Date of Award

1-1-1986

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Physiology and Pharmacology

Abstract

PN200-110 is an analogue of the 1,4-dihydropyridine class of calcium antagonists, which have previously been shown to be efficacious in lowering blood pressure in essential hypertension. In our study, PN200-110 was found to be effective in lowering systolic blood pressures both acutely, in normotensive and spontaneously hypertensive rats, and chronically in the hypertensive group. Heart rates were increased above pretreatment values following PN200-110 therapy, but these changes were statistically insignificant.The in vitro binding of (+)- methyl-('3)H PN200-110 to synaptosomal P(,2) membranes was found to be saturable, specific, reversible, temperature-dependent, and of high affinity to a single set of dihydropyridine receptor sites. Optimal receptor density (B(,MAX)) and apparent binding affinity (K(,D)) occurred at 25(DEGREES)C. Various cations were found to inhibit labeled PN200-110 in the following order of potency: Zn('2+) > La('3+) > Rh('3+), Al('3+) > Co('2+), Ni('2+), Mn('2+) > Ca('2+), Mg('2+) > Ba('2+) > Sr('2+). The binding of (+)- methyl-('3)H PN200-110 to frontal cortex-derived synaptosomes was found to be species- and agonist-dependent. The maximal number of receptor sites and the apparent affinity were determined to be higher in rat than in dog. In addition, these two binding parameters were higher when nifedipine was used as the agonist in comparison to PN200-110.The receptor densities (B(,MAX)) and the respective K(,D) values for labeled PN200-110 binding were found to be higher in cardiac and neural membranes derived from spontaneously hypertensive (SHR) compared to normotensive (SD) rats. PN200-110 treatment, however, caused the binding affinity to be higher in membranes obtained from normotensive compared to hypertensive animals. Chronic in vivo d-cis-diltiazem treatment modified the binding parameters of (+)- methyl-('3)H PN200-110 in membranes obtained from SHR and SD groups. Diltiazem therapy increased the density of specific dihydropyridine receptor sites without significantly altering the accompanying binding affinities. In comparison, chronic in vivo PN200-110 treatment decreased receptor densities without significantly altering the corresponding binding affinities for (+)- methyl-('3)H PN200-110. In vivo treatment with structurally dissimilar calcium channel blockers caused modifications in receptor density but not binding affinities for (+)- methyl-('3)H PN200-110.

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