Wei-Min Li

Cellular basis of angiotensin-(1-7)-induced augmentation of left ventricular functional performance in heart failure

BACKGROUNDnAngiotensin-(1-7) [Ang-(1-7)] exhibits cardiovascular effects opposite those of angiotensin II (Ang II), thus providing protection against heart disease. However, how Ang-(1-7) imparts cardioprotection is unclear, and its direct cardiac effects are controversial. Whether heart failure (HF) alters cardiac contractile responses to Ang-(1-7) remains undetermined. We tested the hypothesis that in HF, Ang-(1-7) may produce positive modulation on [Ca2+]i regulation, enhancing left ventricular (LV) and myocyte contraction and relaxation via Ang-(1-7) Mas receptor coupled with nitric oxide (NO)/bradykinin (BK)-mediated mechanism.nnnMETHODS AND RESULTSnWe measured LV contractility changes after Ang-(1-7) (650ng/kg, iv) and compared myocyte functional and [Ca2+]i transient ([Ca2+]iT) responses to Ang-(1-7) superfusion in 24 normal rats and 34 rats with isoproterenol-induced HF (3months after 170mg/kg, s.q. for 2days). To assess the mechanisms of altered HF responses to Ang-(1-7), subsets of HF myocytes were pretreated to inhibit NO synthase (L-NAME), BK (HOE-140), and Mas receptor (A-779) followed with Ang-(1-7). In normal rats, Ang-(1-7) produced no significant changes in LV and myocyte function. In HF rats, Ang-(1-7) significantly augmented LV contractility and relaxation with increased EES (51%), but decreased τ compared to baseline. Ang-(1-7) also significantly increased myocyte contraction (dL/dtmax, 30%), relaxation (dR/dtmax, 41%), and [Ca2+]iT. L-NAME increased, HOE-140 decreased, and A-779 prevented HF myocyte contractile responses to Ang-(1-7).nnnCONCLUSIONSnIn a rat model of HF, Ang-(1-7) increases [Ca2+]iT, and produces positive inotropic and lusitropic effects in the LV and myocytes. These effects are mediated by the Mas receptor and involve activation of NO/BK pathways.

Overexpression myocardial inducible nitric oxide synthase exacerbates cardiac dysfunction and beta-adrenergic desensitization in experimental hypothyroidism

BACKGROUNDnAltered nitric oxide synthase (NOS) has been implicated in the pathophysiology of heart failure (HF). Recent evidence links hypothyroidism to the pathology of HF. However, the precise mechanisms are incompletely understood. The alterations and functional effects of cardiac NOS in hypothyroidism are unknown. We tested the hypothesis that hypothyroidism increases cardiomyocyte inducible NOS (iNOS) expression, which plays an important role in hypothyroidism-induced depression of cardiomyocyte contractile properties, [Ca(2+)]i transient ([Ca(2+)]iT), and β-adrenergic hyporesponsiveness.nnnMETHODS AND RESULTSnWe simultaneously evaluated LV functional performance and compared myocyte three NOS, β-adrenergic receptors (AR) and SERCA2a expressions and assessed cardiomyocyte contractile and [Ca(2+)]iT responses to β-AR stimulation with and without pretreatment of iNOS inhibitor (1400 W, 10(-5)mol/L) in 26 controls and 26 rats with hypothyroidism induced by methimazole (~30 mg/kg/day for 8 weeks in the drinking water). Compared with controls, in hypothyroidism, total serum T3 and T4 were significantly reduced followed by significantly decreased LV contractility (EES) with increased LV time constant of relaxation. These LV abnormalities were accompanied by concomitant significant decreases in myocyte contraction (dL/dtmax), relaxation (dR/dtmax), and [Ca(2+)]iT. In hypothyroidism, isoproterenol (10(-8)M) produced significantly smaller increases in dL/dtmax, dR/dtmax and [Ca(2+)]iT. These changes were associated with decreased β1-AR and SERCA2a, but significantly increased iNOS. Moreover, only in hypothyroidism, pretreatment with iNOS inhibitor significantly improved basal and isoproterenol-stimulated myocyte contraction, relaxation and [Ca(2+)]iT.nnnCONCLUSIONSnHypothyroidism produces intrinsic defects of LV myocyte force-generating capacity and relaxation with β-AR desensitization. Up-regulation of cardiomyocyte iNOS may promote progressive cardiac dysfunction in hypothyroidism.

C-Type Natriuretic Peptide Improves Left Ventricular Functional Performance at Rest and Restores Normal Exercise Responses after Heart Failure

In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise. C-type natriuretic peptide (CNP) is elevated in HF; however, its functional effects are unclear. We tested the hypotheses that CNP with vasodilating, natriuretic, and positive inotropic and lusitropic actions may prevent this abnormal exercise response after HF. We determined the effects of CNP (2 μg/kg plus 0.4 μg/kg per minute, i.v., 20 minutes) on plasma levels of cGMP before and after HF and assessed LV dynamics during exercise in 10 chronically instrumented dogs with pacing-induced HF. Compared with the levels before HF, CNP infusion caused significantly greater increases in cGMP levels after HF. After HF, at rest, CNP administration significantly reduced LV end-systolic pressure (PES), arterial elastance (EA), and end-diastolic pressure. The peak mitral flow (dV/dtmax) was also increased owing to decreased minimum LVP (LVPmin) and the time constant of LV relaxation (τ) (P < 0.05). In addition, LV contractility (EES) was increased. The LV-arterial coupling (EES/EA) was improved. The beneficial effects persisted during exercise. Compared with exercise in HF preparation, treatment with CNP caused significantly less important increases in PES but significantly decreased τ (34.2 vs. 42.6 ms) and minimum left ventricular pressure with further augmented dV/dtmax. Both EES, EES/EA (0.87 vs. 0.32) were increased. LV mechanical efficiency improved from 0.38 to 0.57 (P < 0.05). After HF, exogenous CNP produces arterial vasodilatation and augments LV contraction, relaxation, diastolic filling, and LV arterial coupling, thus improving LV performance at rest and restoring normal exercise responses after HF.

Critical role of the chymase/angiotensin-(1–12) axis in modulating cardiomyocyte contractility

BACKGROUNDnAngiotensin-(1-12) [Ang-(1-12)] is a chymase-dependent source for angiotensin II (Ang II) cardiac activity. The direct contractile effects of Ang-(1-12) in normal and heart failure (HF) remain to be demonstrated. We assessed the hypothesis that Ang-(1-12) may modulate [Ca2+]i regulation and alter cardiomyocyte contractility in normal and HF rats.nnnMETHODS AND RESULTSnWe compared left ventricle (LV) myocyte contractile and calcium transient ([Ca2+]iT) responses to angiotensin peptides in 16 SD rats with isoproterenol-induced HF and 16 age-matched controls. In normal myocytes, versus baseline, Ang II (10-6u202fM) superfusion significantly increased myocyte contractility (dL/dtmax: 40%) and [Ca2+]iT (29%). Ang-(1-12) (4u202f×u202f10-6 M) caused similar increases in dL/dtmax (34%) and [Ca2+]iT (25%). Compared with normal myocytes, superfusion of Ang II and Ang-(1-12) in myocytes obtained from rats with isoproterenol-induced HF caused similar but significantly attenuated positive inotropic actions with about 42% to 50% less increases in dL/dtmax and [Ca2+]iT. Chymostatin abolished Ang-(1-12)-mediated effects in normal and HF myocytes. The presence of an inhibitory cAMP analog, Rp-cAMPS prevented Ang-(1-12)-induced inotropic effects in both normal and HF myocytes. Incubation of HF myocytes with pertussis toxin (PTX) further augmented Ang II-mediated contractility.nnnCONCLUSIONSnAng-(1-12) stimulates cardiomyocyte contractile function and [Ca2+]iT in both normal and HF rats through a chymase mediated action. Altered inotropic responses to Ang-(1-12) and Ang II in HF myocytes are mediated through a cAMP-dependent mechanism that is coupled to both stimulatory G and inhibitory PTX-sensitive G proteins.