Monoclonal antibodies against human renin. Blood pressure effects in the marmoset.

Wood, J. M.; Heusser, Christoph; Gulati, Neelam; Forgiarini, Peter; Hofbauer, Karl G.

doi:10.1161/01.hyp.8.7.600

Cited by 26 publications

(5 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Others have reported that inhibiting renin by either pharmacological intervention or use of monoclonal antibodies against renin had no significant effect on blood pressure in nephrectomized animals. 17 In our study, the efficacy of A-64662 at 0.1 and 1.0 mg/kg doses was restored in the anephric monkeys to a response that was comparable to normal monkeys by replacing the plasma renin pool through an infusion of human renin. These data suggest that inhibition of PRA is involved in the primary action of A-64662.…”

Section: Discussionsupporting

confidence: 48%

Effects of the renin inhibitor A-64662 in monkeys and rats with varying baseline plasma renin activity.

et al. 1988

View full text Add to dashboard Cite

SUMMARY The efficacy of the potent, primate selective renin inhibitor A-64662 was studied in monkeys and rats with varying baseline plasma renin activity (PRA) to elucidate the relationship between PRA and the hypotensive response induced by this compound. The effect of a single bolus of vehicle or A-64662 at 0.001, 0.01,0.1,1.0, and 10.0 mg/kg i.v. was compared in 30 normal and 30 saltdepleted, anesthetized monkeys (n = 5/dose). Baseline mean arterial pressure (MAP) was similar among all groups, but baseline PRA was elevated in salt-depleted monkeys. A-64662 induced a comparable dose-related fall in MAP, affecting the magnitude and duration of action, accompanied by inhibition of PRA, the duration of which was dose-related in both the normal and salt-depleted groups. However, the minimum effective doses required to reduce MAP by approximately 10% were 0.01 mg/kg for the salt-depleted monkeys and 0.1 mg/kg for the normal monkeys. In a second study, three consecutive boluses of vehicle or A-64662 at 0.1, 1.0, and 10.0 mg/kg were administered to anephric monkeys, human renin-infused anephric monkeys, and normal monkeys (n = 4/group). A dose of 0.1 mg/kg was ineffective, but the 1.0 mg/kg dose lowered MAP by 11 ± 3% (mean ± SE)inthe anephric monkeys. The infusion of renin into anephric monkeys restored the efficacy of A-64662 at the 0.1 and 1.0 mg/kg doses to responses comparable to those of the normal monkeys. A-64662 at 10.0 mg/kg caused a similar fall in MAP of 50 to 60% in anephric, renin-infused anephric, and normal monkeys in the absence of detectable PRA. A-64662, which is inactive against rat renin in vitro, was given as a 1.0 mg/kg i.v. bolus followed by a 0.1 mg/kg/min infusion and was without effect on MAP and PRA in sham-operated and two-kidney, one clip conscious rats (n = 6/group). We conclude that 1) PRA is involved, at least in part, in mediating the observed hypotension and 2) A-64662 may exert actions secondary to its effect on PRA. (Hypertension 11: 613-619, 1988) KEY WORDS monkeys renin inhibitors • hypotension • plasma renin activity • cynomolgus R ENIN is the enzyme that catalyzes the first and rate-limiting step in the formation of angioten-.. sin II. Unlike angiotensin converting enzyme, which has multiple substrates, renin is selective for a single naturally occurring substrate, angiotensinogen. 1Although angiotensin converting enzyme inhibitors provide an effective blockade of the renin-angiotensinaldosterone system and are successful therapeutic agents in the treatment of hypertension and congestive

show abstract

Section: Discussionsupporting

confidence: 48%

Effects of the renin inhibitor A-64662 in monkeys and rats with varying baseline plasma renin activity.

et al. 1988

View full text Add to dashboard Cite

show abstract

“…The mechanism of entry of the N-terminal part of angiotensinogen into the cleft is thought to require retroflexion of the flap overlying the active site (Positions 79-91). Since R3-36-16 is a very potent inhibitor of renin activity, 8 it would be expected to bind close to the active site. For example, it may increase the access and tum- over of small substrates such as TOP to the active site by improving stereochemical complementarity.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of inhibition of human renin by monoclonal antibodies.

1988

Self Cite

View full text Add to dashboard Cite

SUMMARY The mechanism by which monoclonal antibodies directed against human renin (R3-36-16 and R3-47-10) inhibit renin activity was investigated using various substrates. Both antibodies acted as potent inhibitors of human renin activity when human angiotensinogen was used as a substrate. However, their effects differed clearly in the presence of synthetic tetradecapeptide. When low concentrations of tetradecapeptide were used as substrate, renin activity was only partially inhibited by R3-47-10, whereas it was stimulated by R3-36-16. At higher synthetic substrate concentrations, both antibodies stimulated angiotensin I production. This effect was independent of the pH. Both antibodies exerted their effects in the presence of CGP 29287, a peptidic transition-state competitive renin inhibitor, indicating that their binding sites differed from that of CGP 29287. In combination, the stimulatory effect of R3-36-16 was not blocked by R3-47-10, but the inhibition produced by R3-47-10 was reversed by R3-36-16. Both antibodies may prevent the large natural substrate angiotensinogen from entering the enzymatic cleft by steric hindrance. At a low substrate concentration, R3-47-10 may also partially hinder the access of synthetic tetradecapeptide into the active cleft by steric hindrance. In contrast, the stimulating effect of both antibodies may be due to a conformational change in the renin molecule, allowing an increased access of tetradecapeptide or a more rapid release of the product from the enzymatic cleft. (Hypertension 11: 209-216, 1988

show abstract

“…Secondary hypertension is high blood pressure that is a result of another underlying condition, such as kidney damage (renal ischemia), involving the RAAS. The author and his colleagues in the 1970s proposed the role of RAAS in renovascular hypertension based on their research performed on rats and monkeys (Carretero and Gulati, , Gulati et al , , Gulati et al , , Gulati et al , , Gulati et al , , Gulati et al , , Hofbauer et al , , Niarchos et al , , Wood et al , , Wood et al , , Wood et al , ). This had led to the development of ACE inhibitors (enalapril and captopril) and angiotensin II antagonists (saralasin) used by the author and his colleagues (Gulati et al , , Gulati et al , ) as pharmacological tools in their basic research in 1980s.…”

Section: Hypertensionmentioning

confidence: 99%

Pycnogenol® in Metabolic Syndrome and Related Disorders

Gulati

2015

Phytotherapy Research

View full text Add to dashboard Cite

The present review provides an update of the biological actions of Pycnogenol® in the treatment of metabolic syndrome and related disorders such as obesity, dyslipidaemia, diabetes and hypertension. Pycnogenol® is a French maritime pine bark extract produced from the outer bark of Pinus pinaster Ait. Subsp. atlantica. Its strong antioxidant, antiinflammatory, endothelium-dependent vasodilator activity, and also its anti-thrombotic effects make it appropriate for targeting the multifaceted pathophysiology of metabolic syndrome. Clinical studies have shown that it can reduce blood glucose levels in people with diabetes, blood pressure in mild to moderate hypertensive patients, and waist circumference, and improve lipid profile, renal and endothelial functions in metabolic syndrome. This review highlights the pathophysiology of metabolic syndrome and related clinical research findings on the safety and efficacy of Pycnogenol®. The results of clinical research studies performed with Pycnogenol® are discussed using an evidence-based, target-oriented approach following the pathophysiology of individual components as well as in metabolic syndrome overall.

show abstract

Monoclonal antibodies against human renin. Blood pressure effects in the marmoset.

Cited by 26 publications

References 26 publications

Effects of the renin inhibitor A-64662 in monkeys and rats with varying baseline plasma renin activity.

Effects of the renin inhibitor A-64662 in monkeys and rats with varying baseline plasma renin activity.

Mechanism of inhibition of human renin by monoclonal antibodies.

Pycnogenol® in Metabolic Syndrome and Related Disorders

Contact Info

Product

Resources

About