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Studies on the stimulant action of human gamma-globulin on spontaneous contractility: interaction with K⁺-channel openers and postaglandin inhibitors

University of British Columbia

The aim of this thesis was to investigate the stimulatory action of human gamma-globulin on the spontaneous activity of the rat mesenteric portal vein. Previous studies in our laboratory have identified human gamma-globulin and IgG as stimulatory factors which may be responsible for the smooth muscle abnormality associated with the etiology of essential hypertension (Pillai, 1989). This thesis is comprised of three studies. The first study examined whether or not human gamma-globulin exerts its stimulatory action only on spontaneously-active smooth muscles. The second study was to determine if the stimulatory action of human gamma-globulin on the spontaneous activity of the rat mesenteric portal vein is due to decreased potassium conductance. The aim of the third study was to determine if prostaglandins play a role in the stimulatory effects of human gamma-globulin. Human gamma-globulin significantly increased the contractile activity of spontaneously-active muscles (rat mesenteric portal vein and guinea-pig taenia-caeci) with respect to frequency, force, and integrated response of contraction, whereas it had no significant effect on the contractile activity of quiescent muscles (rat aorta and guinea-pig trachea). At a concentration of 4.35 mg/ml human gamma-globulin caused a 63% increase above the maximum integrated response obtained with the time/volume/pH control in the rat mesenteric portal vein and a 23% increase in integrated response above that of the time/volume/pH control in guinea-pig taenia-caeci. Human gamma-globulin had no significant effect on the actions of noradrenaline on the rat mesenteric portal vein. Glibenclamide, a potassium channel antagonist, potentiated the action of human gamma-globulin on the portal vein by 45% and on its own had a biphasic (increase followed by a decrease) effect on the spontaneous activity of the portal vein . Glibenclamide and human gamma-globulin in combination increased the degree of contracture or baseline tone of the portal vein . Diazoxide, a potassium channel opener, noncompetitively inhibited the action of human gamma-globulin on the rat mesenteric portal vein by 63%. Both concentrations of pinacidil (0.5 and 5 μM), which is a potassium channel opener, non-competitively inhibited the action of human gamma-globulin by 61% and 78%, respectively. Lemakalim, a potassium channel opener, decreased the spontaneous activity of the portal vein in a concentration-dependent manner. Lemakalim non-competitively antagonized the actions of both noradrenaline and glibenclamide on the rat mesenteric portal vein. Lemakalim potentiated the stimulatory action of human gamma-globulin on the integrated force of the spontaneous contractions of the rat mesenteric portal vein by 40% and 49% at concentrations of 0.5 and 5 μM, respectively. It did so in a manner similar to glibenclamide by interacting with human gamma-globulin to increase the contracture or baseline tone of the portal vein. Indomethacin, meclofenamic acid, corticosterone, phenylbutazone, aspirin, ibuprofen, and piroxicam all inhibited the stimulatory action of human gamma-globulin on the rat mesenteric portal vein, but only indomethacin, meclofenamic acid, and corticosterone did so to a significant level . Indomethacin was the most potent inhibitor of human gamma-globulin, decreasing the maximum integrated response of the rat mesenteric portal vein to human gamma-globulin by 40% and 60% at concentrations of 1x10⁻¹⁰ M and 1x10⁻⁶ M . Meclofenamic acid was the second most potent inhibitor of human gamma-globulin, decreasing the maximum integrated response of the rat mesenteric portal vein to human gamma-globulin by 15% and 52% at concentrations of 1x10⁻¹⁰ M and 1x10⁻⁶ M. Corticosterone decreased the maximum integrated response to human gamma-globulin in the rat mesenteric portal vein by 22% at a concentration of 1x10⁻⁵ M . The order of potency for the remaining NSAIDs was found to be phenylbutazone > aspirin > ibuprofen > piroxicam. In the ex vivo experiment, 10 mg/kg of indomethacin caused a statistically significant decrease in the response of the rat mesenteric portal vein to human gamma-globulin. It is concluded from these studies that human gamma-globulin exerts its stimulatory effects only on spontaneously active smooth muscle preparations. Findings from these studies may be taken to suggest that human gamma-globulin, which is a protein, may act by directly modulating a potassium channel such as the maxi-K⁺ channel. It also appears that prostaglandins play a role in the stimulatory action of human gamma-globulin on the rat mesenteric portal vein.

Thesis/Dissertation

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2008-07-16

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http://hdl.handle.net/2429/1017

Pharmacology

University of British Columbia

UBCV

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