Ph.D. - Biomedical Sciences (Pharmacology)

Permanent URI for this collection


Recent Submissions

Now showing 1 - 5 of 9
  • Item
    Effects of adrenergic agonists and antagonists in potassium intoxication
    ([Honolulu], 1973) Lockwood, Raymond H.
    Studies were performed to assess the role of the sympathetic nervous system in regulating the metabolism of an administered load of potassium in anesthetized cats. A nonlethal intravenous infusion of KCl (10 mg/Kg/min for 10 minutes) produced effects indicative of a sympatho-adrenal discharge; these effects included an increase in heart rate, a rise in blood pressure and an increase in blood glucose. The increases in heart rate and blood pressure were abolished by acute adrenalectomy and by pretreatment with reserpine. Propranolol pretreatment antagonized the heart rate but not the blood pressure response associated' with the KCl infusion. Acute adrenalectomy as well as pretreatment with reserpine, propranolol and 1-(4'methylphenyl)-2- isopropylamino-propanol (H35/25) increased the susceptibility of the animals to KCl intoxication; thus, a significant number of fatalities occurred in these animals when they received a rate of KCl infusion (10 mg/Kg/min) which produced no deaths in intact, non-pretreated controls. The fatalities were correlated with higher plasma K+ values than in the controls. Butoxamine pretreatment did not significantly increase the susceptibility to KCl intoxication from a mortality standpoint but did significantly increase the hyperkalemic response to the KCl infusion. The above suggested that the sympatho-adrenal system has an important attenuating effect on the rise in plasma K+ produced by infusion of the ion. Chlorisondamine and bretylium pretreatment failed to increase the susceptibility of the animals to KCl intoxication. Evidence is presented which suggests that these latter two agents may not effectively antagonize the sympatho-adrenal discharge elicited by KCl infusion. The i.v. infusion of epinephrine completely protected animals against an infusion of KCl (12 mg/Kg/min for 10 minutes) which was lethal to most control animals. Plasma K+ data showed that the protection was related to an ability of epinephrine to attenuate the hyperkalemia produced by infusion of the ion. Similar effects on mortality and plasma K+ were produced by isoproterenol (a beta adrenergic stimulant) but not by phenylephrine (an alpha adrenergic stimulant). The epinephrine-induced protection against death due to KCl infusion as well as the plasma K+ lowering effect were abolished by propranolol and sotalol (beta blocking agents) but not by phenoxybenzamine (an alpha blocking agent). Acute nephrectomy or pancreatectomy did not affect the protective action of epinephrine. An infusion of glucose (which produced blood glucose levels higher than those in the epinephrine series) did not protect against KGI intoxication. The K+ content of skeletal and cardiac muscle in animals given an infusion of KCl was significantly greater in animals infused with epinephrine than in controls infused with saline. The foregoing suggests that epinephrine protected against KCl intoxication in these experiments by virtue of a direct beta stimulant action which promoted the entry of K+ into cells and thus prevented plasma K+ from reaching a lethal level. Studies were also performed to determine the "subtype" of beta receptor subserving the above effect on K+. Butoxamine and H35/25 were very effective in antagonizing the effects of epinephrine in potassium intoxication. Practolol, which blocked the cardiostimulant effect of epinephrine, did not block the protective effect or attenuation of hyperkalemia during KCI infusion by this catecholamine. Salbutamol and soterenol had effects similar to epinephrine, but l-isopropylamino-3-(2-thiazoloxy)2-propanol (ITP) failed to protect against KCl intoxication. The above spectrum of agonism and antagonism would be consistent with a beta-2 type of adrenergic receptor according to the Lands classification, although the adequacy of this classification in delineating the beta receptors found in different tissues has been questioned.
  • Item
    The chemistry and pharmacology of a central nervous system stimulant from the sea anemone, Stoichactis kenti
    ([Honolulu], 1971) Turlapaty, Prasad D.M.V.
    A central nervous system stimulant has been isolated from the sea anemone, Stoichactis kenti. A chromatographically homogeneous fraction has been obtained from the crude extract by dialysis and gel filtration on Sephadex G-50. Attempts were made to purify the active fraction further by ion exchange column chromatography, but the specific activity of the active fraction was not increased. The active substance was found to be water soluble, heat and acid labile and stable to alkali. It showed a positive color reaction with ninhydrin on paper (circular) chromatography, using n-butanol: acetic acid:water (4:1:5) system. Steroids, steroidal glycosides, nucleic acids, lipids and carbohydrates were found to be absent in the active fraction, when tested with specific reagents. The active fraction has a characteristic u.v. maximum at 277.5 nm. Determination of protein by Lowry's method and estimation of nitrogen by Kjeldahl's method indicated the active fraction was rich in protein. An acid and alkaline hydrolysis of the active fraction was carried out and hydrolysates were analyzed both by two dimensional chromatography and Technicon auto aminoacid analyzer. The following amino acids were identified by comparing with standard aminoacids: cysteine, aspartic acid (asparagine), threonine, serine, glutamic acid (glutamine), proline, glycine, alanine, valine, cystine, isoleucine, leucine, tyrosine, phenylalanine, lysine, histidine and arginine. From these results it was concluded that the active fraction was a polypeptide containing seventeen different aminoacids. Based on behavior on Sephadex G-50, the approximate molecular weight of the active fraction was estimated to be in the range of 2,500 - 3,000. Signs of central nervous system stimulatory activity produced by the active fraction in male mice included fighting episodes, increased motor activity and clonic convulsions. The ED50 of the active fraction based on fighting episodes was 6.4 mg/kg. The fighting episodes occurred at a frequency of 2-3 times/minute. After the administration of the active fraction intraperitoneally, the fighting episodes started within 4-6 minutes, peaked at 15 minutes and waned within about 30 minutes. The LD50 dose of the active fraction was 12.2 mg/kg. Toxic symptoms such as ataxia, catalepsy and tonic convulsions were observed before death. Phenobarbital sodium, chlorpromazine and methocarbamol completely blocked the fighting response of the active fraction even at the ED100 dose level but did not change the LD50. The antagonism of the active fraction induced stimulant activity (as measured by fighting episodes) by these drugs suggests that this activity was probably mediated centrally. Reserpine and tetrabenazine pretreatment markedly increased the stimulant effect of the active fraction by decreasing the ED50 of the active fraction by 50%. Such treatment increased toxicity twofold. a-methyl p-tyrosine methylester Hel (α-MPT) pretreatment did not alter the ED50, while the LD50 was significantly decreased. When α-MPT treatment was incorporated in reserpine or tetrabenazine treated animals, the stimulatory activity of the active fraction was completely blocked even at the ED100 (9.3 mg/kg) dose level. The active fraction produced a significant decrease in brain norepinephrine content at the ED50 and the ED100 doses during the stimulation period. Both the active fraction and reserpine produced a hyperthermic response in mice. DL-dopa treatment restored the active fraction induced stimulant action (fighting episodes) which was abolished after combined treatment with a-MPT and reserpine and reserpine and disulfiram. DL-dopa also increased the LD50 of the active fraction. The active fraction at the ED50 dose significantly decreased brain dopamine content. Pretreatment with p-chlorophenylalanine did not alter the ED50 and the LD50 of the active fraction. No change in brain serotonin content was observed after administration of the active fraction at the ED50 dose. The active fraction at the ED50 dose significantly inhibited the re-uptake mechanism of norepinephrine during the stimulation period. It also elevated normetanephrine levels at the ED50 dose. Propranolol but not phentolamine treatment completely blocked the stimulatory action of the active fraction, with no change in the LD50. Atropine treatment decreased the toxicity, with no change in the ED50. On the other hand physostigmine blocked the stimulatory action and increased toxicity by twofold. In conclusion, the results suggest that the active fraction causes stimulant action by releasing active norepinephrine from functional pools and inhibiting its re-uptake, thus making more norepinephrine available at adrenergic receptors.
  • Item
    The nature and action of a hypotensive agent from Eucalyptus robusta
    ([Honolulu], 1969) Read, George Wesley
    Extracts of some species of Eucalyptus have been found to be hypotensive in rats, guinea pigs, cats, and dogs. Of the 29 species of this genus available for assay, Eucalyptus robusta contained the highest concentration of the hypotensive principle. Active and inactive species were randomly distributed throughout the sections and subsections of the genus, indicating that activity is not associated with any particular group of the eucalypts. The active principle occurs in highest concentration in the leaves but is also found in the phloem, roots, and to a lesser extent in the xylem. Little or no activity is present in> the bark. The hypotensive factor is soluble in water, lower alcohols and acetone but insoluble in chloroform or ether. Addition of chloroform or ether to the alcoholic extracts precipitated a more purified fraction. Attempts to purify the active component further by adsorption, steam distillation, gel filtration, heavy metal ion precipitation, liquid-liquid extraction, and dialysis met With little success. The molecular weight of the active principle was found to be approximately 3000, using Craig's dialysis method. The active component's molecular weight, solubility characteristics, precipitability by heavy metals (especially ferric chloride), base lability, strong adsorptive tendencies especially to Sephadex), non-volatility, ease of oxidation, and ineffectiveness orally indicate that it is probably a specific tannin. Five mg/kg of the partially purified material depressed the blood pressure of rats to less than 50% of its original value for approximately 15 minutes. Larger doses lowered the blood pressure to 30% of normal and for periods greater than several hours. The active agent was effective intravenously and intraperitoneally but ineffective orally. The absence of an effect when it was given to the vascularly isolated heads of cross-circulated animals indicated that the agent's action was peripheral. Prior treatment with hexamethonium, reserpine, phenoxybenzamine, pronethalol, and atropine had little or no effect on the action of the Eucalyptus factor. The antihistaminics tripellenamine and diphenhydramine, however, did attenuate the depressor effect of the extracts. When the active principle was given first, it had little or no effect on the response to subsequently administered phenylephrine, angiotensin, isoproterenol, or methacholine. However, there was an interference with the response to histamine. These results suggest that the hypotensive agent acts on the histamine pathway. Depletion of the histamine stores With the drug 48/80 blocked the action of the hypotensive agent, as did a one-week pretreatment With the agent itself. These results, along With the blockade by antihistamines and the interference with the response to histamine, indicate that the active principle is a histamine liberator.
  • Item
    Chemistry and pharmacology of adrenergic blocking agents
    ([Honolulu], 1969) Ghouri, Mohammad Sarfraz Khan
  • Item
    The contractile mechanisms of sodium metavanadate in isolated vascular smooth muscle
    ( 1995) Zhou, Qin
    The mechanism of the contractile effect of vanadate on vascular smooth muscle was investigated in the rat aorta. Sodium metavanadate (NaV03) (10-5 M - 3 x 10-3 M) induced contractile responses in a concentration-dependent manner. Removal of endothelium did not affect the response to NaV03. NaV03 has the most efficacy agent to cause contraction as compared to vanadyl sulphate and vanadium trichloride. The response to NaV03 was inhibited by nifedipine, a voltage depedent Ca2+-channel inhibitor, 2-nitro-4-carboxyphenylN, N-diphenylcarbramate (NCDC), a phospholipase C inhibitor, H-7, a protein kinase C inhibitor, indomethacin, a cyclooxygenase inhibitor, and AA861, a 5Iipoxygenase inhibitor, but not by ouabain, a Na+, K+-ATPase inhibitor, prazosin, a a1 receptor inhibitor, methysergide, a serotonin receptor inhibitor, tripelennamine, a histamine receptor inhibitor, glyburide, a KATP-channel inhibitor, -apamin, a Kca-channel inhibitor, or Mg2+-removal, a condition to inhibit Ca2+ATPase activity. The response to arachidonic acid was also inhibited by indomethacin, AA861 , nifedipine and NCDC. H-7 inhibited the response to NaV03 but not to arachidonic acid. However, in the presence of indomethacin and AA861 , H-7 did cause inhibition of the residual response to NaV03. In Ca2+-free medium with EGTA (0.02 mM), NaV03 (3 x 10-4 M) induced a phasic contraction of rat aortas. This residual response to NaV03 was partly inhibited by NCDC and indomethacin, but not by nifedipine. The subsequent addition of Ca2+ (1.2 mM) in the presence of NaV03 caused sustained contraction. In addition, the response to Ca2 + in the presence of NaV03 was completely inhibited by both NCDC and nifedipine, but only partially inhibited by indomethacin. In rat aortas, NaV03 increased the levels of inositol monophosphate (InsP) and prostaglandin F2a. Indomethacin, AA861, and NCDC inhibited the InsP increase. In addition, NCDC and indomethacin, but not AA861 , inhibited the PGF2a increase. These results suggest that the response to NaV03 may be due to the increased phosphoinositide metabolites and partly due to a subsequent increase in the metabolism of arachidonic acid.