Cicletanine avoids the proliferation of vascular smooth muscle in the spontaneously hypertensive rat

The vasodilator and antiproliferative effects of the antihypertensive agent, cicletanine, were studied on mesenteric arteries (MA) and cultured mesenteric artery myocytes derived from spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats. Cicletanine induces relaxation of precontracted MA with an 1050 value of approximately 30-50 microM. Cicletanine inhibits the proliferation of cultured myocytes (passage 5) with an 1050 of 440 +/- 24 microM for SHR and 517 +/- 12 microM for WKY, p less than 0.05, indicating that a log-unit shift in sensitivity exists between its vasodilator and antiproliferative actions. Preliminary experiments suggest that the antiproliferative action of cicletanine is accompanied by an inhibition of DNA synthesis [( 3H] - thymidine uptake) in myocytes of SHR and a stimulation of DNA synthesis in myocytes of the WKY. Cicletanine also lowers free intracellular Ca2+ (determined using fura-2) in myocytes of SHR but not the WKY. In other cell systems, cicletanine has been shown to stimulate prostacyclin production. However, in the present experiments, inhibition of the cyclooxygenase pathway (5 microM indomethacin) attenuated the antiproliferative action of cicletanine by only 30% in cells of the SHR and was without affect in the WKY. In summary, we have shown that cicletanine has distinct antiproliferative effects cultured vascular myocytes. In SHR myocytes, the antiproliferative action is accompanied by a fall in intracellular Ca2+, stimulation of the cyclooxygenase pathway and an inhibition of DNA synthesis. Different mechanisms may be operant in cells of the WKY. It is proposed that the antiproliferative effects of cicletanine may play a role its antihypertensive actions.