Inhibition of Angiotensin I-Initiated Hemodynamic Changes in Anesthetized Dogs by a Synthetic Nonapeptide

Keim, G. R.; Kirpan, J.; Peterson, A. E.; Murphy, Barbara F.; Hassert, G. L.; Poutsiaka, John W.

doi:10.3181/00379727-140-36413

Cited by 29 publications

(11 citation statements)

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“…Since arterial BP did not change and exogenous administration of a previously vasoconstrictive dose of Al was without effect, it appears that the renal vascular bed may be more sensitive to the vasoconstrictive action of All than systemic vascular smooth muscle. Hollenberg et al 20 and Keim et al 21 provided some support for this possibility.…”

Section: Figure 4 Comparison Of Percent Changes In Urinary Sodium Exmentioning

confidence: 93%

Effects of SQ 20,881 on the intact kidney of dogs with two-kidney, one clip hypertension.

Masaki¹,

Ferrario²,

Bumpus³

1980

Hypertension

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SUMMARY It has been suggested that in two-kidney, one clip hypertension, the undamped kidney (UK) actively contributes to hypertension by reducing its excretory ability in response to increased levels of Circulating angiotensin II. By exteriorizing the ureter to the dog's flank several weeks beforehand, we measured renal function directly from the UK of six chrogic renal hypertensive (> 3 weeks) and six normal dogs (ND). IT HAS BEEN suggested that overactivity of the renin-angiotensin system in the acute phase of two-kidney, one clip hypertension depresses renal function in the undamped kidney, preventing diuresis and enhancing sodium and water retention.1 Whether these effects are still present during the chronic phase of renal hypertension continues to await clarification, due in part to technical limitations that have precluded evaluation of the function of the untouched kidney in conscious chronic 649hypertensive animals before and after blockade of the endogenous formation of angiotensin II (All). Technical difficulties impeding progress in this area of hypertension research were recently resolved in this laboratory, first by the development of a procedure that provides a reliable model of chronic two-kidney one clip hypertension in the dog* and, second, by implementation of a modified method of surgical diversion of the ureter that allows for unilateral renal function studies.3 Because these problems were circumvented, we are now able to report the changes in the function of the untouched kidney of dogs with chronic two-kidney, one clip hypertension both before and after acute blockade of the endogenous formation of angiotensin II with the converting enzyme inhibitor (CEI) SQ-20,881. MethodsBefore and during the studies, 12 male mongrel dogs weighing 18-25 kg were fed a normal diet (Ken-L-Ration Biskit, The Quaker Oats Co., Chicago, Illinois) containing 60 mEq/day of sodium and 45 mEq/day of potassium; water was given ad libitum.

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Section: Figure 4 Comparison Of Percent Changes In Urinary Sodium Exmentioning

confidence: 93%

Effects of SQ 20,881 on the intact kidney of dogs with two-kidney, one clip hypertension.

Masaki¹,

Ferrario²,

Bumpus³

1980

Hypertension

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“…The latter is regarded as the most active substance biologically of the renin-angiotensin system. The nonapeptide SQ 20881 (Pyr-Trp-Pro-Arg-Pro-GlnIle-Pro-Pro) has been shown to be a potent inhibitor of the converting enzyme in vitro (Igic, Erd6s, Yeh, Sorrelss & Nakajima, 1972) and in vivo (Keim, Kirpen, Peterson, Murphy, Hassert & Poutsiaka, 1972 Angiotensin I infusion studies. Twenty min after the start of the angiotensin infusion (0.093 mg kg-" h-') 4 ml of blood were collected from the abdominal aorta of rats lightly anaesthetized with ether.…”

Section: Introductionmentioning

confidence: 99%

Effect of Converting Enzyme Blockade on Isoprenaline‐ and Angiotensin I‐induced Drinking

Hertting

Meyer

1974

British J Pharmacology

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1 Intravenous infusion of 0.072,gmol kg-' h'1 (1-Asp, 5-Ile) angiotensin I, 0.116,umol kg-' h'1 of (1-Asp ,B-amid, 5-Val) angiotensin II or of (1-Asp, 5-Ile) angiotensin II, caused food-deprived and water-satiated rats to drink about 3.0 ml of water per animal. This indicates that angiotensin I has a 1.6 times stronger dipsogenic effect than the angiotensin II preparations when infused intravenously. 2 The converting-enzyme-inhibitor SQ 20881 (Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro) (1.0 mg/kg i.v.) had no intrinsic dipsogenic effect. 3 SQ 20881 given in combination with angiotensin I or angiotensin II potentiated the dipsogenic effect of angiotensin I, but not that of the two angiotensin II preparations. 4 The drinking induced by isoprenaline (100,g/kg, i.m.) was potentiated by SQ 20881 to the same extent as drinking produced by angiotensin I infusion. 5 Angiotensin I plasma levels were determined after angiotensin I infusion and isoprenaline application. Both were significantly raised by SQ 20881. 6 It is concluded that one of the mechanisms which mediate the dipsogenic effect of isoprenaline is stimulation of the renin-angiotensin system and that increased plasma levels of angiotensin I may play a substantial role in this type of drinking.

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“…Competitive inhibitors of angiotensin II binding have varying agonist/antagonist activity (1,2), which undermines their effectiveness. Angiotensin I-converting enzyme inhibitors have been studied (3,4), but their potential interaction with the kallikrein system (5,6) and their inhibition of other enzymes unrelated to the renin-angiotensin system clouds interpretation of physiologic responses (7). Competitive inhibitors of renin, based on the sequence of the natural substrate (angiotensinogen), have been synthesized (8), but they have been of insufficient potency and solubility for in vivo studies (9).…”

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confidence: 99%

Specific inhibition of renin by an angiotensinogen analog: studies in sodium depletion and renin-dependent hypertension.

Burton¹,

Cody²,

Herd³

et al. 1980

Proc. Natl. Acad. Sci. U.S.A.

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The angiotensin substrate analog Pro-HisPro-Phe-His-Phe-Phe-Val-Tyr-Lys has no significant effect on blood pressure in sodium-replete monkeys (Macaca fascicularis) but blocks the pressor response to infused human renin. Pressor responses to angiotensin I and angiotensin II are not attenuated. In five studies in sodium-depleted monkeys, an infusion of 2 mg of the peptide per kg of body weight resulted in a reduction of mean arterial pressure (MAP) from 105 i 4 to 79 + 3 mm Hg, which is not significantly different from the response to 1 mg of the angiotensin I-converting enzyme inhibitor teprotide per kg. In uninephrectomized monkeys, inflation of a suprarenal aortic cuff caused an increase in MAP from 107 + 3 to 131 + 3 mm Hg. Infusion of 0.6 mg of the renin-inhibitory peptide per kg was followed by a return of blood pressure to 107 + 4 mm Hg-a depressor response similar to that observed with teprotide. This specific in vivo inhibitor of renin can now be applied to a wide variety of physiologic studies.The renin-angiotensin system plays an important role in normal cardiovascular homeostasis and in some forms of hypertension. Clear definition of this role remains elusive, partly because of the inability to inhibit specifically the initial steps in this pathway by pharmacologic methods. Competitive inhibitors of angiotensin II binding have varying agonist/antagonist activity (1, 2), which undermines their effectiveness. Angiotensin I-converting enzyme inhibitors have been studied (3, 4), but their potential interaction with the kallikrein system (5, 6) and their inhibition of other enzymes unrelated to the renin-angiotensin system clouds interpretation of physiologic responses (7). Competitive inhibitors of renin, based on the sequence of the natural substrate (angiotensinogen), have been synthesized (8), but they have been of insufficient potency and solubility for in vivo studies (9). We have synthesized a decapeptide with a modification of'the amino acid sequence between positions 6 and 13 of equine natural substrate. This peptide, unlike previous analogs, is not only a potent competitive inhibitor but also exhibits adequate solubility and has a prolonged in vio halflife. Additionally, specific in vio blockade of the pressor response to exogenous renin but not to angiotensin I or II has been demonstrated.We report the administration of this renin inhibitory peptide to sodium-depleted normotensive and renin-dependent hypertensive monkeys. The results demonstrate the potential utility of this peptide for evaluating the role of renin in cardiovascular homeostasis and renin-dependent hypertension. METHODSSynthesis and Characterization of the Renin-Inhibitory Peptide. A soluble peptide with the sequence Pro-His-ProPhe-His-Phe-Phe-Val-Tyr-Lys was prepared as described (8). After synthesis and lyophilization under sterile conditions, the peptide was dissolved in physiologic saline (2 mg/ml) for animal studies. Plasma concentrations of infused 3H-labeled peptide were measured and the half-life was determined to...

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Inhibition of Angiotensin I-Initiated Hemodynamic Changes in Anesthetized Dogs by a Synthetic Nonapeptide

Cited by 29 publications

References 1 publication

Effects of SQ 20,881 on the intact kidney of dogs with two-kidney, one clip hypertension.

Effects of SQ 20,881 on the intact kidney of dogs with two-kidney, one clip hypertension.

Effect of Converting Enzyme Blockade on Isoprenaline‐ and Angiotensin I‐induced Drinking

Specific inhibition of renin by an angiotensinogen analog: studies in sodium depletion and renin-dependent hypertension.

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