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Endothelin-1 and arterial hypertension
AlH-APRIL 1996-VOL. 9, NO.4, PART 2
POSTERS: Vasoactive Peptides-Angiotensm. Vasopressin, Endothelin, ANP 8SA
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RENAL AND EXTRARENAL ENDOTHELIN (ET)-I SYSTEMS IN GENETICALLY HYPERTENSIVE RATS. V Vogel,lU Kramer·, A Blicker, J Heller l , H Meyer-Lehnert. Renal Section,Med Policlinic, Univ of Bonn, FRG, and IDept Exp Med, Inst Clin Exp Med, Prague, CZ. We have previously shown that ET synthesis and receptors in inner medullary collecting ducts may modulate renal tubular function in an autocrine manner. Our data suggest that, via super-high affinity ET81 receptors, ET controls fluid absorption by attenuating AVP-induced cAMP synthesis. Since ET may also play a role in hypertension we studied plasma and urine ET by RIA and ET-I mRNA by competitive PCR in renal tissue, adrenals, aorta and lung tissue of each 6-9 male Prague hypertensive (PHR) (SBP 180 ± 6 mmHg) and normotensive rats (PNR) (SBP 121 ± 3 mmHg) bred from Wistar rats. Plasma ET-I,2 (Amersham FRG) was 10.5 ± 1.9 and 12.3 ± 1.3 fmol/rnl , respectively, thus lower in PHR than in PNR (p < 0.05), with similar urinary ET excretion in PNR and PHR. Quantitative measurements revealed ET-I mRNA in renal cortex of21 ± 4 vs 28 ± 5, medulla 45 ± 14 vs 33 ± 10, papilla <17 vs 49 ± 8, adrenals 14 ± 3 vs 25 ± 3, and lung tissue 245 ± 65 vs 563 ± 123 amol ET-I mRNAlmg total RNA (p< 0.05). ET-I mRNA was below the detection limit in aortic smooth muscle of PHR and PNR. Although our previous data of greater B.... in glomeruli and lower B.... in papillae ofPHR vs PNR suggested a role ofET in controlling fluid balance via modulation of renal hemodynamics and tubular function, the present results do not support a pathogenetic role of ET-I in this model of genetic hypertension.
ENDOTHELIN-I AND ARTERIAL HYPERTENSION. AN EVALUATION IN CHRONIC RENAL FAILURE, IN HEMODIALYZED AND IN ESSENTIAL HYPERTENSIVE PATIENTS. S.Cottone, A Vadala. N Panepinto, F Vaccaro,G Mull!, FP Picone,MC Vella. and G Cerasola* ; Chair of Internal Medicine and Hypertension Centre, and Division of Dialysis and Transplantation, University of Palermo, Italy Objective: To analyze plasma Big Endothelin (Big-En and Endothelin-I (Ef-I) levels in hypertensive patients with chronic renal failure (CRF), and in hemodialysis (HD) and to compare them with those of essential hypertensives (EH). Design and Methods: The study included 10 hypertensive CRF, 10 hypertensive HD, 10 EH. and 14 normotensive healthy controls (NT). The subjecs of the 4 groups were age matched (mean age 43±5 years). Blood samples for BigEf and Ef-I were taken after an overnight fast and rest, and analyzed by ELISA method. All patients underwent 24h blood pressure monitoring, and evaluation of serum creatinine (Cs) and creatinineclerance (Ccr) . Results: In NT Big-Ef and Ef-I were correlated (r 0.88, p
Key Words: ET-I mRNA, kidney, adrenals, lung. aorta, genetic hypertension, rat
Key Words: Plasma Endothelin, Arterial Hypertension
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ADRENOMEDVLLIN PRODUCES VASODILATATION IN THE HUMAN FOREARM VASCULAR BED John Cockcroft, Janet Gardner-Medwin and Terry Bennett. Depts. Therapeutics and Physiology Pharmacology Queen's Medical Centre, Nottingham, UK Adrenomedullin (ADM) is a novel, 52 amino acid, vasodilator peptide first isolated from human phaeochromocytoma tissue. ADM has a degree of sequence homology with calcitonin generelated peptide (CRGP), and exerts a potent hypotensive effect in animals, but as yet has not been studied in a human vascular bed in vivo. In the present study we compared the effects of ADM and CGRP in the human forearm vascular bed in vivo. In a single blind protocol 8 healthy subjects (6M, 2F) aged 19-28, who gave written informed consent, were studied on 2 occasions, 1week apart. On the first occasion subjects received a brachial arterial infusion of saline followed by a stepped infusion of ADM (0.3-30 pmol/min) each dose for 6 min. On the second occasion, subjects were infused with CRGP (0.3-30 pmol/min). Forearm blood flow (FBF, mI/IOOml/min) was measured by venous occlusion plethysmography for the final 3 min o~ each infusion period. ~DM increased FBF from 3.4±0.5 during salme to 13.0±1.I at the highest dose (30 pmol/min) (p
ANGIOTENSIN D REQUIRES PDGF-BB OR SERUM TO INDUCE ONA-SYNTIIESIS IN RAT MESANGIAL CELLS S, Higueruelo, R. Romero. Nephrology Research Unit, Hospital Germans Trias i Pujol, Badalona, Spain.
In conclusion, these studies in healthy subjects demonstrate that ADM produces vasodilatation in the human forearm vascular bed, and is similar in potency and duration to CGRP. Whether ADM plays a physiological role in the maintenance of normal vascular tone in man remains to be established. Key Words: Adrenomedullin, Calcitonin gene related peptide, blood flow, man.
We report herein in vitro experiments using synchronized rat mesangial cen (MC) cultures to determine the relative contnbition ofPDGF-BB (6 ng/ml), bFGF (6 ng/ml), insulin (5 J.lg)ml) and serum (10%) to angiotensin II (Ang D)-induced MC DNA-synthesis. MC were cultured for 48h in both quiescent (0.5% serum) and proliferative (10% serum) medium supplemented with growth factors listed above. All experiments were setted with or without Ang II. DNA-Synthesis was assessed as BrdU uptake. Results showed that Ang II caused no increase in BrdU uptake (0.24±O.01 vs 0.2I±O.01) but it exerted a significant synergistic effect on PDGF-BB-induced DNA-synthesis in quiescent medium (0.52±0.01 vs 0.57±0.01, p<0.05). In proliferative medium Ang II tended to stimulate BrdU uptake (0.74±0.03 vs 0.81±0.02, p=0.09). PDGF·BB had the maximal stimulatory effect in DNA-synthesis both in quiescent (0.24±O.01 vs 0.52±0.0I, p<0.05) and proliferative media (0.74±0.03 vs 0.86±0.03, p<0.05). bFGF and insulin induced a significant increase in DNA-synthesis only in quiescent medium (0.24±0.01 vs 0.3*0.01 and 0.31*0.02 respectively, p<0.05) and its effects were no modificated by the presence of Ang II. We conclude that Ang II is a growth factor for MCs but requires the POGF-BD or serum to be effective.
Key Words: Angiotensin II, mesangial cell DNA-synthesis.
POSTERS: Vasoactive Peptides-Angiotensm. Vasopressin, Endothelin, ANP 8SA
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RENAL AND EXTRARENAL ENDOTHELIN (ET)-I SYSTEMS IN GENETICALLY HYPERTENSIVE RATS. V Vogel,lU Kramer·, A Blicker, J Heller l , H Meyer-Lehnert. Renal Section,Med Policlinic, Univ of Bonn, FRG, and IDept Exp Med, Inst Clin Exp Med, Prague, CZ. We have previously shown that ET synthesis and receptors in inner medullary collecting ducts may modulate renal tubular function in an autocrine manner. Our data suggest that, via super-high affinity ET81 receptors, ET controls fluid absorption by attenuating AVP-induced cAMP synthesis. Since ET may also play a role in hypertension we studied plasma and urine ET by RIA and ET-I mRNA by competitive PCR in renal tissue, adrenals, aorta and lung tissue of each 6-9 male Prague hypertensive (PHR) (SBP 180 ± 6 mmHg) and normotensive rats (PNR) (SBP 121 ± 3 mmHg) bred from Wistar rats. Plasma ET-I,2 (Amersham FRG) was 10.5 ± 1.9 and 12.3 ± 1.3 fmol/rnl , respectively, thus lower in PHR than in PNR (p < 0.05), with similar urinary ET excretion in PNR and PHR. Quantitative measurements revealed ET-I mRNA in renal cortex of21 ± 4 vs 28 ± 5, medulla 45 ± 14 vs 33 ± 10, papilla <17 vs 49 ± 8, adrenals 14 ± 3 vs 25 ± 3, and lung tissue 245 ± 65 vs 563 ± 123 amol ET-I mRNAlmg total RNA (p< 0.05). ET-I mRNA was below the detection limit in aortic smooth muscle of PHR and PNR. Although our previous data of greater B.... in glomeruli and lower B.... in papillae ofPHR vs PNR suggested a role ofET in controlling fluid balance via modulation of renal hemodynamics and tubular function, the present results do not support a pathogenetic role of ET-I in this model of genetic hypertension.
ENDOTHELIN-I AND ARTERIAL HYPERTENSION. AN EVALUATION IN CHRONIC RENAL FAILURE, IN HEMODIALYZED AND IN ESSENTIAL HYPERTENSIVE PATIENTS. S.Cottone, A Vadala. N Panepinto, F Vaccaro,G Mull!, FP Picone,MC Vella. and G Cerasola* ; Chair of Internal Medicine and Hypertension Centre, and Division of Dialysis and Transplantation, University of Palermo, Italy Objective: To analyze plasma Big Endothelin (Big-En and Endothelin-I (Ef-I) levels in hypertensive patients with chronic renal failure (CRF), and in hemodialysis (HD) and to compare them with those of essential hypertensives (EH). Design and Methods: The study included 10 hypertensive CRF, 10 hypertensive HD, 10 EH. and 14 normotensive healthy controls (NT). The subjecs of the 4 groups were age matched (mean age 43±5 years). Blood samples for BigEf and Ef-I were taken after an overnight fast and rest, and analyzed by ELISA method. All patients underwent 24h blood pressure monitoring, and evaluation of serum creatinine (Cs) and creatinineclerance (Ccr) . Results: In NT Big-Ef and Ef-I were correlated (r 0.88, p
Key Words: ET-I mRNA, kidney, adrenals, lung. aorta, genetic hypertension, rat
Key Words: Plasma Endothelin, Arterial Hypertension
A35
A36
ADRENOMEDVLLIN PRODUCES VASODILATATION IN THE HUMAN FOREARM VASCULAR BED John Cockcroft, Janet Gardner-Medwin and Terry Bennett. Depts. Therapeutics and Physiology Pharmacology Queen's Medical Centre, Nottingham, UK Adrenomedullin (ADM) is a novel, 52 amino acid, vasodilator peptide first isolated from human phaeochromocytoma tissue. ADM has a degree of sequence homology with calcitonin generelated peptide (CRGP), and exerts a potent hypotensive effect in animals, but as yet has not been studied in a human vascular bed in vivo. In the present study we compared the effects of ADM and CGRP in the human forearm vascular bed in vivo. In a single blind protocol 8 healthy subjects (6M, 2F) aged 19-28, who gave written informed consent, were studied on 2 occasions, 1week apart. On the first occasion subjects received a brachial arterial infusion of saline followed by a stepped infusion of ADM (0.3-30 pmol/min) each dose for 6 min. On the second occasion, subjects were infused with CRGP (0.3-30 pmol/min). Forearm blood flow (FBF, mI/IOOml/min) was measured by venous occlusion plethysmography for the final 3 min o~ each infusion period. ~DM increased FBF from 3.4±0.5 during salme to 13.0±1.I at the highest dose (30 pmol/min) (p
ANGIOTENSIN D REQUIRES PDGF-BB OR SERUM TO INDUCE ONA-SYNTIIESIS IN RAT MESANGIAL CELLS S, Higueruelo, R. Romero. Nephrology Research Unit, Hospital Germans Trias i Pujol, Badalona, Spain.
In conclusion, these studies in healthy subjects demonstrate that ADM produces vasodilatation in the human forearm vascular bed, and is similar in potency and duration to CGRP. Whether ADM plays a physiological role in the maintenance of normal vascular tone in man remains to be established. Key Words: Adrenomedullin, Calcitonin gene related peptide, blood flow, man.
We report herein in vitro experiments using synchronized rat mesangial cen (MC) cultures to determine the relative contnbition ofPDGF-BB (6 ng/ml), bFGF (6 ng/ml), insulin (5 J.lg)ml) and serum (10%) to angiotensin II (Ang D)-induced MC DNA-synthesis. MC were cultured for 48h in both quiescent (0.5% serum) and proliferative (10% serum) medium supplemented with growth factors listed above. All experiments were setted with or without Ang II. DNA-Synthesis was assessed as BrdU uptake. Results showed that Ang II caused no increase in BrdU uptake (0.24±O.01 vs 0.2I±O.01) but it exerted a significant synergistic effect on PDGF-BB-induced DNA-synthesis in quiescent medium (0.52±0.01 vs 0.57±0.01, p<0.05). In proliferative medium Ang II tended to stimulate BrdU uptake (0.74±0.03 vs 0.81±0.02, p=0.09). PDGF·BB had the maximal stimulatory effect in DNA-synthesis both in quiescent (0.24±O.01 vs 0.52±0.0I, p<0.05) and proliferative media (0.74±0.03 vs 0.86±0.03, p<0.05). bFGF and insulin induced a significant increase in DNA-synthesis only in quiescent medium (0.24±0.01 vs 0.3*0.01 and 0.31*0.02 respectively, p<0.05) and its effects were no modificated by the presence of Ang II. We conclude that Ang II is a growth factor for MCs but requires the POGF-BD or serum to be effective.
Key Words: Angiotensin II, mesangial cell DNA-synthesis.