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Biomedical subjects

D Regoli

Publications and source records attributed to D Regoli.

At least 325 records · Page 18Linked to original sources
PubMed1981

Inactivation of substance P and its C-terminal fragments in rat plasma and its inhibition by Captopril.

The metabolic degradation of substance P(SP), some of its C-terminal fragments, and some analogues by rat plasma has been evaluated from the disappearance of the biological activities of these peptides on the guinea pig isolated ileum. The experiments were performed by dissolving each peptide in saline and by adding 20% (v/v) of rat plasma for incubation at 37 degrees C for various periods of time. It was found that SP and octapeptide 4-11 are inactivated quite rapidly and at approximately the same rate whereas SP-free acid, heptapeptide 5-11, hexapeptide 6-11, and [D-Trp8]-SP are inactivated more slowly. The replacement of Phe7 by D-Trp does not protect the undecapeptide SP from inactivation. The degradation of SP and of all the C-terminal fragments was completely blocked by Captopril at a concentration of 10 micrograms/mL of plasma. Under these conditions, Captopril also slightly reduced the rate of inactivation of bradykinin and of SP-free acid. These results were interpreted as indicative of the presence in rat plasma of an endopeptidase that hydrolyses a peptide bond in the C-terminal pentapeptide sequence of SP. This endopeptidase is completely inactivated by Captopril, which thus appears to be not as specific for the angiotensin-converting enzyme as it was thought to be.

Animals↗
PubMed1980

Pharmacological studies of neurotensin, several fragments and analogous in the isolated perfused rat heart.

Neurotensin (NT) induced a dose-dependent increase of the coronary perfusion pressure (CPP) in the isolated perfused rat heart. This effect was not modified by pretreating the organ with methysergide (8.5 x 10(-6) M), atropine (3.4 x 10(-6) M), a mixture of phentolamine (3.1 x 10(-6) M) and practolol (1.5 x 10(-5) M), 8-leucine-angiomine (2.9 x 10(-5) M) thus suggesting the existence of specific NT receptors in the coronary vessels of rat. The structure-activity studies performed using several NT fragments and analogues in the isolated perfused rat heart led us to the following conclusions: (1) the minimum structure required for the full expression of the biological activity of NT is H-Arg9-Pro10-Tyr11-Ile12-Leu13-OH; (2) the amino acid Tyr in position 11 appears to play a key role in the process of NT receptor activation. The replacement of Tyr11 with Tyr(Me) gave a compound which inhibits selectively the increase in coronary perfusion pressure induced by NT, but still exhibits some NT-like activity, specially when used in concentrations higher than 10(-6) M. [Tyr(Me)11]NT did not antagonize the stimulant effects of NT in rat stomach strips and guinea pig atria, thus suggesting that the receptors mediating the constrictor effect of NT in coronary vessels of the rat are pharmacologically different from those subserving the stimulant effect of NT in rat stomach strip and guinea pig atria.

Animals↗
PubMed1980

Pharmacological properties of two analogues of angiotensin II containing carboranylalanine (Car).

The pharmacological properties of two angiotensin II analogues containing carboranylalanine (Car) are reported. Sar-Arg-Val-Tyr-Val-His-Pro-Car is a weak partial agonist showing 15% intrinsic activity and a very long lasting action, specific for the angiotensin II receptor of the rabbit aorta. Sar-Arg-Val-Car-Val-His-Pro-Phe is inactive on the angiotensin II receptor. These properties are discussed in view of recent findings on the action of angiotensin II on its smooth muscle receptor.

Angiotensin II↗
PubMed1980

Pharmacological characterization of neurotensin receptors in the rat isolated portal vein using analogues and fragments of neurotensin.

The contractile effects of the tridecapeptide neurotensin (NT) and several NT fragments and analogues were evaluated and compared in the rat isolated portal vein. The removal of the sequence pGlu1-Leu2-Tyr3-Glu4-Asn5-Lys6-Pro7 produced practically no change in the myotropic activity of NT while the deletion of Leu13 or the last 3 C-terminal amino acids (e.g. Tyr11, Ile12 and Leu13) gave compounds with very low agonist activity (NT(1-12)) or devoid completely of affinity and intrinsic activity (NT(1-10)). Replacing Tyr11 with Ala, Leu, D-Tyr or D-Phe markedly decreased the stimulant effect of NT but did not confer to the molecule antagonistic properties. On the other hand, the substitution of Try11 with D-Trp or Tyr(Me) gave NT analogues which behave as specific and competitive antagonist of the contractile effect of NT in the portal vein. pA2 values of [D-Trp11]-NT and [Tyr(Me)11]-NT measured in the venous preparation were similar to those found in the coronary vasculature of the rat. Taken all together, these results suggest that: (1) the minimum structure required for the full expression of the myotropic activity of NT in the rat portal vein is -Arg9-Pro10-Tyr11-Ile12-Leu13-OH; (2) Tyr11 appears to be closely involved in the process of NT receptor activation since its replacement with D-Trp or Tyr(Me) produced specific and competitive antagonist of NT; (3) the receptors mediating the contractile effect of NT in the rat portal vein appear to be pharmacologically similar to those found in the coronary vessels of the rat. The possibility for the existence of different types of NT receptor in other tissues is discussed.

Animals↗
PubMed1980

Selective blockade of neurotensin-induced coronary vessel constriction in perfused rat hearts by a neurotensin analogue.

[D-Trp11]-NT, an analogue of neurotensin (NT) in which Tyr11 was replaced with D-Trp, was found to antagonize selectively NT-induced coronary vessel constriction in perfused rat hearts, in concentrations varying between 1.3 x 10(-7) and 1.1 x 10(-6) M. Higher concentrations of [D-Trp11]-NT displayed NT-like activity. In rat stomach strips and guinea pig atria, [D-Trp11]-NT exhibits full intrinsic activity, markedly reduced affinity for NT receptors, but no inhibitory effect against NT. These results suggest that the receptors mediating the constrictor action of NT in the coronary vessels of rat hearts are pharmacologically distinct from those subserving the stimulant effects of NT in rat stomach strips and guinea pig atria.

Animals↗
PubMed1980

Studies on the mechanism of action of glucagon in strips of rabbit renal artery.

1 The vasodilator effects of glucagon and adenosine cyclic 3',5'-monophosphate (cyclic AMP) were evaluated in strips of rabbit renal artery contracted with noradrenaline (NA) in the absence and presence of phosphodiesterase inhibitors or calcium (Ca(2+)) antagonists.2 The vascular relaxant effect of glucagon was markedly potentiated by various concentrations of four different phosphodiesterase inhibitors (papaverine, theophylline, 3-isobutyl-l-methylxanthine (IBMX) and indomethacin), while that of cyclic AMP was potentiated by only two of them (papaverine and indomethacin) and inhibited by the others (theophylline and IBMX).3 Amongst the four phosphodiesterase inhibitors, IBMX (10 mug/ml) was found to produce the largest potentiation (e.g. the sensitivity increased by a factor of 10) of glucagon-induced vascular relaxations (ED(50) of glucagon in the presence of IBMX = 9.2 +/- 1.0 ng/ml).4 Ca(2+) antagonists such as verapamil and SKF 525A produced a dose-dependent inhibition of the vasodilator action of glucagon. Verapamil (2.5 mug/ml) also antagonized cyclic AMP-induced vascular relaxations.5 The vasodilator effect of verapamil was inhibited dose-dependently by raising the concentration of extracellular Ca(2+) from 0.05 to 0.2 g/l (or 1.25 to 5.0 mM) while those elicited by glucagon or cyclic AMP were not influenced, thus suggesting that the latter two drugs do not interfere with Ca(2+) influx.6 Disodium edetate (Na(2)EDTA, 210 to 840 mug/l) produced a dose-dependent vasodilator effect which was attributed to the facilitation of Ca(2+) extrusion from the smooth muscle cells and/or Ca(2+) binding to the cell membrane. The relaxation produced by Na(2)EDTA was significantly blocked by verapamil (10 mug/ml) or SKF 525A (10 mug/ml).7 The results were taken as an indication that glucagon produces at least a fraction of its vasodilator effect by promoting Ca(2+) extrusion from the vascular smooth muscle cells and/or Ca(2+) binding to or sequestration into intracellular sites, presumably via a cyclic AMP-dependent mechanism.

1-Methyl-3-isobutylxanthine↗
PubMed1980

Structure-activity studies with neurotensin: analysis of positions 9, 10 and 11.

1 The stimulant effects of neurotensin (NT) and NT analogues modified in positions 9, 10 or 11 were evaluated and compared in two pharmacological preparations: the rat stomach strip and the isolated spontaneously beating atria of guinea-pig. 2 The data derived from our structure-activity study suggest that Arg9 and Pro10 mainly contribute to the affinity of neurotensin for its cardiac and smooth muscle receptors. Tyr11 seems to be more closely involved in the process of receptor activation by NT. 3 The order of potency of some NT analogues modified in position 11 (e.g. [D-Phe11]-NT, [D-Tyr11]-NT) was strikingly different from that described in other systems (e.g. hypothermia test and specific mast cell binding). The importance of this observation is discussed.

Animals↗
PubMed1980

Studies on the mechanism of action of various vasodilators.

1 The vascular relaxant effects of histamine, adenosine, isoprenaline nitroglycerine, papaverine and 3-isobutyl-l-methylxanthine (IBMX) were assessed individually, in strips of rabbit renal artery moderately contracted with noradrenaline (NA) in the absence or presence of phosphodiesterase inhibitors (papaverine and IBMX) or verapamil, a Ca(2+) antagonist.2 The vasodilator effect of histamine was potentiated by papaverine (6.1 x 10(-7) M) and IBMX (4.4 x 10(-5) M) but inhibited dose-dependently by verapamil (5.1 and 51.0 x 10(-7) M).3 Adenosine-induced vascular relaxations were greatly increased in the presence of papaverine (6.1 x 10(-7) M) but significantly reduced in the presence of IBMX (4.4 x 10(-5) M) or verapamil (5.1 and 51.0 x 10(-7) M).4 The vasodilatation produced by isoprenaline was increased in the presence of IBMX (4.4 x 10(-5) M) or papaverine (6.1 x 10(-7) M), but inhibited by verapamil (5.1 and 51.0 x 10(-7) M).5 The vascular relaxant effects of nitroglycerine and papaverine were inhibited in the presence of IBMX (4.4 x 10(-5) M) or verapamil (5.1 and 51.0 x 10(-7) M). Papaverine (6.1 x 10(-7) M) also antagonized nitroglycerine-induced vascular relaxation.6 The vasodilator effect of IBMX was greatly reduced in the presence of papaverine (6.1 x 10(-7) M) or verapamil (5.1 and 51.0 x 10(-7) M).7 The vascular relaxant effect of verapamil was reduced proportionally by raising the extracellular Ca(2+) concentration from 1.25 to 5.0 mM while those elicited by histamine, adenosine, isoprenaline, nitroglycerine, papaverine and IBMX were not modified by this procedure.8 These results were taken as an indication that several vasodilators (e.g. histamine, adenosine, isoprenaline, nitroglycerine, papaverine and IBMX), but not a Ca(2+) antagonist such as verapamil, produce a fraction of their vasodilator effects by promoting Ca(2+) extrusion from and/or Ca(2+) sequestration into the vascular smooth muscle cells, via a cyclic adenosine 3',5'-monophosphate-dependent mechanism.

1-Methyl-3-isobutylxanthine↗
PubMed1980

The stimulatory effects of neurotensin and related peptides in rat stomach strips and guinea-pig atria.

1 The stimulatory effects of neurotensin (NT) and several NT fragments were evaluated in two pharmacological preparations: rat stomach strips and isolated spontaneously beating atria of guinea-pigs.2 In rat stomach strips, NT elicited a dose-dependent contractile effect in concentrations varying between 1.3 x 10(-9) and 5.4 x 10(-7) M.3 The contractile effect of NT (1.3 and 5.4 x 10(-8) M) in this tissue was not modified by atropine (3.4 x 10(-7) M), methysergide (2.0 x 10(-6) M), a mixture of cimetidine (8.0 x 10(-6) M) and diphenhydramine (7.8 x 10(-6) M), indomethacin (1.4 x 10(-5) M), 8-Leu-angiotensin II (1.0 x 10(-6) M), glucagon (2.0 x 10(-6) M) or somatostatin (3.0 x 10(-7) M).4 Rat stomach strips desensitized by bradykinin (6.1 x 10(-6) M) or substance P (7.4 x 10(-6) M) maintained their sensitivities to NT (1.3 and 5.4 x 10(-8) M).5 In guinea-pig atria, NT produced a dose-dependent positive inotropic action in concentrations varying between 5.4 x 10(-10) and 2.7 x 10(-7) M.6 The inotropic effect of NT (2.7 x 10(-9) M) was not influenced by methysergide (2.8 x 10(-6) M), atropine (3.4 x 10(-7) M), practolol (1.5 x 10(-5) M), 8-Leu-angiotensin II (1.0 x 10(-6) M), or indomethacin (1.4 x 10(-5) M), but it was reduced by 37% by cimetidine (4.0 x 10(-5) and 2.0 x 10(-4) M). A combination of cimetidine (4.0 x 10(-5) M) and diphenhydramine (3.9 x 10(-6) M) did not produce a greater inhibition of NT than cimetidine alone.7 Atria desensitized by bradykinin (6.1 x 10(-6) M) or glucagon (2.0 x 10(-6) M) maintained their sensitivities to NT (2.7 x 10(-9) M). Substance P was inactive both as an agonist or antagonist of NT.8 These results suggest the existence of specific NT receptors in rat stomach strips and guinea-pig atria.9 The data derived from our structure-activity study suggest that the minimum structure required for the full stimulation of NT receptors in these two preparations is H-Arg(9)-Pro(10)-Tyr(11)-Ile(12)-Leu(13)-OH. The sequence PyroGlu(1)-Leu(2)-Tyr(3)-Glu(4)-Asn(5)-Lys(6)-Pro(7)-Arg(8)- and the amino acids Ile(12) and Leu(13) appear to contribute mainly to the affinity or binding of NT to its receptor. The chemical groups responsible for the full activation (intrinsic activity) of NT receptors seem to be located in the sequence -Arg(9)-Pro(10)-Tyr(11).

Animals↗
PubMed1980

Synthesis of peptides by the solid-phase method. V. Substance P and analogs.

We have synthesized a series of 12 analogs of the undecapeptide substance P in order to perform a structure-activity study of this peptide. In the present work, each residue was substituted by L-alanine, and the C-terminal amide was replaced by the free carboxyl in order to pinpoint biologically important side chains and functional groups. The synthesis of the analogs was carried out by the automatic solid-phase method. Couplings were performed by the symmetrical anhydride procedure. After cleavage with liquid HF, the peptides were purified by gel filtration and ion-exchange chromatography. Their purity was assessed by thin-layer chromatography, paper electrophoresis, amino acid and elemental analyses, and high pressure liquid chromatography. They were tested for biological activity in vitro on the ileum of the guinea pig, the mesenteric vein of the rabbit, and the vas deferens of the rat, and in vivo by measuring their effect on the blood pressure of the rat.

Animals↗
PubMed1980

Kinin receptors in experimental inflammation.

The contractile response of the rat isolated urinary bladder to kinins is meated by receptors of the B1 and of the B2 types, as this preparation responds to des-Arg9-bradykinin (des-Arg9-BK), a fairly selective stimulant of receptor B1 and to [Tyr(Me)8]-BK, a potent agonist on receptor B2. Des-Arg10-[Leu9]-kallidin, a specific and competitive antagonist of the action of kinins on receptor B1, has been found to block the effect of des-Arg9-BK in concentrations similar to those required in the rabbit aorta; therefore, the B1 receptor of the rat urinary bladder is analogous to that of the rabbit vascular tissue. The response of the rat urinary bladder to des-Arg9-BK increases progressively from near null level during the incubation in vitro and can be abolished by cycloheximide; this suggests that receptor B1 of the rat urinary bladder is formed de novo. The inflammation of the bladder induced by intravesical injection of the detergent Triton X-100 enhances the initial response to des-Arg9-BK without modifying the response to other agents. The B1 receptor is formed in vivo in the rat urinary bladder submitted to the Triton X-100 treatment but not in the control untreated organ. The local de novo synthesis of B1 receptors for kinins that follows a noxious stimulus is proposed as a possible mechanism implicated in the chemical mediation of the inflammatory process.

Animals↗
PubMed1980

The dog common carotid artery: a sensitive bioassay for studying vasodilator effects of substance P and of kinins.

In order to develop a sensitive pharmacological preparation which would allow the measurement of the inhibitory effects of kinins and substance P (SP) in vascular smooth muscles, several large arteries of the dog were studied in vitro. The common carotid artery was found to be one of the most sensitive preparations to SP and kinins. When contracted with low concentrations of noradrenaline (between 3.0 x 10(-8) and 3.0 x 10(-7) M), this artery responds to SP (6.5 x 10(-11)-6.5 x 10(-9) M) and bradykinin (BK) (8.1 x 10(-11)-9.1 x 10(-8) M) with relaxations that are proportional to the concentrations of the two peptides. SP and BK appear to exert their relaxant effects through the activation of specific receptors as the exposure of the common carotid artery to concentrations of [Leu8]-angiotensin II, propranolol, methysergide, cimetidine, or atropine sufficient to inhibit the effects of the corresponding agonists do not affect the relaxing effect of SP and BK. [Leu8]-des-Arg9-BK (1.0 x 10(-6) M), indomethacin (2.8 x 10(-5) M), and lioresal (4.7 x 10(-5) M) are also inactive. When the dog common carotid artery is desensitized with high concentrations of SP, BK, eledoisin, and physalaemin a cross-desensitization is observed only between SP and physalaemin. These results support the conclusion that SP and kinins act on different receptors. The order of potency of kinins is the following: BK = [Tyr(Me)8]-BK greater than des-Arg9-BK, suggesting that the receptor for kinins is of the B2 type. The order of potency of peptides related to SP is SP greater than C-terminal 4-11 greater than C-terminal hexapeptide 6-11, similar to that observed in other vascular preparations. The results summarized in this paper indicate that the dog common carotid artery is a preparation sensitive to SP and BK and useful for studying the relaxant effect of these two peptides on vascular smooth muscles.

Animals↗
PubMed1980

Vascular reactivity to angiotensin and noradrenaline in rats. Effect of aging and of uninephrectomy.

The effects of angiotensin II (ATII), and noradrenaline (NA) were measured in vivo and in several vascular preparations taken from normotensive intact or from uninephrectomized rats receiving NaCl 0.9% for drinking. The study was directed to evaluate the effects of aging and of uninephrectomy plus NaCl administration on vascular reactivity. Aging neither change the response in vivo or the myotropic effects of the agents in the isolated portal vein, while the effect of ATII was specifically increased in the perfused kidney, and both the response to ATII and NA were decreased in rat hindquarters and thoracic aortae. Uninephrectomy and NaCl administration were accompanied by a selective increase of sensitivity to ATII in vivo and in the isolated kidney, by a stronger effect of both ATII and NA in the hindquarter, while the response of the portal vein did not change and those of the thoracic aorta to ATII and NA showed a tendency to diminish. These results indicate that aging and uninephrectomy have to be taken into account in studies intended to evaluate the sensitivity of vascular preparations of normotensive and hypertensive rats.

Aging↗
PubMed1980

Vascular reactivity to angiotensin and noradrenaline in rats maintained on a sodium free diet or made hypertensive with desoxycorticosterone acetate and salt (DOCA/salt).

The pressor response to angiotensin II (ATII) and to noradrenaline (NA), as well as the response of vascular beds (hindquarter and kidney) isolated and perfused with Krebs' solution, and the contractions of strips of thoracic aortae, portal veins to the same agents were measured in animals and organs taken from rats maintained on a sodium free diet or made hypertensive with DOCA/salt and in several groups of controls. The myoptropic effects of ATII and of 5HT were compared in stomach fundi. The main purpose of the study was to find out how a reduction or an increase of total body sodium and the associated changes of renin production can influence the vascular response to angiotensin and to catecholamines. Reduction of sodium in the diet was accompanied by no changes or a decrease of the responses of isolated vascular beds and tissues to ATII and NA; the pressor effect of ATII was also reduced, while that of NA was definitely increased. Treatment with DOCA/salt and the resulting hypertension were accompanied by an increased vascular response to ATII in vivo, to ATII and NA in the isolated hindquarter, while the other preparations (the perfused kidney, the thoracic aorta and the stomach fundus) showed a decreased response specific for ATII (in the kidney and the aorta) and to both ATII and 5HT (in the stomach). The responses of the portal vein to ATII and NA were unchanged. These results are discussed in relation to the changes of renin production, occuring in the two experimental conditions, and with respect to the various mechanisms currently considered for explaining the changes of vascular reactivity in hypertension.

Angiotensin II↗