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Role of endogenous cardiac natriuretic peptides after chronic inhibition of endothelin activity in heart failure
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Journal of Cardiac Failure Vol. 4 No. 3 Suppl. 2 1998
109 ATRIAL NATRIURETIC PEPTIDE INHIBITS CARDIAC HYPERTROPHY INDUCED BY VOLUME OVERLOAD IN RATS WITH AORTOCAVAL SHUNT Akira Yamaki, Mayumi Furuya, Naomi Oka, Kayoko Kawashima, Toshinori Hidaka, and Norio Inomata Suntory Institute for Biomedical Research, Shimomoto-cho, Mishima-gun, Osaka 618-8503, Japan It is known that secretion of atrial natriuretic peptide (ANP) from heart increases in patients with heart failure, while physiological effects of ANP on cardiac hypertrophy have not fully been elucidated. We have previously reported that chronic ANP infusion could prevent the left ventricuiar hypertrophy induced by pressure overload in aortic-banded rats. In the present study, we investigated whether ANP could also inhibit the volume-overload induced cardiac hypertrophy in rats with aortocaval shunts. The intravenous infusion of vehicle (5% glucose) or ANP (0.1 microg/kg/min) was begun 2 weeks after shunt or shamoperation and was continued until week-4 after operation. There were no differences in systolic arterial pressure and heart rate in all groups. Right atrial pressure and the ratio of each heart chamber weight to body weight were significantly higher in shunt rats than sham-operated rats, indicating that the increased cardiac preload resulted in cardiac hypertrophy. Treatment with ANP did not affect right atrial pressure, but significantly reduced the ratios of right atrial, right ventricular, and left atrial weights related to body weight in comparison with those of shunt rats. ANP also significantly diminished the increased ratio of lung weight to body weight induced by volume overload. ACS enhanced the expressions of endogenous ANP and BNP mRNAs in the ventricle and the plasma ANP levels, which were suppressed by exogenous ANP. The plasma levels of rat ANP in sham-operated, vehicle, ANP-treated rats were 43+/-11, 854+/-265, 419+•-202 pg/ml, respectively. While, the expression of prepro ET-1 mRNA elevated by ACS was not changed by ANP. Thus ANP treatment improved cardiac hypertrophy and pulmonary congestion without reducing cardiac preload. These results suggest that ANP has a clinical benefit for treatment of congestive heart failure.
111 EFFECT OF ATRIAL NATRIURETICPEPTIDE INFUSION ON ACUTE HEART FAILURE UNDER NITRATETOLERANCE Teijin Sumi, Yoji Hirayama,Yoshifurni Takata,TakashiOgawa, Toshikazu Ishii, Genzo Shiokawa, Shinichi Osa, Sadamichi Kiyomi, Chiharu Ibukiyama Second Department of Internal Medicine, Tokyo Medical College, Tokyo 160-0023, Japan Nitrates stimulate solbule guanylate cyclase activity to p rod uce cyclic GMP. On the other hand, atrialnatriuretic peptide (ANP) produce cyclic GMP by the different way of stimulating particulate cyclase activity. This study was designed to evaluate the effect of ANP on nitrate tolerance during continuous nitrate therapy in dogs with acute heart failure. Sixteen dogs were received transdermal isosorbide dinitrate (ISDN) (40mg/day) and oral ISDN (40rag/day) for seven days. The hemodynamic and neurohumoral effects of ANP were examined in these dogs with low-output heart failure produced by volume expansion, ligation of left anterior descending coronary artery, and methoxamine infusion. The dogs were classified by two groups. One was nitroglycerin infusion group (N group:3fz g/kg/min, for 60 min), the other was ANP infusion group (A group:l/~ g/kg/min, for 60 min). In the N group, no significant change in hemodynamic parameterswas noted, although in the A group, RAP, PCWP and LVEDP significantly decreased (RAP;5.1 +_0.9~2.7+_0.5 mmHg, PCWP; 18.5 _+1.7~ 12.6_+3.6mmHg, LVEDP;30.1 _+2.0--19.6+_3.8 mmHg, p<0.01). In the A group, total systemic resistance tended to reduce and cardiac output tended to increase. These findings indicate ANP is auseful alternativeto nitroglycerin in the treatment of acute heart failure under the condition with nitrate tolerance. These results also suggest that an important mechanism of nitrate tolerance is related to the process before cyclic GMP production.
110 ROLEOFENDOGENOUSCARDIACNATRIURETICPEPTIDESAFTER CHRONICINHIBITIONOFENDOTHELINACTIVITYIN HEARTFAILURE MasatoOhnishi,AtsuyukiWad&Takay0shiTsutamoto,DaisukeFukai,Masahide Sawaki,MasanoriFujii,KeikoMaeda,NaokoMabuchi,MasahikoKinoshita. First Departmentof InternalMedidne,ShigaUniversityof MedicalScience, Otsu,520-2192, Japan To elucidate the pathophysiological role of endogenous cardiac natriuretic peptides (NPs) after chronic inhibition of endothelin (ET) activity in heart failure (HF), we used HS-142-1 (HS, 3mg/kg), a specific antagonist for the NPs guanylate cyclase coupled receptor, to dogs with HF induced by rapid right ventricular pacing (270ppm, 22days) after chronic administration of an ET receptor antagonist, T0201 (0.3mg/kg/day, for 15 days) or placebo as acontrol. HF (n=6) _ HF+T-0201 (n=6) Baseline PostHS Baseline PostHS Plasmaatrial NP(pg/ml) 395 550 1 237 # 318 * PlasmacGMP(pmol/ml) 33.7 10.2 t 40.2 14.7 1PlasmaNE(pg/ml) 811 1250 1 562 # 680 * PRA(ng/ml/hr) 5.5 12.1 * 7.5 11.6* MAP(mmHg) 87.2 93.0 96.2 99.8 PCWP(mmHg) 19.0 21.6 16.9 # 20.1 [ RAP (mmHq) 10.7 11.8 11.3 13.3t * p<0.05, ~<0.01 vs Baseline;#p<0.05vs HFgroup,cGMP;cyclicGMP, NE;norepinephrine,PRA:plasmareninactivity,MAP;meanarterial pressure, PCWP;pulmonarycapillarywedgepressure,RAP; right atrial pressure. Chronic treatment with T-0201 prevented the progressive development of HF by inhibiting the elevation of plasma atrial NP, NE, and PCWP. HS significantly suppressed the plasma cGMP levels and increased the plasma NE and PRA in both groups, suggesting that endogenous NPs inhibited neurohumoral activation in HF. In contrast, HS significantly increased PCWP and RAP only in the T-0201-treated dogs, indicating that chronic inhibition of ET activity improves the attenuated vasodilative action of NPs.
112 ATRIAL NATRIURETIC PEPTIDE AS A RISK OF THROMBOEMBOLISM IN PATIENTS WITH CHRONIC HEART FAILURE Tadakazu Hirai, Keiko Nakagawa, Shutaro Takashima, Noriko Shinokawa, Tomoki Kameyama, Hidetsugu Asanoi, Hiroshi Inoue. The 2nd Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan. Clinical trials have shown that cardiogenic embolism is a serious complication in patients (pts) with chronic heart failure (CHF) and atrial fibrillation. To identify the risk of thromboembolism in CHF, 32 pts with CHF (DCM, n = 21 ; OMl, n = 11) and atrial fibrillation were studied with transesophageal echocardiography with regard to the left atrial appendage function and its relation to the cardiogenic embolism. The neurohumoral factors (plasma atrial natriuretic peptide (ANP), renin, aldosterone and norepinephrine etc.) were also studied because these factors per se might have a specific predictive value for thromboembolism. All pts underwent brain computed tomography or nuclear magnetic resonance imaging. Embolic cerebral infarction (CI) was found in 31% of all pts. The grade of left atrial spontaneous echo contrast was significantly higher in pts with CI than in those without CI (2.2_+0.3 vs 1.6_+0 5), while there was no significant difference in left atrial appendage flow velocity between pts with and without CI (25+_8 vs 29+_10 cm/sec). Pts with CI showed an increase in ANP when compared with pts without CI. Multiple regression analysis revealed that ANP was an independent predictor of CI (p<0.05). Thus, increased plasma concentration of ANP appears to be useful in predicting the risk of thromboembolism in pts with CHF.
Journal of Cardiac Failure Vol. 4 No. 3 Suppl. 2 1998
109 ATRIAL NATRIURETIC PEPTIDE INHIBITS CARDIAC HYPERTROPHY INDUCED BY VOLUME OVERLOAD IN RATS WITH AORTOCAVAL SHUNT Akira Yamaki, Mayumi Furuya, Naomi Oka, Kayoko Kawashima, Toshinori Hidaka, and Norio Inomata Suntory Institute for Biomedical Research, Shimomoto-cho, Mishima-gun, Osaka 618-8503, Japan It is known that secretion of atrial natriuretic peptide (ANP) from heart increases in patients with heart failure, while physiological effects of ANP on cardiac hypertrophy have not fully been elucidated. We have previously reported that chronic ANP infusion could prevent the left ventricuiar hypertrophy induced by pressure overload in aortic-banded rats. In the present study, we investigated whether ANP could also inhibit the volume-overload induced cardiac hypertrophy in rats with aortocaval shunts. The intravenous infusion of vehicle (5% glucose) or ANP (0.1 microg/kg/min) was begun 2 weeks after shunt or shamoperation and was continued until week-4 after operation. There were no differences in systolic arterial pressure and heart rate in all groups. Right atrial pressure and the ratio of each heart chamber weight to body weight were significantly higher in shunt rats than sham-operated rats, indicating that the increased cardiac preload resulted in cardiac hypertrophy. Treatment with ANP did not affect right atrial pressure, but significantly reduced the ratios of right atrial, right ventricular, and left atrial weights related to body weight in comparison with those of shunt rats. ANP also significantly diminished the increased ratio of lung weight to body weight induced by volume overload. ACS enhanced the expressions of endogenous ANP and BNP mRNAs in the ventricle and the plasma ANP levels, which were suppressed by exogenous ANP. The plasma levels of rat ANP in sham-operated, vehicle, ANP-treated rats were 43+/-11, 854+/-265, 419+•-202 pg/ml, respectively. While, the expression of prepro ET-1 mRNA elevated by ACS was not changed by ANP. Thus ANP treatment improved cardiac hypertrophy and pulmonary congestion without reducing cardiac preload. These results suggest that ANP has a clinical benefit for treatment of congestive heart failure.
111 EFFECT OF ATRIAL NATRIURETICPEPTIDE INFUSION ON ACUTE HEART FAILURE UNDER NITRATETOLERANCE Teijin Sumi, Yoji Hirayama,Yoshifurni Takata,TakashiOgawa, Toshikazu Ishii, Genzo Shiokawa, Shinichi Osa, Sadamichi Kiyomi, Chiharu Ibukiyama Second Department of Internal Medicine, Tokyo Medical College, Tokyo 160-0023, Japan Nitrates stimulate solbule guanylate cyclase activity to p rod uce cyclic GMP. On the other hand, atrialnatriuretic peptide (ANP) produce cyclic GMP by the different way of stimulating particulate cyclase activity. This study was designed to evaluate the effect of ANP on nitrate tolerance during continuous nitrate therapy in dogs with acute heart failure. Sixteen dogs were received transdermal isosorbide dinitrate (ISDN) (40mg/day) and oral ISDN (40rag/day) for seven days. The hemodynamic and neurohumoral effects of ANP were examined in these dogs with low-output heart failure produced by volume expansion, ligation of left anterior descending coronary artery, and methoxamine infusion. The dogs were classified by two groups. One was nitroglycerin infusion group (N group:3fz g/kg/min, for 60 min), the other was ANP infusion group (A group:l/~ g/kg/min, for 60 min). In the N group, no significant change in hemodynamic parameterswas noted, although in the A group, RAP, PCWP and LVEDP significantly decreased (RAP;5.1 +_0.9~2.7+_0.5 mmHg, PCWP; 18.5 _+1.7~ 12.6_+3.6mmHg, LVEDP;30.1 _+2.0--19.6+_3.8 mmHg, p<0.01). In the A group, total systemic resistance tended to reduce and cardiac output tended to increase. These findings indicate ANP is auseful alternativeto nitroglycerin in the treatment of acute heart failure under the condition with nitrate tolerance. These results also suggest that an important mechanism of nitrate tolerance is related to the process before cyclic GMP production.
110 ROLEOFENDOGENOUSCARDIACNATRIURETICPEPTIDESAFTER CHRONICINHIBITIONOFENDOTHELINACTIVITYIN HEARTFAILURE MasatoOhnishi,AtsuyukiWad&Takay0shiTsutamoto,DaisukeFukai,Masahide Sawaki,MasanoriFujii,KeikoMaeda,NaokoMabuchi,MasahikoKinoshita. First Departmentof InternalMedidne,ShigaUniversityof MedicalScience, Otsu,520-2192, Japan To elucidate the pathophysiological role of endogenous cardiac natriuretic peptides (NPs) after chronic inhibition of endothelin (ET) activity in heart failure (HF), we used HS-142-1 (HS, 3mg/kg), a specific antagonist for the NPs guanylate cyclase coupled receptor, to dogs with HF induced by rapid right ventricular pacing (270ppm, 22days) after chronic administration of an ET receptor antagonist, T0201 (0.3mg/kg/day, for 15 days) or placebo as acontrol. HF (n=6) _ HF+T-0201 (n=6) Baseline PostHS Baseline PostHS Plasmaatrial NP(pg/ml) 395 550 1 237 # 318 * PlasmacGMP(pmol/ml) 33.7 10.2 t 40.2 14.7 1PlasmaNE(pg/ml) 811 1250 1 562 # 680 * PRA(ng/ml/hr) 5.5 12.1 * 7.5 11.6* MAP(mmHg) 87.2 93.0 96.2 99.8 PCWP(mmHg) 19.0 21.6 16.9 # 20.1 [ RAP (mmHq) 10.7 11.8 11.3 13.3t * p<0.05, ~<0.01 vs Baseline;#p<0.05vs HFgroup,cGMP;cyclicGMP, NE;norepinephrine,PRA:plasmareninactivity,MAP;meanarterial pressure, PCWP;pulmonarycapillarywedgepressure,RAP; right atrial pressure. Chronic treatment with T-0201 prevented the progressive development of HF by inhibiting the elevation of plasma atrial NP, NE, and PCWP. HS significantly suppressed the plasma cGMP levels and increased the plasma NE and PRA in both groups, suggesting that endogenous NPs inhibited neurohumoral activation in HF. In contrast, HS significantly increased PCWP and RAP only in the T-0201-treated dogs, indicating that chronic inhibition of ET activity improves the attenuated vasodilative action of NPs.
112 ATRIAL NATRIURETIC PEPTIDE AS A RISK OF THROMBOEMBOLISM IN PATIENTS WITH CHRONIC HEART FAILURE Tadakazu Hirai, Keiko Nakagawa, Shutaro Takashima, Noriko Shinokawa, Tomoki Kameyama, Hidetsugu Asanoi, Hiroshi Inoue. The 2nd Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan. Clinical trials have shown that cardiogenic embolism is a serious complication in patients (pts) with chronic heart failure (CHF) and atrial fibrillation. To identify the risk of thromboembolism in CHF, 32 pts with CHF (DCM, n = 21 ; OMl, n = 11) and atrial fibrillation were studied with transesophageal echocardiography with regard to the left atrial appendage function and its relation to the cardiogenic embolism. The neurohumoral factors (plasma atrial natriuretic peptide (ANP), renin, aldosterone and norepinephrine etc.) were also studied because these factors per se might have a specific predictive value for thromboembolism. All pts underwent brain computed tomography or nuclear magnetic resonance imaging. Embolic cerebral infarction (CI) was found in 31% of all pts. The grade of left atrial spontaneous echo contrast was significantly higher in pts with CI than in those without CI (2.2_+0.3 vs 1.6_+0 5), while there was no significant difference in left atrial appendage flow velocity between pts with and without CI (25+_8 vs 29+_10 cm/sec). Pts with CI showed an increase in ANP when compared with pts without CI. Multiple regression analysis revealed that ANP was an independent predictor of CI (p<0.05). Thus, increased plasma concentration of ANP appears to be useful in predicting the risk of thromboembolism in pts with CHF.