Enhanced negative modulation of urotensin II on cardiac function and [Ca2+]i regulation in a diabetic rat model: Insights into molecular and cellular mechanisms.

The direct cardiac effects of urotensin II (UII) in normal and diabetic subjects remain controversial. The alteration and functional significance of cardiac UII/UII receptor (UT) in diabetes are still unclear. We assessed the hypothesis that in diabetes, the cardiomyocyte UII/UT system is increased. This augmentation is proposed to exacerbate the dysfunctional [Ca²⁺]_i regulation, enhance inhibitions of left ventricle (LV) and myocyte contraction and relaxation, leading to worsening cardiac dysfunction. We compared LV myocyte UII and UT expression, LV and myocyte contractile, [Ca²⁺]_i transient ([Ca²⁺]_iT) and calcium current (I_Ca,L) responses to UII stimulation in male Sprague-Dawley rats (12/group) with streptozotocin-induced diabetes mellitus and controls. We found that UII and UT protein levels were significantly greater in diabetic myocytes than in control myocytes. Compared with control rats, UII (400 pmol/kg, i.p.) administration produced greater decreases in LV contractility of E_ES (diabetes mellitus: 32% vs C: 13%) and M_SW with significantly increased LV time constant relaxation in diabetes. In response to UII (10^-5 M) superfusion, diabetic myocytes had much greater decreases in the velocity of shortening and relengthening accompanied by significantly larger decreases in the peak systolic [Ca²⁺]_iT and I_Ca,L (29% vs 15%). These responses were abolished by pretreatment of diabetic myocytes with urantide, pertussis toxin, or dibutyryl-cAMP, respectively. We conclude that UII has direct negative inotropic and lusitropic cardiac effects in both normal and diabetic rats. In diabetes, cardiac UII/UT is upregulated, enhancing UII-caused negative modulation on cardiac function and [Ca²⁺]_i regulation. This may contribute to the progression of cardiac dysfunction in diabetes and diabetic cardiomyopathy. SIGNIFICANCE STATEMENT: Urotensin II (UII) has direct negative inotropic and lusitropic cardiac effects in both normal and diabetic rats. Compared with normal rats, cardiac UII/UII receptors (UT) were upregulated in diabetic rats, resulting in significantly greater decreases in [Ca²⁺]_iT and I_Ca,L and increased inhibitions of left ventricle and myocyte contraction and relaxation. These effects are coupled with UT and mediated by G_i proteins. These data provide new insights and evidence that upregulation of cardiomyocyte UII/UT may promote the progressive cardiac dysfunction in diabetes and diabetic cardiomyopathy.