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Cardiovascular and metabolic effects of the vasopeptidase inhibitor, omapatrilat in spontaneously hypertensive rats
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AJH–APRIL 2000 –VOL. 13, NO. 4, PART 2
ASH XV ABSTRACTS
reduced renal mass-saline hypertension, PST administration for 4 weeks reduced BP (P ⬍ 0.01) to the same degree as potassium canrenoate and doxazosin mesylate. These findings suggest that OLC may contribute to the elevated BP in reduced renal mass-saline hypertension and that PST may be an effective antihypertensive agent in several forms of hypertension characterized by increased OLC levels. Key Words: Ouabain; ouabain-like compound; sodium dependent hypertension; potassium canrenoate. CICLETANINE ANTAGONIZES ENDOGENOUS LIGAND OF ␣-1 NaK-ATPase, MARINOBUFAGENIN, IN DAHL HYPERTENSION O.V. Fedorova, N.I. Agalakova, E.G. Lakatta, A.Y. Bagrov. Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Baltimore, MD The Na,K-ATPase (NKA) is involved in regulation of membrane transport and in the hypertrophic signaling, and is regulated by many factors including digitalis-like ligands and protein kinases. Cicletanine (CIC) (IPSEN, France) is an antihypertensive compound with direct vascular and natriuretic actions. We found that CIC, via a PKC sensitive mechanism, reverses vasoconstriction and NKA inhibition by an endogenous NKA inhibitor, marinobufagenin (MBG). We tested whether this mechanism may be relevant to the greater efficacy of CIC in salt-sensitive hypertension in which digitalis-like factors, including MBG, are elevated. Dahl-salt sensitive rats (DS) were put on 8% NaCl diet and were treated with CIC (50 mg/kg orally) for 3 weeks. (Table 1). 3 weeks on 8% NaCl intake SBP (mm Hg) LV/BW ratio (mg/100 g)
CIC
Vehicle
175 ⫾ 6 174 ⫾ 2
235 ⫾ 6 197 ⫾ 5
24 hour MBG excretion of MBG in NaCl loaded DS was elevated (117 ⫾ 21 pmol) compared to that in DS on low NaCl intake (39 ⫾ 6 pmol, P ⬍ 0.01). CIC antagonized MBG NKA inhibitory effect at the levels of high-affinity binding sites in left ventricular sarcolemma obtained from DS after 3 weeks on 8% NaCl diet, (Table 2).
MBG ligh-affinity IC50 (nmol/L) MBG low-affinity IC50 (mol/L)
CIC (ⴚ)
CIC (ⴙ)
0.8 ⫾ 0.02 57 ⫾ 2
65 ⫾ 7 96 ⫾ 7
Thus, in DS, CIC treatment lowered the blood pressure and reduced LV/body weight ratio. These results suggest that efficacy of CIC is, at least in part, due to its antagonism
of the effect of MBG to inhibit the NKA at the level of high affinity (␣-1) receptor sites. (*)-P ⬍ .01 vs. vehicle, ANOVA and Neuman-Keuls test. Key Words: Dahl hypertension; Na,K-ATPase; marinobufagenin; protein kinase C; left ventricular hypertrophy CARDIOVASCULAR AND METABOLIC EFFECTS OF THE VASOPEPTIDASE INHIBITOR, OMAPATRILAT IN SPONTANEOUSLY HYPERTENSIVE RATS M. Ginoza, A.G. Marques, M.L.R. Cesaretti, C.R.S. Neves, A.S. Pereira, N.E.B. Kohlmann, A. Tavares, M.T. Zanella, A.B. Ribeiro, O. Kohlmann. Kidney and Hypertension Hospital Nephrology Division, Federal University of Sa˜o Paulo, Sa˜o Paulo, Brazil Objective: To evaluate the effects of Omapatrilat (Oma) upon blood pressure (BP), systemic hemodynamics (Hemo) and insulin sensitivity (IS) in Spontaneously Hypertensive Rats (SHR). Rationale: Oma inhibits simultaneously two enzymes involved in the formation/degradation of various vasoactive peptides: ACE and NEP. Material and Methods: Male SHRs were treated with Oma (100 mol/kg/day) for 12 weeks (SHR ⫹ OMA, n ⫽ 17). As controls 18 SHR (SHR) receiving the vehicle were used. BP was measured twice a week. At the 12th week, in 7 SHR ⫹ Oma and 8 SHR the Hemo parameters (Cardiac Index, Stroke Index and Total Peripheral Resistance ⫺ TPR) were determined by a thermodilution method. Upon animal sacrifice the left ventricle was weighted. In a second set 10 rats of each group were submitted to an euglicemic hyperinsulinemic clamp for glucose uptake and the IS determination. Results: Mean ⫾ SEM, *p ⬍0.05 vs control
BP (mmHg) MAP (mmHg) Heart Rate (bpm) Cardiac Index (ml/min/100 g) Stroke Index (ml/beat/100 g) TPR index (mmHg/ml/min) LV weight/Body weight (mg/g) Glucose Uptake (ml/min) Insulin Sensitivity (ml/min/mU)
SHR ⴙ Oma
SHR
127 ⫾ 15* 92.6 ⫾ 2.47* 324.6 ⫾ 2.47 72.63 ⫾ 6.83* 217.12 ⫾ 21.56* 0.134 ⫾ 0.016* 2.42 ⫾ 0.09* 25.8 ⫾ 6.9* 15.9 ⫾ 5.6*
194 ⫾ 12 173.6 ⫾ 11.36 333.90 ⫾ 12.68 50.30 ⫾ 4.05 153.75 ⫾ 16.69 0.351 ⫾ 0.038 2.896 ⫾ 0.065 18.7 ⫾ 8.4 11.7 ⫾ 6.5
Conclusion: In SHR, Omapatrilat lowers BP, and this effect is associated with an improvement in all systemic hemodynamic parameters, regression of LVH and enhancement in insulin sensitivity. The improvement in glucose metabolism may account at least in part for the cardiovascular effects of this vasopeptidase inhibitor Key Words: Omapatrilat; vasopeptidase inhibitor; systemic hemodynamics; insulin sensitivity
AJH–APRIL 2000 –VOL. 13, NO. 4, PART 2
ASH XV ABSTRACTS
reduced renal mass-saline hypertension, PST administration for 4 weeks reduced BP (P ⬍ 0.01) to the same degree as potassium canrenoate and doxazosin mesylate. These findings suggest that OLC may contribute to the elevated BP in reduced renal mass-saline hypertension and that PST may be an effective antihypertensive agent in several forms of hypertension characterized by increased OLC levels. Key Words: Ouabain; ouabain-like compound; sodium dependent hypertension; potassium canrenoate. CICLETANINE ANTAGONIZES ENDOGENOUS LIGAND OF ␣-1 NaK-ATPase, MARINOBUFAGENIN, IN DAHL HYPERTENSION O.V. Fedorova, N.I. Agalakova, E.G. Lakatta, A.Y. Bagrov. Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Baltimore, MD The Na,K-ATPase (NKA) is involved in regulation of membrane transport and in the hypertrophic signaling, and is regulated by many factors including digitalis-like ligands and protein kinases. Cicletanine (CIC) (IPSEN, France) is an antihypertensive compound with direct vascular and natriuretic actions. We found that CIC, via a PKC sensitive mechanism, reverses vasoconstriction and NKA inhibition by an endogenous NKA inhibitor, marinobufagenin (MBG). We tested whether this mechanism may be relevant to the greater efficacy of CIC in salt-sensitive hypertension in which digitalis-like factors, including MBG, are elevated. Dahl-salt sensitive rats (DS) were put on 8% NaCl diet and were treated with CIC (50 mg/kg orally) for 3 weeks. (Table 1). 3 weeks on 8% NaCl intake SBP (mm Hg) LV/BW ratio (mg/100 g)
CIC
Vehicle
175 ⫾ 6 174 ⫾ 2
235 ⫾ 6 197 ⫾ 5
24 hour MBG excretion of MBG in NaCl loaded DS was elevated (117 ⫾ 21 pmol) compared to that in DS on low NaCl intake (39 ⫾ 6 pmol, P ⬍ 0.01). CIC antagonized MBG NKA inhibitory effect at the levels of high-affinity binding sites in left ventricular sarcolemma obtained from DS after 3 weeks on 8% NaCl diet, (Table 2).
MBG ligh-affinity IC50 (nmol/L) MBG low-affinity IC50 (mol/L)
CIC (ⴚ)
CIC (ⴙ)
0.8 ⫾ 0.02 57 ⫾ 2
65 ⫾ 7 96 ⫾ 7
Thus, in DS, CIC treatment lowered the blood pressure and reduced LV/body weight ratio. These results suggest that efficacy of CIC is, at least in part, due to its antagonism
of the effect of MBG to inhibit the NKA at the level of high affinity (␣-1) receptor sites. (*)-P ⬍ .01 vs. vehicle, ANOVA and Neuman-Keuls test. Key Words: Dahl hypertension; Na,K-ATPase; marinobufagenin; protein kinase C; left ventricular hypertrophy CARDIOVASCULAR AND METABOLIC EFFECTS OF THE VASOPEPTIDASE INHIBITOR, OMAPATRILAT IN SPONTANEOUSLY HYPERTENSIVE RATS M. Ginoza, A.G. Marques, M.L.R. Cesaretti, C.R.S. Neves, A.S. Pereira, N.E.B. Kohlmann, A. Tavares, M.T. Zanella, A.B. Ribeiro, O. Kohlmann. Kidney and Hypertension Hospital Nephrology Division, Federal University of Sa˜o Paulo, Sa˜o Paulo, Brazil Objective: To evaluate the effects of Omapatrilat (Oma) upon blood pressure (BP), systemic hemodynamics (Hemo) and insulin sensitivity (IS) in Spontaneously Hypertensive Rats (SHR). Rationale: Oma inhibits simultaneously two enzymes involved in the formation/degradation of various vasoactive peptides: ACE and NEP. Material and Methods: Male SHRs were treated with Oma (100 mol/kg/day) for 12 weeks (SHR ⫹ OMA, n ⫽ 17). As controls 18 SHR (SHR) receiving the vehicle were used. BP was measured twice a week. At the 12th week, in 7 SHR ⫹ Oma and 8 SHR the Hemo parameters (Cardiac Index, Stroke Index and Total Peripheral Resistance ⫺ TPR) were determined by a thermodilution method. Upon animal sacrifice the left ventricle was weighted. In a second set 10 rats of each group were submitted to an euglicemic hyperinsulinemic clamp for glucose uptake and the IS determination. Results: Mean ⫾ SEM, *p ⬍0.05 vs control
BP (mmHg) MAP (mmHg) Heart Rate (bpm) Cardiac Index (ml/min/100 g) Stroke Index (ml/beat/100 g) TPR index (mmHg/ml/min) LV weight/Body weight (mg/g) Glucose Uptake (ml/min) Insulin Sensitivity (ml/min/mU)
SHR ⴙ Oma
SHR
127 ⫾ 15* 92.6 ⫾ 2.47* 324.6 ⫾ 2.47 72.63 ⫾ 6.83* 217.12 ⫾ 21.56* 0.134 ⫾ 0.016* 2.42 ⫾ 0.09* 25.8 ⫾ 6.9* 15.9 ⫾ 5.6*
194 ⫾ 12 173.6 ⫾ 11.36 333.90 ⫾ 12.68 50.30 ⫾ 4.05 153.75 ⫾ 16.69 0.351 ⫾ 0.038 2.896 ⫾ 0.065 18.7 ⫾ 8.4 11.7 ⫾ 6.5
Conclusion: In SHR, Omapatrilat lowers BP, and this effect is associated with an improvement in all systemic hemodynamic parameters, regression of LVH and enhancement in insulin sensitivity. The improvement in glucose metabolism may account at least in part for the cardiovascular effects of this vasopeptidase inhibitor Key Words: Omapatrilat; vasopeptidase inhibitor; systemic hemodynamics; insulin sensitivity