug extracts and their dominant mechanisms of action shows that they correlate very well with the clinically relevant overall pharmacological profile of the multi-herbal drug combination. This comprises modulatory effects on gastro-intestinal motility, anti-inflammatory action, inhibitory effects on gastric acid production and anti-oxidative and radical-inhibiting properties. As a multi-drug preparation with a multitude of therapeutic targets relevant in functional gastrointestinal diseases, its pharmacological profile of action in accordance with the multi-target principle.

Anti-Inflammatory Agents↗
PubMed2005

Analysis of pharmacologic and nonpharmacologic prescription patterns of general practitioners and specialists in the AMICA study.

OBJECTIVE: To evaluate the prescription modalities of general practitioners (GPs) and specialists in symptomatic osteoarthritis (OA) patients enrolled in the AMICA study. PATIENTS AND METHODS: This study started in 2001 as a cohort investigation of OA patients seen by 2764 GPs and 316 specialists. Enrolled were 28,981 patients with symptomatic OA of the hand, hip, or knee. RESULTS: GPs and physical medicine specialists treated OA less frequently with pharmacological therapy than rheumatologists (OR 0.35; CI 0.26 to 0.47) or orthopedic surgeons (OR 0.65; CI 0.54 to 0.77). Pharmacological therapies (alone or in association with nonpharmacological modalities) were selected by 97% of the GPs, 96% of the rheumatologists, 94% of the orthopedic surgeons, and 85% of the physical medicine specialists. In comparison with GPs, all of the specialists more frequently used disease-modifying OA drugs (DMOADs) (rheumatologists: OR 6.86, CI 6.03 to 7.80; orthopedic surgeons: OR 2.20, CI 1.94 to 2.49; physical medicine specialists: OR 2.11, CI 1.69 to 2.63). Nonpharmacological therapies were selected by 44% of the GPs, 54% of the rheumatologists, 71% of the orthopedic surgeons, and 90% of the physical medicine specialists. They were used alone uncommonly (by 3% of the GPs, 3% of the rheumatologists, 6% of the orthopedic surgeons, and 15% of the physical medicine specialists). GPs use nonpharmacological treatment less than specialists: OR 0.53; CI 0.47 to 0.60 versus rheumatologists; OR 0.20; CI 0.18 to 0.21 versus orthopedic surgeons; and OR 0.07; CI 0.05 to 0.09 versus physical medicine specialists. Ultrasound (US) (11%) and transcutaneous electrical nerve stimulation (TENS) (7%) were the nonpharmacological therapies most frequently prescribed by GPs. Among the specialists, physical medicine specialists most frequently prescribed US (35%) and TENS (21%); US was also preferred by rheumatologists, whereas the orthopedic surgeon's choice was magnetotherapy (21%). Exercises and other passive or active rehabilitation strategies were prescribed for only 13% of the patients seen by GPs, but all 3 categories of specialists prescribed exercises and manual techniques far more frequently: rheumatologists, OR 1.63: 1.40 to 1.63; orthopedic surgeons, OR 1.67: 1.48 to 1.88; physical medicine specialists, OR 3.19: 2.66 to 3.82. CONCLUSIONS: Italian rheumatologists and orthopedic surgeons are the specialists who most frequently use pharmacological treatment for OA. Nonpharmacological treatment is used commonly among both GPs and specialists but rarely as single therapy. Exercise and passive or active rehabilitation strategies are not frequently prescribed, although they are recommended by all the published guidelines.

Aged↗
PubMedDate not supplied

The rat spinal cord slice: Its use in generating pharmacological evidence for cholinergic transmission using the alpha7 subtype of nicotinic receptors in the central autonomic nucleus.

Lamina X surrounds the central canal of the spinal cord and is an important site for the convergence of somatic and visceral afferent inputs relaying nociceptive information. Lamina X contains sympathetic preganglionic neurons (SPN) in the so-called central autonomic nucleus which may participate to viscero-autonomic reflexes. Here, we describe a transversal slice preparation of postnatal rat thoracolumbar spinal cord which allows the detailed characterization of the morphology, electrophysiological properties, synaptic activities and receptor pharmacology of neurons surrounding the central canal. By means of the patch clamp technique, in its whole cell configuration, and by the use of various pharmacological tools, we show here that lamina X neurons of the central autonomic nucleus express functional alpha7 nicotinic receptors which are located postsynaptically on SPNs where they are involved in a fast cholinergic transmission. Thus, this in vitro preparation is useful to study the mechanisms and the pharmacology of viscero-autonomic reflexes.

Aconitine↗
PubMedDate not supplied

Challenges and lessons learned since implementation of the safety pharmacology guidance ICH S7A.

The International Conference on Harmonization, Topic S7A guidance (ICH S7A) on safety pharmacology for human pharmaceuticals has been in effect for 3 years in Europe, the United States and Japan. Surveys of the pharmaceutical industry, regulatory agencies and the audience attending the 4th Annual Meeting of the Safety Pharmacology Society have helped identify and address areas of controversy, as well as those challenges that have emerged since implementation of the guidance worldwide. Overall, ICH S7A has been successfully implemented. The guidance provides for "Good Laboratory Practice" compliant "safety pharmacology core battery" of studies that are generally performed prior to first administration to humans. The approach is science-driven and specifies the use of robust and sophisticated in vitro and/or in vivo assays. There are, however, some areas that require further refinement/clarification such as the specifics of study design including the selection of dose/concentration, choice of species, modeling of the temporal pharmacodynamic changes in relation to pharmacokinetic profile of parent drug and major metabolites, use of an appropriate sample size, statistical power analysis as a means of demonstrating the sensitivity of the model system, testing of human-specific metabolites and demonstrating not only the model's sensitivity, but also its specificity for predicting adverse events in humans. There was also discussion of when these studies are needed in relation to the clinical development plan. Representatives from the pharmaceutical industry and regulatory agencies see the implementation of ICH S7A as a major step forward towards identifying the risk to Phase 1 and 2 volunteers and patients. It remains to be seen, however, whether and in what ways the ICH S7A-based strategy will contribute to the modification of the integrated risk assessment during the latter stages of clinical development or once drugs have been introduced to the marketplace.

Animals↗
PubMed2006

The object recognition task in rats and mice: a simple and rapid model in safety pharmacology to detect amnesic properties of a new chemical entity.

INTRODUCTION: The aim of the present study was to evaluate the potential usefulness of the object recognition learning paradigm to detect the potential amnesic properties of a new drug for use in the characterisation of its safety pharmacology profile. METHODS AND RESULTS: In the first experiment, the time-dependent decay of object recognition memory was characterised in Sprague-Dawley rats and C57Bl/6J mice. Under our experimental conditions, it takes between 3 and 4 post-training hours for the rats and between 1 and 2 post-training hours for the mice to forget the respective value of the objects. In the second experiment, the effects of scopolamine (0.03-1 mg/kg) were investigated in both rats and mice when administered 30 min prior to training in the object recognition task. Memory retention was tested 2 h after training in rats and 1 h after training in mice. Scopolamine impairs the object recognition memory at doses of 0.1, 0.3, and 1 mg/kg in rats and at doses of 0.3 and 1 mg/kg in mice. In the last experiment, effects of two benzodiazepines (alprazolam and diazepam) were assessed in the mouse model of object recognition task. Diazepam and alprazolam were intraperitoneally administered 30 min prior to training and memory retention was tested 10 min and 1 h after training. At 0.2 mg/kg, both benzodiazepines impair object recognition memory when testing is performed 1 h after training. However, when testing is performed 10 min after training, both benzodiazepines at 0.2 mg/kg failed to disrupt memory processes. DISCUSSION: Taken together, these results show that the object recognition task can easily be performed in rats and mice for safety pharmacology studies related to CNS function. Because of the ageing population and the increasing number of drugs prescribed to elderly patients, it becomes important to evaluate the potential side effects of a new chemical entity on memory function during evaluation of its safety profile. The object recognition task, which is simple, rapid, and reliable, should be of great use in safety pharmacology to detect amnesic properties of new compounds.

Alprazolam↗
PubMed2005

Intraperitoneal carboplatin infusion may be a pharmacologically more reasonable route than intravenous administration as a systemic chemotherapy. A comparative pharmacokinetic analysis of platinum using a new mathematical model after intraperitoneal vs. intravenous infusion of carboplatin--a Sankai Gynecology Study Group (SGSG) study.

OBJECTIVE: To clarify the pharmacological advantage of carboplatin-based intraperitoneal chemotherapy using the three-compartment mathematical model. METHODS: Eleven consecutive patients in one institution underwent intraperitoneal administration of carboplatin, and 11 consecutive patients in another institution received intravenous administration. Carboplatin (AUC=6 mg x min/ml) was diluted in 500 ml 5% glucose and administered either as an intraperitoneal bolus infusion or intravenous drip infusion during 1 h. Patients undergoing intravenous injection also received an infusion of 500 ml 5% glucose to obtain intraperitoneal samples. Intraperitoneal fluid and blood samples were obtained, immediately and 1, 2, 4, 8, 12, and 24 h after administration. The mathematical model consisting of a three-compartment model was applied to analyze the pharmacokinetics. The model was created with simultaneous differential equations and was solved by the Runge-Kutta method. RESULTS: The rate constants of platinum diffusion from the peritoneal cavity to serum, serum to peritoneal cavity, serum to peripheral space, peripheral space to serum, and elimination were 0.94+/-0.79 (mean+/-SD), 1.28+/-2.50, 16.50+/-9.26, 0.99+/-0.62, and 4.14+/-1.45 (h-1), respectively. When the theoretical pharmacological concentration of platinum was calculated using this mathematical model, 24-h platinum AUC in the serum was exactly the same regardless of intraperitoneal or intravenous administration of carboplatin. However, the 24-h platinum AUC in the peritoneal cavity was approximately 17 times higher when carboplatin was administered by the intraperitoneal route. CONCLUSION: The present pharmacological analysis suggests that intraperitoneal infusion of carboplatin is feasible not only as an intraperitoneal regional therapy but also as a more reasonable route for systemic chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Clinical, exercise electrocardiographic, and pharmacologic stress echocardiographic findings for risk stratification of hypertensive patients with chest pain.

Exercise electrocardiography (ECG) is of limited usefulness in hypertensive patients, whereas pharmacologic stress echocardiography can provide diagnostic and prognostic information. The aim of this study was to compare the prognostic value of clinical data, exercise ECG, and pharmacologic stress echocardiography in hypertensive patients with chest pain and to identify the best strategy for their risk stratification. Three hundred sixty-seven hypertensive patients (189 men, age 61 +/- 9 years) with chest pain of unknown origin underwent exercise ECG and pharmacologic stress echocardiography (237 with dipyridamole and 130 with dobutamine) and were followed up for 31 +/- 24 months. Positive exercise ECG (ST-segment shift of > or =1 mm at 80 ms after the J point) and stress echocardiography (new wall motion abnormalities) were found in 130 (35%) and 86 (23%) patients, respectively. During follow-up, there were 13 deaths and 16 myocardial infarctions. Additionally, 43 patients underwent coronary revascularization and were censored accordingly. Of 12 clinical, electrocardiographic, and echocardiographic variables analyzed, a positive result of stress echocardiography was the only multivariate predictor of either death (hazard ratio [HR] 4.7, 95% confidence interval [CI] 1.5 to 14.5, p = 0.007) or hard events (death, myocardial infarction) (HR 4.1, 95% CI 1.8 to 9.3, p = 0.0009). Using an interactive stepwise procedure, stress echocardiography provided additional prognostic information to clinical evaluation and exercise ECG. However, the negative predictive value of the 2 tests was similarly (p = NS) high in assessing 4-year event-free survival. In conclusion, a negative exercise electrocardiographic test identifies low-risk hypertensive patients with chest pain and should be the first-line approach for risk stratification. In contrast, positive exercise ECG is unable to distinguish between patients with different levels of risk. In this case, stress echocardiography provides strong and incremental prognostic power over clinical and exercise electrocardiographic data.

Cardiotonic Agents↗
PubMed1998

Preclinical and clinical pharmacology of cerivastatin.

Cerivastatin, a new, entirely synthetic, and enantiomerically pure 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is pharmacologically potent and hepatically selective, with an uncomplicated pharmacokinetic profile. In vitro and acute in vivo studies in animals demonstrated that cerivastatin is markedly more pharmacologically potent than other statins. In rats and dogs, cerivastatin inhibited hepatic cholesterol synthesis at concentrations 100-150 times lower than lovastatin. Cerivastatin's potent inhibition of HMG-CoA reductase (the rate-limiting step in cholesterol biosynthesis) is confirmed by its cholesterol-lowering properties, combined with significant triglyceride-decreasing effects, and dose-dependent increases in low-density lipoprotein (LDL) receptor binding in the liver. The antiatherogenic effects of cerivastatin extend beyond serum lipid and lipoprotein reductions to potent inhibition of migration of smooth muscle cells in vitro and reductions in the accumulation of cholesterol ester in the arterial tissue of rabbits. The high pharmacologic potency of cerivastatin, coupled with high liver selectivity, enable cerivastatin to be administered at 1-5% of the dose of currently available HMG-CoA reductase inhibitors. At ultra-low doses in the range 0.01-0.8 mg/day, cerivastatin proved to be both safe and well tolerated when administered to healthy volunteers in a series of ascending single- and multiple-dose studies. Cerivastatin has an uncomplicated pharmacokinetic profile; it can be administered to both young and elderly patients, male and female, without the need for dosage adjustments. Because no clinically significant pharmacokinetic drug interactions occur with cerivastatin, it may be the preferred HMG-CoA reductase inhibitor for patients on multiple-drug therapy including warfarin and digoxin.

Animals↗
PubMed2002

Comparative pharmacology of H1 antihistamines: clinical relevance.

H1 antihistamines have similar efficacy in the treatment of allergic disorders; however, they differ in terms of their chemical structure, clinical pharmacology, and safety. This review focuses on the clinical pharmacology (pharmacokinetics and pharmacodynamics) of the newer oral H1 antihistamines (acrivastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, and mizolastine). Understanding the pharmacokinetics and pharmacodynamics of these H1 antihistamines provides an objective basis for selection of appropriate dosages and dose intervals. Pharmacokinetic and pharmacodynamic studies provide a rationale for the modified dosage regimens that may be required in special populations, such as the very young, the elderly, those with hepatic or renal dysfunction, or those taking other medications concurrently. Many H1 antihistamines are currently available for use. Clinical pharmacology studies help physicians to select the best H1 antihistamines for their patients.

Administration, Oral↗
PubMed1981

Myocardial protection from permanent injury during aortic cross-clamping: effectiveness of pharmacological cardiac arrest combined with topical cardiac hypothermia.

In two groups of animals (6 and 9 dogs), the aorta was cross-clamped 60 and 90 minutes, respectively, during hypothermic cardiopulmonary bypass. Immediately after cross-clamping, pharmacological cardiac arrest was induced by injecting 100 ml of a cold cardioplegic solution into the aortic root. Topical cardiac hypothermia was added. In hearts undergoing 90 minutes of ischemia, a repeat injection of the cardioplegic solution was done at 45 minutes. In 14 dogs (control group), only topical cardiac hypothermia was instituted for myocardial protection during 60 minutes of ischemia. Seven weeks after operation the surviving animals (6 in each group) were killed. Study of myocardial performance failed to demonstrate significant differences among the groups. Microscopic examination of transmural samples taken from anatomically defined sides of both ventricles, disclosed isolated, punctuate subendocardial scars in only 2 hearts of the control group. All the hearts having 90 minutes of pharmacological cardiac arrest and topical cardiac hypothermia exhibited diffuse fibrosis replacing 10 to 20% of the left ventricular myocardium. Extent and incidence of fibrosis were significantly higher in these hearts in comparison to those of the other groups. We conclude that pharmacological cardiac arrest plus topical cardiac hypothermia makes a safe and efficient method of myocardial protection during aortic cross-clamping only if the ischemic intervals is limited to 60 minutes. It cannot prevent permanent myocardial injury if the ischemic arrest is extended to 90 minutes.

Animals↗
PubMed2000

Pharmacology of the receptors for the phorbol ester tumor promoters: multiple receptors with different biochemical properties.

The phorbol ester tumor promoters and related analogs are widely used as potent activators of protein kinase C (PKC). The phorbol esters mimic the action of the lipid second messenger diacylglycerol (DAG). The aim of this commentary is to highlight a series of important and controversial concepts in the pharmacology and regulation of phorbol ester receptors. First, phorbol ester analogs have marked differences in their biological properties. This may be related to a differential regulation of PKC isozymes by distinct analogs. Moreover, it seems that marked differences exist in the ligand recognition properties of the C1 domains, the phorbol ester/DAG binding sites in PKC isozymes. Second, an emerging theme that we discuss here is that phorbol esters also target receptors unrelated to PKC isozymes, a concept that has been largely ignored. These novel receptors lacking kinase activity include chimaerins (a family of Rac-GTPase-activating proteins), RasGRP (a Ras exchange factor), and Unc-13/Munc-13 (a family of proteins involved in exocytosis). Unlike the classical and novel PKCs, these "non-kinase" phorbol ester receptors possess a single copy of the C1 domain. Interestingly, each receptor class has unique pharmacological properties and biochemical regulation. Lastly, it is well established that phorbol esters and related analogs can translocate each receptor to different intracellular compartments. The differential pharmacological properties of the phorbol ester receptors can be exploited to generate specific agonists and antagonists that will be helpful tools to dissect their cellular function.

Animals↗