Myotropic affinities of angiotensin II and des-Asp1-angiotensin II in rabbit aorta and femoral artery by microassay

1979 ◽  
Vol 57 (11) ◽  
pp. 1256-1266 ◽  
Author(s):  
William H. Waugh ◽  
Theodore E. Bales
Keyword(s):  
Angiotensin Ii ◽  
Femoral Artery ◽  
Rabbit Aorta ◽  
Mass Action ◽  
Intrinsic Activity ◽  
Angiotensin Receptors ◽  
Response Curves ◽  
Contractile Responses ◽  
Increased Sensitivity ◽  
Dose Dependent

Dose-dependent isometric contractions to [Asp1,Ile5]-angiotensin II (AII) and des-Asp1-[Ile5]-angiotensin II (AIII) were obtained with 3-mm-wide rings of rabbit thoracic aorta and femoral artery in microbaths. A period of 2.5–3 h was required to obtain reproducible contractile responses of increased sensitivity. Contractions developed faster and they were much more forceful but less sustained in femoral arterial rings than in aortic rings. Noncumulative dose–response curves with AII and AIII were parallel and reached the same maximum. Peak contractile responses were linearly proportional to the receptor stimulation predicted from the mass action equation and the concept of intrinsic activity relating bath dosage of agonist to the number of myotropic receptors occupied by AII and by AIII. These findings validated measurement of the myotropic affinities of both tissues for AII and AIII by the obtained ED50 values. In 0.6-mL baths, developed with the use of a meshed screen for reoxygenation, the apparent affinities of aortic muscle for AII and AIII averaged 0.149 and 0.0030 nM, respectively. The mean affinities were much greater at 0.594 and 0.236 nM, respectively, in femoral arterial muscle. The myotropic affinity for AIII relative to that for AII averaged 2.26% in the aorta but 40.8% in the femoral artery. The apparent affinities were reduced and contractions less forceful in 0.24-mL baths without regassing. The results suggest that AII and AIII may stimulate the same angiotensin receptors in aorta and femoral artery and that the receptors may be different in structure or immediate environment in these two vascular tissues.

Application of Drug–Receptor Theories to Angiotensin

1973 ◽  
Vol 51 (9) ◽  
pp. 665-672 ◽  
Author(s):  
F. Rioux ◽  
W. K. Park ◽  
D. Regoli
Keyword(s):  
New York ◽  
Smooth Muscle ◽  
Rabbit Aorta ◽  
Biologically Active ◽  
Mass Action ◽  
Intrinsic Activity ◽  
Rat Stomach ◽  
Response Curves ◽  
Threshold Phenomenon ◽  
Specific Receptors

The myotropic action of angiotensin II has been studied on two smooth muscle preparations: the strip of rat stomach and of rabbit thoracic aorta. Contractions evoked by angiotensin are not modified by atropine, methysergide, and diphenhydramine on the rat stomach or by phentolamine, methysergide, and diphenhydramine on the rabbit aorta. It appears that angiotensin acts directly on specific receptors and not through release of acetylcholine on the stomach or of noradrenaline on the aorta. Interference by intramural prostaglandins is excluded because angiotensin is equally active on tissues pretreated or not with indomethacin.Dose–response curves obtained with angiotensin on the two tissues are close to the theoretical curves predicted by the mass–action law. The relations stimulus effect is linear, indicating that the extent of the contraction is proportional to the number of receptors occupied by the agonist. No threshold phenomenon or spare receptor capacity could be demonstrated in either tissue. It is therefore concluded that the interaction of angiotensin with its specific receptors in the two smooth muscle preparations can be analyzed quantitatively with the occupation theory by applying the concepts of affinity and intrinsic activity as defined by Ariens in 1964. (Molecular pharmacology. Vol. 1. The mode of action of biologically active compounds. Academic Press, New York.)

The Pressor and Myotropic Effects and the Antagonistic Properties of Several Analogues of Angiotensin II

1972 ◽  
Vol 50 (2) ◽  
pp. 99-112 ◽  
Author(s):  
D. Regoli ◽  
W. K. Park
Keyword(s):  
Angiotensin Ii ◽  
Chemical Structure ◽  
Biological Activities ◽  
Unnatural Amino Acid ◽  
Intrinsic Activity ◽  
Rat Stomach ◽  
Response Curves ◽  
Isolated Organs ◽  
The Right ◽  
The Relationship

The substitution of an unnatural amino acid, 1-aminocyclopentanecarboxylic acid (Acpc), for each of the eight amino acids of angiotensin (AT) has been used to study the relationship between chemical structure and biological activities of angiotensin. The pressor and the myotropic activities of the various ATII derivatives have been tested on the rat blood pressure and on three isolated organs: rat isolated colon, rat stomach strip, and rabbit isolated kidney.The results indicate that 6-His and 8-Phe are essential for the activities of angiotensin II. Moreover, (8-Acpc)-ATII, but not (6-Acpc)-ATII, antagonizes the pressor and myotropic effects of ATII and ATI. αE and pD2 of all analogues have been estimated on the isolated rat stomach strip to evaluate intrinsic activity and affinity for the receptors. (1-, (2-, (3-, (4-, and (5-Acpc)-ATII have the same intrinsic activities as ATII, while those of (6-, (7-, and (8-Acpc)-ATII are much lower.Analogues of ATII substituted in position 8 antagonize specifically the myotropic and pressor effects of ATII and ATI. On the contrary, the effects of other smooth muscle stimulating agents (acetylcholine, 5-hydroxytryptamine, bradykinin, and vasopressin) are not modified.Log dose response curves of ATII and ATI are shifted to the right in the presence of antagonists, but remain parallel. The antagonism is rapidly reversible and may be competitive.

Differential effect of vasopressin on angiotensin and norepinephrine pressor action in rats

1984 ◽  
Vol 247 (6) ◽  
pp. H973-H977 ◽  
Author(s):  
F. Elijovich ◽  
C. R. Barry ◽  
L. R. Krakoff ◽  
M. Kirchberger
Keyword(s):  
Heart Rate ◽  
Angiotensin Ii ◽  
Dependent Manner ◽  
Response Curves ◽  
Rightward Shift ◽  
Vasopressin Infusion ◽  
Dose Responses ◽  
Vascular Receptor ◽  
Dose Dependent ◽  
Mediated Reduction

The effect of vasopressin infusion on the pressor dose responses to angiotensin II and norepinephrine was studied in pentobarbital-anesthetized and unanesthetized nephrectomized rats. Pressor vasopressin (2–15 ng X kg-1 X min-1) given to anesthetized rats decreased sensitivity to angiotensin II in a dose-dependent manner (r = 0.88), an effect completely reversible by dPMeTyrAVP, a vasopressin vascular antagonist. Subpressor vasopressin (0.5-1 ng X kg-1 X min-1) given to unanesthetized rats diminished sensitivity to angiotensin II in the presence or absence of pentolinium (10 mg/kg). Shifts in dose-response curves to angiotensin II were always parallel. In contrast, dose responses to norepinephrine were not modified by vasopressin in pentolinium-treated rats and showed a small nonparallel rightward shift in animals without pentolinium. In animals without pentolinium, the baroreflex-mediated reduction in heart rate elicited by angiotensin II was not altered by vasopressin infusion. Our data suggest that vasopressin reduces angiotensin II pressor action by diminishing pressor sensitivity to the peptide. They indicate that the effect may be specific, mediated through the vascular receptor for vasopressin and independent of actions of this hormone on the autonomic nervous system.

Metabolism of angiotensin II and some analogs in intact strips and in muscle preparations of rabbit aortae

1978 ◽  
Vol 56 (1) ◽  
pp. 39-47 ◽  
Author(s):  
J. Magnan ◽  
D. Regoli
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Smooth Muscle Cells ◽  
Rabbit Aorta ◽  
Muscle Preparation ◽  
Response Curves ◽  
Aortic Strip ◽  
Complete Relaxation ◽  
Maximal Tension ◽  
Apparent Diffusion

The purpose of this work was twofold: (a) to develop a muscle preparation of the rabbit aorta free of adventitia and endothelium, and (b) to measure the metabolism of angiotensin II (ATII) in this preparation. The muscle was prepared by 'shucking-off' the adventitia layer and by eliminating the endothelium. Concentration–response curves to ATII and noradrenaline (NA) measured in the muscle preparation provided pD2 values for ATII and NA not significantly different from those observed in the intact aortic strip. However, the maximal tension developed by the two agonists averaged 20–30% of the maximal tension of the intact strips. Apparent diffusion of ATII, in and out of the tissue, was faster in the muscle while NA diffusion was not significantly different. Metabolism of ATII was measured at the plateau of contraction and after complete relaxation in both the muscle and the intact strip. Ten percent of ATII was metabolized at the plateau of the contraction and 50% after complete relaxation. Heptapeptide 1–7 was the metabolite found in both preparations. 1-β-Asp ATII was also broken down to heptapeptide 1–7 while 1-β-Asp,8-Phe-OMe-ATII resisted the degradation and was found unchanged even after 90 min of incubation. It is suggested that the enzyme which inactivates ATII is located in the smooth muscle cells and that it is a carboxypeptidase.

Endothelium-dependent desensitization to angiotensin II in rabbit aorta: the mechanisms involved

2001 ◽  
Vol 79 (6) ◽  
pp. 481-489 ◽  
Author(s):  
S Jerez ◽  
M Peral de Bruno ◽  
A Coviello
Keyword(s):  
Angiotensin Ii ◽  
Methyl Ester ◽  
Dose Response ◽  
Rabbit Aorta ◽  
Mechanisms Of Action ◽  
Maximal Response ◽  
Aortic Tissue ◽  
Ang Ii ◽  
Response Curves

The aim of this study was to characterize the role of the endothelium in angiotensin II-desensitization and its mechanisms of action. Rabbit aortic rings were exposed to increasing doses of angiotensin II (Ang II, 10–9 to 2.5 × 10–6) to generate two cumulative dose-response curves (CDRC I and II). A 50-min interval separated CDRC I and II. Desensitization was observed at all doses in unrubbed aortic tissue and at lower doses in rubbed aortic tissue. Tachyphylaxis was greater in arteries with endothelium. Treatment of intact rings with L-NG-nitroarginine methyl ester (L-NAME, 10–4 M) did not prevent this phenomenon. However, indomethacin (10–5 M) and miconazol (10–6 M) attenuated Ang II-desensitization. Treatment of unrubbed rings with nifedipine (10–6 M) and cromakalim (10–6 M) inhibited the effect of indomethacin. To confirm the involvement of K+ channels, unrubbed and rubbed aortic rings were treated with the KCa2+ blockers apamin (10–7 M), tetraethylammonium (TEA, 10–3 M), and iberiotoxin (10–8 M), and the KATP blocker glibenclamide (10–5 M). In both arteries apamin, TEA, and glibenclamide abolished the tachyphylaxis without changes in the maximal response. Iberiotoxin diminished Ang II-desensitization in rubbed but not unrubbed arteries. Results from this study suggest that Ang II-desensitization involves endothelium-dependent and -independent mechanisms. Endothelium-dependent desensitization could be mediated by a cyclooxygenase-cytochrome P450 product, which could act by increasing KCa2+ channel activity.Key words: angiotensin II, rabbit aorta, desensitization, endothelium, cyclooxygenase products.

Characteristics Of The Contractions Induced By Prostaglandin E2-Like Activity In The Rat Stomach Strip And By Thromboxane A2-Like Activity In The Rabbit Aorta And Mesenteric Artery

1981 ◽  
Author(s):  
F J Zijlstra ◽  
J E Vincent
Keyword(s):  
Angiotensin Ii ◽  
Mesenteric Artery ◽  
Thromboxane A2 ◽  
Rabbit Aorta ◽  
Prostaglandin E ◽  
Rat Stomach ◽  
Cascade System ◽  
Response Curves ◽  
Rabbit Mesenteric Artery

The dose-response curves obtained in the measurement of the prostaglandin E (PGE) and thromboxane-A2 (TxA2)-like activity using a cascade system cons isting of a rat stomach strip , a rabbit aorta strip and a mesenteric artery were determined. The following linear relat ionships were observed:log dose-activity for PGE2 and the stomach strip , do se-activity for angiotensin II (All) and the rabbit aorta, log dose-log activity for angiotensin II and the rabbit mesenteric artery.The do se-activity curves for All and TxA2 are different when the rabbit aorta is used whereas the log dose-log activity curves are much more similar for the rabbit mesenteric artery. Therefore, AI I can only be used as a reference substance in the last case. A comparison was made of the TxA2 like activity measured by bioassay and the TxB2 determined by a radioimmunoassay in platelets after aggregation. The curves were parallel when the TxA2 like activity was measured with the mesenteric artery.The different contractile characteristics of these organs should be taken into account in the determination of the PGE2 like and TxA2 like activity with these tests.

Characterization of angiotensin receptors in rabbit isolated atria

1976 ◽  
Vol 54 (3) ◽  
pp. 229-237 ◽  
Author(s):  
F. Rioux ◽  
W. K. Park ◽  
D. Regoli
Keyword(s):  
Smooth Muscles ◽  
Rabbit Aorta ◽  
Angiotensin Receptors ◽  
Response Curves ◽  
Renin Substrate ◽  
Inotropic Effects ◽  
Isolated Atria ◽  
High Doses ◽  
The Right ◽  
Stimulation Of

Rabbit isolated left atria have been used to study the inotropic action of angiotensin II (ATII). The peptide is active at doses ranging from 1.0 × 10−9 to 2.8 × 10−6 M and its inotropic effect is not modified by sotalol, phentolamine, burimamide, and indomethacin. We therefore propose that this effect results from the stimulation of receptors specific for ATIIDose–response curves of ATII obtained in presence of increasing concentrations of 8-Gly-ATII are gradually displaced to the right, but high doses of the antagonist depressed the maximum contractions caused by ATII.pA2 value for 8-Gly-ATII in this preparation is similar to those observed in vascular and intestinal smooth muscles. Order of potency of analogues of ATII (2-, 3- and 5-Ala-ATII), acting as full agonists, but with reduced affinity, is similar to that found in rabbit aorta strips. It is therefore proposed that receptors for ATII in rabbit isolated left atria are pharmacologically similar to those present in vascular smooth muscles.Positive inotropic effects of angiotensin I, undecapeptide (1-11), dodecapeptide (1-12) and tetradecapeptide (1-14) renin substrate are antagonized by 8-Gly-ATII in a similar way as the effect of ATIIThis suggests that the action of these peptides is mainly due to stimulation of receptors for ATII. The contribution of myocardial converting enzyme to the action of these peptides is discussed.

Receptors for bradykinin in rabbit aortae

1977 ◽  
Vol 55 (4) ◽  
pp. 855-867 ◽  
Author(s):  
D. Regoli ◽  
J. Barabé ◽  
W. K. Park
Keyword(s):  
Dose Response ◽  
Rabbit Aorta ◽  
Inhibitory Effect ◽  
Mass Action ◽  
Response Curves ◽  
Terminal Fragment ◽  
Mass Action Law ◽  
New Type ◽  
Specific Receptors ◽  
Stimulation Of

Rabbit aorta strips respond to bradykinin (BK) and to the C-terminal fragment of BK, the octapeptide 1-8 BK (Octa) with sustained contractions which are presumably due to the stimulation of specific receptors, because they remain unchanged in presence of phentolamine, methysergide, mepyramine, 8-Leu-ATII, and indomethacin. Experimental dose–response curves of BK and Octa are very similar to the theoretical curves predicted by the mass-action law and show the classical hyperbolic shape; ratios of doses producing 16% and 84% of maximum effects are 1:20 for Octa and 1:19 for BK. The relations of stimulus and effect are linear, suggesting that the extents of the contractions are proportional to the number of receptors occupied by the agonists.Structure–activity studies performed with fragments and analogues of BK and with analogues of Octa have shown that 8-Phe is essential for activation of the aortic receptor, and plays an important role for the affinity. The octapeptide 1-8 sequence is more favorable than the nonapeptide, because BK (pD2 = 6.40) is less potent than Octa (pD2 = 7.19) and 9-Ala BK is a partial agonist.Antagonists for both Octa and BK have been found by replacing 8-Phe with aliphatic residues (Ala, Nle, Leu, Leu-OMe) in the octapeptide. Affinities of 8-Leu-Octa (pA2 = 6.75) and 8-Leu-OMe-Octa (pA2 = 6.66) for the aortic receptors are fairly high and the antagonism appears to be of the competitive type because pA2 – pA10 is close to 0.95 for both compounds.The inhibitory effect of these two compounds are specific for Octa and BK. It is concluded that rabbit aortae contain a new type of receptor for BK, different from those found in the intestine and the uterus of several species.

In vitro and in vivo biological approach to validate folkloric claims of Trianthema triquetra Rottler & Willd

2021 ◽  
Vol 50 (1) ◽  
pp. 21-28
Author(s):  
Fatima Saqib ◽  
Mehwish Shaukat ◽  
Sana Javad ◽  
Muhammad Riaz ◽  
Zahid Khan ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Analgesic Activity ◽  
Rabbit Aorta ◽  
Lipoxygenase Activity ◽  
Traditional Practices ◽  
Response Curves ◽  
In Vivo Testing ◽  
Dose Dependent

Trianthema triquetra Rottler & Willd (Tt.Cr) is used in traditional practices as a remedy for various ailments. Hence current research was commenced to authenticate the folkloric uses. To discover spasmolytic potential, Tt.Cr was applied to isolate jejunum, while isolated tracheal and aorta tissues were used to determine the tissue relaxing properties of the extract. Anti-lipoxygenase activity was determined in vitro using Baicalein as standard. In vivo testing was carried to examine the potentiality of the herb to treat pyrexia and pain. Tt.Cr showed dose-dependent (0.01 - 3.0 mg/ml) spasmolytic effects in jejunum tissues and relaxed K+ (80 mM)-induced spasm and triggered rightwards shift of Ca+2 concentration-response curves. Carbachol (1μM)- together with K+ (80 mM) - induced tracheal spasm was also relaxed by Tt.Cr (0.01 to 1.0 mg/ml). Additionally, Tt.Cr (0.01 - 1.0 mg/ml) relaxed phenylephrine (1 μM) and K+ (80 mM) - treated constricted rabbit aorta. Tt.Cr (0.5 mM) inhibited lipoxygenase enzyme. Tt.Cr (80 mg/kg) settled pyrexia in rabbits comparable to aspirin and prolonged tail deflection time in mice (100 mg/kg) hence proving analgesic activity. The Tt.Cr demonstrated antispasmodic, bronchodilation and vasodilation properties probably by blocking calcium channels. These outcomes generate logic behind ancient application of herb for numerous ailments such as asthma, cough, heart problems and spasm.

scholarly journals Pharmacological basis for the folkloric uses of Buxus wallichiana in gastrointestinal, respiratory and vascular disorders

2015 ◽  
Vol 10 (2) ◽  
pp. 260 ◽  
Author(s):  
Musaddique Hussain ◽  
Shahid Masood Raza ◽  
Khalid Hussain Janbaz
Keyword(s):  
Crude Extract ◽  
Rabbit Aorta ◽  
Channel Blockade ◽  
Response Curves ◽  
Vascular Disorders ◽  
The Right ◽  
Dose Dependent ◽  
Higher Doses ◽  
Pharmacological Basis

<p><em>In vitro</em> study was carried out to explore the pharmacological basis of crude extract of <em>Buxus wallichiana </em>for its folkloric uses in gastrointestinal, respiratory and vascular disorders. In jejunum preparations, crude extract (0.03 ± 1.0 mg/mL) caused a transient spasmogenic effect followed by the spasmolytic effect at higher doses (3.0–10 mg/mL). In atropinized jejunum preparation, crude extract inhibited the spontaneous and K<sup>+ </sup>(80 mM)-induced contraction, suggesting that spasmolytic effect is mediated through the Ca<sup>+2</sup>-channel blockade. The Ca<sup>+2</sup>-channel blockade effect was confirmed when pretreatment of tissue with extract produced a dose-dependent shift in Ca<sup>+2 </sup>concentration-response curves to the right, similarly as verapamil. Furthermore, crude extract exhibited non-specific relaxant effect on carbachol- (1 µM) and K<sup>+ </sup>(80 mM)-induced tracheal contractions, suggesting the coexistence of anticholi-nergic and Ca<sup>+2</sup>-antagonistic properties. Moreover, it relaxed the K<sup>+ </sup>(80 mM)- and phenylephrine (1 µM)-induced contraction in rabbit aorta, suggesting the Ca<sup>+2</sup>-channel blockade. These findings may validate the folkloric uses of <em>B. wallichiana</em> in constipation, bronchitis, asthma and hypertension.</p>

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