Role of calcium in angiotensin II-induced prostaglandin release and DNA synthesis in rat vascular smooth muscle cells.
Cellular calcium modulates enzyme activity, cell proliferation, and differentiation. In vascular smooth muscle cells (VSMC), calcium may contribute to increased vascular contractility and structural alterations in both hypertension and atherosclerosis. We investigated the role of calcium in angiotensin II (AII)-induced prostaglandin release and DNA synthesis in VSMC. Prostaglandin levels were determined by radioimmunoassay, and DNA synthesis was determined by the incorporation of [3H]thymidine. AII dose-dependently stimulated the release of prostaglandin E2 and prostaglandin I2, and this effect was synergistically enhanced by the Ca2+ ionophore A23187. Conversely, the AII response was inhibited by EGTA, a chelator of Ca2+ ions and by verapamil and nifedipine, two Ca2+ channel blockers or by incubation of the cells without exogenous Ca2+. TMB-8, an inhibitor of calcium mobilization, also strongly reduced angiotensin response. Similar results were obtained for angiotensin III (AIII) and vasopressin, two other agonists of prostaglandin production. AII- or serum-stimulated DNA synthesis was almost abolished by EGTA, whereas TMB-8, verapamil, and nifedipine had little or no effect. The production of prostaglandins triggered by angiotensins and vasopressin in VSMC is dependent on both intracellular and extracellular calcium, with calcium entering through L-type Ca2+ channels. Extracellular calcium is important for AII and serum mitogenic activity, but L-type Ca2+ channels do not appear to be implicated.
Catalioto
R M
RM
Department of Pharmacology, Laboratori Guidotti SpA, Pisa.
Renzetti
A R
AR
Criscuoli
M
M
Morbidelli
L
L
Subissi
A
A
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis*; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000378:metabolism*; D005707:Gallic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D002121:Calcium Channel Blockers; D007476:Ionophores; D000804:Angiotensin II; D000001:Calcimycin; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D005707:Gallic Acid; D004247:DNA; D011464:Epoprostenol; D015232:Dinoprostone; D002118:Calcium