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Date of Award

1996

Document Type

Dissertation - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Denis Meerdink

First Committee Member

James Blankenship

Second Committee Member

Donald Floriddia

Third Committee Member

John Livesey

Fourth Committee Member

Hubert Stanton

Fifth Committee Member

Eric Thomas

Abstract

To investigate the mechanism of polyamine- and acetylpolyamine-induced vasodilation, aortic rings from anesthetized New Zealand white rabbits (2.0-2.5 kg) were incubated in modified Krebs-Henseleit buffer, precontracted with phenylephrine (PE), and isometric tension measured. Concentration-response curves were constructed for polyamines (putrescine, spermidine, and spermine) and acetylpolyamines ($N\sp1$-acetylputrescine, $N\sp1$-acetylspermidine, $N\sp8$-acetylspermidine, and $N\sp1$-acetylspermine) in both endothelium-intact and -denuded rings. In both types of rings, all polyamines and acetylpolyamines except $N\sp1$-acetylputrescine produced concentration-dependent relaxation (potency, spermine $>$ spermidine $>$ putrescine for polyamines; $N\sp1$-acetylspermine $>\ N\sp1$-acetylspermidine $>$ $N\sp8$-acetylspermidine for acetylpolyamines). The inhibition of endothelium-derived relaxing factor (EDRF)/nitric oxide (NO) by reduced hemoglobin and $N\sp\omega$-nitro- sc L-arginine methyl ester (sc L-NAME), and the inhibition of soluble guanylate cyclase by methylene blue did not affect the ability of polyamines or acetylpolyamines to relax vascular smooth muscle with and without endothelium, respectively. Indomethacin had no effect on polyamine- or acetylpolyamine-induced vasodilation in endothelium-intact aortic rings. In endothelium-denuded rings, Ca$\sp{2+}$ agonist, Bay K 8644, induced concentration-dependent contraction in segments of rabbit aorta, partially depolarized with 15 mM KCl. This was blocked by Ca$\sp{2+}$ antagonists, nifedipine and verapamil, and polyamines and acetylpolyamines in a concentration-dependent manner, shifting the concentration-response curve of Bay K 8644 to the right. Polyamines and acetylpolyamines as nifedipine and verapamil shifted concentration-response curves of K$\sp+$ and PE to the right in a concentration-dependent manner. Polyamines and acetylpolyamines also decreased contractions invoked by the Ca$\sp{2+}$ ionophore A23187. The concentration-dependent contraction curve for exogenous Ca$\sp{2+}$ in K$\sp+$-depolarization medium (K$\sp+$ = 120 mM) was shifted to the right by polyamines and acetylpolyamines. Both polyamines and acetylpolyamines also reduced the potentiation of K$\sp+$-induced contraction and Ca$\sp{2+}$ concentration-dependent contraction induced by Bay K 8644. The results indicate that polyamines and acetylpolyamines, as endogenous vasodilators, dilate vascular smooth muscle independent of EDRF/NO, vasodilatory prostaglandins, and by activation of soluble guanylate cyclase. Furthermore, these results suggest that polyamines and acetylpolyamines may relax vascular smooth muscle at the plasma membrane level by a mechanism that involves Ca$\sp{2+}$ influx, although may other mechanism may be possible. Further studies are needed to determine if polyamines and acetylpolyamines have calcium antagonistic properties that are involved in the mechanism of vasodilation of rabbit aortic vascular smooth muscle.

Pages

199

ISBN

9780591261998 , 0591261995

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