This project is concerned with the relation between hypertension and altered electrolyte exchange of vascular smooth muscle (VSM). It is also concerned with basic mechanisms of ion exchange in VSM. Rats made hypertensive with aldosterone and salt treatment (Aldo) will be the hypertensive model and the aorta, femoral and small mesenteric arteries will be studied. The measurements include radioisotope fluxes (42K, 36Cl, 24Na, and 45Ca), contraction, cAMP and cGMP contents, and fluorescence from Ca probes in single cells by means of a microspectrofluorometer which is to be assembled. The primary hypotheses to be tested are: 1) VSM from Aldo rats has a primary defect concerning the influx of Ca through potential dependent channels, and this defect leads to secondary changes in fluxes of K and Cl, 2) elevation in cytoplasmic Ca leads to increased 42K efflux via Ca dependent K channels, 3) cAMP and cGMP have primary action on Ca-release and Ca-transport out of VSM.
The specific aims under hypertensive mechanisms include the determination of whether: a) increased efflux of monovalent ions is secondary to increases in cellular Ca, b) alterations of 42K and 36Cl efflux can be returned to control levels by inhibitors of Ca or Na entry, c) both 24Na and 45Ca influxes are elevated and whether Ca-channel antagonists inhibit both 45Ca and 24Na influx, d) increasing cAMP by forskolin (FR) and cGMP by nitroprusside (NP) can reverse ion transport and contractile alterations in Aldo.
The specific aims under basic transport mechanisms are to determine: a) whether Ca-dependent 36Cl effluxes are secondary to 42K effluxes, b) whether increased cell volume contributes to increased 42K efflux, c) the relations between increased cAMP (FR) and cGMP (NP), and the inhibition of norepinephrine (NE) and KCl induced increases in 24Na and 45Ca influx and contraction, d) the relation between increased cAMP (FR) and cGMP (NP) and inhibition of 45Ca efflux and contraction, e) the relations between increased cAMP (FR) and cGMP (NP) and inhibition of NE and KCl induced increases in 42K and 36Cl efflux and contraction, f) the relations between cAMP (FR) and cGMP (NP) and stimulation of active (ouabain sensitive) 24Na and 42K transport.
A final aim i s to develop a microspectrofluorometer to measure fluorescence from Ca probes (FURA-2) in single cells which will allow us to study altered Ca transport in Aldo on cells from small arteries, and to relate changes in cyclic nucleotides to cytoplasmic Ca and, in turn, to 42K efflux.
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