published_or_final_version / Pharmacology / Doctoral / Doctor of Philosophy

published_or_final_version / Physiology / Master / Master of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

abstract / Medicine / Master / Master of Philosophy

Thermoregulatory, analgesic and respiratory depressive responses as well as tolerance to morphine were investigated in young (3 to 5 months), mature (10 to 12 month) and senescent (26 to 28 month) male Fischer 344 rats. The thermoregulatory system of senescent rats was not able to maintain body temperature in hot and cold environments as well as the thermoregulatory system of young rats. Additionally, senescent rats had basal rectal temperatures which were approximately one degree lower than basal temperatures in young rats. Subcutaneous morphine caused biphasic effects on body temperature ie. hyperthermia at low doses and hypothermia at high doses. Senescent rats were less responsive to the hypothermic effects of subcutaneous morphine than young rats, but this was not due to decreased subcutaneous blood flow or inability to lose heat. Morphine injections intracerebroventricularly showed no age-related differences. A two site model for the actions of morphine on thermoregulation was proposed and it was suggested that the age-related differences are due to changes in a non periventricular site. Previously reported increased lethality of intravenous morphine in aged rodents was shown to be due to decreased respiratory reserve rather than increased sensitivity to respiratory depression. Senescent rats were also found to acquire tolerance to the thermic effects of morphine less readily than young rats regardless of the route of administration. Normal aging has been characterized as a decrease in adaptability, and it was suggested that senescent rats were less able to compensate for the thermic effects of morphine as well as young rats. In order to determine the mechanisms of decreased adaptability, neurotransmitters proposed to be involved in thermoregulation were injected intracerebroventricularly in morphine tolerant rats. The results suggested a shift from catecholaminergic to cholinergic transmitters with aging.

The premature infant is subject to pathological alterations of the cardiovascular system leading to insufficient pulmonary blood flow and/or sudden surges of pressure to fragile cerebral blood vessels, conditions which are often associated with hypotension. Dobutamine appears to be a potentially useful agent to increase pulmonary blood flow and correct hypotension. In view of this potential, the alpha-adrenergic characteristics of dobutamine acts were studied in the isolated rabbit femoral and pulmonary arteries. Dobutamine on the post synaptic membrane of these tissues as a high affinity, low intrinsic activity alpha adrenergic agonist. No action of dobutamine to modulate stimulation evoked release of norepinephrine was found, although dobutamine did increase spontaneous release of norepinephrine. This effect was not blocked by antagonists of uptake 1 and uptake 2. To further evaluate dobutamine for use in the neonate, contractile responses of the femoral and pulmonary arteries and aorta to dobutamine and norepinephrine were studied in dogs of various ages from newborn to 6 weeks. Maximal contractile responses to norepinephrine in the pulmonary artery and aorta increased with age. Dobutamine produced small or no responses in all newborn tissues studied and also showed increasing responsiveness with age. To allow future study of the mechanism of these changes a method of radioligand binding was established for vascular smooth muscle using the ligands prazosin and rauwolscine in the dog and rabbit pulmonary artery and aorta. This binding was found to demonstrate the properties of saturability, sterospecificity and rank order of potency. Possible variables that could account for the observed changes in response during maturation were mathematically modeled to provide a theoretical basis for future studies combining measurement of contractile response and radioligand binding techniques.

Monocrotaline is a pyrrolizidine alkaloid found in plants implicated in livestock and human poisoning. Laboratory rats given monocrotaline develop pulmonary hypertension and right heart hypertrophy in the weeks following administration of the chemical. Lung weight increases and right heart hypertrophy correlate with increased pulmonary artery pressure. Rats which consumed monocrotaline drinking water (20 mg/l) for only 4 days developed significant increases in lung and heart weights 14 days after exposure began. This exposure was equivalent to a dose of 15 mg/kg. Other treatment combinations of time (0-10 days exposure) and monocrotaline concentration (5-60 mg/l in drinking water) were tested. The accumulative dose calculated for each of the treatment combinations which produced toxicity was in the range of 15 to 20 mg/kg. Monocrotaline injury appears to be cumulative, but organ weight increases reverse once exposure is stopped. As pulmonary hypertension develops and pulmonary arteries hypertrophy, the force with which isolated pulmonary artery segments contract decreases. This is a loss of efficacy rather than potency to the contracting agents KCl, norepinephrine, and 5-hydroxytryptamine. Relaxation of arteries under conditions of potassium-return (a measure of Na⁺/K⁺ ATPase activity) was also altered by monocrotaline treatment. In vivo monocrotaline treatment had little effect on the force of K⁺-return relaxation. However, the rate at which arteries relaxed was significantly decreased following 4 days ingestion of monocrotaline drinking water (20 mg/l). In vitro ouabain treatment and endothelial injury also decreased the rate of K⁺-return relaxation. Another Na⁺/K⁺ ATPase activity, ⁸⁶Rb⁺ uptake, was decreased following monocrotaline treatment only when 5-hydroxytryptamine was present and only uptake associated with the endothelium was affected. These studies utilized a very low exposure to monocrotaline (4 days ingestion of 20 mg/l monocrotaline drinking water or 15 mg/kg) to produce toxicity in rats. Monocrotaline-induced toxicity measured 20 days after treatment included right heart and lung hypertrophy and decreased contractions of isolated pulmonary arteries. Monocrotaline treatment decreased the rate of Na⁺/K⁺ ATPase-dependent relaxation of isolated pulmonary arteries 4 days after treatment began.

In the glasshouse, two cultivars of alfalfa growing in non-sterile soil were evaluated for their response to inoculation with 4 VA mycorrhizal fungi and 3 strains of Rhizobium meliloti. Alfalfa cultivar Hayden PX-1 had significantly greater dry stem weights (p = 0.05) when inoculated with Glomus fasciculatum, G. deserticola or an undescribed Glomus sp. compared to mycorrhizal controls. Alfalfa cultivar Lew HI Nod had significantly less dry stem weights when inoculated with G. fasciculatum, G. mosseae or the undescribed Glomus sp. Addition to R. meliloti did not impart increased growth responses with either alfalfa cultivar probably due to the high nitrogen content of the soil. In the field, alfalfa cultivar Hayden PX-1 was both transplanted and direct-seeded. Transplanted alfalfa had been preinoculated with VA mycorrhizal fungi and R. meliloti. Inocula containing VA mycorrhizal fungi and R.meliloti were Layered below the seed in direct-seeded plots. Phosphorus, as treble super phosphate, was also added as a treatment. At first harvest, transplanted alfalfa inoculated with the undescribed Glomus sp. had significantly greater (p = 0.05) dry whole plot weights compared to controls regardless of R. meliloti or phosphorus treatments. Inoculation of alfalfa with G. deserticola significantly increased dry whole plot weights over controls but significantly (p = 0.05) only with added R. meliloti and phosphorus. Second harvest data maintained the trend for yield increases over controls with addition of the undescribed Glomus sp. and G. deserticola; however, only significantly (p = 0.05) with inoculation with the undescribed Glomus sp. including R. meliloti and phosphorus. Yield increases were not obtained for the final three transplanted alfalfa harvests or for any of the direct-seeded alfalfa harvests. Statistically significant differences in phosphorus and protein content of alfalfa were not found between any of the treatments. Also, differences were not found in soil populations of R. meliloti in mycorrhizal inoculated plots compared to control plots.

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