Showing papers in "General Pharmacology-the Vascular System in 1990"
TL;DR: It is suggested that classes of receptors for adenine dinucleotides exist which are distinct from either P1- or P2-purinoceptors and may yet be discovered in autonomic neurones and serve as neurotransmitters.
Abstract: 1. 1. The pharmacological actions of adenine dinucleotides, in particular β-nicotinamide adenide dinucleotide (NAD), β-nicotinamide adenine dinucleotide phosphate (NADP) and a homologous series of α,ω-adenine dinucleotide polyphosphates has been reviewed. 2. 2. It is apparent that many actions of NAD can be explained in terms of activation of P 1 -purinoceptors, but actions of NADP cannot be explained in terms of activation of P 1 - or P 2 -purinoceptors. 3. 3. Similarly, pharmacological activities of P 1 ,P 3 -diadenosine triphosphate and P 1 ,P 4 -diadenosine tetraphosphate are not in keeping with activation of P 1 - or P 2 -purinoceptors. 4. 4. In the vas deferens and urinary bladder, P 1 ,P 4 -diadenosine tetraphosphate, P 1 ,P 5 -diadenosine pentaphosphate and P 1 ,P 6 -diadenosine hexaphosphate act on P 2x -purinoceptors and can cause desensitization of these receptors. 5. 5. It is suggested that classes of receptors for adenine dinucleotides exist which are distinct from either P 1 - or P 2 -purinoceptors. 6. 6. It is also suggested that in view of the finding of high concentrations of α,ω-adenine dinucleotide polyphosphates in adrenal medullary chromaffin cells, and of the involvement of the P 2x -purinoceptor in the vas deferens and urinary bladder with purinergic neuromuscular transmission, that α,ω-adenine dinucleotide polyphosphates may yet be discovered in autonomic neurones and serve as neurotransmitters.
83 citations
TL;DR: It is suggested that EDRF produces a physiological inhibitory modulation of vascular smooth muscle tone and its alteration produces or facilitates the development of diseases such as hypertension or coronary and cerebral vasospasm.
Abstract: 1. Endothelial cells of blood vessels generate factors which can modulate underlying smooth muscle tone, inducing vasorelaxation, (endothelium-derived relaxing factor, EDRF, and endothelium-derived hyperpolarizing factor) and/or vasoconstriction (endothelium-derived contracting factors, EDCFs, including the peptide endothelin). 2. EDRF is nitric oxide (NO) or a RNO compound from which this oxide is released. Its half-life is very short (6-50 sec), and it produces rapid vasodilations and inhibits platelet aggregation. 3. NO is formed from the terminal guanidino of L-arginine, but not of D-arginine. NO effects and NO formation are inhibited by NG-monomethyl-L-arginine (L-NMMA), but not by D-NMMA. These inhibitory effects are blocked by L-arginine. 4. Removal of endothelium or pathological situations that can induce endothelial dysfunction (atherosclerosis, diabetes, hypertension or subarachnoid hemorrhage) cause increases on the vascular contractility elicited by agonists (noradrenaline, serotonin, EDCFs, etc.). These findings suggest that EDRF produces a physiological inhibitory modulation of vascular smooth muscle tone and its alteration produces or facilitates the development of diseases such as hypertension or coronary and cerebral vasospasm.
73 citations
TL;DR: Treatment of neuroleptic malignant syndrome must be "active" rather than "passive", in order to avert fatalities and/or unfortunate sequelae from this iatrogenic and incompletely understood disease.
Abstract: 1. Neuroleptic drugs (antipsychotics) produce numerous side effects which include serious extrapyramidal symptoms consisting of akathisia, dystonia, neuroleptic malignant syndrome, parkinsonian reactions such as postural abnormality, tremor, akinesia or bradykinesia, rigidity, and tardive dyskinesia. 2. Among the complications of neuroleptic chemotherapy, the most serious and potentially fatal complication is malignant syndrome, which is characterized by extreme hyperthermia, "lead pipe" skeletal muscle rigidity causing dyspnea, dysphagia, and rhabdomyolysis, autonomic instability, fluctuating consciousness, leukocytosis, and elevated creatine phosphokinase. 3. Neuroleptic malignant syndrome should be differentiated from malignant hyperthermia, lethal catatonia, and other pathological states producing some of these same symptoms. 4. In addition to neuroleptics, malignant syndrome has been caused by thymoleptics (antidepressants), metoclopramide (antiemetic), metoclopramide combined with cimetidine, tetrabenazine, overdosage of benzodiazepine, phenelzine, dothiepin and alcohol, and amphetamine. 5. Factors leading to and/or facilitating the emergence of neuroleptic malignant syndromes are reportedly organic brain syndrome, dehydration, exhaustion, external heat load, excessive sympathetic discharge, use of long acting neuroleptics, high doses of neuroleptics, rapid dose titration with neuroleptics, abrupt discontinuation of antiparkinsonism agents, and concurrent lithium therapy. 6. Although, the pathogenesis of neuroleptic malignant syndrome is not understood completely, a blockade of dopaminergic receptors in the hypothalamus, spinal cord and striatum, an alteration of dopaminergic-serotonergic transmission in the body, an enhanced synthesis and action of prostaglandin E1 and E2, and a modification of calcium-mediated signal transduction in the body have been suggested. 7. The treatment of malignant syndrome includes immediate withdrawal of neuroleptic drugs, i.v. infusion of dantrolene, and oral administration of bromocriptine; or alternatively i.v. infusion of dantrolene and the combination of levodopa-carbidopa. 8. Other measures to enhance the therapeutic effectiveness of the aforementioned regimens are to include the use of anticholinergic drugs such as benztropine to enhance the effectiveness of bromocriptine, of lorazepam if catatonic symptoms persist, or of electroconvulsive therapy (ECT) if psychotic symptoms persist. 9. These treatments, however, must be "active" rather than "passive", in order to avert fatalities and/or unfortunate sequelae from this iatrogenic and incompletely understood disease.
72 citations
TL;DR: It was determined that after the administration of MPTP in mice, the drug was rapidly metabolized in the periphery and excreted as MPTP N-oxide, which may directly or indirectly increase the neurotoxic action of MP TP in mice.
Abstract: 1. 1. The effect of probenecid on striatal dopamine depletion in acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice was examined. 2. 2. Mice treated with a single dose of MPTP (15 mg/kg, s.c.) showed a significant depletion of striatal dopamine throughout a time-course of 7 days. Interestingly, this MPTP-induced striatal dopamine depletion was potentiated by a concomitant injection with a single dose of probenecid (250 mg/kg, i.p.). 3. 3. However, this potentiation of dopamine depletion by probenecid was only a transient phenomenon seen at 4–5 days after the treatment. 4. 4. In a long-term study, mice were treated with the same dosages of MPTP or probenecid plus MPTP twice a week for 5 weeks, we detected that probenecid plus MPTP caused a persistent depletion of striatal DA for 6 months. 5. 5. During this period a partial recovery of DA levels was seen with MPTP alone-treated mice. 6. 6. The detailed mechanisms by which probenecid causes acute potentiation and persistent long-term depletion of striatal dopamine by MPTP are still unclear. 7. 7. With the evidence presented in this study, we determined that after the administration of MPTP in mice, the drug was rapidly metabolized in the periphery and excreted as MPTP N-oxide. 8. 8. Probenecid was shown to inhibit the excretion of urine and urinary MPTP N-oxide shortly after MPTP administration, which may directly or indirectly increase the neurotoxic action of MPTP in mice.
68 citations
TL;DR: The effects of ovariectomy and/or of female hormonal treatments on open-field behavior, apomorphine-induced stereotypies and haloperidol-induced catalepsy were studied in rats and a possible interference of estrogen and/ or progesterone on dopaminergic transmission at the level of the nigroestratial pathway was discussed.
Abstract: 1. 1. The effects of ovariectomy and/or of female hormonal treatments on open-field behavior, apomorphine-induced stereotypies and haloperidol-induced catalepsy were studied in rats. 2. 2. Rat's locomotion frequency was significantly decreased by 17β-estradiol and estradiol plus progesterone treatments; this open-field parameter was not affected by progesterone administration per se . 3. 3. 17β-estradiol and progesterone treatments, alone or in combination decreased apomorphine-stereotyped behavior. 4. 4. Haloperidol effects were higher in both 17β-estradiol and 17β-estradiol plus progesterone treated rats. 5. 5. Progesterone treatment alone, decreased the duration of catalepsy induced by the minor (1.0 mg/kg) neuroleptic dose. 6. 6. These results were discussed in the light of a possible interference of estrogen and/or progesterone on dopaminergic transmission at the level of the nigroestratial pathway.
56 citations
TL;DR: It is concluded that norepinephrine mediated increase in oxygen uptake by the perfused rat hindlimb results from its vasoconstrictor action.
Abstract: 1. 1. The effect of noradrenaline as well as of vasopressin and angiotensin II to increase oxygen uptake and perfusion pressure by the isolated perfused rat hindlimb were completely inhibited by the vasodilators, nitroprusside (0.5 mM), nifedipine (2.5 μM) and isoprenaline (50 nM). 2. 2. Oxygen uptake due to sciatic nerve stimulation of skeletal muscle contraction was not inhibited by 0.5 mM nitroprusside but was found to increase further that produced by a maximum dose of either noradrenaline or angiotensin II. 3. 3. Analysis of high energy phosphates in samples of freeze-clamped hindlimb muscle showed no difference before and after vasoconstrictor addition or with muscle sampled in vivo. 4. 4. It is concluded that norepinephrine mediated increase in oxygen uptake by the perfused rat hindlimb results from its vasoconstrictor action.
52 citations
TL;DR: The data suggests that multiple receptor interactions are involved in the respiratory depressant effects of these drugs; the apnea response is primarily mediated through peripheral mu receptors but minute volume depression involves both mu receptors and non-mu sites.
Abstract: 1. Respiratory depressant effects of five drugs of the fentanyl series have been studied in anaesthetised rats. 2. The potency ratios of the fentanyl drugs to produce apnea and depress minute volume were dissimilar. Further, in vivo naloxone pA2 values were identical for blockade of apnea for the fentanyl drugs but different for antagonism of minute volume. 3. Differences in agonist potency and in naloxone pA2 values were also seen in vagotomised rats where only depression of minute volume is observed. 4. The data suggests that multiple receptor interactions are involved in the respiratory depressant effects of these drugs; the apnea response is primarily mediated through peripheral mu receptors but minute volume depression involves both mu receptors and non-mu sites.
52 citations
TL;DR: An attempt is made to explain some similarities and differences in the behavioral effects of the drugs tested (and those observed in other studies) by the changes they induce in brain biogenic monoamines.
Abstract: 1. The effects of Adafenoxate (Adf), meclofenoxate (Mf) and citicholine (CCh) administered at a daily dose of 100 mg/kg for 7 days on the levels of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the frontal cerebral cortex, striatum, hippocampus and hypothalamus of rats were studied. 2. Adafenoxate increased the NA level in the striatum and decreased it in the hypothalamus; it increased the DA level in the cerebral cortex and hypothalamus and decreased it in the striatum; it increased the 5-HT level in the cerebral cortex and decreased it in the hippocampus. 3. Meclofenoxate decreased the NA level in the cerebral cortex and hypothalamus; it increased the DA level in the hippocampus and hypothalamus and the 5-HT level in the cerebral cortex, striatum, hippocampus and hypothalamus. 4. Citicholine increased the NA level in the cerebral cortex and hypothalamus; it increased the DA level in the striatum and the 5-HT level in the cerebral cortex, striatum and hippocampus. 5. An attempt is made to explain some similarities and differences in the behavioral effects of the drugs tested (and those observed in other studies) by the changes they induce in brain biogenic monoamines.
51 citations
TL;DR: It is suggested that inhibition of calcium entry through calcium channels induced by verapamil and diltiazem may play a role in analgesia development.
Abstract: 1. The analgesic effects of diltiazem and verapamil, both per se and together with morphine, were studied using subcutaneous (s.c.) and intracerebroventricular (i.c.v.) administrations, in the hot-plate test in mice. 2. The i.c.v. injection of verapamil (15-120 micrograms/mouse) and diltiazem (60-120 micrograms/mouse) induced dose-dependent analgesic effects. 3. The i.c.v. administration of verapamil (30-120 micrograms/mouse) and diltiazem (60-120 micrograms/mouse) significantly enhanced, in a dose-dependent way, the analgesic effects of morphine and produced a parallel displacement to the left of the morphine log dose-response line. 4. When these calcium channel blockers were administered subcutaneously at doses of 40 and 80 mg/kg, they exerted no analgesic actions, but dose-dependently potentiated the analgesic effects of morphine, producing a parallel shift to the left of the morphine log dose-response line. 5. These results suggest that inhibition of calcium entry through calcium channels induced by verapamil and diltiazem may play a role in analgesia development.
47 citations
TL;DR: The rat hindlimb, kidney and intestine were each perfused in a nonrecirculating mode at 25 degrees C using an artificial perfusate and the effects of vasopressin and noradrenaline on oxygen uptake and perfusion pressure determined.
Abstract: 1. The rat hindlimb, kidney and intestine were each perfused in a nonrecirculating mode at 25°C using an artificial perfusate (initial pressure 85 ± 5 mmHg) and the effects of vasopressin and noradrenaline on oxygen uptake and perfusion pressure determined. 2. Both vasopressin (K0.5 = 0.1 nM) and noradrenaline (K0.5 = 2 nM) increased oxygen uptake as well as perfusion pressure by the perfused hindlimb; changes in oxygen uptake were closely matched by changes in pressure. The maximum increase in oxygen uptake was approx. 9 μmol/hr per g wet wt of hindlimb. 3. The perfused kidney also responded to vasopressin and noradrenaline with parallel increases in oxygen uptake and perfusion pressure for each agent. The largest increase in oxygen uptake was approx. 30 μmol/hr per g wet wt but this was not maximal. 4. Vasopressin increased oxygen uptake and pressure by the perfused intestine over the range 0.01–2 nM, but the changes in pressure only became significant at doses >0.1 nM. 5. Noradrenaline inhibited oxygen uptake and increased perfusion pressure in a dose-dependent manner at pharmacological concentrations (> 30 nM) when shunting of perfusate may have contributed to unperfused regions. 6. A network of mesenteric blood vessels estimated to contain approx. 6% vascular tissue by weight, with the remainder white fat cells, lymphatics and connective tissue, was also perfused. 7. Vasopressin (K0.5 = 0.3 nM) and noradrenaline (K0.5 = 30 nM) each increased oxygen uptake and perfusion pressure in a dose-dependent manner. 8. Calculations, based on the vascular tissue content and the overall oxygen uptake in the mesenteric artery preparation suggest that perfused blood vessels consume oxygen at very high rates (115 μmol/hr per g wet wt at 25°C) and that this consumption is further increased by 75% when the smooth muscle constricts. 9. It is concluded that agonist-mediated constriction of blood vessels is energetically expensive and that the consumption of oxygen for this process has significant implications for whole body thermogenesis.
45 citations
TL;DR: The systemic administration of Bay K 8644, a dihydropyridine analogue, having the ability to stimulate calcium entry into cells produced a dose-dependent increase in clonic and tonic convulsions and other epileptic phenomena, which were prevented by pretreatment with nimodipine or nitrendipine.
Abstract: 1. The anticonvulsant activity of calcium channel antagonists, was studied after intraperitoneal or oral administration in genetically epilepsy prone rats (GEPR). 2. Flunarizine, dihydropyridines and HA 1004, administered intraperitoneally, were the most potent compounds. Diltiazem, prenylamine, perhexiline, verapamil and methoxyverapamil, given intraperitoneally, were able to reduce the incidence of the tonic phase but were completely ineffective in preventing clonic and running phases of sound-induced seizures in GEPR. Similar anticonvulsant activity was observed when these compounds were administered orally. 3. After intracerebroventricular administration of some of the hydrosoluble calcium antagonists studied, the anticonvulsant effects were similar to those observed after systemic administration. 4. The systemic administration of Bay K 8644, a dihydropyridine analogue, having the ability to stimulate calcium entry into cells produced a dose-dependent increase in clonic and tonic convulsions and other epileptic phenomena, which were prevented by pretreatment with nimodipine or nitrendipine. 5. The possible role of purinergic, excitatory amino acid, GABA-benzodiapine mechanisms as well as the role of Ca2(+)-calmodulin and calcium channel binding sites on the anticonvulsant effects of some calcium antagonists are discussed.
TL;DR: The magnitude of the hypoglycaemic effects varied with the dosage used and the time of storage (except with A. heterophyllus, whose activity did not change with storage even up to 3 days).
Abstract: 1. Investigations were carried out to determine whether aqueous extracts of Osbeckia octandra, Artocarpus heterophyllus and Bambusa vulgaris truly possess oral hypoglycaemic activity. 2. All three plant extracts significantly lowered the fasting blood glucose level and markedly improved glucose tolerance in Sprague-Dawley rats. 3. A maximum hypoglycaemic activity was observed at +3 hr with O. octandra and B. vulgaris; with A. heterophyllus a maximum effect was not observed even at +5 hr. 4. The hypoglycaemic activity of O. octandra was comparable with that of tolbutamide while that of A. heterophyllus or B. vulgaris was better than that of tolbutamide. 5. The magnitude of the hypoglycaemic effects varied with the dosage used and the time of storage (except with A. heterophyllus, whose activity did not change with storage even up to 3 days).
TL;DR: The data suggest that aggressive muricidal behavior in rats with syndrome of social isolation is connected with the decreased activity of brain 5-HT1 receptors.
Abstract: 1. 1. Prolonged (3 month) individual housing of Wistar rats produced aggressive muricidal behavior in 28% of the animals. 2. 2. Binding studies with [3H]5-HT showed that the affinity (Kd) of 5-HT1 receptors in the frontal cortex, striatum, hippocampus and hypothalamus of isolated aggressive rats was significantly decreased as compared to that in grouped rats. 3. 3. The affinity of 5-HT1 receptors was also significantly decreased in the striatum, hippocampus and hypothalamus of isolated nonaggressive rats. 4. 4. The number (Bmax) of 5-HT1 receptors was significantly decreased in the hippocampus and hypothalamus of isolated aggressive rats and in isolated nonaggressive rats it was decreased only in the hypothalamus. 5. 5. The data suggest that aggressive muricidal behavior in rats with syndrome of social isolation is connected with the decreased activity of brain 5-HT1 receptors.
TL;DR: 5-HT is the most potent vasoconstrictor agent of all those tested, whose effects appear to be mediated by 5-HT2- but not by alpha 1-adrenergic receptors; (2) chorionic vessels also possess H1-receptors; and ketanserin has more affinity to block 5- HT2- receptors than to blockalpha 1- adrenergic- and H 1-receptionors.
Abstract: 1. The effect of different vasoactive agents on segments of human chorionic arteries and veins was analyzed. 2. The order of these agents to produce maximal contractile responses was: 5-hydroxytryptamine (5-HT) = histamine (H) = K+ greater than noradrenaline (NA) greater than or equal to phenylephrine (PHEN) greater than clonidine (CLON), and with regard to their potencies (EC50 values) was: 5-HT greater than or equal to NA greater than or equal to H greater than PHEN greater than CLON greater than K+. Dopamine and isoproterenol did not elicit any type of response. 3. The receptors involved on the contractions elicited by agonists were analyzed. 4. The results obtained suggest that: (1) 5-HT is the most potent vasoconstrictor agent of all those tested, whose effects appear to be mediated by 5-HT2- but not by alpha 1-adrenergic receptors; (2) chorionic vessels also possess H1-receptors; and (3) ketanserin has more affinity to block 5-HT2-receptors than to block alpha 1-adrenergic- and H1-receptors.
TL;DR: It is suggested that ginseng extract at high doses produces analgesia and hypothermia in the rat by a non-opiate mechanism, and antagonizes the acute pharmacological effects of morphine.
Abstract: 1. 1. The effects of intraperitoneal administration of a standard extract of Panax ginseng alone and in combination with morphine were determined in male Sprague-Dawley rats. 2. 2. Ginseng extract at 200 mg/kg produced analgesia and hypothermia. These effects of ginseng were not reversed by naltrexone. 3. 3. A dose of morphine (8 mg/kg) produced analgesia and hyperthermia. The analgesic response to morphine was antagonized by 25 and 50 mg/kg doses of ginseng but not by 12.5, 100 and 200 mg/kg doses. 4. 4. Morphine-induced hyperthermia was antagonized by 12.5–200 mg/kg doses of ginseng. 5. 5. Administration of morphine (50 mg/kg) produced cataleptic effect which was antagonized by 25 mg/kg of ginseng. 6. 6. The results suggest that ginseng extract at high doses produces analgesia and hypothermia in the rat by a non-opiate mechanism, and antagonizes the acute pharmacological effects of morphine.
TL;DR: The data suggests that low level ingestion of marine fish oil has a beneficial effect on lipids and possibly the clotting profiles in healthy men.
Abstract: 1. This study was undertaken to evaluate the effects of low dose ingestion of omega-3 fatty acids on clotting profiles in healthy men ingesting 3 g of MaxEPA (900 mg omega-3 fatty acids) daily for 30 days. 2. No effect was noted on either platelet aggregation or circulating prostaglandin levels. 3. Significant decreases were noted for total cholesterol and low density lipoprotein. 4. Clotting factor decreases were noted for factors primarily of the intrinsic pathway and several factors which promote fibrinolysis. 5. The data suggests that low level ingestion of marine fish oil has a beneficial effect on lipids and possibly the clotting profiles in healthy men.
TL;DR: Pinaverium bromide is the only Ca2(+)-antagonist with known therapeutic efficacy in the treatment of irritable bowel syndrome and certain other functional intestinal disorders and does not elicit adverse cardiovascular side-effects at doses that effectively relieve GI spasm, pain, transit disturbances and other symptoms related to motility disorders.
Abstract: 1 1 The evidence reviewed here indicates that pinaverium bromide (Dicetel ® ) relaxes gastrointestinal (GI) structures primarily by inhibiting Ca 2+ influx through potential-dependent channels of surface membranes of smooth muscle cells 2 2 The in vivo selectivity of pinaverium bromide for the GI tract appears to be due mainly to its pharmacokinetic properties Because of its low absorption (typical for quaternary ammonium compounds) and marked hepatobiliary excretion, most of the orally-administered dose of pinaverium bromide remains in the GI tract 3 3 Orally-administered pinaverium bromide does not elicit adverse cardiovascular side-effects at doses that effectively relieve GI spasm, pain, transit disturbances and other symptoms related to motility disorders 4 4 Pinaverium bromide is the only Ca 2+ -antagonist with known therapeutic efficacy in the treatment of irritable bowel syndrome and certain other functional intestinal disorders
TL;DR: It was revealed that the decrease in atrial beta-adrenergic responses was associated with a reduction in serum levels of thyroid hormones, suggesting that thyroid hormones are needed for insulin to normalize the alterations observed in diabetic atria.
Abstract: 1. The influence of alloxan-induced diabetes was studied on spontaneously beating rat atria. Diabetic atria were found to have decreased rates, increased contractility and decreased responsiveness to both inotropic and chronotropic effects of isoprenaline. 2. Thyroid hormone levels were significantly reduced in diabetic animals. This revealed that the decrease in atrial β-adrenergic responses was associated with a reduction in serum levels of thyroid hormones. 3. Insulin treatment of diabetic rats for 10 days corrected the changes observed in diabetic atria. Serum levels of thyroid hormones returned to normal following insulin treatment as well. 4. Administration of insulin to thyroidectomized-diabetic rats did not reverse the diabetes-induced changes suggesting that thyroid hormones are needed for insulin to normalize the alterations observed in diabetic atria.
TL;DR: It is suggested that 7-O-ethyl and 7- O-isopropyl derivatives as well as TD can be considered as potential antihypertensive drugs because of the gradual onset and long duration of their hypotensive action in SHRSP.
Abstract: 1. 1. Structure and hypotensive activity relationships of tetrandrine (TD), an alkaloid isolated from the Chinese herb Radix stephaniae tetrandrae and its derivatives were investigated in conscious stroke-prone spontaneously hypertensive rats (SHRSP). 2. 2. Derivatives substituted at the 7-O position with various types of alkyl group produced varying degrees of hypotensive effect. 3. 3. While the demethylated derivative, fangchinoline (FC), and its acetylated compound had no effect on blood pressure, 7-O-methyl FC (TD), and 7-O-ethyl and 7-O-isopropyl FC at oral doses of 25 and 50 mg/kg produced a gradual and sustained hypotensive effect without any significant effects on heart rate and plasma renin concentration. 4. 4. Substitution at the 7-O position with longer side chains such as n-propyl, n-butyl and n-pentyl groups reduced both the degree and duration of hypotensive activity. 5. 5. Substitution of N-methyl groups at the 2 and 2′ positions with quaternary ammonium or N-oxide attenuated the hypotensive activity. 6. 6. The results of this study suggest a possibility that 7-O-ethyl and 7-O-isopropyl derivatives as well as TD can be considered as potential antihypertensive drugs because of the gradual onset and long duration of their hypotensive action in SHRSP.
TL;DR: The oral administration of endrin resulted in dose- and time-dependent decreases in hepatic and renal glutathione content with maximum depletion occurring in liver at approximately 24 hr post-treatment.
Abstract: 1. Recent studies have shown that endrin induces lipid peroxidation and may produce toxicity through an oxidative stress. We have therefore examined the effect of endrin administration to rats on glutathione content and the activities of glutathione metabolizing enzymes. 2. The oral administration of endrin resulted in dose- and time-dependent decreases in hepatic and renal glutathione content with maximum depletion (90%) occurring in liver at approximately 24 hr post-treatment. 3. Decreases in glutathione content were also observed in lung, brain, spleen and heart. 4. Endrin (4 mg/kg) decreased selenium dependent glutathione peroxidase activity in liver and kidney by 64 and 50%, respectively, while small increases were observed in the activities of glutathione reductase and glutathione S-transferase. 5. The toxicity of endrin may be at least in part related to oxidative tissue damage associated with depletion of glutathione and inhibition of glutathione peroxidase activity.
TL;DR: Evidence from a variety of biochemical and pharmacological experimental approaches, support the existence of an interelation between the calcium modulators and the opioid drugs, which agrees with the novel neuropharmacological hypothesis that a common very high affinity binding site for multiple neurotransmitters could exist.
Abstract: 1. 1. The findings, derived from different experimental models, examined in this review, provide evidence that the calcium channel blockers and related drugs possess analgesic effects. 2. 2. The antinociceptive action that some analgesic drugs exhibit may be related to calcium channel blockade. 3. 3. Evidence from a variety of biochemical and pharmacological experimental approaches, support the existence of an interelation between the calcium modulators and the opioid drugs. 4. 4. This idea agrees with the novel neuropharmacological hypothesis that a common very high affinity binding site for multiple neurotransmitters could exist, as has been proposed by Pasternak and Wood (1986). 5. 5. This hypothesis could be extended to the neuromodulators or other neuromediators.
TL;DR: Vascular endothelium releases different substances (endothelium-derived contractile factors, EDCFs), which mediate vasoconstrictor responses induced by several agents, which have been implicated in the local mechanisms involved in blood flow regulation, as well as in some pathological conditions, such as hypertension or cerebral vasospasm.
Abstract: 1. Vascular endothelium releases different substances (endothelium-derived contractile factors, EDCFs), which mediate vasoconstrictor responses induced by several agents. 2. Clear differences have been reported in endothelium-dependent contractions, which suggest at least three distinct EDCFs, named EDCF1, EDCF2 and EDCF3, respectively. 3. EDCF1 is a cyclooxygenase metabolite(s) of arachidonic acid. EDCF2 is a polypeptide released from cultured endothelial cells. It has been isolated and identified as a 21-amino acid peptide called endothelin, which is described as the most potent vasoconstrictor agent known to date. EDCF3 is an unidentified contractile factor(s), which is neither EDCF1 nor EDCF2. 4. The physiological role of these endothelial contractile factors is not yet clear. However, they have been implicated in the local mechanisms involved in blood flow regulation, as well as in some pathological conditions, such as hypertension or cerebral vasospasm.
TL;DR: Whereas CADO significantly attenuated the induction of morphine tolerance, D- and L-PIA did not affect the process and Morphine-induced antinociception was increased by pretreatment with adenosine agonists.
Abstract: 1. The analogs of adenosine d - and l -phenylisopropyladenosine ( d - and l -PIA) and chloroadenosine (CADO) induced analgesia in mice (hot-plate test). 2. The antinociceptive effects of the three adenosine agonists were antagonized by caffeine but were unaffected by naloxone. 3. Morphine-induced antinociception was increased by pretreatment with adenosine agonists. 4. Whereas CADO significantly attenuated the induction of morphine tolerance, d - and l -PIA did not affect the process.
TL;DR: It is shown that peptides of the endothelin family exert a potent contractile effect on various human smooth muscles and participation of dihydropyridine- and voltage-sensitive calcium channels in the contractile response produced by these peptides may vary from one organ to another.
Abstract: 1 1 Endothelin-1 (ET-1), endothelin-3 (ET-3) and sarafotoxin S6b (SRFTX) produced a concentration-dependent tonic contraction of the human isolated urinary bladder, renal pelvis and renal artery with threshold at nM concentration 2 2 In the bladder, the following order of potency was found: ET-1 > SRFTX > ET-3 In the renal pelvis, all peptides displayed similar affinity but, at high concentrations the maximal response was highest for SRFTX followed by ET-1 and ET-3 In the renal artery ET-1 and SRFTX were about equipotent and equieffective while ET-3 produced only a slight and inconsistent (2 out of 5 cases) vasoconstrictor response 3 3 As shown previously for the human bladder muscle, the response to ET-1 in the renal pelvis was nifedipine (1 μM)-resistant while a consistent fraction of the response was blocked by nifedipine in the human renal artery 4 4 These findings indicate that peptides of the endothelin family exert a potent contractile effect on various human smooth muscles Participation of dihydropyridine-and voltage-sensitive calcium channels in the contractile response produced by these peptides may vary from one organ to another
TL;DR: Jatrophone (JAT), a diterpene isolated from the plant Jatropha elliptica, caused a concentration-dependent relaxation effect against acetylcholine (Ach)-oxytocin (Ot)- and KCl-induced uterine sustained contraction and inhibited CaCl2-induced contraction in K+-depolarized preparations.
Abstract: 1. Jatrophone (JAT), a diterpene isolated from the plant Jatropha elliptica (1-300 microM), caused a concentration-dependent relaxation effect against acetylcholine (Ach)-oxytocin (Ot)- and KCl-induced uterine sustained contraction. The relative potency order was: Ach greater than Ot greater than KCl. 2. The relaxant effect of JAT was not modified by phorbol ester, forskolin, MIX, TMB-8 and W-7. The increase concentration of calcium (0.2-2 mM) in the medium did not reverse the inhibitory effect caused by JAT. 3. Pre-incubation of the preparations with JAT (16-32 microM) for 20 min, caused a concentration-dependent inhibition of KCl-induced contractile response. At 30 microM, JAT inhibited in an apparently non-competitive manner CaCl2-induced contraction in K+-depolarized preparations. High concentrations of JAT (100 microM) also caused a time-dependent relaxation in CaCl2-induced sustained uterine contraction (T1/2 = approx. 15 min). 4. JAT (30 microM) inhibited the dihydropyridine calcium channel agonist Bay K 8644-induced uterine contraction in an apparently non-competitive fashion, while verapamil (0.1 microM) caused an rightward displacement of Bay K 8644 contraction and marked inhibition of the maximal response.
TL;DR: It is concluded that there exists a similar population of adenosine A1 and A2 receptors in chorionic vessels, which mediateAdenosine relaxation, which appears to be mainly produced by inhibition of Ca influx, but not by a cAMP-dependent mechanism.
Abstract: 1. 1. Adenosine induced concentration-dependent relaxations in segments of human chorionic arteries and veins precontracted with 75 mM K+, which were attenuated by l-methyl-3-isobutylxanthine (MIX). In the same conditions, l -phenylisopropyladenosine ( l -PIA), N-ethylcarboxamideadenosine (NECA) and dibutyryl-cyclic AMP (Db-cAMP) also produced concentration-dependent vasodilations. 2. 2. The order of potency with respect to EC50 was in arteries: NECA ⩾ l -PIA > Db-cAM P ⩾ adenosine, and in veins: l -PIA ⩾ NECA > adenosine ⩾ Db-cAMP. 3. 3. In segments precontracted with 10−6 M PGF2α, adenosine, NECA and l -PIA induced similar relaxations, which were markedly larger than those found in K+ contracted segments. 4. 4. Db-cAMP (15 min preincubation) inhibited more potently K+ (75 mM) contractions than adenosine. 5. 5. Adenosine reduced Ca addition-induced contractions in depolarized segments exposed to Ca-free medium, as well as 45Ca uptake elicited by 75 mM K+. 6. 6. It is concluded that there exists a similar population of adenosine A1 and A2 receptors in chorionic vessels, which mediate adenosine relaxation. This effect appears to be mainly produced by inhibition of Ca influx, but not by a cAMP-dependent mechanism.
TL;DR: Additional studies with specific serotoninergic drugs are needed to clarify the role of this transmitter in attack by female mice on lactating intruders.
Abstract: 1 1 The impact of the serotoninergic receptor on the attack directed by female mice towards lactating intruders was assessed by studying the effects of 8-OH-DPAT (a serotoninergic agonist) and fluoxetine (an inhibitor of serotonin reuptake) on this paradigm at a range of doses and post-injection durations 2 2 The specificity of these drug actions behaviour were examined by studying their effects on wheel running activity and performance in the open field Non-sedative doses of 200 and 250 μg/kg of 8-OH-DPAT reduced attack by resident females on lactating intruders 3 3 Higher doses (12–16 mg/kg) of fluoxetine reduced activity measures whereas lower non-sedative doses (up to 8 mg/kg) were without action on this aggression paradigm 4 4 Additional studies with specific serotoninergic drugs are needed to clarify the role of this transmitter in attack by female mice on lactating intruders