Preliminary biochemical characterization of two angiotensin II receptor subtypes

Whitebread, Steven; Mele, Michèle; Kamber, B.; Gasparo, Marc de

doi:10.1016/0006-291x(89)92133-5

Cited by 759 publications

(362 citation statements)

References 13 publications

Supporting

Mentioning

335

Contrasting

Unclassified

Order By: Relevance

“…15 Membranes prepared from rat arterial smooth muscle cells maintained in culture were used as the source of AT, receptors. The radioactive ligand used was 125 I-[Sar', Ile 8 ]Ang II (2,200 Ci/mmol; Anawa, Wangen, Switzerland).…”

Section: Plasma Concentrations Of Valsartanmentioning

confidence: 99%

Kidney is an important target for the antihypertensive action of an angiotensin II receptor antagonist in spontaneously hypertensive rats.

1993

View full text Add to dashboard Cite

Inhibitors of the renin-angiotensin system lower blood pressure of spontaneously hypertensive rats, although plasma renin is not elevated. To test the hypothesis that the actions of angiotensin II within the kidney may contribute to the high blood pressure in spontaneously hypertensive rats, we infused valsartan, a subtype 1 angiotensin II receptor antagonist, via the suprarenal artery into the right kidney of conscious, freely moving, unilaterally nephrectomized (left) spontaneously hypertensive rats (12 to 14 weeks old). Valsartan (03 mg/kg per day for 48 hours) lowered blood pressure (change in blood pressure, -7 ± 3 , -1 9 ± 4 , and -2 6 ± 4 mm Hg, n = l l , at 12, 24, and 48 hours) after intrarenal administration but had no significant effect on blood pressure after intravenous administration (change in blood pressure, 1±5, -3 ± 4 , and 10±5 mm Hg, n=l, at 12, 24, and 48 hours). Infusion of vehicle (0.9% saline) intrarenally had no significant effect on blood pressure (change in blood pressure, 2±5, -1 ± 6 , and 0±7 mm Hg, n = l l , at 12, 24, and 48 hours). The maximum fall in blood pressure reached after intrarenal administration of this dose of valsartan was similar to the maximum fall induced after intravenous administration of higher doses (change in blood pressure, -1 4 ± 5 , -27±4, and -3 2 ± 5 mm Hg, n=7, at 12,24, and 48 hours after 3 mg/kg per day i.v.). Thus, endogenous angiotensin II acting within the kidney appears to play an important role in the maintenance of high blood pressure in spontaneously hypertensive rats. Renal function studies have shown that renal hemodynamic abnormalities may be involved in the initiation of hypertension in SHR. Young SHR (4 to 6 weeks) are moderately hypertensive and have a reduced glomerular filtration rate and renal blood flow and an increased renal vascular resistance compared with the normotensive Wistar-Kyoto control strain. 2 -3 Moreover, an exaggerated salt and water retention has been detected in young SHR. 2 As the hypertension develops, renal hemodynamic abnormalities become normalized (after 12 to 14 weeks of age). The low renal blood flow and glomerular filtration rate in young SHR may be a stimulus for BP to increase and return renal perfusion to normal. SHR have a normal to low plasma renin activity 4 -5 and have not generally been considered to be a renindependent model of hypertension. 6 However, the antihypertensive efficacy of renin inhibitors, 7 angiotensin converting enzyme (ACE) inhibitors, 7 " 9 and angiotensin II (Ang II) receptor antagonists 510 in SHR implicates an involvement of the renin-angiotensin system in the pathogenesis of hypertension in this animal model. Treatment of SHR with an ACE inhibitor normalizes glomerular filtration rate, renal blood flow, renal vascular resistance, and BP, 9 suggesting a role for Ang II in both the renal hemodynamic abnormalities and development of hypertension. The observation that the antihypertensive response induced by renin inhibition, ACE inhibition, or Ang II receptor antagonism in SHR is abol...

show abstract

Section: Plasma Concentrations Of Valsartanmentioning

confidence: 99%

Kidney is an important target for the antihypertensive action of an angiotensin II receptor antagonist in spontaneously hypertensive rats.

1993

View full text Add to dashboard Cite

show abstract

“…4) [20]) with an IDs0 of ~ 3 nM (data not shown). The AT2-specific ligand, CGP 42112 [12], similarly had no effect on [~25I]Ang I binding to IEC-18 cells at concentrations up to 10 /aM (Fig. 4).…”

Section: Resultsmentioning

confidence: 90%

“…For example, depending on the target cell )r tissue, the peptide stimulates phosphoinositide turnover, infibits adenylate cyclase, activates guanylate cyclase, releases )rostaglandins and regulates Ca 2+ channels (reviewed in [6][7][8]). in view of these pleiotrophic actions of Ang II, multiple angioensin receptor subtypes have been postulated for some years [9][10][11][12]. However, their existence has only been confirmed in "ecent years with the introduction of highly-selective non-pepide antagonists which have allowed a classification of angioensin receptors into AT1 and AT2 subtypes [13 16].…”

Section: ~ In~oducfionmentioning

confidence: 99%

Identification of atypical (non‐AT₁, non‐AT₂) angiotensin binding sites with high affinity for angiotensin I on IEC‐18 rat intestinal epithelial cells

Smith

1995

FEBS Letters

View full text Add to dashboard Cite

show abstract

“…Andrew Chiu and other members of the DuPont group therefore concluded that two distinct subtypes of angiotensin II receptors exist, subsequently named AT 1 (inhibited by losartan) and AT 2 (inhibited by PD123177 and CGP42112) (Chiu, Herblin, McCall et al 1989). The research group at CibaGeigy independently drew the same conclusions from similar studies with receptor antagonists (Whitebread, Mele, Kamber et al 1989). While there had been various but diverging reports about possible angiotensin II receptor subtypes before, it was only these two results obtained with selective antagonists that reliably characterized and firmly established the two subtypes.…”

Section: Characterizing a Functional Receptormentioning

confidence: 91%

Integrating research and development: the emergence of rational drug design in the pharmaceutical industry

Adam

2005

Studies in History and Philosophy of Science Part C: Studies in

View full text Add to dashboard Cite

Appears in Studies in History and Philosophy of Biological and Biomedical Sciences 36 (2005). AbstractRational drug design is a method for developing new pharmaceuticals that typically involves the elucidation of fundamental physiological mechanisms. It thus combines the quest for a scientific understanding of natural phenomena with the design of useful technology and hence integrates epistemic and practical aims of research and development. Case studies of the rational design of the cardiovascular drugs propranolol, captopril and losartan provide insights into characteristics and conditions of this integration. Rational drug design became possible in the 1950s when theoretical knowledge of drug-target interaction and experimental drug testing could interlock in cycles of mutual advancement. The integration does not, however, diminish the importance of basic research for pharmaceutical development. Rather, it can be shown that still in the 1990s, linear processes of innovation and the close combination of practical and epistemic work were interdependent.

show abstract

Preliminary biochemical characterization of two angiotensin II receptor subtypes

Cited by 759 publications

References 13 publications

Kidney is an important target for the antihypertensive action of an angiotensin II receptor antagonist in spontaneously hypertensive rats.

Kidney is an important target for the antihypertensive action of an angiotensin II receptor antagonist in spontaneously hypertensive rats.

Identification of atypical (non‐AT₁, non‐AT₂) angiotensin binding sites with high affinity for angiotensin I on IEC‐18 rat intestinal epithelial cells

Integrating research and development: the emergence of rational drug design in the pharmaceutical industry

Contact Info

Product

Resources

About

Preliminary biochemical characterization of two angiotensin II receptor subtypes

Cited by 759 publications

References 13 publications

Kidney is an important target for the antihypertensive action of an angiotensin II receptor antagonist in spontaneously hypertensive rats.

Kidney is an important target for the antihypertensive action of an angiotensin II receptor antagonist in spontaneously hypertensive rats.

Identification of atypical (non‐AT1, non‐AT2) angiotensin binding sites with high affinity for angiotensin I on IEC‐18 rat intestinal epithelial cells

Integrating research and development: the emergence of rational drug design in the pharmaceutical industry

Contact Info

Product

Resources

About

Identification of atypical (non‐AT₁, non‐AT₂) angiotensin binding sites with high affinity for angiotensin I on IEC‐18 rat intestinal epithelial cells