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Carvedilol inhibits vascular smooth muscle cell proliferation
C P Sung1, A J Arleth, E H Ohlstein
1Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406.
Abstract:
The antiproliferative properties of carvedilol, a newly developed multiple-action antihypertensive agent, were evaluated in early passage cultured rat aortic vascular smooth muscle cells. Carvedilol (10(-7)-10(-5) M) produced concentration-dependent decreases in basal and endothelin-1-stimulated mitogenesis of rat aortic vascular smooth muscle cells. The IC50 for inhibition of [3H]thymidine incorporation by carvedilol in both basal and endothelin-1-stimulated rat aortic vascular smooth muscle cells was approximately 1 microM. Carvedilol (10 microM) inhibited basal mitogenesis by approximately 65%, and endothelin-1-stimulated mitogenesis by approximately 95%. Carvedilol (1-10 microM) also produced significant concentration-dependent inhibition of the mitogenic response mediated by thrombin (0.5 U/ml), epidermal growth factor (1 nM), platelet-derived growth factor (1 nM), and angiotensin II (5 nM). Endothelin-1- or PDGF A/B-induced increases in cell number were also significantly inhibited by carvedilol (10 microM). The antimitogenic effect of carvedilol on cell growth was reversible. The inhibitory effect of carvedilol was not shared by other beta-adrenoceptor antagonists such as labetalol (10 microM), celiprolol (10 microM), or sotalol (10 microM), which did not significantly affect [3H]thymidine incorporation in rat vascular smooth muscle cells. Propranolol (10 microM) was the only beta-adrenoceptor antagonist tested that inhibited [3H]thymidine incorporation, with effects of approximately 50 and 75% on basal and endothelin-1-mediated stimulation, respectively. In contrast, celiprolol (10 microM) produced significant stimulation of DNA synthesis (125% over basal). The calcium channel antagonist nifedipine (10 microM) inhibited basal and endothelin-1-mediated mitogenesis by 58 and 72%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Carvedilol significantly inhibits vascular smooth muscle cell proliferation, acting as an antimitogenic agent. This effect was concentration-dependent and reversible, distinguishing it from other beta-blockers.
Area of Science:
- Pharmacology
- Cardiovascular Research
- Cell Biology
Background:
- Vascular smooth muscle cell (VSMC) proliferation contributes to cardiovascular diseases.
- Antihypertensive agents are being investigated for broader cellular effects.
Purpose of the Study:
- To evaluate the antiproliferative effects of carvedilol on rat aortic VSMCs.
- To compare carvedilol's effects with other beta-adrenoceptor antagonists and a calcium channel blocker.
Main Methods:
- Cultured rat aortic VSMCs were treated with carvedilol at various concentrations.
- Mitogenesis was assessed by [3H]thymidine incorporation.
- Responses to growth factors (endothelin-1, thrombin, EGF, PDGF, angiotensin II) were measured.
Main Results:
- Carvedilol demonstrated concentration-dependent inhibition of basal and stimulated VSMC mitogenesis.
- The IC50 for carvedilol's inhibitory effect was approximately 1 microM.
- Carvedilol's antimitogenic effect was reversible and not shared by labetalol, celiprolol, or sotalol, but was seen with propranolol.
Conclusions:
- Carvedilol possesses significant antiproliferative properties on VSMCs.
- Its mechanism differs from non-selective beta-blockers and calcium channel blockers.
- Carvedilol's antimitogenic action may contribute to its therapeutic benefits in hypertension.