Depressed inotropic response to beta-adrenoceptor agonists in the presence of advanced cardiac hypertrophy in hearts from rats with induced aortic stenosis and from spontaneously hypertensive rats.

OBJECTIVE: To study the inotropic response to beta-adrenoceptor stimulation in isolated hypertrophied hearts from hypertensive rats. DESIGN AND METHODS: Cardiac hypertrophy was induced in Wistar rats by stenosing the abdominal aorta. Functional responses to isoprenaline, dobutamine, terbutaline and salbutamol were measured in paced (5 Hz), aortically stenosed hearts (18-20 and 32-34 weeks of age) and compared with those of sham-operated spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. RESULTS: Following aortic stenosis, which was accompanied by less hypertension than that sustained by SHR, the Wistar rat hearts showed more pronounced cardiac hypertrophy. An initially equal inotropic response to the beta-adrenoceptor agonists (18-20 weeks) was reduced to 45% at 32-34 weeks in SHR but not in WKY rat hearts. The response to beta-adrenoceptor stimulation in the hypertrophied Wistar rat hearts was reduced at 18-20 weeks to 30% and at 32-34 weeks to 10% of controls, respectively. The response by all hypertrophied hearts to forskolin and N,2'-O-dibutyryladenosine 3':5' monophosphate was also diminished. CONCLUSIONS: The impaired contractile response to beta-adrenoceptor agonism is more clearly related to cardiac hypertrophy than to hypertension.

Impaired inotropic response to alpha 1- but not to beta-adrenoceptor stimulation in isolated hearts from spontaneously hypertensive rats.

OBJECTIVES: Hypertension in humans and experimental animals is known to be associated with an increase in left ventricular myocardial mass. The development of cardiac hypertrophy is not caused by increased blood pressure alone; the autonomic nervous system may also play an important role. DESIGN: The functional responses to the beta-adrenoceptor agonists isoprenaline, dobutamine, salbutamol and terbutaline, and the alpha 1-adrenoceptor agonists methoxamine, cirazoline and phenylephrine were studied in isolated (Langendorff) hearts from spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) controls. The results were compared with data from radioligand binding experiments. RESULTS: There was no significant difference in the increase of left ventricular pressure induced by all beta-adrenoceptor agonists studied in SHR and WKY rat hearts. Although there was no significant difference in the response to phenylephrine, the inotropic responses to cirazoline and methoxamine proved to be significantly weaker in hearts from SHR than in those from WKY rats. Binding experiments with 3H-prazosin revealed no differences in density or affinity for cardiac tissues from SHR and WKY rats. CONCLUSIONS: Long-standing hypertension leads to an impaired response of the isolated heart to alpha 1-adrenoceptor stimulation, without changes in alpha 1-receptor density or affinity. It seems likely that changes in postreceptor events are responsible for the impaired inotropic response to alpha 1-adrenoceptor agonists in hearts from SHR.

Differential response of hypertrophied rat hearts to various alpha 1-adrenoceptor agonists.

With respect to the heart, the prolonged existence of hypertension, both in man and in experimental animals is predominantly characterized by an increase in left ventricular myocardial mass. In this process, the autonomic nervous system plays an important role. Although endogenous catecholamine stimulation of the heart is mainly exerted via the beta-adrenoceptors, in several mammalian species, the stimulation of cardiac alpha 1-adrenoceptors also mediates positive inotropic actions. We investigated the functional responses of isolated hypertrophied hearts taken from spontaneously hypertensive rats (SHR) and rats with an induced aortic stenosis (ASR) to various alpha 1-adrenoceptor agonists and compared them with those from age matched Wistar Kyoto (WKY) and "sham" operated controls. Accordingly, we studied the functional response to: methoxamine (alpha 1), cirazoline (alpha 1) and phenylephrine (alpha 1 > beta 1). The inotropic response to the alpha 1-adrenoceptor agonists cirazoline and methoxamine proved to be significantly weaker in hypertrophied hearts from SHR and ASR than in non-hypertrophied hearts from WHY and "sham" operated controls (p < 0.05). The inotropic response to phenylephrine remained intact in hypertrophied myocardial tissue. However, it was significantly reduced when the hearts were pre-treated with the intracellular Ca(2+)-antagonists ryanodine and TMB-8. These findings show that the mechanism of sarcolemmal Ca2+ release, activated by phenylephrine, is still intact in the hypertrophied myocardial cell. In conclusion, these data show that cardiac hypertrophy, be it of genetical or mechanical origin, leads to a reduced response of the isolated heart to alpha 1-adrenoceptor stimulation.

Improved HPLC-ECD analysis of mitomycin C, porfiromycin, VP 16-213 and VM 26 by implantation of software filters.

In high performance liquid chromatography with electrochemical detection (HPLC/ECD) much attention has been paid to the performance of the applied detection system with respect to reliability and sensitivity. In general, insufficient attention has been paid to relatively easy to implant devices for improved collection and handling of detection signals. Four models of software filtering are studied and compared with hardware filtering. In the investigated chromatographic-electrochemical system, off-line parabolic filtering after on-line averaging of sixteen measurements proved to be the system of first choice, with respect to execution time, noise level, signal to noise ratio, peak height and resolution.

[HIV-related non-Hodgkin lymphoma in 45 patients; a retrospective analysis]. / Met HIV samenhangend non-Hodgkin-lymfoom bij 45 patiënten; een retrospectieve analyse.

Non-Hodgkin lymphoma is seen in approximately 5% of patients with AIDS. In recent years, the incidence has increased due to an extension of the average lifespan of HIV-infected individuals. In this article we describe the histological and clinical features of 45 patients with HIV-related non-Hodgkin lymphoma seen at the Academic Medical Centre between 1984 and 1991. There were 43 men and 2 women with a median age of 40 years. Most patients had high-grade B-cell lymphoma; 85% had extranodal sites. Prognosis was poor: overall median survival was only 3.8 months. Twelve patients were treated with 3 or more courses of chemotherapy: their median survival was 8 months. In 7 of 12 patients a complete remission was obtained; their median survival was 18 months. A history of AIDS was a poor prognostic factor.

Intracytoplasmic glutathione levels in heifer oocytes cultured in different maturation media and its effect on embryo development.

The present study was carried out to study the effect of different maturation media on embryo development of heifer oocytes and on their glutathione (GSH) synthesis during in vitro maturation (IVM). Immature heifer oocytes were matured in parallel in one of four maturation media: (i) Tissue Culture Medium (TCM)-199 supplemented with 10 ng/ml of epidermal growth factor (EGF); (i) TCM-199 supplemented with 10 ng/ml of EGF plus 1 microg/ml of FSH; (iii) TCM-199 supplemented with 10% of foetal bovine serum (FBS) and (iv) TCM-199 supplemented with 10% of FBS plus 1 microg/ml of FSH. Cow oocytes were used as control and were matured in TCM-199 supplemented with 10 ng/ml of EGF. No differences were observed in blastocyst rate among the different heifer oocyte groups (8.8, 7.5. 8.4 and 6.8%, respectively) however, the percentage of blastocysts obtained from cow oocytes was significantly higher (30%; p < 0.01) than those obtained from heifer oocytes. De novo GSH synthesis during oocyte maturation of heifer and cow oocytes was detected. No significant differences in intracytoplasmic GSH levels were observed among the experimental heifer oocyte groups or between heifer and cow oocytes both before and after IVM. In conclusion, the blastocyst yield obtained from heifer oocytes was lower than that from cow oocytes and this fact could not be explained by significant differences in intracytoplasmic GSH contents of oocytes before or after IVM.

Sensitivity of cardiac tissues with moderate and advanced hypertrophy to calcium ions.

1. Prolonged existence of hypertension is known to induce a compensatory increase in cardiac weight, later followed by a loss of functional responsiveness to biological stimuli. 2. It was the aim of the present study to investigate the functional responses of hypertrophied hearts to rising levels of intracellular calcium. The experiments were performed using two different degrees of cardiac hypertrophy, the first as obtained in spontaneously hypertensive rats (SHR) of 18-20 weeks old, the second by using rats, 32-34 weeks old, with a surgically induced stenosis of the thoracic aorta (ASR). The ASR, which showed signs of overt heart failure, may be presented as a model for hypertension-induced end-stage cardiac hypertrophy. Age-matched normotensive Wistar-Kyoto rats (WKY) and sham-operated Wistar rats served as respective controls. 3. Different methods were employed such as increasing the extracellular Ca2+ concentration, stimulation of calcium influx by means of the calcium entry promoter Bay K 8644, or altering the sodium-calcium exchange by means of the sodium ionophore monensin. 4. The inotropic responses induced by increasing the extracellular Ca2+ concentration or provoked by the calcium entry promoter Bay K 8644 proved more pronounced in hearts taken from SHR of 18 weeks old than in those from normotensive control rats, whereas the response to monensin was found to be the same in both types of hearts. In the hearts of ASR, however, the inotropic responses to Ca2+, Bay K 8644 and monensin were strongly impaired. 5. These data demonstrate that in functional experiments the sensitivity to Ca2+, which represents the main pathway in establishing a contraction, is strongly reduced in advanced cardiac hypertrophy.

Impaired vasodilator and chronotropic responses to 5-hydroxytryptamine in two models of hypertension-associated cardiac hypertrophy.

OBJECTIVE: In connection with hypertension, research concerning 5-hydroxytryptamine (5-HT) receptors and subtypes in the cardiovascular system has so far been predominantly focused on various vascular tissues. In this study, the effects of 5-HT were investigated in isolated hearts with experimental cardiac hypertrophy. DESIGN AND METHODS: Cardiac hypertrophy was induced by stenosing the abdominal aorta (ASR) of 5-week-old Wistar rats. The functional response to serotonin was measured in unpaced, ASR hearts (18-20 weeks) and compared with those of "sham" operated SHR and WKY rats. RESULTS: The ASR, less hypertensive than SHR, showed more pronounced cardiac hypertrophy. The positive chronotropic and coronary vasodilator response to 5-HT was reduced in hypertrophied hearts from SHR and ASR when compared to "sham" operated and normotensive controls. The positive chronotropic effect of 5-HT could be antagonised with ketanserin, without affecting the coronary vasodilation. 5-HT did not induce any change in contractile force. CONCLUSIONS: Cardiac hypertrophy is associated with impaired coronary vasodilator and chronotropic responsiveness to serotonin. The chronotropic response to 5-HT is mediated by the 5-HT2-receptor subtype.

Predictive performance of computer-controlled infusion of remifentanil during propofol/remifentanil anaesthesia.

BACKGROUND: The predictive performance of the available pharmacokinetic parameter sets for remifentanil, when used for target-controlled infusion (TCI) during total i.v. anaesthesia, has not been determined in a clinical setting. We studied the predictive performance of five parameter sets of remifentanil when used for TCI of remifentanil during propofol anaesthesia in surgical patients. METHODS: Remifentanil concentration-time data that had been collected during a previous pharmacodynamic interaction study in 30 female patients (ASA physical status I, aged 20-65 yr) who received a TCI of remifentanil and propofol during lower abdominal surgery were used in this evaluation. The remifentanil concentrations predicted by the five parameter sets were calculated on the basis of the TCI device record of the infusion rate-time profile that had actually been administered to each individual. The individual and pooled bias [median performance error (MDPE)], inaccuracy [median absolute performance error (MDAPE)], divergence and wobble of the remifentanil TCI device were determined from the pooled and intrasubject performance errors. RESULTS: A total of 444 remifentanil blood samples were analysed. Blood propofol and remifentanil concentrations ranged from 0.5 to 11 micro g ml(-1) and 0.1 to 19.6 ng ml(-1) respectively. Pooled MDPE and MDAPE of the remifentanil TCI device were -15 and 20% for the parameter set of Minto and colleagues (Anesthesiology 1997; 86: 10-23), 1 and 21%, -6 and 21%, and -6 and 19% for the three parameter sets described by Egan and colleagues (Anesthesiology 1996; 84: 821-33, Anesthesiology 1993; 79: 881-92, Anesthesiology 1998; 89: 562-73), and -24 and 30% for the parameter set described by Drover and Lemmens (Anesthesiology 1998; 89: 869-77). CONCLUSIONS: Remifentanil can be administered by TCI with acceptable bias and inaccuracy. The three pharmacokinetic parameter sets described by Egan and colleagues resulted in the least bias and best accuracy.

The influence of coarctation hypertension on the pharmacodynamic behaviour of rat isolated conduit vessels.

We have studied the effects of coarctation hypertension on the reactivity of the aorta with respect to alpha 1-adrenoceptor mediated vasoconstriction and methacholine-induced endothelium-dependent vasodilation. The experiments were performed in aortic rings taken from rats that had been subjected to banding of the abdominal aorta, aortic stenosis rats (ASR), and from SHAM operated control rats. As expected, the thoracic aorta was subjected to elevated blood pressure, whereas the pressure in the abdominal aorta region was much lower. Concomitantly, the thoracic and abdominal aorta regions were studied separately as isolated vessels. Both the thoracic and abdominal aortic rings taken from ASR were more sensitive to phenylephrine than those obtained from control rats. The increase in sensitivity cannot be explained by elevated pressure alone and neurohormonal factors are likely to play a role. The maximal relaxation induced by methacholine in thoracic aortic rings obtained from ASR was significantly less when compared with that in preparation taken from SHAM rats. No changes in maximal relaxation were observed in the abdominal aortic rings. It is concluded that i) the enhanced responsiveness of the rat aorta to alpha 1-adrenoceptor stimulation cannot be explained by elevated blood pressure alone and ii) coarctation hypertension impairs the endothelium-dependent relaxation of the aortic region exposed to high blood pressure.

Propofol alters the pharmacokinetics of alfentanil in healthy male volunteers.

BACKGROUND: The influence of propofol on the pharmacokinetics of alfentanil is poorly understood. The authors therefore studied the effect of a pseudo-steady state concentration of propofol on the pharmacokinetics of alfentanil. METHODS: The pharmacokinetics of alfentanil was studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While breathing 30% O2 in air, 12.5 microg/kg intravenous alfentanil was given in 2 min, followed by 25 microg.kg(-1).h(-1) for 58 min (sessions A and B). During session B, a target controlled infusion of propofol (target concentration, 1.5 microg/ml) was given from 10 min before the start until 6 h after termination of the alfentanil infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the plasma alfentanil concentration were collected until 6 h after termination of the alfentanil infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of propofol and mean arterial pressure were constructed. RESULTS: A three-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of alfentanil Propofol decreased the elimination clearance of alfentanil by 15%, rapid distribution clearance by 68%, slow distribution clearance by 51%, and lag time by 62%. Mean arterial pressure and systemic vascular resistance were significantly lower in the presence of propofol. Scaling the pharmacokinetic parameters to the mean arterial pressure instead of propofol improved the model. CONCLUSIONS: Propofol alters the pharmacokinetics of alfentanil. Hemodynamic changes induced by propofol may have an important influence on the pharmacokinetics of alfentanil.

Pharmacodynamic interaction of eltanolone and alfentanil during lower abdominal surgery in female patients.

We have studied the influence of eltanolone on intraoperative alfentanil requirements in 18 female patients undergoing lower abdominal surgery receiving target-controlled infusions of eltanolone and alfentanil. While target concentrations of eltanolone were maintained constant, target concentrations of alfentanil changed in response to the presence or absence of responses. With serum eltanolone concentrations increasing from 500 to 2000 ng ml-1, the EC50 of alfentanil for suppression of responses to surgical stimulation decreased from 233 to 9 ng ml-1. The findings suggest that the interaction between eltanolone and alfentanil is synergistic.

Reduced muscarinic cholinoceptor density and sensitivity in various models of experimental cardiac hypertrophy.

1. In the present study we investigated functional and binding characteristics of muscarinic receptors in experimental cardiac hypertrophy. 2. As models of cardiac hypertrophy we used hearts of spontaneously hypertensive rats (SHR) and Wistar rats with surgically induced abdominal aorta stenosis (ASR). Wistar Kyoto rats (WKY) and sham operated Wistar rats were used as respective controls. 3. The hypertrophy was more pronounced in hearts of ASR compared to SHR, although the mean arterial pressure was found to be lower. 4. Isolated, perfused Langendorff heart preparations (paced with 5 Hz) from both groups of hypertrophied hearts were less sensitive to the muscarinic agonists oxotremorin and methacholine (P < 0.05, all n = 6) when compared with control organs. The maximal reduction in contractile force induced by methacholine was 59.3 +/- 4.5% in SHR and 41.6 +/- 3.4% in ASR hearts versus 26.4 +/- 4.1% and 25.0 +/- 2.6% in control organs, respectively. 5. The density (fmol/mg protein-1) of muscarinic receptors in membrane homogenates of hearts from SHR (127.6 +/- 11.5) was unchanged, whereas in hearts from ASR (221.0 +/- 8.9) it was found to be reduced (P < 0.05) when compared to the respective controls (142.5 +/- 14.7 and 308.8 +/- 16.1, respectively, all n = 6). 6. From the present data we conclude that cardiac hypertrophy results in a loss of sensitivity towards muscarinic receptor stimulation. A corresponding reduction of left ventricular receptor density could only be demonstrated in massively hypertrophied hearts of ASR.

Clinical management of cytotoxic drug overdose.

In this article the pharmacological management of accidental drug overdose is discussed, with various treatments for overdose proposed, as supported by clinical facts and speculation. Current knowledge is outlined concerning dacarbazine, nitrosourea compounds, melphalan, procarbazine, cyclophosphamide, VP-16.213, l-asparaginase (colaspase), 6-mercaptopurine, mustine (nitrogen mustard), intravenous or intrathecal methotrexate (amethopterin), cytarabine (cytosine arabinoside), fluorouracil and bleomycin.

Heterogeneity in morphological characteristics of coronary arteries and aortae in various models of hypertension.

OBJECTIVE: Hypertension is associated with important structural and functional changes in vascular smooth muscle. The question arises whether different vascular beds and different models of hypertension react similarly or in a heterogeneous manner to the hypertensive state. METHODS: We quantitatively investigated the morphology of the coronary arteries and thoracic aortae taken from 4, 30 and 52-week-old spontaneously hypersensitive rats (SHR) and Wistar Kyoto rats (WKY), respectively, and from hypertensive rats with aortic stenosis (ASR). RESULTS: In coronary arteries taken from the SHR the media area was slightly increased compared with those obtained from the age-matched WKY. Increasing age caused a significant increase in media area of the SHR vessels, but not in WKY tissues. No differences were found in the media area values of the coronary arteries obtained from the ASR compared with those obtained from SHAM (operated control rats) rats. The media area of the aortae taken from SHR was increased when compared with those from the age-matched WKY rats. In addition, the media area of the aortae from the surgically induced aortic stenosis rats (ASR) when compared with tissues from SHAM rats was significantly increased. CONCLUSIONS: Different animal models of hypertension appear to develop largely heterogeneous profiles of vascular hypertrophy, with different morphometric characteristics.

The iontophoresis of fentanyl citrate in humans.

BACKGROUND: Iontophoresis is a method of transdermal administration of ionizable drugs in which the electrically charged components are propelled through the skin by an external electric field. This study was designed to determine whether iontophoresis could be used to deliver clinically significant doses of fentanyl in humans and whether there is a charge-dose relation in the delivery of fentanyl by iontophoresis. METHODS: Five adult volunteers were tested three times on separate days, once receiving passive treatment of 0.0 mA for 2 h (0 mA.min), iontophoresis 1.0 mA for 2 h (120 mA.min), and iontophoresis 2.0 mA for 2 h (240 mA.min) in an open, randomized, crossover design. Respiratory rate, heart rate, blood pressure, and hemoglobin oxygen saturation were monitored throughout the study. Plasma fentanyl concentrations were measured several times before, during, and after iontophoresis. Plasma fentanyl concentrations were measured by radioimmunoassay. RESULTS: No fentanyl was detected after passive (0.0-mA) fentanyl delivery. The following results were obtained for the 1.0- and 2.0-mA deliveries, respectively. Mean times to detectable concentrations of plasma fentanyl were 33 and 19 min; mean times to maximum concentration were 122 and 119 min; maximum concentrations were 0.76 and 1.59 ng/ml (P = 0.010); mean areas under the curve of the plasma fentanyl concentration versus time relation were 233 and 474 ng.ml-1.min (P = 0.003); and mean elimination half-lives were 354 and 413 min (P = 0.326). Only minor adverse side effects related to iontophoresis occurred. However, typical opioid-related effects occurred frequently in the 1.0- and 2.0-mA administration groups. CONCLUSIONS: Clinically significant doses of fentanyl can be administered by iontophoresis for delivery periods of 2 h. A charge-dose relation exists after administration with currents of 1.0 and 2.0 mA. Future research into the iontophoresis of fentanyl as a method of potent opioid administration is indicated.