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CLINICAL STUDIES

Chronic L-arginine treatment increases cardiac cyclic guanosine 5'-monophosphate in rats with aortic stenosis: effects on left ventricular mass and beta-adrenergic contractile reserve

^a Charles A. Dana Research Institute, Beth Israel Deaconess Medical Center, Harvard School, Boston, Massachusetts, USA
^b The Harvard-Thorndike Laboratory, Beth Israel Deaconess Medical Center, Harvard School, Boston, Massachusetts, USA
^c Department of Medicine, Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

Manuscript received January 14, 1998; revised manuscript received April 17, 1998, accepted April 27, 1998.

Address for correspondence: Dr. Beverly H. Lorell, Cardiovascular Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, Massachusetts 02215
blorell{at}bidmc.harvard.edu

Objectives. We tested the hypothesis that nitric oxide (NO) cyclic guanosine 5'-monophosphate (GMP) signaling is deficient in pressure overload hypertrophy due to ascending aortic stenosis, and that long-term L-arginine treatment will increase cardiac cyclic GMP production and modify left ventricular (LV) pressure overload hypertrophy and beta-adrenergic contractile response.

Background. Nitric oxide cyclic GMP signaling is postulated to depress vascular growth, but its effects on cardiac hypertrophic growth are controversial.

Methods. Forty control rats and 40 rats with aortic stenosis left ventricular hypertrophy ([LVH] group) were randomized to receive either L-arginine (0.40 g/kg/day) or no drug for 6 weeks.

Results. The dose of L-arginine did not alter systemic blood pressure. Animals with LVH had similar LV constitutive nitric oxide synthase (cNOS) mRNA and protein levels, and LV cyclic GMP levels as compared with age-matched controls. In rats with LVH L-arginine treatment led to a 35% increase in cNOS protein levels (p = 0.09 vs untreated animals with LVH) and a 1.7-fold increase in LV cyclic GMP levels (p < 0.05 vs untreated animals with LVH). However, L-arginine treatment did not suppress LVH in the animals with aortic stenosis. In contrast, in vivo LV systolic pressure was depressed in L-arginine treated versus untreated rats with LVH (163 ± 16 vs 198 ± 10 mm Hg, p < 0.05). In addition, the contractile response to isoproterenol was blunted in both isolated intact hearts and isolated myocytes from L-arginine treated rats with LVH compared with untreated rats with LVH. This effect was mediated by a blunted increase in peak systolic intracellular calcium in response to beta-adrenergic stimulation.

Conclusions. Left ventricular hypertrophy due to chronic mechanical systolic pressure overload is not characterized by a deficiency of LV cNOS and cyclic GMP levels. In rats with aortic stenosis, L-arginine treatment increased cardiac levels of cyclic GMP, but it did not modify cardiac mass in rats with aortic stenosis. However, long-term stimulation of NO-cyclic GMP signaling depressed in vivo LV systolic function in LVH rats and markedly blunted the contractile response to beta-adrenergic stimulation.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   BW = body weight   [Ca2+]i = intracellular calcium   GMP = guanosine 5'-monophosphate   LV = left ventricular   LV devP = left ventricular developed pressure   LV dP/dt = first derivative of left ventricular pressure   LVEDP = left ventricular end-diastolic pressure   LVH = left ventricular hypertrophy   LVSP = left ventricular systolic pressure   NO = nitric oxide   NOS = nitric oxide synthase

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