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Effect of L-name on vascular endothelin-1 gene expression in normal rats
82A ASH XI ABSTRAcrS
A21 EFFECT OF NEONATAL SYMPA11IECTOMYON 11IE SLOW PRESSOR ACTION OF ANGIOlENSIN II. B ~,G Simon·. VA Medical Center and University of Minnesota. Minneapolis. MN. The slow pressor action of angiotensin II (ANG II) is characterized by increased vasoconstrictor responses to ANG II itself (autopotentiation) and to nerve stimulation in the early stages, and by generalized increase in vasoconstrictor activity and the establishment of hypenension in the chronic stages. The effect of neonatal sympathectomy on these responses to ANG II administration was investigated. Neonatallysympathectomized and non-sympathectomized male Sprague· Dawley rats. aged 4 months, received 200 ng/kg/min ANG II for 7-10 days ip or for 4 weeks sc. Sham-infused sympathectomized and non-sympathectomized rats were controls. Vasoconstrictor responses to ANG II, norepinephrine, vasopressin and periarterial nerve stimulation were measured in the mesentery of rats, pump-perfused with the rats' own arterial blood. In sympathectomized shaminfused rats, tail SBP was 12 mmHg lower than in nonsympathectomized controls, vasoconstrictor responses to nerve stimulation were abolished (denervation) and to norepinephrine were potentiated (denervation hypersensitivity). In ANG II-treated, non-sympathectomized rats: I) tail SBP was unchanged at 7-10 days and increased by 65 mmHg at 4 weeks (p
AIR-APRIL 1996-VOL. 9, NO.4, PART 2
A22 EFFECT OF ANGIOTENSIN CONVERTING ENZYME INHIBITION OR CAlCIUM CHANNEL BLOCKADE ON SMALL CORONARY AND RENAL ARTER! ES OF SHR J.-S. Li, A.Turgeon, E.L.Schiffrin, Clinical Research Institute of Montr6al, University of Montreal, Montr6al, Qu6bec, Canada. The effects of an angiotensin converting enzyme inhibitor (ACEI) and a calcium channel blocker (CCB) on small arteries of different vascular beds were compared. Ten week old SHR were treated per os for 14 weeks With lhe CCB mibefradll (50 mg/Kg/day) or the ACEI cllazapril (1.5-10 mglKg/day). Systolic blood pressure was measured by the tailcuff method. Small arteries were studied on a wire myograph. Blood pressure was significantly reduced by treatment In SHR from >200 mmHg to 155 ± 2 mmHg by mibefradll and to 138 ± 1 mmHg by cilazapril (p
Angiotensin converting enzyme Inhibitors. calcium Key Words: channel blockers, small arteries, vascular hypertrophy, SHR.
A23
A24
EXPRESSION OF ENDOTHELlN-l GENE AND EFFECT OF ENDOTHELIN ANTAGONISM IN RENOVASCULAR HYPERTENSION IN THE RAT J.-S. LI, P. Sventek, E L Schlffrjn. Clinical Research Institute of Montr6al, University of Montr6al, Montr6al, Qu6bec, Canada. Expression of vascular endothelin-l mRNA and response to the endothelin receptor antagonist bosentan was examined in renovascular hypertensive rats. Endothelin-l geM expression in l-K lC and 2·K lC hypertensive rats was examined by Northem blot analysis of RNA extracted from aorta and mesenteric artertes. Rats were treated for two weeks with bosentan 100 mg/Kg per day in their chow and blood pressure was measured by the tail-cuff method. Structure of renal, coronary, mesenteric and femoral small arteries was studied on a wire-myograph. After 4 weeks of application of the silver clip to the renal artery of unilaterally nephrectomized rats, the aorta and mesenteric arteries exhibited a 2.5-fold increase in the intensity of the 2.3 kb band corresponding to hybridization with endothelin-l mRNA in comparison to results obtained in control unilaterally nephrectomized rats. No increase could be noted In the blood vessels of 2-K 1C hypertensive rats at 4 weeks, but a 2-fold Increase were found at 8 weeks in aorta, but not in mesenteric arteries. Treatment With bosentan for two weeks did not result In significant change In systolic blood pressure or the structure of small arteries In 1K or 2-K 1C hypertensive rals. Modest elevations of endothelin-l gene expression (2·fold) in blood vessels In renovascular hypertension are not associated with hypotensive responses or regression of vascular hypertrophy during chronic trealment with endothelin antagonists. This contrasts with the response of DOCA-salt hypertensive rats, which exhibit very dramatic Increases in endothelin-l expression (5-8-fold) and do respond to endothelin antagonism with blood pressure lowering and regression of vascular hypertrophy.
EFFECT OF L-NAME ON VASCULAR ENDOTHELIN-l GENE EXPRESSION IN NORMAl. RATS. P. Svenlek , A. Turgeon, eJ.. Schiffrin. Clinical Research Institute of Montr6al, University of Montrhl, Montr6al, Qu6bec, Canada. Nonnotensive rats which receive a nitric oxide synthase Inhibitor (L-NAME), develop hypertension. Surprisingly, they exhibit very little evidence of cardiovascular hypertrophy. Previous experiments have suggested that vascular expression of the endothelin-l gene Is associated with severe vascular hypertrophy, for example in DOCA·salt hypertensive rats. We hypothesized that since L·NAME-treated rats did not exhibit significant vascular hypertrophy, they should not present an increase in vascular endothelin-l gene expression. Sprague.Dawley rats were treated with L-NAME 100 mglkg per day for 3 weeks. Systolic blood pressure rose in treated rats to 190 ± 1.6 mmHg (p< 0.001). Plasma renin activity and plasma endothelin immunoreactivity (the latter 2.25 ± 0.06 vs 2.08 ± 0.06 fmoVmL) were similar In L-NAMEtreated and untreated rats. There was no evidence of cardiovascular hypertrophy. Endothelin-l gene expression measured in aorta and mesenteric arteries as abundance of endothelin-l mRNA by Northem blot analysis demonstrated that there were no differences between nonnotensive and hypertensive L-NAME-treated rats. These resulls suggest that the endothelin system does not participate in the mechanisms leading to elevated blood pressure after nitric oxide synthesis inhibition with L-NAME in nonnal rats. They suggest that endothelin antagonism will not result in hypotensive responses In this model of hypertension.
Endothelin gene expression, endothelin receptor Key Words: antagonist, vascular hypertrophy. renovascular hypertension.
Key Words: Endothelin gene expression, nitric oxide synthase inhibition, vascular hypertrophy, endothelin receptor antagonist.
A21 EFFECT OF NEONATAL SYMPA11IECTOMYON 11IE SLOW PRESSOR ACTION OF ANGIOlENSIN II. B ~,G Simon·. VA Medical Center and University of Minnesota. Minneapolis. MN. The slow pressor action of angiotensin II (ANG II) is characterized by increased vasoconstrictor responses to ANG II itself (autopotentiation) and to nerve stimulation in the early stages, and by generalized increase in vasoconstrictor activity and the establishment of hypenension in the chronic stages. The effect of neonatal sympathectomy on these responses to ANG II administration was investigated. Neonatallysympathectomized and non-sympathectomized male Sprague· Dawley rats. aged 4 months, received 200 ng/kg/min ANG II for 7-10 days ip or for 4 weeks sc. Sham-infused sympathectomized and non-sympathectomized rats were controls. Vasoconstrictor responses to ANG II, norepinephrine, vasopressin and periarterial nerve stimulation were measured in the mesentery of rats, pump-perfused with the rats' own arterial blood. In sympathectomized shaminfused rats, tail SBP was 12 mmHg lower than in nonsympathectomized controls, vasoconstrictor responses to nerve stimulation were abolished (denervation) and to norepinephrine were potentiated (denervation hypersensitivity). In ANG II-treated, non-sympathectomized rats: I) tail SBP was unchanged at 7-10 days and increased by 65 mmHg at 4 weeks (p
AIR-APRIL 1996-VOL. 9, NO.4, PART 2
A22 EFFECT OF ANGIOTENSIN CONVERTING ENZYME INHIBITION OR CAlCIUM CHANNEL BLOCKADE ON SMALL CORONARY AND RENAL ARTER! ES OF SHR J.-S. Li, A.Turgeon, E.L.Schiffrin, Clinical Research Institute of Montr6al, University of Montreal, Montr6al, Qu6bec, Canada. The effects of an angiotensin converting enzyme inhibitor (ACEI) and a calcium channel blocker (CCB) on small arteries of different vascular beds were compared. Ten week old SHR were treated per os for 14 weeks With lhe CCB mibefradll (50 mg/Kg/day) or the ACEI cllazapril (1.5-10 mglKg/day). Systolic blood pressure was measured by the tailcuff method. Small arteries were studied on a wire myograph. Blood pressure was significantly reduced by treatment In SHR from >200 mmHg to 155 ± 2 mmHg by mibefradll and to 138 ± 1 mmHg by cilazapril (p
Angiotensin converting enzyme Inhibitors. calcium Key Words: channel blockers, small arteries, vascular hypertrophy, SHR.
A23
A24
EXPRESSION OF ENDOTHELlN-l GENE AND EFFECT OF ENDOTHELIN ANTAGONISM IN RENOVASCULAR HYPERTENSION IN THE RAT J.-S. LI, P. Sventek, E L Schlffrjn. Clinical Research Institute of Montr6al, University of Montr6al, Montr6al, Qu6bec, Canada. Expression of vascular endothelin-l mRNA and response to the endothelin receptor antagonist bosentan was examined in renovascular hypertensive rats. Endothelin-l geM expression in l-K lC and 2·K lC hypertensive rats was examined by Northem blot analysis of RNA extracted from aorta and mesenteric artertes. Rats were treated for two weeks with bosentan 100 mg/Kg per day in their chow and blood pressure was measured by the tail-cuff method. Structure of renal, coronary, mesenteric and femoral small arteries was studied on a wire-myograph. After 4 weeks of application of the silver clip to the renal artery of unilaterally nephrectomized rats, the aorta and mesenteric arteries exhibited a 2.5-fold increase in the intensity of the 2.3 kb band corresponding to hybridization with endothelin-l mRNA in comparison to results obtained in control unilaterally nephrectomized rats. No increase could be noted In the blood vessels of 2-K 1C hypertensive rats at 4 weeks, but a 2-fold Increase were found at 8 weeks in aorta, but not in mesenteric arteries. Treatment With bosentan for two weeks did not result In significant change In systolic blood pressure or the structure of small arteries In 1K or 2-K 1C hypertensive rals. Modest elevations of endothelin-l gene expression (2·fold) in blood vessels In renovascular hypertension are not associated with hypotensive responses or regression of vascular hypertrophy during chronic trealment with endothelin antagonists. This contrasts with the response of DOCA-salt hypertensive rats, which exhibit very dramatic Increases in endothelin-l expression (5-8-fold) and do respond to endothelin antagonism with blood pressure lowering and regression of vascular hypertrophy.
EFFECT OF L-NAME ON VASCULAR ENDOTHELIN-l GENE EXPRESSION IN NORMAl. RATS. P. Svenlek , A. Turgeon, eJ.. Schiffrin. Clinical Research Institute of Montr6al, University of Montrhl, Montr6al, Qu6bec, Canada. Nonnotensive rats which receive a nitric oxide synthase Inhibitor (L-NAME), develop hypertension. Surprisingly, they exhibit very little evidence of cardiovascular hypertrophy. Previous experiments have suggested that vascular expression of the endothelin-l gene Is associated with severe vascular hypertrophy, for example in DOCA·salt hypertensive rats. We hypothesized that since L·NAME-treated rats did not exhibit significant vascular hypertrophy, they should not present an increase in vascular endothelin-l gene expression. Sprague.Dawley rats were treated with L-NAME 100 mglkg per day for 3 weeks. Systolic blood pressure rose in treated rats to 190 ± 1.6 mmHg (p< 0.001). Plasma renin activity and plasma endothelin immunoreactivity (the latter 2.25 ± 0.06 vs 2.08 ± 0.06 fmoVmL) were similar In L-NAMEtreated and untreated rats. There was no evidence of cardiovascular hypertrophy. Endothelin-l gene expression measured in aorta and mesenteric arteries as abundance of endothelin-l mRNA by Northem blot analysis demonstrated that there were no differences between nonnotensive and hypertensive L-NAME-treated rats. These resulls suggest that the endothelin system does not participate in the mechanisms leading to elevated blood pressure after nitric oxide synthesis inhibition with L-NAME in nonnal rats. They suggest that endothelin antagonism will not result in hypotensive responses In this model of hypertension.
Endothelin gene expression, endothelin receptor Key Words: antagonist, vascular hypertrophy. renovascular hypertension.
Key Words: Endothelin gene expression, nitric oxide synthase inhibition, vascular hypertrophy, endothelin receptor antagonist.