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The angiotensin II receptor antagonist irbesartan reduces blood pressure and glomerular injury in obese zucker rats
AIR-APRIL 1996-VOL. 9, NO.4, PART 2
80A ASH XI ABSTRAcrS
A13
A14
THE REGULATION OF SODIUM EXCRETION IN MICE DEFiCIENT FOR GUANYLYL CYCLASE-A, AN ATRIAL NATRIURETIC PEPTIDE RECEPTOR I KJshimoto. DL Garbers. and SK DubOIs. Howard Hughes Medical institute and Departments of Pharmacology and Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX Recently, we disrupted tile gene for guanylyl cyclase (GC)-A, one of tile receptors for atnal natnuretic peptide (ANP). and found tIlat the mice lacking GC-A displayed a salt-resistant elevation in blood pressure (Lopez et aI., Nature 378:65, 1995). Because salt-resistant hypertenSIOn compnses approxllnately half of essential hypertensIOn m humans, and because ANP has pOlent diuretic and natriuretic actIvity, It IS important to understand the mechamsm for salt excretion in these animals. Thus we exammed natriureSIS m mice lackmg GC-A hotll under chromc conscIous condllions m metabolic cages, and m tile acute setting during ANP mfusion. Wild-type mice were used as controls. In the metabolic cage, mIce were fed a 0.7% NaCI diet for 10 days and then changed to an 8% NaCI diet. Blood pressure was measured by tall-cuff during the last 3 days of each dietary phase. On hotll standard and high salt diets, wild-type and GC-A null mice excreted sodium in tile unne at a similar rate, despite marked differences in blood pressure. In the acute selling, mice were anesthetized with methoxyflurane, and received ANP (500 ng/kg/mm) via a femoral venous catheter. The bladder was cannulated, and urine was collected at 15 min intervals. In Wild-type controls, ANP increased botll unne output and sodium excretion approximately 3-fold over basal rate withm 30 min. In cuntrast, GCA defiCient mice had no response to ANP infUSIOn. These results mdicate that although tIley lack ANP-mduced dIUresis and natriuresis, GC-A deficient nuce can respond normally to an oral sail load witllout changing blood pressure. The results also confirm that the diuretic and natrIUretic effect of ANP IS due to activation of GC-A.
ANGIOTENSIN II (ANO II) AND 11JMOR NECROSIS FACfOR-a (TNF) INTERACTIONS AFFECT BLOOD PRESSURE. Nicholas R. Ferreri Department of Pharmacolgy. New York Medical College. Valhalla, New York 10595 TNF derived from the medullary thick ascending limb of Henle's loop (mTALH), acts in an autoerine manner to inhibit s6Rb uptake via a proslanOld-dependent mecharnsm. These effects may contribute to TNF-mediated natriurests and hypotension. mTALH tubules obtained from rats made hypertensIve by Ang II infusion (200 ng/min. s.c.) for 10 days (but not three days). produced approxunately 2- to 5fold more TNF and POE, compared to normotensive controls. Ang II-TNF tOteracUons occur also in the vasculature. The aona from Ang II-hypertensive rats produced approximately 3- to 4-fold more TNF and POE, compared to normotensive controls. However. the kinctics of Ang II-mediated TNF and POE, production by the aona differ from those observed in the mTALH as the effects in the former were observed after Ang II infusions as early as the third day. Inhtbltion of NO formation by administraUon of ~-nitro-L-argiD1ne methyl ester (10 mg/kg, i.v), I hr before isolation of mTALH tubules. inlubited TNF production by approximately 50% in normotensive and Ang II-hypertensive rats, suggesting that NO may regulate TNF production in the mTALH. Neutralization of TNF acuvity with TNF antisera increased mean arterial pressure (MAP) m Ang II-hypertensive rats from ISO ± 3 to 172 ± 5 men Hg and did not affect MAP of normotensive rats. Thus, constitutive and Ang II-induced TNF production may be upregulated by NO produced by the mTALH. TNF appears to exen a prostanoid-dependent blood pressure lowering effect via its inhibitory effects on ion transpon to the mTALH. and by a counter-regulatory intluence on the pressor actions of Ang II.
KeyWords:
guanylyl cyclase, atrial natnuretlc peptide, hypertensIOn. saltreSistance, natriuresis, cGMP
t:)l{~~~; Eicosanoids. AngiotenslD II
A15
A16
THE ANGIOTENSIN II RECEPTOR ANTAGONIST IRBESARTAN
TIME COURSE OF HEMODYNAMIC RESPONSES TO
REDUCES BLOOD PRESSURE AND GLOMERULAR INJURY IN OBESE ZUCKER RATS. MP O'ponnell. BL Kaslske, WF Keane. and JR Powell. Hennepin County Medical Center, Minneapolis. MN, and Brlltc*Myell Squibb Pharmaceutical Research Institute, Prlnceton. NJ. Agents that Interfere with the renin-angiotensin system may ameliorate progressive renal Injury. In the present study. we evaluated the effectl of Irbesartan (IRB) In obese Zucker rets (OZR), an operlmenlaI model of nonlnsulln-dependent diabetes mellitus (NIDDM) characterized by Insulin resistance, hypertension. and progressive glomerular sclerosis. OZR also demonstrate reduced plasma renin activity and Intrarenal renin contort IRB was administered for 18 weeks In the drinking water, beginning at 26 weeks of age when OZR had established albuminuria. The effeels of IRB on systolic blood pressure (BP; mmHg), urine elbumln excretion (UA; mg/24h), and glomerular histology were measured. Results (meaniSE; ·p<0.05 vs. untreated OZR): «weeks 26 weeks ~
Be
UA
Be
UA
Untreated OZR
128 i2
77
i12
1« :t5
OZR+IRB (15mglkg)
130 i3
72 i8
132 :t4
i32
OZR+IRB (50mglkg)
131 :t3
113 i26
117· :t2
iS1
(ns 8)
(11"8) (ns
8)
310 i58 234
190
~
INTRAVENOUS BRADYKININ DURING NO-SYNIllASE INHIBmON IN THE DOG. ~ KHauer, MHartman. T Elbers. KM McDonald. and IN Cobn·. University of Minnesota, Minneapolis, MN. Systemic administration of L-nilroarginine (L-NA) induces inhibition of nitric oxide (NO) syntllesis resulting in bypertension. In order to analyze tile time course of this effect, Sbealthy awake and tigbtly sedated dogs were given L-NA 20 mg/kg intravenously (iv) and lheir bemodynamic responses monitored for 24 bours (brs) during whicb lime the effects of bradykinin (BK) boluses were studied. BK doses (200-800 ng/kg iv) which decreased MAP at baseline by a minimum of ID-15mmHg were used. Data are expressed as means± S.E. Hemodynamic response to L-NA (20 mg/kg iv): Baseline 1 hr 24hr MAP(mmHg) 103±6 I3I±S' lIl±S PA(mmHg) 15±.9 17±1 IS±2 PCWP(mmHg) 7±1 12±!' 7±.9 RA(mmHg) 4±.9 9±1· S±.9 HR(bpm) 72±5 42±4· 44±2' CO(I/m) 3±.4 2±.3· 2±.S 'p
Baseline
Ihr -17±7.3
-15±1.6 'p
1S·
Bradycanba induced by L-NA was urunediate. sustained and vagally mediated (iv atropine: HR increase from 42±2 to 10716 bpm; p
i2
12·
i3
Baseline vllues (26 weeks) of BP and UA were similar In the
N().{Iependcncy.
three groups. IRB caused dose-related reductions In BP and UA
at « weeks and reduced the peccent of glomeruli with sclerosis (%GS) by approximalely one-half. We conclude that angiotensin II receptor antagonism with IRB can lower BP and ameliorate glomerular Injury In an experimental low-renin model of NIDDM.
Key Words.
Key Words:
glomerular sclerosis angiotensin II diabetes
24hr ·7±1.2·
30 i3
proteinuria
L-nitroarginine, nitric oxide, bradykinin, bradycanba. bypenensiOll
80A ASH XI ABSTRAcrS
A13
A14
THE REGULATION OF SODIUM EXCRETION IN MICE DEFiCIENT FOR GUANYLYL CYCLASE-A, AN ATRIAL NATRIURETIC PEPTIDE RECEPTOR I KJshimoto. DL Garbers. and SK DubOIs. Howard Hughes Medical institute and Departments of Pharmacology and Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX Recently, we disrupted tile gene for guanylyl cyclase (GC)-A, one of tile receptors for atnal natnuretic peptide (ANP). and found tIlat the mice lacking GC-A displayed a salt-resistant elevation in blood pressure (Lopez et aI., Nature 378:65, 1995). Because salt-resistant hypertenSIOn compnses approxllnately half of essential hypertensIOn m humans, and because ANP has pOlent diuretic and natriuretic actIvity, It IS important to understand the mechamsm for salt excretion in these animals. Thus we exammed natriureSIS m mice lackmg GC-A hotll under chromc conscIous condllions m metabolic cages, and m tile acute setting during ANP mfusion. Wild-type mice were used as controls. In the metabolic cage, mIce were fed a 0.7% NaCI diet for 10 days and then changed to an 8% NaCI diet. Blood pressure was measured by tall-cuff during the last 3 days of each dietary phase. On hotll standard and high salt diets, wild-type and GC-A null mice excreted sodium in tile unne at a similar rate, despite marked differences in blood pressure. In the acute selling, mice were anesthetized with methoxyflurane, and received ANP (500 ng/kg/mm) via a femoral venous catheter. The bladder was cannulated, and urine was collected at 15 min intervals. In Wild-type controls, ANP increased botll unne output and sodium excretion approximately 3-fold over basal rate withm 30 min. In cuntrast, GCA defiCient mice had no response to ANP infUSIOn. These results mdicate that although tIley lack ANP-mduced dIUresis and natriuresis, GC-A deficient nuce can respond normally to an oral sail load witllout changing blood pressure. The results also confirm that the diuretic and natrIUretic effect of ANP IS due to activation of GC-A.
ANGIOTENSIN II (ANO II) AND 11JMOR NECROSIS FACfOR-a (TNF) INTERACTIONS AFFECT BLOOD PRESSURE. Nicholas R. Ferreri Department of Pharmacolgy. New York Medical College. Valhalla, New York 10595 TNF derived from the medullary thick ascending limb of Henle's loop (mTALH), acts in an autoerine manner to inhibit s6Rb uptake via a proslanOld-dependent mecharnsm. These effects may contribute to TNF-mediated natriurests and hypotension. mTALH tubules obtained from rats made hypertensIve by Ang II infusion (200 ng/min. s.c.) for 10 days (but not three days). produced approxunately 2- to 5fold more TNF and POE, compared to normotensive controls. Ang II-TNF tOteracUons occur also in the vasculature. The aona from Ang II-hypertensive rats produced approximately 3- to 4-fold more TNF and POE, compared to normotensive controls. However. the kinctics of Ang II-mediated TNF and POE, production by the aona differ from those observed in the mTALH as the effects in the former were observed after Ang II infusions as early as the third day. Inhtbltion of NO formation by administraUon of ~-nitro-L-argiD1ne methyl ester (10 mg/kg, i.v), I hr before isolation of mTALH tubules. inlubited TNF production by approximately 50% in normotensive and Ang II-hypertensive rats, suggesting that NO may regulate TNF production in the mTALH. Neutralization of TNF acuvity with TNF antisera increased mean arterial pressure (MAP) m Ang II-hypertensive rats from ISO ± 3 to 172 ± 5 men Hg and did not affect MAP of normotensive rats. Thus, constitutive and Ang II-induced TNF production may be upregulated by NO produced by the mTALH. TNF appears to exen a prostanoid-dependent blood pressure lowering effect via its inhibitory effects on ion transpon to the mTALH. and by a counter-regulatory intluence on the pressor actions of Ang II.
KeyWords:
guanylyl cyclase, atrial natnuretlc peptide, hypertensIOn. saltreSistance, natriuresis, cGMP
t:)l{~~~; Eicosanoids. AngiotenslD II
A15
A16
THE ANGIOTENSIN II RECEPTOR ANTAGONIST IRBESARTAN
TIME COURSE OF HEMODYNAMIC RESPONSES TO
REDUCES BLOOD PRESSURE AND GLOMERULAR INJURY IN OBESE ZUCKER RATS. MP O'ponnell. BL Kaslske, WF Keane. and JR Powell. Hennepin County Medical Center, Minneapolis. MN, and Brlltc*Myell Squibb Pharmaceutical Research Institute, Prlnceton. NJ. Agents that Interfere with the renin-angiotensin system may ameliorate progressive renal Injury. In the present study. we evaluated the effectl of Irbesartan (IRB) In obese Zucker rets (OZR), an operlmenlaI model of nonlnsulln-dependent diabetes mellitus (NIDDM) characterized by Insulin resistance, hypertension. and progressive glomerular sclerosis. OZR also demonstrate reduced plasma renin activity and Intrarenal renin contort IRB was administered for 18 weeks In the drinking water, beginning at 26 weeks of age when OZR had established albuminuria. The effeels of IRB on systolic blood pressure (BP; mmHg), urine elbumln excretion (UA; mg/24h), and glomerular histology were measured. Results (meaniSE; ·p<0.05 vs. untreated OZR): «weeks 26 weeks ~
Be
UA
Be
UA
Untreated OZR
128 i2
77
i12
1« :t5
OZR+IRB (15mglkg)
130 i3
72 i8
132 :t4
i32
OZR+IRB (50mglkg)
131 :t3
113 i26
117· :t2
iS1
(ns 8)
(11"8) (ns
8)
310 i58 234
190
~
INTRAVENOUS BRADYKININ DURING NO-SYNIllASE INHIBmON IN THE DOG. ~ KHauer, MHartman. T Elbers. KM McDonald. and IN Cobn·. University of Minnesota, Minneapolis, MN. Systemic administration of L-nilroarginine (L-NA) induces inhibition of nitric oxide (NO) syntllesis resulting in bypertension. In order to analyze tile time course of this effect, Sbealthy awake and tigbtly sedated dogs were given L-NA 20 mg/kg intravenously (iv) and lheir bemodynamic responses monitored for 24 bours (brs) during whicb lime the effects of bradykinin (BK) boluses were studied. BK doses (200-800 ng/kg iv) which decreased MAP at baseline by a minimum of ID-15mmHg were used. Data are expressed as means± S.E. Hemodynamic response to L-NA (20 mg/kg iv): Baseline 1 hr 24hr MAP(mmHg) 103±6 I3I±S' lIl±S PA(mmHg) 15±.9 17±1 IS±2 PCWP(mmHg) 7±1 12±!' 7±.9 RA(mmHg) 4±.9 9±1· S±.9 HR(bpm) 72±5 42±4· 44±2' CO(I/m) 3±.4 2±.3· 2±.S 'p
Baseline
Ihr -17±7.3
-15±1.6 'p
1S·
Bradycanba induced by L-NA was urunediate. sustained and vagally mediated (iv atropine: HR increase from 42±2 to 10716 bpm; p
i2
12·
i3
Baseline vllues (26 weeks) of BP and UA were similar In the
N().{Iependcncy.
three groups. IRB caused dose-related reductions In BP and UA
at « weeks and reduced the peccent of glomeruli with sclerosis (%GS) by approximalely one-half. We conclude that angiotensin II receptor antagonism with IRB can lower BP and ameliorate glomerular Injury In an experimental low-renin model of NIDDM.
Key Words.
Key Words:
glomerular sclerosis angiotensin II diabetes
24hr ·7±1.2·
30 i3
proteinuria
L-nitroarginine, nitric oxide, bradykinin, bradycanba. bypenensiOll