Alteration in coronary artery vascular reactivity of hypertensive Ren-2 transgenic rats

BACKGROUND: The renin-angiotensin system and endothelium-derived nitric oxide (EDNO) are important regulators of vascular tone. This study was designed to investigate endothelial and vascular smooth muscle function in coronary arteries of Ren-2 transgenic rats. METHODS AND RESULTS: Left anterior descending coronary arteries and aortas were isolated from transgenic rats and Sprague-Dawley control rats at 6 (young) and 12 (adult) weeks of age and examined in myographs or organ chambers for isometric tension recording. Systolic blood pressure was significantly higher in transgenic rats (young, 229 +/- 6 mm Hg; adult, 239 +/- 8 mm Hg) than in control rats (young, 126 +/- 2 mm Hg; adult, 118 +/- 3 mm Hg; P < .005). N omega-Nitro-L-arginine methyl ester (L-NAME, 10(-7) to 10(-4) mol/L) evoked marked endothelium-dependent contractions in coronary arteries (young, 52 +/- 8% of the contraction to 100 mmol/L KCl; adult, 40 +/- 8%) but not aortas (young, 3 +/- 1%; adult, 2 +/- 1%). In coronary arteries, this response was significantly smaller in adult (n = 9) than in young (n = 8, P < .05) control rats. Young transgenic rats (56 +/- 9%, n = 8) showed slightly stronger contractions in response to L-NAME than young control rats (NS), which almost totally disappeared in adult transgenic rats (6 +/- 3%, n = 7; P < .05 versus adult control rats; P < .01 versus young transgenic rats). Endothelium-dependent relaxations in response to acetylcholine (10(-9) to 10(-4) mol/L) were totally blocked by L-NAME (10(-4) mol/L) but were unaffected by the thromboxane receptor antagonist SQ30741 (10(-7) mol/L). This stimulated release of EDNO, endothelium-independent relaxations in response to the nitrovasodilator linsidomine (10(-9) to 10(-5) mol/L), and contractions in response to KCl (100 mmol/L) were comparable in all groups of rats. CONCLUSIONS: Ren-2 transgenic rats develop fulminant hypertension that is associated with a selective decrease in endothelium-dependent contractions in response to L-NAME, whereas endothelium-dependent relaxations in response to acetylcholine as well as smooth muscle function remain unaffected

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Hemodynamic and neurohumoral effects of selective endothelin A (ET(A))receptor blockade in chronic heart failure: the Heart Failure ET(A) Receptor Blockade trial (HEAT)

Background- The endothelin (ET-1) system is activated in chronic heart failure (CHF). Whether, what type, and what degree of selective ET blockade is clinically beneficial is unknown. We investigated hemodynamic and neurohumoral effects of 3 weeks of treatment with various dosages of the orally available ET(A) antagonist darusentan in addition to modern standard therapy in patients with CHF. Methods and Results- A total of 157 patients with CHF (present or recent NYHA class III of at least 3 months duration), pulmonary capillary wedge pressure ≥12 mm Hg, and a cardiac index ≤2.6 L · min−1 · m−2 were randomly assigned to double-blind treatment with placebo or darusentan (30, 100, or 300 mg/d) in addition to standard therapy. Short-term administration of darusentan increased the cardiac index, but this did not reach statistical significance compared with placebo. The increase in cardiac index was significantly more pronounced after 3 weeks of treatment (P<0.0001 versus placebo). Pulmonary capillary wedge pressure, pulmonary arterial pressure, pulmonary vascular resistance, and right atrial pressure remained unchanged. Heart rate, mean artery pressure, and plasma catecholamines remained unaltered, but systemic vascular resistance decreased significantly (P=0.0001). Higher dosages were associated with a trend to more adverse events (including death), particularly early exacerbation of CHF without further benefit on hemodynamics compared with moderate dosages. Conclusions- This study demonstrates for the first time in a large patient population that 3 weeks of selective ET(A) receptor blockade improves cardiac index in patients with CHF. However, long-term studies are needed to determine whether ET(A) blockade is beneficial in CHF