nitroarginine and Hypertrophy--Left-Ventricular

Hypertension demands cardiac synthetic and metabolic adaptations to increased afterload. We studied gene expression in two models of mild hypertension without overt left ventricular hypertrophy using the NO synthase inhibitor nitro-L-arginine (L-NNA) and the glutathione depletor buthionine-S,R-sulfoximine (BSO). Mice were administered L-NNA, BSO, or water for 8 weeks. RNA of left ventricles was pooled per group, reverse transcribed, Cy3 and Cy5 labeled, and hybridized to cDNA microarrays. Normalized log(2) Cy3/Cy5 ratios of > or =0.7 or < or =-0.7 were considered significant. L-NNA and BSO both caused hypertension. Gene expression was regulated in cytoskeletal components in both models, protein synthesis in L-NNA-treated mice, and energy metabolism in BSO-treated mice. Energy metabolism genes shared several common transcription factor-binding sites such as Coup-Tf2, of which gene expression was increased in BSO-treated mice, and COMP-1. Characterization of the left ventricular adaptations as assessed with gene expression profiles reveals differential expression in energy and protein metabolism related to the pathogenetic background of the hypertension.

Topics: Animals; Binding Sites; Blood Pressure; Body Weight; Buthionine Sulfoximine; Cluster Analysis; Energy Metabolism; Enzyme Inhibitors; Female; Gene Expression; Gene Expression Profiling; Glutamate-Cysteine Ligase; Glutathione; Glycolysis; Heart; Heart Ventricles; Hypertension; Hypertrophy, Left Ventricular; Mice; Mice, Inbred C57BL; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Oligonucleotide Array Sequence Analysis; Organ Size; Protein Biosynthesis; Proteinuria; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors

The influence of left ventricular hypertrophy (LVH) on the endothelial function of resistance endocardial arteries is not well established. The aim of this study was to characterise the mechanisms responsible for UK-14,304 (alpha(2)-adrenoreceptor agonist)-induced endothelium-dependent dilation in pig endocardial arteries isolated from hearts with or without LVH. LVH was induced by aortic banding 2 months before determining endothelial function. Following euthanasia, hearts were harvested and endocardial resistance arteries were isolated and pressurised to 100 mmHg in no-flow conditions. Vessels were preconstricted with acetylcholine (ACh) or high external K(+) (40 mmol l(-1) KCl). Results are expressed as mean+/-s.e.m. UK-14,304 induced a maximal dilation representing 79+/-6% (n=8) of the maximal diameter. NO synthase (l-NNA, 10 micromol l(-1), n=7) or guanylate cyclase (ODQ, 10 micromol l(-1), n=4) inhibition reduced (P<0.05) UK-14,304-dependent dilation to 35+/-6 and 18+/-7%, respectively. Apamin and charybdotoxin reduced (P<0.05) to 39+/-8% (n=4) the dilation induced by UK-14,304. In depolarised conditions, however, this dilation was prevented (P<0.05). UK-14,304-induced dilation was reduced (P<0.05) by glibenclamide (Glib, 1 micromol l(-1)), a K(ATP) channel blocker, either alone (35+/-10%, n=5) or in combination with l-NNA (34+/-9%, n=4). In LVH, UK-14,304-induced maximal dilation was markedly reduced (25+/-4%, P<0.05) compared to control; it was insensitive to l-NNA (21+/-5%) but prevented either by the combination of l-NNA, apamin and charybdotoxin, or by 40 mmol l(-1) KCl. Activation of endothelial alpha(2)-adrenoreceptor induces an endothelium-dependent dilation of pig endocardial resistance arteries. This dilation is in part dependent on NO, the release of which appears to be dependent on the activation of endothelial K(ATP) channels. This mechanism is blunted in LVH, leading to a profound reduction in UK-14,304-dependent dilation.

Topics: Adenosine Triphosphate; Animals; Bradykinin; Brimonidine Tartrate; Canada; Charybdotoxin; Coronary Vessels; Disease Models, Animal; Drug Therapy, Combination; Endocardium; Endothelium, Vascular; Glyburide; Guanylate Cyclase; Hemodynamics; Hypertrophy, Left Ventricular; Indomethacin; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Nitroprusside; Oxadiazoles; Potassium Channels; Quinoxalines; Swine; Vascular Resistance; Vasodilation

Portal hypertension induces neuroendocrine activation and a hyperkinetic circulation state. This study investigated the consequences of portal hypertension on heart structure and function. Intrahepatic portal hypertension was induced in male Sprague-Dawley rats by chronic bile duct ligation (CBDL). Six weeks later, CBDL rats showed higher plasma angiotensin-II and endothelin-1 (P <.01), 56% reduction in peripheral resistance and 73% reduction in pulmonary resistance (P <.01), 87% increase in cardiac index and 30% increase in heart weight (P <.01), and increased myocardial nitric oxide (NO) synthesis. In CBDL rats, macroscopic analysis demonstrated a 30% (P <.01) increase in cross-sectional area of the left ventricular (LV) wall without changes in the LV cavity or in the right ventricle (RV). Histomorphometric analysis revealed increased cell width (12%, P <.01) of cardiomyocytes from the LV of CBDL rats, but no differences in myocardial collagen content. Myocytes isolated from the LV were wider (12%) and longer (8%) than right ventricular myocytes (P <.01) in CBDL rats but not in controls. CBDL rats showed an increased expression of ANF and CK-B genes (P <.01). Isolated perfused CBDL hearts showed pressure/end-diastolic pressure curves and response to isoproterenol identical to sham hearts, although generated wall tension was reduced because of the increased wall thickness. Coronary resistance was markedly reduced. This reduction was abolished by inhibition of NO synthesis with N-nitro-L-arginine. Expression of eNOS was increased in CBDL hearts. In conclusion, portal hypertension associated to biliary cirrhosis induces marked LV hypertrophy and increased myocardial NO synthesis without detectable fibrosis or functional impairment. This observation could be relevant to patients with cirrhosis.

Topics: Animals; Bile Ducts; Cyclic GMP; Enzyme Inhibitors; Heart; Hypertension, Portal; Hypertrophy, Left Ventricular; In Vitro Techniques; Isoenzymes; Ligation; Liver Cirrhosis, Biliary; Male; Myocardium; Nitric Oxide Synthase; Nitroarginine; Organ Size; Rats; Rats, Sprague-Dawley

To determine the effects of chronic nitric oxide (NO) blockade on the pulmonary vasculature, 58-day-old spontaneously hypertensive rats of the stroke-prone substrain (SHRSP) and Wistar-Kyoto rats (WKY) received N(omega)-nitro-L-arginine (L-NNA; 15 mg. kg(-1). day(-1) orally for 8 days). Relaxation to acetylcholine (ACh) in hilar pulmonary arteries (PAs), the ratio of right ventricular (RV) to body weight (RV/BW) to assess RV hypertrophy (RVH), and the percent medial wall thickness (WT) of resistance PAs were examined. L-NNA did not alter the PA relaxation, RV/BW, or WT in WKY. Although the PA relaxation and RV/BW in control SHRSP were comparable to those in WKY, the WT was increased (31 +/- 2 vs. 19 +/- 1%). L-NNA-treated SHRSP showed two patterns: in one group, the relaxation, RV/BW, and WT were comparable to those in the control SHRSP; in the other, impaired relaxation (36 +/- 7 vs. 88 +/- 4% for WKY) was associated with an increase in WT (37 +/- 1%) and RV/BW (0. 76 +/- 0.05). Thus the abnormal pulmonary vasculature in SHRSP at <10 wk of age is not accompanied by impaired relaxation in PAs or RVH; however, impaired relaxation is associated with increased WT and RVH.

Topics: Animals; Blood Pressure; Blood Vessels; Cyclic AMP; Cyclic GMP; Endothelium, Vascular; Enzyme Inhibitors; Genetic Predisposition to Disease; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Hypertrophy, Right Ventricular; Lung; Nitric Oxide Synthase; Nitroarginine; Pulmonary Circulation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stroke; Vasodilation

1. The effects of graded inhibition of nitric oxide synthase (NOS) on blood pressure in the genetically hypertensive (GH) rat strain and NOS activity in regions of the brain (cerebellum, striatum, hippocampus, frontal cortex and medulla oblongata) as a measure of body NOS inhibition were studied. 2. Male GH and normotensive (N) rats (n = 7-10 per group) were given N(G)-nitro-L-arginine methyl ester (L-NAME; 2, 5, 10 or 20 mg/kg per day in drinking water) from age 7 weeks. Age- and weight-matched controls received water only. Systolic blood pressure (SBP) was measured weekly by the tail-cuff method from age 6 weeks. By age 10 weeks, rats were killed and NOS activity was measured. 3. Some GH rats that received over 5 mg/kg per day L-NAME developed stroke-like symptoms and were killed before the end of the treatment period. 4. No difference in NOS activity was found between untreated N and GH strains but, in those that received treatment, a graded inhibition was observed with increasing L-NAME dose levels. The frontal cortex in the GH strain given 20 mg/kg per day L-NAME had NOS inhibition of 90% where the N strain had 73% inhibition. Similar results were seen in the other areas of the brain. 5. Left ventricular mass, weight related, was significantly greater in the GH compared with N and was further elevated by treatment with L-NAME. 6. The SBP at 10 weeks was significantly elevated in GH rats by NOS inhibition with L-NAME in a dose-dependent manner; 25% for 2 mg/kg per day, 31% for 20 mg/kg per day (P < 0.001). There was a non-significant increase in BP in the N-treated groups (average change of 7.5%). 7. Nitric oxide synthase inhibition causing increased SBP in GH rats suggests an abnormality in the nitric oxide-L-arginine pathway in this strain.

Topics: Animals; Blood Pressure; Brain; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hypertension; Hypertrophy, Left Ventricular; Male; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Wistar; Survival Rate

When exercise in the presence of a coronary artery stenosis results in subendocardial ischemia, administration of a nitric oxide (NO) donor increases subendocardial blood flow, whereas NO synthesis blockade worsens subendocardial hypoperfusion. Because left ventricular hypertrophy (LVH) is also associated with subendocardial hypoperfusion during exercise, this study tested the hypothesis that alterations of NO availability can similarly influence subendocardial blood flow in the hypertrophied heart. Studies were performed in seven dogs in which ascending aortic banding resulted in an 80% increase in LV weight. Myocardial blood flow was measured with microspheres during treadmill exercise that increased heart rates to 216 +/- 8 beats/min. During control exercise, mean myocardial blood flow in animals with LVH was similar to that in historic controls, but the ratio of subendocardial to subepicardial blood flow was lower in animals with hypertrophy (0.88 +/- 0.07) than in controls (1.36 +/- 0.08; P < 0.05). Blockade of NO synthesis with NG-nitro-L-arginine (L-NNA; 1.5 mg/kg ic) caused no change in heart rate or LV systolic pressure during exercise. Furthermore, L-NNA did not worsen subendocardial hypoperfusion during exercise. Intracoronary infusion of nitroglycerin (0.4 microgram. kg-1. min-1) did not significantly alter either mean blood flow or the transmural distribution of perfusion during exercise in the hypertrophied hearts. Thus, unlike the subendocardial underperfusion that occurs when a stenosis limits coronary blood flow, alterations of NO availability did not alter subendocardial hypoperfusion in the hypertrophied hearts.

Topics: Animals; Blood Pressure; Coronary Circulation; Dogs; Enzyme Inhibitors; Heart Rate; Hemodynamics; Hypertrophy, Left Ventricular; Motor Activity; Nitric Oxide; Nitroarginine; Nitroglycerin; Vasodilator Agents

To delineate the cardioprotective actions of bradykinin (BK) and the contribution of endogenous kinins to the cardiac effects of the ACE inhibitor ramipril, we used the specific B2 kinin receptor antagonist icatibant (HOE 140) during myocardial ischemia and left ventricular hypertrophy (LVH). In isolated working rat hearts, perfusion with ramiprilat (10 nM to 10 microM) reduced the incidence and duration of ventricular fibrillation, and improved cardiodynamics and myocardial metabolism. BK perfusion (0.1 nM to 10 nM) induced comparable cardioprotective effects. In addition, perfusion with ramiprilat (0.1 microM) markedly increased kinin outflow measured by RIA. The beneficial effects of ramiprilat and BK were abolished by the addition of the specific NO synthase inhibitor NG-nitro-L-arginine (L-NNA 1 microM) or icatibant (1 nM). Similar results were obtained in dogs, rabbits and rats with myocardial infarction induced by ligation of the left descending coronary artery. The influence of the icatibant on the antihypertrophic effect of ramipril and BK in the LVH was investigated in rats made hypertensive by aortic banding. Ramipril at the antihypertensive dose of 1 mg kg-1 day-1 for 6 weeks prevented the increase in blood pressure and the development of LVH. The lower non-antihypertensive dose of ramipril (10 micrograms kg-1 day-1 for 6 weeks) had no effect on the increase in blood pressure or on plasma ACE activity but also prevented LVH after aortic banding. The antihypertrophic effect of the higher and the lower dose of ramipril as well as the antihypertensive action of the higher dose of ramipril were abolished by coadministration of the icatibant.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arginine; Bradykinin; Dogs; Endothelium, Vascular; Humans; Hypertrophy, Left Ventricular; Myocardial Ischemia; Nitroarginine; Ramipril; Rats

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Blood Pressure; Bradykinin; Hypertension; Hypertrophy, Left Ventricular; Male; Nitric Oxide Synthase; Nitroarginine; Organ Size; Rats; Rats, Sprague-Dawley