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.

The rabbit mesenteric vein: a specific bioassay for substance P

1978 ◽  
Vol 56 (4) ◽  
pp. 603-609 ◽  
Author(s):  
A. Bérubé ◽  
F. Marceau ◽  
J. N. Drouin ◽  
F. Rioux ◽  
D. Regoli
Keyword(s):  
Substance P ◽  
De Novo ◽  
Smooth Muscles ◽  
High Sensitivity ◽  
Mass Action ◽  
Response Curves ◽  
Mesenteric Vein ◽  
Mass Action Law ◽  
New Type ◽  
Specific Receptors

The anterior mesenteric vein of the rabbit responds to substance P with dose-dependent contractions and is among the vascular smooth muscles most sensitive to this peptide. In spite of its high sensitivity to numerous other agents, including angiotensin and bradykinin, the rabbit mesenteric vein can be made selective for substance P by the use of specific inhibitors that will prevent the myotropic effects of acetylcholine, catecholamines, histamine, 5-hydroxytryptamine, and of the two above-mentioned peptides, without modifying the contractions elicited by substance P. It appears that this peptide acts directly on specific receptors and not through the release of neurotransmitters. Interference by intramural prostaglandins is excluded because substance P is equally active on tissues pretreated with indomethacin or untreated.Dose–response curves obtained with substance P are close to the theoretical curves predicted by the mass action law. The rabbit mesenteric vein contains a new type of receptor for bradykinin, recently identified (REGOLI, D., MARCEAU, F., and BARABÉ, J. 1978. De novo formation of vascular receptors for bradykinin. Can. J. Physiol. Pharmacol. 56, in press.). The action of bradykinin on this receptor can be prevented with the use of specific and competitive inhibitors and, therefore, the mesenteric vein will distinguish between peptides of the kinins or of the substance P types.

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.)

scholarly journals Distinctive effects of glucagon on gluconeogenesis and ketogenesis in hepatocytes isolated from normal and biotin-deficient rats

1978 ◽  
Vol 172 (3) ◽  
pp. 517-521 ◽  
Author(s):  
E A Siess ◽  
D G Brocks ◽  
O H Wieland
Keyword(s):  
Dose Response ◽  
Redox State ◽  
Fold Increase ◽  
Primary Site ◽  
Hormone Action ◽  
Response Curves ◽  
Mitochondrial Redox State ◽  
Dose Response Curves ◽  
20 Nm ◽  
Stimulation Of

In hepatocytes from 48 h-starved rats identical glucagon dose-response curves were obtained for the stimulation of gluconeogenesis from lactate, for ketogenesis and for the decreasing of the C5-dicarboxylate pool. Glucagon (20 nM) caused a 5-fold increase in 3-hydroxybutyrate formation, but decreased acetoacetate production 50% of that of the control. In hepatocytes from biotin-deficient rats glucagon no longer stimulated gluconeogenesis from lactate, but still produced its effects on the mitochondrial redox state and the C5-dicarboxylate pool. The results suggest that the primary site of the hormone action on gluconeogenesis is located within the mitochondria rather than in the cytosol.

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.

VIP stimulation of β-naphthylamidase activity in guinea-pig thyroid sections

1985 ◽  
Vol 109 (4) ◽  
pp. 505-510 ◽  
Author(s):  
P. A. Ealey ◽  
N.J. Marshall ◽  
R. P. Ekins
Keyword(s):  
Dose Response ◽  
Response Curve ◽  
Receptor Site ◽  
Dose Response Curve ◽  
Tsh Receptor ◽  
Maximal Response ◽  
Cytochemical Bioassay ◽  
Order Of Magnitude ◽  
Specific Receptors ◽  
Stimulation Of

Abstract. Subsequent to the discovery of vasoactive intestinal peptide (VIP) in the thyroid gland, VIP has been shown to stimulate various thyroid functions. The site of interaction of VIP with the thyroid follicular cell is at present not known, and this study has used the ultrasensitive cytochemical bioassay (CBA) for thyroid stimulators to investigate this further. Exposure of thyroid sections for 3 min to VIP resulted in increased naphthylamidase activity, with half-maximal response observed at 3 × 10−13 m VIP. This response to such low doses of VIP is consistent with the CBA being ultrasensitive to other thyroid stimulators e.g. TSH, thyroid stimulating antibodies and forskolin. The response to VIP was abolished by rabbit anti-VIP antiserum. The dose-response curve to VIP was bell-shaped (as with the other stimulators), maximal stimulation occurring at 10−12 m VIP. In contrast, however, to other thyroid stimulators, namely TSH, LATS-B and 3 monoclonal stimulating antibodies, whose ascending limbs of the doseresponse curves extended over 3-4 orders of magnitude, the VIP curve rose rapidly from basal to maximal tissue stimulation from 10−13 to 10−12m VIP, i.e. one order of magnitude. This unusual dose-response curve to VIP was parallel to that produced by forskolin. 11E8, a monoclonal 'blocking' antibody which is a potent inhibitor of TSH stimulation, did not 'block' forskolin stimulation, consistent with the belief that forskolin acts at a post-receptor site. However, unlike forskolin, VIP was inhibited by monoclonal 11E8, which may imply a hitherto unexpected involvement of the TSH receptor in VIP stimulation of the thyroid or, alternatively, steric inhibition by 11E8 when bound to the TSH receptor of VIP interaction with adjacent VIP-specific receptors.

scholarly journals Time-dependence of biological activity induced by covalent insulin-receptor complexes in rat adipocytes

1985 ◽  
Vol 232 (1) ◽  
pp. 49-53 ◽  
Author(s):  
A Schüttler ◽  
C Diaconescu ◽  
D J Saunders ◽  
D Brandenburg
Keyword(s):  
Insulin Receptor ◽  
Inhibitory Effect ◽  
Receptor Complex ◽  
Half Time ◽  
Simple Method ◽  
Receptor Complexes ◽  
Maximal Stimulation ◽  
Monocomponent Insulin ◽  
Specific Receptors ◽  
Stimulation Of

Lipogenesis in isolated adipocyte preparations is stimulated when photosensitive insulin derivatives are attached covalently to specific receptors. This response was compared quantitatively with that to reversibly associated insulin, and it was shown that both covalent and reversible insulin-receptor complexes behave very similarly. The extent of stimulation of lipogenesis was studied as a function of time. Cells were incubated in buffer for various times before addition to vials containing 0 (basal) or 10 ng of monocomponent insulin/ml (maximal) and [U-3H]glucose. After 60 min, the toluene-soluble [3H]lipids were measured. The maximal stimulation induced by reversibly bound insulin was virtually constant over a period of 4 h. In contrast, adipocytes to which N alpha B2-(2-nitro-4-azidophenylacetyl)-des-PheB1-insulin had been covalently attached at the start of the experiment showed a loss of stimulation with time when incubated at 37 degrees C. This loss was decreased in the presence of lysosomotropic agents such as chloroquine at concentrations (approx. 200 microM) that had very little or no effect on the basal and maximal lipogenesis rates. A simple method was used to transform the measured rate of loss of stimulation into a rate of loss of effective units. A half-time of 80 min was calculated for the effective covalent insulin-receptor units in adipocytes at 37 degrees C at pH 7.4. This is very close to values reported by others for the internalization of covalent complexes in these cells, suggesting that this may be the causative event for the deactivation of the insulin-receptor unit. The inhibitory effect of chloroquine on the deactivation may indicate that the insulin-receptor complex can function even after internalization.

Role of Endothelial K + Channels in NO-Dependent Vasorelaxant Responses to Acetylcholine in Rat Aorta.

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 698-698
Author(s):  
John Quilley ◽  
Yue Qiu
Keyword(s):  
Dose Response ◽  
Response Curve ◽  
Rat Aorta ◽  
Dose Response Curve ◽  
Response Curves ◽  
K Channels ◽  
Voltage Dependent ◽  
The Right ◽  
Stimulation Of

P30 Endothelium-dependent vasorelaxant responses to acetylcholine (Ach) in rat aorta are mediated solely by NO. Rings precontracted with U46619 were used to investigate the role of endothelial K + channels. Thus, any effect of K + channel inhibitors on Ach responses in the absence of an effect on those to nitroprusside (NP) can be attributed to interference with Ach-induced stimulation of NO. Vasorelaxant responses to Ach (log EC 50 -7.29M) were abolished by removal of the endothelium or inhibition of NO synthesis with nitroarginine (100μM) which potentiated responses to NP (log EC 50 -9.41M vs -8.47M for control). In the presence of TEA (10mM) to inhibit K + channels, the dose-response curve for Ach, but not NP, was shifted to the right (log EC 50 -6.06). Elevation of extracellular K + (25mM KCl)also shifted the dose-response curve for Ach to the right. Inhibitors of specific types of K + channels: BaCl 2 (30μM), apamin (100nM), glibenclamide (10μM), charybdotoxin (50nM) and iberiotoxin (100nM) were without effect on dose-response curves to either Ach or NP. However, the combination of apamin (100nM) and charybdotoxin (50nM) but not apamin plus iberiotoxin, reduced relaxant responses to Ach (log EC 50 -6.95M) without affecting those to NP.These results confirm that Ach-induced relaxation of rat aorta is mediated entirely by endothelium-derived NO, the release of which apparently involves hyperpolarization of the endothelium. This effect is dependent on activation of a K + channel that is blocked by a combination of apamin/charybdotoxin but neither agent alone, possibly indicating characteristics of both Ca 2+ - activated and voltage-dependent K + channels.

LIPOTROPIC DOSE–RESPONSE STUDIES IN RATS: COMPARISONS OF CHOLINE, BETAINE, AND METHIONINE

1956 ◽  
Vol 34 (1) ◽  
pp. 713-720 ◽  
Author(s):  
R. J. Young ◽  
C. C. Lucas ◽  
Jean M. Patterson ◽  
C. H. Best
Keyword(s):  
Dose Response ◽  
Liver Fat ◽  
Normal Range ◽  
Response Curves ◽  
Molar Basis ◽  
Weanling Rats ◽  
Dose Response Curves ◽  
Kidney Lesions ◽  
Stimulation Of

Dose–response curves have been obtained showing the effects, in weanling rats, of graded doses of choline, betaine, and methionine, respectively, when added to a hypolipotropic diet. A comparison of the lipotropic activity made on the steep portions of the dose–response curves showed that at all liver fat values from normal to 27%, the ratio of betaine to choline necessary to produce a given level of fat was 3: 1. Essentially similar ratios were observed in the prevention of hemorrhagic kidney lesions and in the stimulation of growth. Methionine, at the lower doses, was as effective as betaine, on a molar basis, in maintaining a given level of liver fat. However, the higher levels of methionine were not as efficient. Methionine at the highest dosage used did not bring the liver fat entirely within the normal range.

scholarly journals Comparison of the AT1-receptor blockers candesartan, irbesartan and losartan for inhibiting renal microvascular constriction

2001 ◽  
Vol 2 (1_suppl) ◽  
pp. S204-S210 ◽  
Author(s):  
William F van Rodijnen ◽  
Ton A van Lambalgen ◽  
Marco E van Teijlingen ◽  
Geert-Jan Tangelder ◽  
Piet M ter Wee
Keyword(s):  
Dose Response ◽  
Inhibitory Effect ◽  
At1 Receptor ◽  
Ang Ii ◽  
Response Curves ◽  
Receptor Blockers ◽  
Dose Response Curves ◽  
The Right ◽  
At1 Receptor Blockers ◽  
Slow Dissociation

Angiotensin II (Ang II) type 1 (AT1) receptor blockers differ in their affinity for the AT1-receptor, suggesting a dissimilar potency for inhibiting Ang II-induced vascular constriction. In the present study, we compared the effects of candesartan, irbesartan and losartan on the renal microvascular constriction to locally-formed Ang II, using isolated, perfused hydronephrotic rat kidneys. Addition of 1 nmol/L angiotensin I (Ang I, the precursor of Ang II) significantly reduced the diameters of interlobular arteries (ILAs; -47.6±2.6%), afferent arterioles (AAs; -43.6±2.3%) and efferent arterioles (EAs; -31.6±2.4%). Candesartan and irbesartan were more potent in antagonising the constriction to Ang I than losartan. By contrast, candesartan and irbesartan differed only slightly in potency. After a washing period of 60 minutes with drug-free medium, a second application of Ang I failed to induce vasoconstriction only in candesartan-treated kidneys. Pretreatment of hydronephrotic kidneys with candesartan, to further explore its antagonistic properties, shifted the dose-response curves of Ang II approximately 2 log units to the right without reducing the maximal Ang II-induced constriction of ILAs, AAs or EAs. Additionally, dose-response curves of Ang II were similar after short (10 minutes) and prolonged (60 minutes) preincubation with candesartan. Our findings indicate that candesartan and irbesartan are more potent inhibitors of renal microvascular constriction to locally-formed Ang II than losartan. The inhibitory effect of candesartan is more prolonged, suggesting a slow dissociation from the AT1-receptor. Additionally, candesartan was found to block the Ang II-induced constriction of renal microvessels in a surmountable manner.

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.

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