Masayuki Fukazawa

Angiographical severity of coronary atherosclerosis predicts death in the first year of hemodialysis

Background: Cardiac deaths andevents tend to cluster within the early-phaseafter starting dialysis. Our goal is toclarify the influence of severity of coronaryatherosclerosis on early-phase death afterstarting hemodialysis (HD) therapy. Patients and Methods: Eighty-threeconsecutive patients [mean age 62 years;male/female 64/19; diabetic nephropathy in 50(54%)] with end-stage renal disease whoadmitted to our hospital to initiate regular HDtreatment, and then received coronaryangiography within 3 months after firstdialysis therapy, were eligible for this study. Angiographical severity of coronaryatherosclerosis was scored by numerically usingGensini scoring system. The patients who diedwithin one year from starting HD were comparedwith those who survived as control by means oflogistic regression analysis.Results: Of 83 patients, 12 (14%) died lessthan one year after starting dialysis therapy. Of these 12 patients, nine died for cardiaccauses. Confirmed predictors of death fromcardiac cause were older age (>70 years),lower mean blood pressure (<100 mmHg),presence of ischemic heart disease (IHD),myocardial infarction (MI), angina pectoris(AP), chronic heart failure (CHF), poor cardiacfunction, abnormal wall motion of leftventricule (LV) and angiographical severity ofcoronary atherosclerosis by univariate model. Adjusting for confounding variables bymultivariate model, only severity of coronaryatherosclerosis (Gensini score >40 points)had a powerful influence, increasing risk forcardiac cause of early-phase death by about 17times. Conclusions: Severity ofcoronary atherosclerosis predicts death in thefirst year of HD. These findings suggest thatthe strategy for prevention of coronaryatherosclerosis should be instituted during theearly phase of chronic renal failure.

Effect of endothelin on angiotensin converting enzyme activity in cultured vascular smooth muscle cells

We evaluated the effect of endothelin-1 (ET) on the angiotensin converting enzyme (ACE) activity in rat aortic smooth muscle cells (VSMCs). ACE activity was determined by radioimmunoassay of the amount of angiotensin II generated after the addition of angiotensin I (500 pg/ml) to cultured VSMCs. The antibody used had less than 0.1% cross-reactivity with angiotensin I. ACE activity increased 1.9-fold 5 hr after the addition of 10(-6) M ET under serum-free conditions. This stimulatory effect of ET on ACE activity in VSMCs was completely inhibited by 10(-7) M captopril. Results suggested that the ACE present in SMCs is stimulated by ET.

Combined Assessment of Cardiac Systolic Dysfunction and Coronary Atherosclerosis Used to Predict Future Cardiac Deaths after Starting Hemodialysis

Background/Aims: Identification of end-stage renal disease (ESRD) patients at high risk for cardiac events is important for clinical dialysis management. The present study determined whether the combination of cardiac function and coronary atherosclerosis could predict future cardiac events after starting renal replacement therapy (RRT). Methods: We prospectively assessed left ventricle ejection fraction (EF) and Gensini score (GS) using angiographic severity of coronary atherosclerosis in 88 consecutive ESRD patients [mean age 62 years; 69 males (78%); 55 patients (64%) with diabetic nephropathy] at the initiation of RRT. EF was analyzed by echocardiogram, and GS was scored by coronary angiography within 3 months after starting RRT. The study end point was cardiac death. For analysis of the association between cardiac death and EF and GS measures, the univariate and multivariate Cox proportional hazards model was used. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value, and accuracy of event-free prediction were evaluated. Results: Twenty-four patients (27%) had low cardiac function (EF <50%; low EF) and 44 patients (50%) had severe coronary atherosclerosis (GS >15; high GS). During a follow-up period of 3 years, cardiac death occurred in 21 patients (24%). The PPV of low EF and high GS was 42 and 39%, respectively; the highest PPV (53%) was obtained when low EF and high GS were combined. The cumulative survival rate at 5 years in patients with both low EF and high GS was significantly lower than those with high EF and low GS (91 vs. 22%, p < 0.0005). Conclusion: The combined assessment of cardiac function and coronary atherosclerosis at the initiation of RRT strongly predicts future cardiac events.

Vascular Smooth Muscle Relaxation by α-Adrenoceptor Blocking Action of Dobutamine in Isolated Rabbit Aorta

We investigated the mechanism of vascular relaxation produced by dobutamine, a positive inotropic agent with beta 1-adrenergic action. Dobutamine concentration-dependently (10 nM-10 microM) relaxed ring segments of rabbit aorta partially precontracted with 1 microM phenylephrine (PE) but did not relax those precontracted with 40 mM K+ or 5 microM prostaglandin F2 alpha (PGF2 alpha). The relaxation was not completely inhibited by pretreatment with 10 microM propranolol. Dobutamine did not significantly increase tissue cyclic AMP levels concomitantly with relaxation as does isoproterenol (ISO) in rabbit aorta. Dobutamine produced a parallel rightward shift in concentration-response curves to PE. The Schild plot analysis resulted in a linear regression of a slope of 1.077 +/- 0.077, which was not significantly different from unity. The pA2 value of dobutamine as compared with PE in rabbit aorta was 6.81 +/- 0.03. Dobutamine causes arterial dilatation mediated not only through a beta-adrenergic action but also through an alpha-adrenergic blocking action in rabbit aorta.

Effect of hyperhomocysteinemia on endothelial activation and dysfunction in patients with end-stage renal disease.

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Reduced endothelium-dependent vasodilation by acetylcholine and bradykinin in isolated nitroglycerin-tolerant blood vessels

1. Rings of porcine pulmonary arteries were mounted in tissue organ baths and incubated in physiological solution. The rings were allowed to equilibrate for > 1 hr under a resting tension of 1.0 g. The presence of endothelium was confirmed by 10(-6) M acetylcholine (ACh)-induced relaxation (60-80%) of 10(-6) M norepinephrine (NE) contraction. 2. Relaxation response generated by nitroglycerin (NTG) (10(-9) - 10(-5) M), ACh (10(-9) - 10(-5) M), bradykinin (BK) (10(-13) - 10(-6) M) and nitric oxide (NO) after NE (10(-6) M) contraction was compared before and after 1 hr treatment of NTG (5 x 10(-4) M). Then tissues were pretreated with NG-monomethyl-L-arginine (LNMMA) (10(-4) M) each before and after NTG treatment respectively, and ACh-induced relaxation was compared. 3. After 1 hr treatment with 5 x 10(-4) M NTG, the relaxation response of NTG at concentrations > 10(-7) M was attenuated significantly. This indicates that 1 hr treatment with 5 x 10(-4) M NTG induces NTG tolerance in isolated porcine pulmonary arterial rings. 4. The relaxation response of ACh at concentrations > 10(-7) M was attenuated significantly after NTG tolerance induction. 5. Relaxation response of BK at concentrations > 10(-10) M was attenuated significantly after NTG tolerance induction. 6. NTG tolerance had no effect on NO-induced vascular smooth muscle relaxation. 7. The relaxation response of ACh pretreated with LNMMA at concentrations higher than 10(-7) M was attenuated after NTG tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of captopril on acetylcholine-induced relaxation in the presence of nitroglycerin tolerance in isolated rabbit aorta.

We investigated the effects of angiotensin converting enzyme inhibitors on acetylcholine-induced endothelium-dependent vasodilation in the presence of nitroglycerin tolerance in rings of rabbit thoracic aorta mounted in tissue baths and precontracted with 10(-6) M norepinephrine. The vasorelaxant effects of acetylcholine were measured before and after 1 h treatment with 5 x 10(-4) M nitroglycerin. The acetylcholine dose-response curve shifted to the right after the induction of nitroglycerin tolerance. Pretreatment with captopril (a sulfhydryl angiotensin converting enzyme inhibitor), but not with M-1 (a metabolite of delapril and a nonsulfhydryl angiotensin converting enzyme inhibitor) restored acetylcholine-induced relaxation. Pretreatment with N-acetylcysteine also restored reduced acetylcholine-induced relaxation. These results suggest that the sulfhydryl group plays a major role in restoration of reduced acetylcholine-induced vasodilation in the presence of nitroglycerin tolerance.