Biomedical subjects

D J de Wildt

Publications and source records attributed to D J de Wildt.

At least 19 recordsLinked to original sources

PubMed2001

Effect of gamma-melanocyte-stimulating hormones on baroreflex sensitivity and cerebral blood flow autoregulation in rats.

OBJECTIVE: In the present paper, we are interested in the effects of gamma-melanocyte-stimulating hormones (gamma-MSHs) on cardiovascular regulatory systems. METHODS: Mean arterial pressure (MAP), cerebral blood flow (CBF) and heart rate (HR) were measured in urethane-anaesthetised rats after intravenous administration of lysgamma(2)-MSH, gamma(2)-MSH, gamma(2)-MSH(6-12) or phenylephrine. RESULTS: The gamma-MSHs caused an increase in MAP, CBF and HR, whereas phenylephrine caused an increase in MAP and CBF and baroreceptor reflex-mediated bradycardia. All tested gamma-MSHs showed a significant impairment of the baroreceptor reflex sensitivity and CBF autoregulation as compared to the phenylephrine group. gamma(2)-MSH shows identical effects on the baroreceptor reflex and CBF as the endogenous occurring lysgamma(2)-MSH. In addition, the C-terminal fragment of gamma(2)-MSH, gamma(2)-MSH(6-12), induced similar effects as gamma(2)-MSH. The level of increase in MAP was comparable between the gamma-MSHs and the phenylephrine group. CONCLUSIONS: The present study suggests that gamma(2)-MSH and the shorter fragment gamma(2)-MSH(6-12) impair baroreceptor reflex sensitivity, due to a strong increase in sympathetic tone and/or change in baroreceptor reflex setpoint, and induce cerebrovasodilatation, which can counteract an autoregulation-mediated cerebrovasoconstriction due to systemic pressor effects. Furthermore, the results indicate that the C-terminal site of gamma(2)-MSH is relevant for its central-mediated inhibitory effects on the baroreceptor reflex and CBF.

Animals↗

PubMed2000

Mepyramine but not cimetidine or clobenpropit blocks pertussis toxin-induced histamine sensitization in rats.

The effects of pertussis toxin (PT) and the role of histaminergic H(1), H(2) and H(3) receptor blockade on the actions of histamine on blood pressure, heart rate, blood gas values, and mortality were studied in anaesthetized rats. Four days after treatment with PT, histamine dose-dependently decreased mean arterial blood pressure (MAP) and PT enhanced the histamine-induced decrease in MAP. In the PT but not in the inactivated PT (IPT) or saline treated group three out of six animals died after the highest dose of histamine (300 mg kg(-1), i.v.) In order to determine the type of histamine receptor that mediates HS, 4 days after PT the selective antagonists mepyramine (H(1)), cimetidine (H(2)) and clobenpropit (H(3)) were administered 20 min before the challenge with histamine. Mepyramine completely inhibited both the enhanced histamine-induced decrease in MAP and mortality brought about by PT. Cimetidine and clobenpropit had no protective effects, but rather enhanced the histamine-induced mortality elicited by PT. The present study shows that PT caused HS in rats which is primarily mediated via H(1) and secondarily via H(2) and H(3) receptors. These results are considered to be a first step in the elucidation of the mechanism(s) of the HS test used in the quality control of acellular pertussis vaccine.

Animals↗

PubMed2000

Relevance of the C-terminal Arg-Phe sequence in gamma(2)-melanocyte-stimulating hormone (gamma(2)-MSH) for inducing cardiovascular effects in conscious rats.

1. The cardiovascular effects by gamma(2)-melanocyte-stimulating hormone (gamma(2)-MSH) are probably not due to any of the well-known melanocortin subtype receptors. We hypothesize that the receptor for Phe-Met-Arg-Phe-amide (FMRFa) or Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-amide (neuropeptide FF; NPFFa), other Arg-Phe containing peptides, is the candidate receptor. Therefore, we studied various Arg-Phe containing peptides to compare their haemodynamic profile with that of gamma(2)-MSH(6 - 12), the most potent fragment of gamma(2)-MSH. 2. Mean arterial pressure (MAP) and heart rate (HR) changes were measured in conscious rats after intravenous administration of gamma(2)-MSH related peptides. 3. Phe-Arg-Trp-Asp-Arg-Phe-Gly (gamma(2)-MSH(6 - 12)), FMRFa, NPFFa, Met-enkephalin-Arg-Phe-amide (MERFa), Arg-Phe-amide (RFa), acetyl-Phe-norLeu-Arg-Phe-amide (acFnLRFa) and desamino-Tyr-Phe-norLeu-Arg-Phe-amide (daYFnLRFa) caused a dose-dependent increase in MAP and HR. gamma(2)-MSH(6 - 12) showed the most potent cardiovascular effects (ED(50)=12 nmol kg(-1) for delta MAP; 7 nmol kg(-1) for delta HR), as compared to the other Arg-Phe containing peptides (ED(50)=177 - 292 nmol kg(-1) for delta MAP; 130 - 260 nmol kg(-1) for delta HR). 4. Peptides, which lack the C-terminal Arg-Phe sequence (Lys-Tyr-Val-Met-Gly-His-Phe-Arg-Trp-Asp-Arg-Pro-Gly (gamma(2)-pro(11)-MSH), desamino-Tyr-Phe-norLeu-Arg-[L-1,2,3,4 tetrahydroisoquinoline-3-carboxylic acid]-amide (daYFnLR[TIC]a) and Met-enkephalin (ME)), were devoid of cardiovascular actions. 5. The results indicate that the baroreceptor reflex-mediated reduction of tonic sympathetic activity due to pressor effects is inhibited by gamma(2)-MSH(6 - 12) and that its cardiovascular effects are dependent on the presence of a C-terminal Arg-Phe sequence. 6. It is suggested that the FMRFa/NPFFa receptor is the likely candidate receptor, involved in these cardiovascular effects.

Amino Acid Sequence↗

PubMed2000

Disturbance of cardiovascular circadian rhythms by pertussis vaccine in freely-moving rats.

Vaccination of young children with diphtheria, tetanus, poliomyelitis and pertussis (DTPoP) vaccine is effective in preventing outbreaks of whooping cough but adverse events sometimes occur. This pilot study shows that in freely-moving rats, multiple treatment with DTPoP (at day 0 and day 5, 6 ml/kg i.v.) increased heart rate (HR) for 5 days after the first treatment and decreased diastolic blood pressure (DBP) for at least 26 days after the first treatment and inhibited the circadian rhythm of HR and DBP for at least 10 days. DTPo vaccine, containing no pertussis vaccine, was free of such effects. Thus, in rats, the pertussis component of DTPoP acts on the cardiovascular system and disturbs its circadian rhythm. The contribution of these findings to clinical adverse effects is as yet unknown and needs further research.

Animals↗

PubMed1999

Inhibition of iron-dependent and ischemia-induced brain damage by the alpha-tocopherol analogue MDL 74,722.

Free radical-induced lipid peroxidation is an important factor in the pathogenesis of ischemic brain damage. We studied the effects of the alpha-tocopherol analogue MDL 74,722 on iron-dependent lipid peroxidation and infarct volume after transient focal cerebral ischemia. The effects of MDL 74,722 on iron-induced lipid peroxidation were tested in cerebellar granule cell cultures by means of a thiobarbituric acid reactive substances (TBARS) assay. The absorbance resulting from mitochondrial reduction of 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) was taken as a measure of cell viability. Besides, in male Wistar rats the left middle cerebral artery (MCA) was occluded for 3 h by means of an intraluminal filament. Rats were treated with vehicle (n = 19) or MDL 74,722 (n = 17), administered intravenously for 3 h in a dose of 2 mg/(kg.h), starting 105 min after MCA occlusion. Infarct volume was measured in coronal brain sections stained with hematoxylin and eosin. In cerebellar granule cell cultures, MDL 74,722 resulted in a dose-dependent inhibition of TBARS formation and prevention of cell toxicity. The compound reduced infarct volume after transient occlusion of the MCA in rats by 49%. It is concluded that MDL 74,722 is a potent inhibitor of lipid peroxidation and reduces infarct volume by about one half, even when treatment is delayed. This contributes to its potential clinical usefulness.

Animals↗

PubMed1998

Rat middle cerebral artery occlusion by an intraluminal thread compromises collateral blood flow.

We compared in Wistar rats collateral blood flow through leptomeningeal anastomoses after middle cerebral artery occlusion using craniotomy ('extravasal occlusion'), which results in a small volume of cerebral infarction, and after intraluminal thread occlusion ('intravasal occlusion'), which produces a large volume of cerebral infarction. Simultaneous laser-Doppler flowmetry with two probes placed on the cerebral cortex was used to measure and compare collateral blood flow. Extravasal occlusion caused a cortical blood flow reduction along a gradient in lateral direction, whereas blood flow reduction after intravasal occlusion was more uniformly distributed. It is concluded that permanent intravasal occlusion compromises collateral blood flow and therefore may not be a suitable model for measuring the ability of pharmacotherapeutic agents, if any, to improve collateral blood flow acutely after middle cerebral artery occlusion. The two models can be useful for testing drugs on parenchymal neuroprotective properties. Thereby, the intraluminal technique is preferred because of the possibility to study reperfusion damage when transient occlusion is applied.

Analysis of Variance↗

PubMed1998

The effect of pertussis toxin and whole-cell pertussis vaccine on haemodynamics and autonomic responsiveness in the rat depends on route of administration and age.

Vaccination of children with Diphtheria, Tetanus, Poliomyelitis and pertussis vaccine (DTPoP-vaccine) containing the whole-cell pertussis component is known to be associated with manifestation of side-effects such as acute encephalopathy, convulsions and hypotensive-hyporesponsive episodes. In young and adult rats the effects of pertussis toxin and DTPoP-vaccine on haemodynamics and autonomic responsiveness are evaluated following treatment with high dose via different routes of administration (s.c., i.p. and i.v.). The effect of pertussis toxin is dose-dependent (between 1 and 20 micrograms kg-1) and largest responses are observed after i.v. administration. At 20 micrograms kg-1, i.v. pertussis toxin decreases baseline diastolic blood pressure and increases baseline heart rate by 31% and inhibits autonomic responsiveness (salbutamol-induced increase in diastolic blood pressure and arecoline-induced decrease in heart rate). In adult rats DTPoP-vaccine induces generally more prominent effects than in young rats. In adult rats DTPoP-vaccine reduces baseline diastolic blood pressure by 25% while no response is observed in young rats. In adult rats DTPoP inhibits the adrenergic response though less compared to treatment of pertussis toxin. After treatment with DTPoP-vaccine (single or twice) only minor differences are observed between young and adult rats. Present results show that adult rats are more sensitive to pertussis toxin and pertussis vaccine than young rats and that the responses depend on the route of administration.

Aging↗

PubMed1998

Repeated administration of whole-cell and acellular pertussis vaccines affects haemodynamics and autonomic responsiveness.

Rats were treated in a repetitive way one to four times with either pertussis toxin, combined Diphtheria-Tetanus-Poliomyelitis-Pertussis vaccine (DTP-IPV vaccine, which includes inactivated polio virus and whole-cell pertussis), DT-IPV vaccine (lacking the whole-cell pertussis component) or acellular pertussis (aP) vaccine or Haemophilus influenzae type b vaccine. Baseline diastolic blood pressure, baseline heart rate and adrenergic and cholinergic responses were evaluated 4 days after last treatment. Pertussis toxin decreased baseline diastolic blood pressure (28-43%) and increased baseline heart rate (28-40%). Adrenergic and cholinergic response were inhibited by 65-75% and 70-78%. Multiple treatments were grossly as effective as single treatment. Similar results were obtained with DTP-IPV, while DT-IPV did not affect any of the four responses measured. Acellular pertussis vaccine did not affect baseline diastolic blood pressure, but significantly increased baseline heart rate (14%) and inhibited the adrenergic (19-23%) and cholinergic response (39-50%). This indicates that the acellular vaccine tested contains pharmacologically active pertussis toxin. As the effects were less pronounced compared to DTP-IPV, it is concluded that acellular pertussis retains less residual toxicological effects than whole-cell pertussis vaccine and may therefore be a safer vaccine. The observed effects on haemodynamics and autonomic control seem to be specific for pertussis toxin and pertussis-related vaccines as Haemophilus influenzae type b vaccine is in this respect virtually inactive.

Animals↗

PubMed1998

Dietary vitamin E levels affect outcome of permanent focal cerebral ischemia in rats.

BACKGROUND AND PURPOSE: A supraphysiological amount of vitamin E in the standard diet of laboratory animals may provide partial protection against cerebral ischemic damage in stroke models. The aim of the present study was to test the effect of dietary vitamin E on infarct volume in rats subjected to permanent focal cerebral ischemia. METHODS: Male Wistar rats were raised on a vitamin E-deficient diet (n=10) or a control diet containing 62.7 mg vitamin E/kg (n=11) for 13 to 16 weeks, from the age of 3 weeks. The left middle cerebral artery (MCA) was permanently occluded by means of an intraluminal silicone-coated 3-0 suture. Blood flow in the left MCA territory was measured before and after occlusion with laser Doppler flowmetry. The area of infarction was measured in hematoxylin-eosin-stained brain sections by means of an image analysis system. The investigator was not aware of the vitamin E status of the rats. RESULTS: Blood flow in the left MCA territory in the second half hour after occlusion was 43+/-17% and 42+/-17% (mean+/-SD) of the baseline value in control and vitamin E-deficient rats, respectively. The mean infarct volume, measured after 48 hours of survival, was 61+/-19 mm3 in control rats and 137+/-76 mm3 in vitamin E-deficient rats (P=0.037). CONCLUSIONS: After permanent focal cerebral ischemia, the infarct is larger in vitamin E-deficient rats than in rats raised on a diet with the usual, supraphysiological amount of vitamin E. This may have consequences for cerebral ischemia studies with experimental animals.

Animals↗

PubMed1998

ACE inhibitor-induced angioedema. Incidence, prevention and management.

Available information from 1980 to 1997 on angiotensin converting enzyme (ACE) inhibitor-induced angioedema and its underlying mechanisms are summarised and discussed. The incidence of angioedema is low (0.1 to 0.2%) but can be considered as a potentially life-threatening adverse effect of ACE inhibitor therapy. This adverse effect of ACE inhibitors, irrespective of the chemical structure, can occur early in treatment as well as after prolonged exposure for up to several years. The estimate incidence is quite underestimated. The actual incidence can be far higher because of poorly recognised presentation of angioedema as a consequence of its late onset in combination with usually long term therapy. Also, a spontaneous reporting bias can contribute to an actual higher incidence of this phenomenon. The incidence can be even higher (up to 3-fold) in certain risk groups, for instance Black Americans. Treatment includes immediate withdrawal of the ACE inhibitor and acute symptomatic supportive therapy followed by immediate (and long term) alternative therapy with other classes of drugs to manage hypertension and/or heart failure. Preclinical and clinical studies for the elucidation of the underlying mechanism(s) of ACE inhibitor-associated angioedema have not generated definite conclusions. It is suggested that immunological processes and several mediator systems (bradykinin, histamine, substance P and prostaglandins) are involved in the pathogenesis of angioedema. A great part of all reviewed reports suggest a relationship between ACE inhibitor-induced angioedema and increased levels of (tissue) bradykinin. However, no conclusive evidence of the role of bradykinin in angioedema has been found and an exclusive role of bradykinin seems unlikely. So far, no clear-cut evidence for an immune-mediated pathogenesis has been found. In addition, ACE gene polymorphism and some enzyme deficiencies are proposed to be involved in ACE inhibitor-induced angioedema. Progress in pharmacogenetic and molecular biological research should throw more light on a possible genetic component in the pathogenesis of ACE inhibitor-associated angioedema.

Angioedema↗

PubMed1996

Differences in striatal extracellular amino acid concentrations between Wistar and Fischer 344 rats after middle cerebral artery occlusion.

We hypothesized that the interstrain difference between Wistar and Fischer-344 (F344) rats in cerebral infarction volume after proximal middle cerebral artery (MCA) occlusion might be explained by differences in excitotoxicity between both rat strains. Using microdialysis we measured during a 5 h period after MCA occlusion the release of aspartate, glutamate and taurine in the cerebral cortex and the striatum. The volume of striatal infarction was comparable in Wistar and F344 rats. We found, however, in Wistar rats a significantly higher striatal efflux of aspartate and glutamate than in F344 rats, whereas the striatal taurine efflux was of a similar magnitude in the two strains. Because of the (variably) smaller volume of cortical infarction in Wistar rats (than that in F344), the location of the microdialysis probe-membrane with respect to the area of cortical infarction differed between Wistar rats. Hence, a reliable comparison between the quantitative amount of amino acids in the dialysate from the cortical probes of both rat strains could not be made. These results, demonstrating differences in striatal excitotoxicity between Wistar and F344 rats after MCA occlusion, are the first to show interstrain differences in striatal pathophysiology of focal ischemia between these normotensive rat strains. They do however not explain why MCA occlusion results in a significantly different volume of cortical infarction between Wistar and F344 rats. The F344 strain will probably show in a more sensitive way, as compared to Wistar rats, neuroprotective effects of agents that diminish excitotoxic damage during focal cerebral ischemia.

Amino Acids↗

PubMed1996

Toxic doses of rac-, (-)-(S)- and (+)-(R)-propranolol in rats and rabbits.

The contribution of the individual enantiomers ([+]-[R]- and [-]-[S]-propranolol) to rac-propranolol intoxication was studied in anaesthetized, spontaneously breathing (SB) rats and artificially ventilated (AV) rats and rabbits. In the SB rat, propranolol (30 mg.kg-1.h-1 i.v.) decreased heart rate and mean arterial blood pressure and caused hypoventilation, serious hypoxaemia, respiratory acidosis, and death by respiratory arrest. Survival time (ST) in the (+)-(R)-propranolol group (ST 91 +/- 5 min) was significantly longer than in the rac-propranolol group (ST. 68 +/- 6 min). In AV rats and rabbits toxic doses of rac-, (-)-(S)- and (+)-(R)-propranolol, 30 mg.kg-1.h-1 and 15 mg.kg-1.h-1 i.v., respectively, induced comparable effects on haemodynamic variables as in the SB rat. Artificial ventilation lengthened ST by a factor of three to four in rats. In the AV rat, ST's were not significantly different between the rac-, (-)-(S)- and (+)-(R)-propranolol groups. In the rabbit, as in the SB rat, ST in the (+)-(R)-propranolol group was significantly longer than ST's in the rac- and (-)-(S)-propranolol groups. The acute respiratory acidosis in SB rats and the prolonged ST in AV rats suggest that respiratory failure is the primary and cardiovascular failure the secondary cause of death in propranolol intoxication. The potentiation of the toxic effect of the enantiomers observed after dosing the racemate instead of the pure enantiomers could not be explained by a stereoselective difference in plasma propranolol concentration.

Adrenergic beta-Antagonists↗

PubMed1996

Cisplatin-induced autonomic neuropathy: does it really exist?

The neurotoxic side-effects of cisplatin affect predominantly the large, myelinated fibres of peripheral nerves, leading to a sensory neuropathy. Several reports of cisplatin-associated autonomic neuropathy have been published. Autonomic dysfunction however, is caused by a neuropathy of small unmyelinated nerve fibres. By using the absolute pupil diameter as a parameter of autonomic nervous system function, we studied autonomic neuropathy in the eye of cisplatin-intoxicated rats. In addition, we examined autonomic cardiovascular function by measuring the change in heart rate (HR) and mean arterial blood pressure (MAP) in response to intravenous phenylephrine (PHE) and tyramine (TYR). No significant differences in mean pupil diameter developed in cisplatin-intoxicated rats (n = 12) in the course of 9 weeks (total cumulative dose cisplatin 18 mg/kg) compared with normal controls (n = 9) MANOVA, F1,19 = 0.88, P < 0.36). The PHE- and TYR-induced changes in MAP and HR were virtually the same in cisplatin-intoxicated rats when compared with normal controls. We conclude that cisplatin probably does not cause autonomic dysfunction, at least not in rats, in doses commonly used and which are known to cause a peripheral sensory neuropathy.

Analysis of Variance↗

PubMed1996

Middle cerebral artery occlusion in Wistar and Fischer-344 rats: functional and morphological assessment of the model.

Cerebral infarction volume after occlusion of a short proximal segment of the middle cerebral artery (MCA) is reported to be different in Wistar compared to Fischer-344 (F344) rats, in both size and variability. Knowledge about the cause of these differences might enable us to explain and perhaps reduce the variation in infarct volume and create a reproducible model of focal cerebral ischemia in the rat. We investigated in Wistar and F344 rats both the effect of occlusion of a long proximal MCA segment on cerebral infarction volume, visualized by magnetic resonance imaging and histology, and the morphology of the major cerebral arteries. Occlusion of a long proximal MCA segment resulted in a striatal and a small cortical infarction in Wistar and a striatal and sizable cortical infarction in F344 rats (as is the case after occlusion of a short proximal MCA segment). In Wistar rats, however, occlusion of a long proximal MCA segment strongly reduced the variability in infarction volume in comparison to occlusion of a small proximal MCA segment. Analysis of the morphology of the major cerebral arteries showed a significantly higher number of proximal side branches of the long proximal MCA segment in Wistar rates than in F344 rats. We conclude that after short-segment proximal MCA occlusion, extreme variability in cerebral infarction volume in Wistar rats compared to F344 rats may be attributable to a significantly greater number of proximal MCA side branches in Wistar rats than in F344 rats.

Animals↗

PubMed1996

Reduced survival after isoprenaline/dopamine in d,l-propranolol intoxicated rats.

1. Respiratory and cardiovascular failure are principle toxic effects of beta-blocker overdose. Respiratory arrest is the primary cause of death in beta-blocker intoxicated rats. 2. The effect of beta-adrenoceptor agonists on respiratory and cardiovascular failure in beta-blocker overdose was investigated in a model of acute d,l-propranolol (30 mg kg-1 h-1) intoxication in spontaneously breathing rats. 3. Neither the aselective, hydrophilic beta-agonist isoprenaline (10, 25, 50 micrograms kg-1 min-1), nor the beta 1-selective, lipophilic beta-agonist flerobuterol (1, 3, 10 microgram kg-1 min-1) and the beta 2-selective, lipophilic beta-agonist clenbuterol (10, 25, 50 micrograms kg-1 min-1) had any beneficial effect on cardiovascular and respiratory variables or survival time in d,l-propranolol intoxicated spontaneously breathing rats. 4. Isoprenaline (10 micrograms kg-1 min-1) had no favourable effect on haemodynamic and respiratory variables in artificially ventilated d,l-propranolol intoxicated rats either. 5. Addition of dopamine to isoprenaline resulted in a significant reduction of survival time, primarily caused by a decreased in mean arterial blood pressure, in artificially ventilated d,l-propranolol intoxicated rats. Addition of glucagon to isoprenaline did not affect survival time. 6. Artificial ventilation is the most important supportive measure in d,l-propranolol intoxication in the rat.

Adrenergic beta-Agonists↗

PubMed1996

Experimental study of the detrimental effect of dopamine/glucagon combination in d,l-propranolol intoxication.

1. Respiratory and cardiovascular failure are the principle toxic effects of beta-blocker overdose. Respiratory arrest is the primary cause of death in beta-blocker intoxicated rats. 2. The effect of glucagon, dopamine and the combination of glucagon/dopamine on respiratory and cardiovascular function and survival time in beta-blocker overdose was investigated in a model of acute d,l-propranolol (resp. 30 and 15 mg kg-1 h-1 in rat and rabbit) intoxication in spontaneously breathing rats and artificially ventilated rats and rabbits. 3. Glucagon (initial dose of 100 micrograms kg-1 (bolus), followed by 1 microgram kg-1 min-1), dopamine (25 micrograms kg-1 min-1) or the combination of glucagon/dopamine did not improve survival time (ST) in d,l-propranolol intoxicated spontaneously breathing rats and artificially ventilated rats and rabbits, although some haemodynamic variables i.e. heart rate (HR), mean arterial blood pressure (MAP), left ventricular pressure (LVPmax) and the differentiated left ventricular pressure (LVdp/dtmax) temporarily improved. 4. Survival time was considerably reduced in d,l-propranolol intoxicated spontaneously breathing and artificially ventilated rats treated with a combination of glucagon/dopamine, which induced a decrease in PaO2 and pH and an increase in PaCO2 partly due to ventilation/perfusion mismatch. 5. The combination of glucagon/dopamine should be used carefully in the treatment of beta-blocker overdose in man.

Adrenergic beta-Antagonists↗

PubMed1995

Toxicokinetics of a single intravenous dose of rac-propranolol versus optically pure propranolol in the rat.

Conscious male Wistar SPF Riv:TOX rats were dosed intravenously with 2.5, 5, or 10 mg/kg rac-propranolol.HCl, or with 5 mg/kg of either (-)-(S)- or (+)-(R)-propranolol.HCl. Disposition of (-)-(S)- and (+)-(R)-propranolol after dosing of rac-propranolol was linear in the dose range examined. Total plasma clearance was not changed in animals dosed with the individual enantiomers compared to the animals that were dosed with rac-propranolol. However, for (-)-(S)-propranolol both volume of distribution and elimination half-life decreased, whereas for (+)-(R)-propranolol increases were observed for these characteristics, in animals dosed with the individual enantiomers. Our observations suggest that the (+)-(R)-enantiomer competes with (-)-(S)-propranolol for plasma protein binding sites, resulting in lower plasma protein binding of the (-)-(S)-enantiomer when the racemate is administered. From recent toxicological experiments, it was concluded that rac-propranolol is more toxic than the individual enantiomers in the rat, when dosed iv at the same total mass. It is concluded that the observed potentiation of toxic effects of propranolol enantiomers when administered as a racemate can at least partly be explained by a pharmacokinetic interaction.

Adrenergic beta-Antagonists↗

PubMed1995

Effect of gamma 2-melanocyte-stimulating hormone on cerebral blood flow in rats.

The effects of the proopiomelanocortin-(POMC)-derived peptide gamma 2-melanocyte-stimulating hormone (gamma 2-MSH) on mean arterial blood pressure (BP: MAP), heart rate (HR), internal and total carotid blood flow (BF) (CFint and CFtot, respectively), and regional cerebrocortical blood flow (CBF) were measured in urethane-anesthetized rats after intravenous (i.v.) and intracarotid (i.car.) administration of the peptide. gamma 2-MSH (1.5-100 nmol/kg) administered i.v. and i.car. caused a dose-dependent increase in MAP and HR. Injection of the peptide i.car. in the middose range resulted in a more pronounced pressor effect. Furthermore, the earlier onset of the hemodynamic effects after i.car. injection suggests that forebrain structures play a role in these effects. In addition to the pressor response, gamma 2-MSH produced a strong increase in CFint, CFtot, and CBF after both routes of administration, suggesting an increased intracerebral BF. Whereas the effects of the higher doses of gamma 2-MSH on MAP and CFtot were quantitatively comparable after either the intravenous or intracarotid administration, the effect on regional CBF and CFint was about twice as high after i.car. infusion, indicating a centrally mediated phenomenon underlying this effect on CBF. The increase in CFint cannot in itself be ascribed to a gamma 2-MSH-mediated higher perfusion pressure (i.e., BP), since an equipressor dose of norepinephrine (NE) caused a significant decrease in CFint. The significant and more than twofold higher increase in CBF after intracarotid administration of gamma 2-MSH in comparison with administration of NE by the same route also suggests a central origin for the enhancement of microcirculatory flow due to the peptide.

Animals↗