Role of angiotensin-converting enzyme and angiotensin II in development of hypoxic pulmonary hypertension

Although angiotensin converting enzyme (ACE) inhibitors are known to attenuate the development of hypoxic pulmonary hypertension in rats, the precise mechanism of this protective effect remains unknown. Thus we utilized specific angiotensin II (ANG II)-receptor antagonists to investigate whether ANG II is involved directly in the hemodynamic and structural changes of pulmonary hypertension, and we tested whether the protective effects of ACE inhibition can be attributed partly to potentiation of bradykinin. During 14 days of hypobaric hypoxia, rats received, via intraperitoneal osmotic minipumps, either 1) the ACE inhibitor captopril, 2) captopril plus the bradykinin B2-receptor antagonist CP-0597, 3) the ANG II type 1 receptor antagonist losartan, 4) the ANG II type 2 receptor antagonist PD-123319, or 5) saline. At 14 days, mean pulmonary arterial pressure (MPAP) was reduced (P < 0.05) in hypoxic rats treated with captopril (26.6 +/- 0.8 mmHg) or losartan (24.4 +/- 1.0 mmHg) compared with saline (32.0 +/- 1.4 mmHg) but was unaffected by PD-123319 (29.5 +/- 1.7 mmHg). Right ventricular hypertrophy was reduced in hypoxic rats treated with captopril or losartan compared with saline-treated rats. Morphometry showed less medial thickening and peripheral muscularization of small pulmonary arteries in hypoxic animals treated with captopril or losartan. Coadministration of CP-0597 did not reverse the protective effects of captopril on pulmonary vascular remodeling. These results suggest a novel role for endogenous ANG II, acting through the type 1 receptor, in the vascular remodeling associated with hypoxic pulmonary hypertension. The beneficial effects of ACE inhibition in this model can be attributed to reduced ANG II production rather than potentiation of bradykinin.

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Inhibition of Tissue Angiotensin-Converting Enzyme With Quinapril Reduces Hypoxic Pulmonary Hypertension and Pulmonary Vascular Remodeling

Circulation ◽

10.1161/01.cir.94.8.1941 ◽

1996 ◽

Vol 94 (8) ◽

pp. 1941-1947 ◽

Cited By ~ 54

Author(s):

Zengxuan Nong ◽

Jean-Marie Stassen ◽

Lieve Moons ◽

De´sire´ Collen ◽

Stefan Janssens

Keyword(s):

Pulmonary Hypertension ◽

Angiotensin Converting Enzyme ◽

Vascular Remodeling ◽

Converting Enzyme ◽

Pulmonary Vascular Remodeling ◽

Hypoxic Pulmonary Hypertension ◽

Tissue Angiotensin

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Mitochondrial angiotensin II receptors regulate oxygen consumption in kidney mitochondria from healthy and type 1 diabetic rats

AJP Renal Physiology ◽

10.1152/ajprenal.00417.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. F683-F688 ◽

Cited By ~ 5

Author(s):

Malou Friederich-Persson ◽

Patrik Persson

Keyword(s):

Nitric Oxide ◽

Oxygen Consumption ◽

Angiotensin Ii ◽

Receptor Antagonist ◽

Diabetic Rats ◽

Kidney Cortex ◽

Ang Ii ◽

Kidney Mitochondria ◽

Receptor Inhibition

Exaggerated activation of the renin-angiotensin-aldosterone system (RAAS) is a key feature in diseases such as hypertension, diabetes, and chronic kidney disease. Recently, an intracellular RAAS was demonstrated with angiotensin II (ANG II) type 1 (AT1) and type 2 (AT2) receptors expressed in nuclei and mitochondria. Diabetes is associated with both mitochondrial dysfunction and increased intracellular ANG II concentration in the kidney cortex. The present study investigated the role of ANG II signaling in kidney cortex mitochondria isolated from control and streptozotocin-induced diabetic rats. Mitochondrial oxygen consumption was evaluated after addition of ANG II alone or after preincubation with candesartan (AT1 receptor antagonist), PD-123319 (AT2 receptor antagonist), or the two in combination. ANG II binds to only mitochondrial AT2 receptors in control rats and both AT1 receptors and AT2 receptors in diabetic rats. ANG II decreased oxygen consumption in mitochondria from both control and diabetic rats. ANG II response was reversed to increased oxygen consumption by the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester. AT1 receptor inhibition did not affect the response to ANG II, whereas AT2 receptor inhibition abolished the response in mitochondria from control rats and reversed the response to increased oxygen consumption through superoxide-induced mitochondrial uncoupling in mitochondria from diabetic rats. ANG II decrease mitochondrial respiration via AT2 receptor-mediated nitric oxide release in both control and diabetic rats. AT1 receptors do not regulate mitochondria function in control rats, whereas ANG II via AT1 receptors increase mitochondria leak respiration in diabetic animals.

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Converting enzyme inhibition modulates sympathetic neurotransmission in vivo via multiple mechanisms

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.264.4.e631 ◽

1993 ◽

Vol 264 (4) ◽

pp. E631-E637 ◽

Cited By ~ 7

Author(s):

J. H. Schwieler ◽

T. Kahan ◽

J. Nussberger ◽

P. Hjemdahl

Keyword(s):

Receptor Antagonist ◽

Ace Inhibition ◽

Ang Ii ◽

Converting Enzyme ◽

Synthesis Inhibitor ◽

Sympathetic Neurotransmission ◽

Muscle Perfusion ◽

Alpha Adrenoceptors ◽

Hoe 140

We investigated the mechanism(s) by which angiotensin-converting enzyme (ACE) inhibition influences peripheral sympathetic neurotransmission. Thus effects of the angiotensin II (ANG II) receptor antagonist losartan (Du Pont 753) were compared with those of the ACE inhibitor benazeprilat on sympathetic neurotransmission in canine gracilis muscle in situ, with alpha-adrenoceptors either intact or irreversibly blocked by phenoxybenzamine. Furthermore, effects of the bradykinin receptor antagonist HOE 140 and the prostaglandin synthesis inhibitor diclofenac were studied after ACE inhibition. Losartan reduced the vasoconstrictor response to exogenous ANG II by 76 +/- 4% at the dose used and lowered muscle perfusion pressures. ACE inhibition by benazeprilat reduced plasma ANG-(1-8) octapeptide levels (from 8 +/- 2 to 2 +/- 1 pM), mean arterial pressure, and muscle perfusion pressures. After ACE inhibition, both HOE 140 (at a dose that reduced the vasodilatory response to exogenous bradykinin by 80 +/- 3%) and diclofenac elevated basal perfusion pressures. Losartan reduced the nerve stimulation-evoked overflow of endogenous norepinephrine (NE) (-14 +/- 6%) and vasoconstrictor responses (alpha-adrenoceptors intact). ACE inhibition increased NE overflow when alpha-adrenoceptors were intact (+12 +/- 5%) and tended to reduce it when alpha-adrenoceptors were blocked (-12 +/- 4%). During ACE inhibition, HOE 140 reduced and diclofenac enhanced the evoked NE overflow. In the absence of ACE inhibition, neither HOE 140 nor diclofenac influenced NE overflow. Our findings indicate that ACE inhibition influences sympathetic neurotransmission via reduced ANG II formation and enhanced bradykinin and prostaglandin accumulation. The effects of ANG II on sympathetic neurotransmission are, however, small under these in vivo conditions.

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