Pioglitazone attenuates hypertension and inhibits growth of renal arteriolar smooth muscle in rats

Abstract

Hypertension is frequently associated with insulin resistance. We evaluated the effects of pioglitazone, an agent that increases insulin sensitivity, on the development of hypertension in the Dahl salt-sensitive (Dahl-S) rat and in the one-kidney, one-clip Sprague-Dawley rat. We also evaluated the effects of pioglitazone on growth of cultured preglomerular renal arteriolar smooth muscle cells. In Dahl-S rats fed a 3% NaCl diet, tail systolic blood pressures and direct arterial pressures were lower (P < 0.05) in pioglitazone-treated (20 mg/kg daily by gavage for 3 wk) than in control rats (n = 10 rats/group). In one-kidney, one-clip Sprague-Dawley rats, systolic blood pressures were also lower in pioglitazone-treated animals (P < 0.0001). In vitro, proliferation of arteriolar smooth muscle cells was stimulated (P < 0.01) by insulin, epidermal growth factor (EGF), and fetal calf serum (FCS); pioglitazone (5 microM) reversibly inhibited (P < 0.01) insulin-, EGF-, and FCS-induced proliferation. Pioglitazone (0.01-100 microM) also inhibited insulin- (1 mU/ml), EGF- (100 ng/ml), and 5% FCS-induced [3H]thymidine incorporation in a concentration-dependent manner (P < 0.01). Thus pioglitazone attenuated the development of hypertension in the Dahl-S rat and the one-kidney, one-clip rat. The ability of pioglitazone to inhibit growth of vascular smooth muscle may contribute to its hypotensive effect.

The vasodilator action of insulin. Implications for the insulin hypothesis of hypertension.

“…Dubey et al 55 reported that pioglitazone decreased arterial pressure in Dahl salt-sensitive and renal hypertensive rats but not in normotensive control rats. Pershadsingh and Kurtz 56 demonstrated that ciglitazone improved insulin sensitivity and lowered arterial pressure in obese, insulin-resistant Zucker rats.…”

“…For example, Dubey et al 55 demonstrated that pioglitazone inhibited the mitogenic effect of several growth factors on cultured arteriolar smooth muscle cells. Pershadsingh and Kurtz 56 found that ciglitazone dramatically attenuated the capacity of platelet-derived growth factor to induce sustained increases in intracellular calcium in rat aortic smooth muscle cells.…”

Therapeutic Roles of Peroxisome Proliferator–Activated Receptor Agonists

“…Vascular remodeling is now established as a key contributory factor in CVD. In vitro and in vivo studies have shown that thiazolidinediones inhibit the proliferation, hypertrophy, and migration of vascular smooth muscle cells (75)(76)(77). These agents also reduce the progression of intima-media thickness that commonly occurs in patients with atherosclerosis and, in some studies, decreases intima-media thickness per se (78,79).…”

Troglitazone inhibits angiotensin II‐induced DNA synthesis and migration in vascular smooth muscle cells

“…As insulin sensitizers these agents could lower blood pressure indirectly by improving insulin resistance [17]. Thiazolidinediones have also been shown to have direct effects on the vasculature [18] and VSMCs [3,19]. It is possible, therefore, that troglitazone and other thiazolidinediones may regulate blood pressure more directly by interfering with the action of growth factors, such as All, involved in the development of hypertension.…”