Chronic endothelin blockade in dogs with pacing-induced heart failure: possible modulation of sympathoexcitation.

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide elaborated by many cell types. Plasma ET-1 levels are significantly augmented in patients and experimental animals with heart failure. Enhanced levels of ET-1 may contribute to myocardial depression and alterations in sympathetic nerve activity in the setting of chronic heart failure. The effects of chronic blockade of endothelin A (ET(A)) receptors on the development and severity of experimental heart failure and sympathoexcitation were evaluated in these experiments using the specific ET(A) antagonist, PD156707. METHODS AND RESULTS: Four groups of conscious, chronically instrumented mongrel dogs were administered either PD156707 (750 mg orally thrice daily) or a placebo starting 1 day before ventricular pacing or a sham (nonpaced) period. Before pacing or the sham period, baseline hemodynamic and plasma norepinephrine (NE) measurements were made. Hemodynamic and NE measurements were made every 3 to 4 days for the next 28 days. All parameters were relatively stable in nonpaced dogs administered placebo. Paced placebo dogs showed classic hemodynamic and sympathoexcitatory changes indicative of heart failure. Nonpaced dogs administered PD156707 showed a significant decrease in mean arterial pressure and total peripheral resistance beginning 3 days after drug administration. Myocardial function was not affected by PD156707 in nonpaced dogs. In paced dogs, PD156707 also reduced arterial pressure and peripheral resistance. Changes in myocardial function were small and insignificant. Paced dogs administered PD156707 showed an approximately 50% lower increase in plasma NE level from days 10 to 24 compared with paced dogs administered placebo (941.8 +/- 122.8 vs 501.1 +/- 92.6 pg/mL at 17 days; P < .01). CONCLUSIONS: These data suggest that ET-1 contributes to the maintenance of arterial pressure in both sham dogs and dogs paced into heart failure. ET-1 does not appear to have a potent effect on inotropic state, but the data strongly suggest that ET-1 may contribute to the progressive deterioration of circulatory function in heart failure by mediating sympathoexcitation and enhancing plasma NE concentration.

Endogenous endothelial nitric oxide synthase-derived nitric oxide is a physiological regulator of myocardial oxygen consumption.

Our objective was to determine the precise role of endothelial nitric oxide synthase (eNOS) as a modulator of cardiac O2 consumption and to further examine the role of nitric oxide (NO) in the control of mitochondrial respiration. Left ventricle O2 consumption in mice with defects in the expression of eNOS [eNOS (-/-)] and inducible NOS [iNOS (-/-)] was measured with a Clark-type O2 electrode. The rate of decreases in O2 concentration was expressed as a percentage of the baseline. Baseline O2 consumption was not significantly different between groups of mice. Bradykinin (10(-4) mol/L) induced significant decreases in O2 consumption in tissues taken from iNOS (-/-) (-28+/-4%), wild-type eNOS (+/+) (-22+/-4%), and heterozygous eNOS(+/-) (-22+/-5%) but not homozygous eNOS (-/-) (-3+/-4%) mice. Responses to bradykinin in iNOS (-/-) and both wild-type and heterozygous eNOS mice were attenuated after NOS blockade with N-nitro-L-arginine methyl ester (L-NAME) (-2+/-5%, -3+/-2%, and -6+/-5%, respectively, P<0.05). In contrast, S-nitroso-N-acetyl-penicillamine (SNAP, 10(-4) mol/L), which releases NO spontaneously, induced decreases in myocardial O2 consumption in all groups of mice, and such responses were not affected by L-NAME. In addition, pretreatment with bacterial endotoxin elicited a reduction in basal O2 consumption in tissues taken from normal but not iNOS (-/-)-deficient mice. Our results indicate that the pivotal role of eNOS in the control of myocardial O2 consumption and modulation of mitochondrial respiration by NO may have an important role in pathological conditions such as endotoxemia in which the production of NO is altered.

Nitric oxide controls cardiac substrate utilization in the conscious dog.

OBJECTIVES: The aim of this study was to determine whether the acute inhibition of nitric oxide (NO) synthase causes changes in cardiac substrate utilization which can be reversed by a NO donor. METHODS: NO synthase was blocked by giving 30 mg/kg of nitro-L-arginine (NLA) i.v. to 15 chronically instrumented dogs. Hemodynamics and blood samples from aorta and coronary sinus were taken at control and at 1 and 2 h after NLA. In five dogs, 0.4 mg/kg of the NO donor 3754 was given i.v. 1 h after NLA. In six dogs, angiotensin II was infused over 2 h (20-40 ng/kg/min) to mimic the hemodynamic effects of NLA. RESULTS: Two h after NLA: mean arterial pressure was 153 +/- 4 mmHg; MVO2 increased by 38%; cardiac uptake of lactate and glucose increased, respectively, from 20.0 +/- 5.0 to 41.0 +/- 9.3 mumol/min and from 1.1 +/- 0.7 to 6.8 +/- 1.5 mg/min (all P < 0.05 vs. control). Cardiac uptake of free fatty acids decreased by 43% after 1 h (P < 0.05) and returned to control values at 2 h. Cardiac respiratory quotient increased from 0.76 +/- 0.03 to 1.05 +/- 0.07, indicating a shift to carbohydrate oxidation. All these changes were reversed by the NO donor. In the dogs receiving angiotensin II infusion, MVO2 increased by 28% and lactate uptake doubled (both P < 0.05), but no other metabolic changes where observed. CONCLUSIONS: The acute inhibition of NO synthase by NLA causes a switch from fatty acids to lactate and glucose utilization by the heart which can be reversed by a NO donor, suggesting an important regulatory action of NO on cardiac metabolism.

Reduced nitric oxide production and altered myocardial metabolism during the decompensation of pacing-induced heart failure in the conscious dog.

The aim of the present study was to determine whether cardiac nitric oxide (NO) production changes during the progression of pacing-induced heart failure and whether this occurs in association with alterations in myocardial metabolism. Dogs (n=8) were instrumented and the heart paced until left ventricular end-diastolic pressure reached 25 mm Hg and clinical signs of severe failure were evident. Every week, hemodynamic measurements were recorded and blood samples were withdrawn from the aorta and the coronary sinus for measurement of NO metabolites, O2 content, free fatty acids (FFAs), and lactate and glucose concentrations. Cardiac production of NO metabolites or consumption of O2 or utilization of substrates was calculated as coronary sinus-arterial difference times coronary flow. In end-stage failure, occurring at 29+/-1.6 days, left ventricular end-diastolic pressure was 25+/-1 mm Hg, left ventricular systolic pressure was 92+/-3 mm Hg, mean arterial pressure was 75+/-2.5 mm Hg, and dP/dtmax was 1219+/-73 mm Hg/s (all P<0.05). These changes in hemodynamics were associated with a fall of cardiac NO metabolite production from 0.37+/-0.16 to -0.28+/-0.13 nmol/beat (P<0.05). O2 consumption and lactate uptake did not change significantly from control, while FFA uptake decreased from 0.16+/-0.03 to 0.05+/-0.01 microEq/beat and glucose uptake increased from -2.3+/-7.0 to 41+/-10 microgram/beat (P<0.05). The cardiac respiratory quotient also increased significantly by 28%. In 14 normal dogs the same measurements were performed at control and 1 hour after we injected 30 mg/kg of nitro-L-arginine, a competitive inhibitor of NO synthase .O2 consumption increased from 0.05+/-0.002 mL/beat at control to 0.071+/-0.003 mL/beat after nitro-L-arginine, while FFA uptake decreased from 0.1+/-0.01 to 0.06+/-0.01 microEq/beat, lactate uptake increased from 0.15+/-0.04 to 0.31+/-0.03 micromol/beat, glucose uptake increased from 8.2+/-5.0 to 35.4+/-9.5 microgram/beat, and RQ increased by 23% (all P<0.05). Our results indicate that basal cardiac production of NO falls below normal levels during cardiac decompensation and that there are shifts in substrate utilization. This switch in myocardial substrate utilization also occurs after acute pharmacological blockade of NO production in normal dogs.

Effects of an orally effective endothelin-A receptor antagonist in dogs with pacing-induced heart failure.

UNLABELLED: Endothelin-1 (ET-1) is a potent vasoconstrictor that has been shown to be elevated in the plasma of humans and animals with heart failure (HF). The role of an increase in endothelin in the setting of chronic HF is not known. METHODS: The present study was designed to determine the hemodynamic effects of a novel ET-A antagonist (PD-156,707) on the development of HF in dogs subjected to chronic ventricular tachycardia. Thirteen dogs were chronically instrumented to measure cardiac output (CO), left ventricular pressure (LVP), left atrial pressure (LAP), and arterial pressure (MAP). They were then paced at 210 bpm for 3 weeks and then at 245 bpm for 1 week (4th week). Two groups of dogs were studied, placebo group and a group of dogs administered the PD-156,707 compound (750 mg) orally three times per day beginning one day prior to the initiation of pacing. Hemodynamic measurements were made every three to four days during the four week pacing regimen. Arterial and venous blood samples were also taken to determine the plasma levels of endothelin-1 and PD-156-707. RESULTS: Endothelin-1 in plasma increased in all dogs with pacing induced HF (placebo control 1.57 +/- 0.5 vs placebo HF 2.2 +/- 0.6 pg/ml and drug control 1.5 +/- 0.16 v.s. drug HF 14.6 +/- 3.8 pg/ml [p < 0.05]). Left ventricular end diastolic pressure (LVEDP) and LAP were equivalently and significantly elevated in both groups (p < 0.001) and LV dp/dt was significantly reduced (p < 0.001) in both groups 4 weeks after pacing. CO was slightly, but not significantly reduced after four weeks in both groups of dogs. However, administration of PD-157,707 significantly and profoundly reduced MAP at all times after 3 days of pacing (placebo HF[week 4]: 83.9 +/- 4.0 mmHg v.s. drug HF [week 4]: 72.4 +/- 2.3 mmHg [p < 0.05]) and total peripheral resistance (p < 0.05) at each time period following the induction of pacing. CONCLUSION: These data indicate that ETA blockade reduces afterload early during the development of chronic HF implicating endothelin-1 as an early compensatory hormone in HF. These results also suggest that blocking the ET-A receptor may have a role as an afterload reducer in the setting of human congestive heart failure.