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Effects of losartan on cavernous tissue in spontaneously hypertensive rats
210A
POSTERS: Renin-Angiotensin-Aldosterone
AJH–April 2002–VOL. 15, NO. 4, PART 2
P-487 EFFECTS OF LOSARTAN ON CAVERNOUS TISSUE IN SPONTANEOUSLY HYPERTENSIVE RATS Jorge E. Toblli, Ine´ s Stella, Elena M.V. de Cavanagh, Leo´ n Ferder, Osvaldo Mazza, Felipe Inserra. Lab. Experimental Medicine, Hospital Alema´ n & Lab. Nephr. Exp. ININCA, Buenos Aires, Argentina. Prevalence of erectile dysfunction is increased in hypertensive patients and it is extremely associated with cardiovascular diseases. Renin-Angiotensin-System interaction by ARBs has demonstrated to be effective in blood pressure control in hypertensive patients. The aim of this study was to evaluate possible beneficial effects of losartan (L) on cavernous tissue (CT) in spontaneously hypertensive rats (SHR). Male SHR and normotensive Wistar-Kyoto (WKY) rats were used in this study. G1 SHR (n⫽ 10); G2 SHR⫹L (n⫽ 10) and G3 WKY (n⫽ 10). G2 received L 40mg/kg/day orally for four months. At the end of the experiment penises were processed by LM, immunohistochemistry and oxidative stress. We evaluated by a semiquantitative score (0-4): 1) Proliferation, a) cavernous smooth muscle (CSM) and b) vascular smooth-muscle (VSM) and 2) CT-fibrosis. Oxidative injury was evaluated by glutathione peroxidase (GPx) in penis homogenates.In conclusion, L showed beneficial effects regarding CT fibrosis and proliferative scores in SHR. Finally, L seems to modify favorably the oxidative stress in CT in SHR. Mean ⴞ SD
G1 SHR
Systolic Blood Pressure (mmHg) CT Fibrosis Score CSM Score VSM Score Collagen III Score GPx (U/mg protein)
190.3 ⫾ 6.2 132.9 ⫾ 5.2** 2.3 ⫾ 0.3 1.1 ⫾ 0.2* 1.8 ⫾ 0.4 1.1 ⫾ 0.2* 1.4 ⫾ 0.3 0.1 ⫾ 0.2* 1.2 ⫾ 0.2 0.8 ⫾ 0.4* 306.4 ⫾ 20.6 168.3 ⫾ 17.5*
G2 SHR ⴙ L
G3 WKY 119.7 ⫾ 1.7 1.3 ⫾ 0.3 1.0 ⫾ 0.5 0.4 ⫾ 0.3 0.8 ⫾ 0.2 165 ⫾ 26
* p ⬍ 0.01 vs. G1 and ** p ⬍ 0.01 vs. G1 and G2.
Key Words: Losartan, Erectile Dysfunction, Arterial Hypertension
P-488 ANTIHYPERTENSIVE EFFECT OF NORI-PEPTIDES DERIVED FROM RED ALGA PORPHYRA YEZOENSIS IN HYPERTENSIVE PATIENTS Masanobu Saito, Masanobu Kawai, Hiroshi Hagino, Jun Okada, Kunio Yamamoto, Manabu Hayashida, Toshio Ikeda. Shirako Research and Development Center, Jinguumae Clinic, Tokyo, Japan. Nori-peptides have a potent angiotensin I converting enzyme (ACE) inhibitory activity. It has been fractionated from red alga porphyrayezoensis(Nori) by using iron-exchange and gel-filtration. Previous report showed that amino acid sequences of ACE inhibitory Nori-peptides were Ile-Tyr, Met-Lys-Tyr, Ala-Lys-Thy-Ser-Thyr, and Leu-Arg-Tyr, and 200mg/kg of Nori-peptides induced a significant blood pressure reduction in spontaneously hypertensive rats (Suetuna K. J Mar Biotechnol 1998; 6:163-167). We examined the efficacy and safety of Nori-peptides in humans. The subjects enrolled in this study were 64 hypertensive patients (36 men and 28 women, 59.9⫾2.0 years) and 29 normotensive subjects (15 men and 14 women, 51.9⫾3.6 years). Nori-peptides 1.8g/ day was administered and change of blood pressure was followed for 35 days. Nori-peptide induced a significant blood pressure reduction in hypertensive patients (157.9⫾14.4/95.1⫾11.1 to 142.3⫾16.0/86.8⫾10.2 mmHg, p⬍0.001), but did not showed a significant depressor effect in normotensive Subjects (121.1⫾10.5/80.2 to 118.0 ⫾15.0/76.6⫾9.4 mmHg). 0895-7061/02/$22.00
There was no significant changes in clinical laboratory findings included blood count, serum creatinine, electrolyte, liver function test or blood glucose. It can be concluded that Nori-peptides have a significant antihypertensive effect in hypertensive patients as well as spontaneously hypertensive rats. Key Words: Angiotensin Converting Enzyme, Peptides, Red Alga
P-489 PLASMA RENIN ACTIVITY AND ALDOSTERONE LEVEL IN PATIENTS WITH ESSENTIAL HYPERTENSION Bernard M.Y. Cheung, Fefe C.Y. Law, Sidney C.F. Tam, Cyrus R. Kumana, Chu-Pak Lau. University Department of Medicine, University of Hong Kong, Hong Kong, Hong Kong; Department of Clinical Biochemistry, Queen Mary Hospital, Hong Kong, Hong Kong. Introduction: Response to different antihypertensive drugs is affected by the status of the renin-angiotensin system (RAS), so we studied the renin and aldosterone levels in hypertensive patients. Method: 77 newly-diagnosed untreated hypertensive patients (40 men, 37 women; age [mean ⫾ S.D.] 46 ⫾ 11 years, range 24-73; blood pressure 142 ⫾ 14 / 94 ⫾ 8 mmHg) were studied. None had hypokalaemia, renal artery stenosis, heart failure or other oedematous conditions. Patients were on their usual diet, which contained 187 ⫾ 73 mmol Na/day and 50 ⫾ 23 mmol K/day. Venous blood was taken according to a strict protocol after prolonged rest in a supine position. Plasma renin activity (PRA) and aldosterone (ALDO) were measured. These were repeated after 3 months in 15 patients to assess reliability. The reference ranges in our laboratory are 0.68-1.36 ng/mL/hr for PRA and 28-444 pmol/L for ALDO. Results: Mean PRA was 1.08 ⫾ 1.03 ng/mL/hr. 49%, 20% and 32% patients had a PRA below, within and above the reference range respectively. PRA was not related to gender and the decrease with age was small (r⫽ -0.25, p ⫽ 0.03). Mean plasma ALDO was 182 ⫾ 104 pmol/L. The ALDO in 2 patients were above the reference range but normalised on repeat measurement. Plasma ALDO was not related to gender but was negatively related to age (r⫽ -0.35, p ⫽ 0.002). Repeated measurements of PRA and ALDO were correlated (PRA r ⫽ 0.66, p ⫽ 0.008; ALDO r ⫽ 0.47, p ⫽ 0.05). Conclusion: Chinese hypertensive patients are heterogeneous in terms of their renin status and there was a trend towards lesser activation of the RAS in older hypertensive patients. Inhibitors of the RAS may be less effective in such patients but more effective in the young. Key Words: Aldosterone, Hypertension, Renin
P-490 DIFFERENTIAL ROLE FOR ERK1/2 AND p38 MAP KINASES IN ACTIVATING NADPH-OXIDASE AND PHOSPHOLIPASE A2 IN ANGIOTENSIN IISTIMULATED PHAGOCYTES Inbal Hazan-Hallevy, Talya Wolak, Tal Levy, Rachel Levy, Esther Paran. Clinical Biochemistry, Faculty of Health Science, Ben Gurion University, Beer-Sheva, Israel; Hypertension Unit, Soroka Medical Center, Beer-Sheva, Israel. We have recently demonstrated that angiotensin II stimulates NADPHoxidase and phospholipase A2 activities in phagocytic cells and the essential requirement of cytosolic phospholipase A2 for NADPH-oxidase activity in phagocytic cells. Since the activation of cytosolic phospholipase A2 is attributed to serine-505 phosphorylation mediated by MAPkinases, the role of p38 MAP-kinases and ERK1/2 in NADPH-oxidase and phospholipase A2 activation was studied in neutrophils and monocytes from normotensive volunteers. Neutrophils and monocytes were © 2002 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
POSTERS: Renin-Angiotensin-Aldosterone
AJH–April 2002–VOL. 15, NO. 4, PART 2
P-487 EFFECTS OF LOSARTAN ON CAVERNOUS TISSUE IN SPONTANEOUSLY HYPERTENSIVE RATS Jorge E. Toblli, Ine´ s Stella, Elena M.V. de Cavanagh, Leo´ n Ferder, Osvaldo Mazza, Felipe Inserra. Lab. Experimental Medicine, Hospital Alema´ n & Lab. Nephr. Exp. ININCA, Buenos Aires, Argentina. Prevalence of erectile dysfunction is increased in hypertensive patients and it is extremely associated with cardiovascular diseases. Renin-Angiotensin-System interaction by ARBs has demonstrated to be effective in blood pressure control in hypertensive patients. The aim of this study was to evaluate possible beneficial effects of losartan (L) on cavernous tissue (CT) in spontaneously hypertensive rats (SHR). Male SHR and normotensive Wistar-Kyoto (WKY) rats were used in this study. G1 SHR (n⫽ 10); G2 SHR⫹L (n⫽ 10) and G3 WKY (n⫽ 10). G2 received L 40mg/kg/day orally for four months. At the end of the experiment penises were processed by LM, immunohistochemistry and oxidative stress. We evaluated by a semiquantitative score (0-4): 1) Proliferation, a) cavernous smooth muscle (CSM) and b) vascular smooth-muscle (VSM) and 2) CT-fibrosis. Oxidative injury was evaluated by glutathione peroxidase (GPx) in penis homogenates.In conclusion, L showed beneficial effects regarding CT fibrosis and proliferative scores in SHR. Finally, L seems to modify favorably the oxidative stress in CT in SHR. Mean ⴞ SD
G1 SHR
Systolic Blood Pressure (mmHg) CT Fibrosis Score CSM Score VSM Score Collagen III Score GPx (U/mg protein)
190.3 ⫾ 6.2 132.9 ⫾ 5.2** 2.3 ⫾ 0.3 1.1 ⫾ 0.2* 1.8 ⫾ 0.4 1.1 ⫾ 0.2* 1.4 ⫾ 0.3 0.1 ⫾ 0.2* 1.2 ⫾ 0.2 0.8 ⫾ 0.4* 306.4 ⫾ 20.6 168.3 ⫾ 17.5*
G2 SHR ⴙ L
G3 WKY 119.7 ⫾ 1.7 1.3 ⫾ 0.3 1.0 ⫾ 0.5 0.4 ⫾ 0.3 0.8 ⫾ 0.2 165 ⫾ 26
* p ⬍ 0.01 vs. G1 and ** p ⬍ 0.01 vs. G1 and G2.
Key Words: Losartan, Erectile Dysfunction, Arterial Hypertension
P-488 ANTIHYPERTENSIVE EFFECT OF NORI-PEPTIDES DERIVED FROM RED ALGA PORPHYRA YEZOENSIS IN HYPERTENSIVE PATIENTS Masanobu Saito, Masanobu Kawai, Hiroshi Hagino, Jun Okada, Kunio Yamamoto, Manabu Hayashida, Toshio Ikeda. Shirako Research and Development Center, Jinguumae Clinic, Tokyo, Japan. Nori-peptides have a potent angiotensin I converting enzyme (ACE) inhibitory activity. It has been fractionated from red alga porphyrayezoensis(Nori) by using iron-exchange and gel-filtration. Previous report showed that amino acid sequences of ACE inhibitory Nori-peptides were Ile-Tyr, Met-Lys-Tyr, Ala-Lys-Thy-Ser-Thyr, and Leu-Arg-Tyr, and 200mg/kg of Nori-peptides induced a significant blood pressure reduction in spontaneously hypertensive rats (Suetuna K. J Mar Biotechnol 1998; 6:163-167). We examined the efficacy and safety of Nori-peptides in humans. The subjects enrolled in this study were 64 hypertensive patients (36 men and 28 women, 59.9⫾2.0 years) and 29 normotensive subjects (15 men and 14 women, 51.9⫾3.6 years). Nori-peptides 1.8g/ day was administered and change of blood pressure was followed for 35 days. Nori-peptide induced a significant blood pressure reduction in hypertensive patients (157.9⫾14.4/95.1⫾11.1 to 142.3⫾16.0/86.8⫾10.2 mmHg, p⬍0.001), but did not showed a significant depressor effect in normotensive Subjects (121.1⫾10.5/80.2 to 118.0 ⫾15.0/76.6⫾9.4 mmHg). 0895-7061/02/$22.00
There was no significant changes in clinical laboratory findings included blood count, serum creatinine, electrolyte, liver function test or blood glucose. It can be concluded that Nori-peptides have a significant antihypertensive effect in hypertensive patients as well as spontaneously hypertensive rats. Key Words: Angiotensin Converting Enzyme, Peptides, Red Alga
P-489 PLASMA RENIN ACTIVITY AND ALDOSTERONE LEVEL IN PATIENTS WITH ESSENTIAL HYPERTENSION Bernard M.Y. Cheung, Fefe C.Y. Law, Sidney C.F. Tam, Cyrus R. Kumana, Chu-Pak Lau. University Department of Medicine, University of Hong Kong, Hong Kong, Hong Kong; Department of Clinical Biochemistry, Queen Mary Hospital, Hong Kong, Hong Kong. Introduction: Response to different antihypertensive drugs is affected by the status of the renin-angiotensin system (RAS), so we studied the renin and aldosterone levels in hypertensive patients. Method: 77 newly-diagnosed untreated hypertensive patients (40 men, 37 women; age [mean ⫾ S.D.] 46 ⫾ 11 years, range 24-73; blood pressure 142 ⫾ 14 / 94 ⫾ 8 mmHg) were studied. None had hypokalaemia, renal artery stenosis, heart failure or other oedematous conditions. Patients were on their usual diet, which contained 187 ⫾ 73 mmol Na/day and 50 ⫾ 23 mmol K/day. Venous blood was taken according to a strict protocol after prolonged rest in a supine position. Plasma renin activity (PRA) and aldosterone (ALDO) were measured. These were repeated after 3 months in 15 patients to assess reliability. The reference ranges in our laboratory are 0.68-1.36 ng/mL/hr for PRA and 28-444 pmol/L for ALDO. Results: Mean PRA was 1.08 ⫾ 1.03 ng/mL/hr. 49%, 20% and 32% patients had a PRA below, within and above the reference range respectively. PRA was not related to gender and the decrease with age was small (r⫽ -0.25, p ⫽ 0.03). Mean plasma ALDO was 182 ⫾ 104 pmol/L. The ALDO in 2 patients were above the reference range but normalised on repeat measurement. Plasma ALDO was not related to gender but was negatively related to age (r⫽ -0.35, p ⫽ 0.002). Repeated measurements of PRA and ALDO were correlated (PRA r ⫽ 0.66, p ⫽ 0.008; ALDO r ⫽ 0.47, p ⫽ 0.05). Conclusion: Chinese hypertensive patients are heterogeneous in terms of their renin status and there was a trend towards lesser activation of the RAS in older hypertensive patients. Inhibitors of the RAS may be less effective in such patients but more effective in the young. Key Words: Aldosterone, Hypertension, Renin
P-490 DIFFERENTIAL ROLE FOR ERK1/2 AND p38 MAP KINASES IN ACTIVATING NADPH-OXIDASE AND PHOSPHOLIPASE A2 IN ANGIOTENSIN IISTIMULATED PHAGOCYTES Inbal Hazan-Hallevy, Talya Wolak, Tal Levy, Rachel Levy, Esther Paran. Clinical Biochemistry, Faculty of Health Science, Ben Gurion University, Beer-Sheva, Israel; Hypertension Unit, Soroka Medical Center, Beer-Sheva, Israel. We have recently demonstrated that angiotensin II stimulates NADPHoxidase and phospholipase A2 activities in phagocytic cells and the essential requirement of cytosolic phospholipase A2 for NADPH-oxidase activity in phagocytic cells. Since the activation of cytosolic phospholipase A2 is attributed to serine-505 phosphorylation mediated by MAPkinases, the role of p38 MAP-kinases and ERK1/2 in NADPH-oxidase and phospholipase A2 activation was studied in neutrophils and monocytes from normotensive volunteers. Neutrophils and monocytes were © 2002 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.