Biomedical subjects

J C Stoclet

Publications and source records attributed to J C Stoclet.

At least 91 records · Page 5Linked to original sources

PubMed1991

[Current data of the membrane receptors of the vascular smooth muscle fibers].

The cell membrane of vascular smooth muscle is lined with many receptor sensitive to signals emitted by the vessel wall or transported in the blood stream. Recent data on the mechanisms by which these receptors regulate vascular tone enable them to be classified into two main groups. The first group includes the receptors carried by the membrane proteins which are under their direct control; ATP-P2x receptors on Na+ and Ca2+ channels, pharmacological receptors (dihydropyridines, diltiazem, phenylalkylamines) situated on a voltage operated channel, receptors to cromakaline-like substances associated with a potassium channel, receptors to atriopeptines (ANF-B) with guanylate cyclase activity. The second group of receptors act through the intermediary of the G protein (which has a high affinity for guanylic nucleotides); it regulates the activity of an effector which may be an enzyme or an ionic channel. The receptors of this type which have been identified in vascular smooth muscle are: --positively (beta-adrenergic, DA1-dopaminergic, P1 purinergic or H2-histaminic) or negatively coupled (alpha 2-adrenergic) to adrenylate cyclase; --positively coupled to C phospholipase (angiotensin II, vasopressin V1, 5-H-T2, alpha 1-adrenergic, M1-cholinergic, H1-histaminic). In addition, the same receptor may act by different mechanisms (V1-vasopressin, alpha 2-adrenergic, for example). Whatever the initial mechanism of action, all these receptors influence the contraction by changing ionic permeability or by producing secondary relaxing (cyclic AMP, cyclic GMP) or contractility messengers (inositol phosphates, diacylglycerol).(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Communication↗

PubMed1991

The L-arginine-NO pathway and cyclic GMP in the vessel wall.

Nitric oxide (NO) formation from L-arginine and subsequent activation of a soluble guanylate cyclase accounts for the effect of the endothelium derived relaxing factor (EDRF). Cyclic GMP produced in smooth muscle cells induces relaxation through a mechanism which involves cyclic GMP kinase, but has not yet been entirely elucidated. Experiments with specific inhibitors of the different cyclic nucleotide phosphodiesterases (PDEs) suggest that a cyclic GMP-inhibited PDE which selectively hydrolyzes cyclic AMP, called PDE III, might also be involved in the relaxing mechanism of cyclic GMP. In arteries removed from endotoxemic rats or exposed to E. coli endotoxin, an extra-endothelial production of NO or a NO-like relaxing factor is induced in smooth muscle cells. Evidence that this phenomenon may be important in endotoxin shock is provided by experiments in which vascular reactivity is restored to control level by inhibitors of NO production in endotoxemic rats. These findings show that the L-arginine-NO pathway and cyclic GMP play a major role in regulating vascular contractility in physiological and pathological conditions.

Animals↗

PubMed1991

Role of endothelium on the effects of neuropeptide Y in mesenteric resistance arteries of spontaneously hypertensive and Wistar-Kyoto normotensive rats.

The role of the endothelium in the effects of neuropeptide Y (NPY) and norepinephrine was investigated in mesenteric resistance arteries of the spontaneously hypertensive rat (SHR) and of the normotensive Wistar-Kyoto rat (WKY). Endothelium-dependent relaxation to acetylcholine (1 microM) was reduced in arteries of SHR compared with WKY. In the presence of the endothelium, the vessels of the two strains responded similarly to norepinephrine and NPY (100 nM) produced only a slight contraction. After removal of the endothelium, the response to norepinephrine was greater in WKY than in SHR. Furthermore, endothelium denudation enhanced markedly contraction elicited by NPY in WKY (up to 40% of the maximal effect of norepinephrine), but not in SHR. NPY potentiated the contractile response to low concentrations of norepinephrine (less than 300 nM) in both strains regardless whether the endothelium was intact or not. These results indicate that the contractile responses to NPY and to norepinephrine are inhibited by the endothelium in vessels of WKY, but not in those of the SHR. Furthermore, the potentiating effect of NPY occurs via an endothelium-independent mechanism in mesenteric arteries of both SHR and WKY. It is proposed that the differential responses between the two strains are related to abnormal function of the endothelium and to decreased responsiveness of smooth muscle cells in mesenteric resistance arteries of SHR compared to WKY.

Animals↗

PubMed1990

Aortic smooth muscle cells are able to convert angiotensin I to angiotensin II.

The role of vascular smooth muscle cells (VSMC) in the intraparietal conversion of angiotensin I (AngI) to angiotensin II (AngII) was investigated in rat aortic tissue. The responses of rat aortic vascular smooth muscle cells to AngI and AngII were assessed by studying contraction of endothelium-denuded aortic rings and by measuring intracellular Ca++ ion concentration in primary cultures of VSMC free of endothelial cells. In both preparations, AngI and AngII induced identical responses which were inhibited by saralasin, a blocker of AngII receptors. In the presence of captopril, an inhibitor of the angiotensin converting enzyme, the increase in calcium caused by AngI was abolished in VSMC cultures and the contractile effect of this peptide in aortic rings was strongly decreased, whereas the responses to AngII remained unaffected. These results demonstrate that VSMC are able to convert AngI to AngII.

Angiotensin I↗

PubMed1990

Production of an arginine-derived relaxing factor induced by IFN-gamma plus endotoxin in murine adenocarcinoma EMT 6 cells.

Treatment of EMT 6 mammary adenocarcinoma cells with Interferon-gamma (IFN-gamma, 10 U.ml-1) plus endotoxin lipopolysaccharide (LPS, 100 ng.ml-1) induces concomitantly a growth arrest and production of citrulline and nitrite from L-arginine. A similar L-arginine-dependent metabolism is responsible for the vascular smooth muscle relaxing effect of stimulated endothelial cells. We therefore investigated the ability of EMT 6 cells to induce the relaxation of endothelium-denuded rat aortic rings precontracted with noradrenaline (1 microM). Pretreatment of EMT 6 cells with IFN-gamma + LPS increased their relaxing potency by 5-10 times. The relaxin effects of control and treated EMT 6 cells were entirely counteracted by NG-monomethyl-L-arginine (300 microM), a specific inhibitor of nitrite and citrulline production from L-arginine, and by methylene blue (10 microM) and LY 83583 (10 microM), two inhibitors of NOo-induced activation of guanylate cyclase. The effect of NG-monomethyl-L-arginine was reversed by L- but not D-arginine (1 mM). It is concluded that IFN-gamma + LPS increase the production of a relaxing factor in EMT 6 cells through the L-arginine-NOo-synthase pathway.

Adenocarcinoma↗

PubMed1990

An L-arginine-derived factor mediates endotoxin-induced vascular hyposensitivity to calcium.

Aortas removed from rats treated with bacterial endotoxin displayed a reduced sensitivity to calcium (CaCl2, 10 microM-10 mM) in depolarizing medium (100 mM K+). Sensitivity was reduced further in the presence of L-arginine (1 mM) but restored to control by N omega-nitroarginine methyl ester (L-NAME, 300 microM) or NG-monomethyl-L-arginine (L-NMMA, 300 microM), inhibitors of nitric oxide synthesis from L-arginine. Furthermore, addition of methylene blue (10 microM), an inhibitor of soluble guanylate cyclase, restored the contractile response to 10 mM CaCl2. The results suggest that vascular hyposensitivity to calcium involves stimulation of guanylate cyclase subsequent to activation of the L-arginine pathway by endotoxin.

Animals↗

PubMed1990

Endotoxin-induced impairment of vascular smooth muscle contractions elicited by different mechanisms.

The current study was designed to analyse the mechanisms which are impaired in the vascular hyporeactivity to contractile agents induced by E. coli lipopolysaccharide endotoxin (LPS). Endothelium-denuded aortic rings were prepared from thoracic aorta removed from control and LPS-pretreated rats (20 mg/kg i.p., 4 h before the experiment). In order to determine whether LPS treatment altered the contractile components that depend on intracellular calcium release and extracellular calcium entry to the same extent, rings were contracted under various experimental conditions. The responses elicited by indanidine, phenylephrine (without and with nitrendipine 1 microM), (-) Bay K 8644, (+) S 202-791 and the calcium ionophore calimycin in the presence of 1.25 mM external CaCl2 were all impaired by LPS pretreatment (maximal contractions 19, 63, 44, 28, 22 and 22% of controls, respectively). Concentration-effect curves for CaCl2 made in depolarizing medium (KCl 40 and 100 mM) and in the presence of calimycin (3 microM) were shifted to the right in rings from LPS-pretreated rats. However, the LPS-induced depression of contraction was overcome by the addition of CaCl2 (up to 30 mM). Additionally, in the absence of external CaCl2, the contraction induced by caffeine (50 mM) was not significantly altered by LPS treatment. It is concluded that LPS treatment does not reduce the ability of aortic smooth muscle cells to contract. The results suggest that LPS treatment impairs mechanisms involved in calcium handling within smooth muscle cells after stimulation of calcium entry through different pathways and activation of intracellular calcium release by alpha 1-adrenoceptor agonists.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1990

Incubation with endotoxin activates the L-arginine pathway in vascular tissue.

Rat aortic rings incubated with a low dose of endotoxin (100 ng ml-1) for 5 h exhibited depressed reactivity to norepinephrine (NE) which was independent of the presence of endothelium. An inhibitor of nitric oxide synthesis from L-arginine NGmonomethyl-L-arginine (300 microM), but not the inactive D-enantiomer, restored the contractile response of endotoxin-treated rings to control. The effect of NGmonomethyl-L-arginine was reversed by L-arginine (1 mM). In the absence of NGmonomethyl-L-arginine, L- but not D-arginine relaxed endotoxin-treated rings but was without effect on control tissues. This response was reversed following inhibition of guanylate cyclase by methylene blue (3 microM). In addition, tissue cyclic GMP content was 10 times greater in endotoxin-treated compared to control tissue. These data indicate that endotoxin can act directly on vascular tissue to induce a hyporeactivity to NE which is secondary to the activation of the L-arginine pathway and subsequent activation of soluble guanylate cyclase.

Animals↗

PubMed1990

Role of cyclic AMP in the prejunctional alpha 2-adrenoceptor modulation of noradrenaline release from the rat tail artery.

Experiments were designed to evaluate the effect of cyclic AMP on the electrically-induced release of noradrenaline from vascular sympathetic nerve terminals. The possible implication of the inhibition of adenylate cyclase in the negative feed-back control by prejunctional alpha 2-adrenoceptors of neurotransmitter release was also investigated. Rat isolated tail arteries were preincubated with [3H]-noradrenaline; the preparations were subsequently perfused/superfused with [3H )-noradrenaline-free medium and their perivascular nerves were field stimulated with 24 pulses at 0.4 Hz (0.3 ms, 200 mA). 2 compounds known to enhance the intracellular concentration of cyclic AMP, namely the membrane permeant analogue 8-Br-cAMP (10-300 mumol/l) and forskolin (0.3-10 mumol/l), an activator of adenylate cyclase, concentration-dependently enhanced the stimulation-evoked tritium overflow. The 1,9-dideoxy derivative of forskolin, which does not stimulate adenylate cyclase, was ineffective. Exposure to the cyclic AMP phosphodiesterase inhibitor rolipram 30 mumol/l produced a moderate increase (about 20%) in tritium overflow. However, in the presence of rolipram the facilitatory effect of forskolin was significantly more pronounced than in its absence. Whereas 8-Br-cAMP produced a slight concentration-dependent enhancement of the stimulation-induced vasoconstriction, forskolin and rolipram depressed it. The alpha 2-adrenoceptor agonist B-HT 933 (3-30 mumol/l) concentration-dependently inhibited the tritium overflow. The effect of B-HT 933 30 mumol/l was slightly, but significantly reduced in the presence of 8-Br-cAMP 100 and 300 mumol/l, but was not changed in the presence of forskolin 3 mumol/l. The facilitatory effect of rauwolscine 1 mumol/l was enhanced in the presence of 8-Br-cAMP 100 mumol/l. During perfusion with 8-Br-cAMP 100 mumol/l, the current strength and frequency were decreased to 150 mA and 0.2 Hz, respectively in order to obtain similar amounts of tritium overflow to those observed in the absence of the cyclic AMP analogue with the initial stimulation parameters. Under these conditions, the inhibition of the overflow by B-HT 933 30 mumol/l and the facilitation by the alpha 2-adrenoceptor antagonist rauwolscine 1 mumol/l were unaltered as compared to controls under initial stimulation conditions. It is concluded that, in the rat tail artery, the terminals of perivascular sympathetic nerves are endowed with an adenylate cyclase system. Cyclic AMP is able to modulate noradrenaline release, but does not appear to play a role in the initiation of the release process itself. In addition, the results do not support the hypothesis that prejunctional alpha 2-adrenoceptors depress noradrenaline release through the inhibition of adenylate cyclase.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1990

Age-related differences in cyclic AMP metabolism and their consequences on relaxation induced by isoproterenol and phosphodiesterase inhibitors in rat isolated aorta.

Experiments were designed to investigate the respective roles of adenylate cyclase and cyclic nucleotide phosphodiesterase in the alterations with age of cyclic AMP metabolism-dependent relaxation in rat aorta. Neither basal nor stimulated aortic adenylate cyclase activities from 7- and 18-week-old rats differed significantly. The maximal cyclic AMP accumulation induced by isoproterenol in the aorta decreased with the age of the rat as did the maximal relaxation produced by the beta-adrenergic agonist in pre-contracted aorta strips. The age-related difference in cyclic AMP accumulation was abolished when the experiment was performed in the presence of a high concentration (500 microM) of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). In addition, four phosphodiesterase inhibitors, IBMX, rolipram, Ro 20-1724 and zaprinast relaxed aorta strips pre-contracted by serotonin with concentration-effect curves which were displaced to the right in the older rats, the maximal effects being unchanged. The results suggest that the previously reported increased phosphodiesterase activity could be responsible for (1) the diminution with age of isoproterenol-induced cyclic AMP accumulation and relaxation in rat aorta; (2) the age-related decrease in potency of phosphodiesterase inhibitors as relaxing agents.

Adenylyl Cyclases↗

PubMed1990

Receptor sites involved in the action of calcium blocking agents.

The affinities of calcium blocking agents (CBAs) for membrane binding sites and for calmodulin were compared to their potencies at inhibiting contraction of various isolated arteries. Two allosterically linked binding sites, the dihydropyridine (DHPS) and benzothiazepine-phenylakylamine (BS) one, were characterized. In spite of a correlation between the affinities of a number of hydrophobic CBAs and calmodulin antagonists for DHPS and for calmodulin, these drugs displayed higher affinities for BS. Furthermore, their potency at inhibiting calcium-induced contraction in depolarized rat aorta rings was correlated to their affinity for the latter site. These results suggest that binding to membrane sites was the basis of the inhibition of depolarization-elicited contraction by all CBAs, including calmodulin antagonists. Differences in sensitivity to CBAs depending on the artery and whether they were depolarized or stimulated by noradrenaline were shown in further experiments on rat cerebral artery and resistance arterioles. These differences in sensitivity did not correspond to differences in the apparent affinity of the drugs. This suggests that the receptors of CBAs (and therefore the associated calcium channels) involved in the responses to depolarization and to the agonist were identical.

Animals↗

PubMed1990

Implication of cyclic AMP in the positive inotropic effects of cyclic GMP-inhibited cyclic AMP phosphodiesterase inhibitors on guinea pig isolated left atria.

The present investigation was performed to characterize the positive inotropic actions of inhibitors of the cyclic GMP-inhibited cyclic AMP phosphodiesterase (CGI-PDE) on the electrically driven guinea pig left atria. With forskolin added at a concentration (1 x 10(-8)-3 x 10(-8) M) that in itself produced a 10.7% increase of the response to electrical stimulation, the EC50 value of isoproterenol was slightly but significantly (p less than 0.01) reduced from 1.5 to 0.9 nM without modification of the maximal developed tension (delta Emax). The positive inotropic effects of milrinone, piroximone, and SK&F 94120 were significantly enhanced by forskolin (percentage of increase at 3 x 10(-5) M CGI-PDE inhibitors concentration was milrinone 43, piroximone 154, and SK&F 94120 133). With 8-Br-cyclic GMP added (10(-4) M) that in itself exerted a small but significant negative inotropic effect (-0.12 g), the EC50 value of isoproterenol was significantly (p less than 0.01) increased from 1.5 to 3 nM without modification of the delta Emax value. The positive inotropic effects of CGI-PDE inhibitors were significantly depressed by 8-Br-cyclic GMP (percentage of decrease at 3 x 10(-5) M was milrinone 35, piroximone 63, and SK&F 94120 39). In identical conditions, neither forskolin nor 8-Br-cyclic GMP produced any significant alteration of the positive inotropic effects of elevated external Ca2+ or protoveratrine B. Together these results strongly suggest that the positive inotropic effect of CGI-PDE inhibitors is mediated by cyclic AMP in guinea pig left atria.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1990

Involvement of rolipram-sensitive cyclic AMP phosphodiesterase in the regulation of cardiac contraction.

The involvement of rolipram-sensitive phosphodiesterase (PDE IV) in regulation of cardiac contraction was investigated by studying the effect of selective inhibitors (rolipram, denbufylline, Ro 20-1724) on guinea pig left atria contraction. In contrast to milrinone and SK&F 94120 (inhibitors of the cyclic GMP-inhibited PDE, PDE III), (+/-)-rolipram and denbufylline (0.1-30 microM) did not produce any positive inotropic effect in normal (2.5 mM) or elevated (3-3.2 mM) external CaCl2 concentration. In these conditions, Ro 20-1724 produced only a slight but significant increase of contraction over control levels. In the presence of forskolin (an adenylate cyclase activator) or SK&F 94120 (a PDE III inhibitor), which produced an increase of the response to electrical stimulation of approximately 10%, (+/-)-rolipram, denbufylline, and Ro 20-1724 all exerted concentration-dependent positive inotropic effects (mean EC50 values were 20, 25, and 125 nM, respectively, in the presence of forskolin). Rolipram exhibited stereospecificity: the (-)-enantiomer was 10 times more potent than the (+)-enantiomer. Neither preincubation of the atria with atenolol nor pretreatment of the guinea pigs with reserpine significantly modified the effect of PDE IV inhibitors obtained in the presence of forskolin. These data show that in the presence of cyclic AMP-dependent positive inotropic agents, PDE IV inhibitors exert a positive inotropic effect which probably does not involve enhanced catecholamine release from sympathetic nerve endings. This suggests that PDE IV may play a role in regulation of cardiac contraction in physiologic conditions in which the sympathetic outflow produces a stimulation of adenylate cyclase in cardiac cells.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1990

Enhancement by neuropeptide Y (NPY) of the dihydropyridine-sensitive component of the response to alpha 1-adrenoceptor stimulation in rat isolated mesenteric arterioles.

1. The mechanism by which neuropeptide Y (NPY) potentiates the vasoconstriction induced by alpha 1-adrenoceptor agonists was investigated in 3rd generation mesenteric arterioles of the rat. 2. At a maximally active concentration, nitrendipine (10(-6) M) displaced to the right the concentration-response curves to noradrenaline (pD2 decreased from 6.2 +/- 0.06 to 5.7 +/- 0.03) and phenylephrine (pD2 decreased from 5.6 +/- 0.03 to 5.3 +/- 0.03). Diltiazem (10(-5) M) also shifted to the right the concentration-response curve to phenylephrine (pD2 decreased from 6.0 +/- 0.06 to 5.5 +/- 0.04). In addition, the maximal response to phenylephrine was significantly decreased in the presence of either nitrendipine or diltiazem. 3. In the absence of a calcium channel blocking agent, NPY (100 nM) produced a leftward shift of the concentration-response curves to noradrenaline (pD2 increased from 6.2 +/- 0.06 to 6.5 +/- 0.05) and phenylephrine (pD2 increased from 5.6 +/- 0.03 to 6.0 +/- 0.06 and from 6.0 +/- 0.06 to 6.3 +/- 0.11). In the presence of either nitrendipine (10(-6) M) or diltiazem (10(-5) M), NPY (100 nM) did not alter the concentration-response curves to either noradrenaline or phenylephrine. 4. NPY was added to arterioles brought to the same level of tension (40% of the maximal contraction) either by phenylephrine alone (1.5 x 10(-6) M) or by a higher concentration of phenylephrine (3 x 10(-6) M) followed by the addition of prazosin (1.3 x 10(-9) M; a concentration at which it partially blocks alpha 1-adrenoceptors). In these conditions, the response to phenylephrine was completely abolished by nitrendipine (10-6 M) or by diltiazem (10-5M). Furthermore, NPY (10-1" to 10-7M) increased the arteriolar tension up to the maximal contractile capacity of the vessels with pD2 values of 8.6 + 0.02 and 8.7 + 0.01, in the absence and presence of prazosin, respectively. 5. Prazosin was replaced in the above protocol by other vasodilator agents acting through different mechanisms. Whether in the presence of 2 x 10-7M forskolin, 6 x 10-7M sodium nitroprusside (which stimulate adenylate cyclase or guanylate cyclase, respectively) or 2 x 10- 7M diltiazem (a concentration at which calcium entry is partially blocked), NPY enhanced phenylephrine-induced contraction to the maximum level with an identical potency (pD2 values of the peptide ranged from 8.3 to 8.7). 6. The results show that, in rat mesenteric arterioles, NPY potentiates only the calcium entry blockersensitive component of contraction induced by stimulation of alpha,-adrenoceptors. In addition, they provide evidence that the peptide counteracts with an equal potency the inhibitory effect of partial block of alpha,-adrenoceptors and of relaxing agents acting through different mechanisms. It is suggested that NPY enhances calcium entry induced by stimulation of alpha l-adrenoceptors in this tissue.

Adrenergic alpha-Agonists↗

PubMed1990

Loss of vascular responsiveness induced by endotoxin involves L-arginine pathway.

The involvement of L-arginine-dependent nitric oxide (NO) production in the vascular failure observed in endotoxemia was investigated in male Wistar rats treated with Escherichia coli lipopolysaccharide (LPS). Contractile responses to norepinephrine (NE) were measured ex vivo in aortas isolated from rats treated with LPS (20 mg/kg ip, 4 h before experiments) and pressor responses to NE were recorded in vivo in rats infused with LPS (5 mg.kg-1.h-1 iv). LPS pretreatment induced a rightward shift of the concentration-response curve to NE and a reduction of the maximal contraction by approximately 43% and 54% (P less than 0.05) in aortic rings with and without functional endothelium, respectively. This was not modified by the presence of indomethacin (10 microM) during the contractile experiments. In contrast, in the presence of NG-monomethyl-L-arginine (L-NMMA, 300 microM) or methylene blue (10 microM), maximal contractions to NE were restored to control values whether functional endothelium was present or not. The effects of L-NMMA were reversed by L- but not by D-arginine. Additionally, the effects of LPS pretreatment on vascular contractility were potentiated by L-arginine. In vivo, LPS infusion produced a reduction in pressor responsiveness to NE (0.1-10 mg/kg), which was also abolished by L-NMMA (30 mg/kg iv). This effect of L-NMMA was reversed by L- but not by D-arginine (100 mg/kg iv). These results demonstrate that activation of the L-arginine pathway has a major role in the production of vascular hyporeactivity in endotoxemia, ex vivo as well as in vivo. Additionally, they suggest that endothelium-independent vascular production of NO may be involved.

Acetylcholine↗

PubMed1990

Pertussis toxin abolishes the effect of neuropeptide Y on rat resistance arteriole contraction.

Pertussis toxin (PTX) was used to investigate the possible involvement of a G protein in the mechanism of action of neuropeptide Y (NPY) on rat mesenteric arterioles. ADP ribosylation of membrane protein was assessed by gel electrophoresis followed by autoradiography. The effect of NPY was studied on contractions elicited either by addition of calcium to depolarized vessels or by the calcium agonist BAY K 8644. Under conditions in which PTX ADP-ribosylated a 40-41 kDa protein, the potentiation of contractions induced by NPY in both protocols was abolished. In contrast, the contraction induced by norepinephrine was unaffected by PTX. It is concluded that a G protein mediates the potentiating effect of NPY on external calcium-dependent contractions in rat mesenteric arterioles.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1989

Subsensitivity of presynaptic adenosine A1-receptors in caudal arteries of spontaneously hypertensive rats.

(-)-N6-(R-phenylisopropyl)-adenosine (R-PIA) depressed tritium overflow and vasoconstriction evoked by electrical stimulation to a similar extent in isolated tail arteries of Wistar rats (WR) preincubated with [3H]noradrenaline. The inhibitory effects of adenosine, 5'-N-ethylcarboxamidoadenosine (NECA) and R-PIA were determined on the constrictor responses of tail arteries obtained from WR, as well as spontaneously hypertensive (SHR) and Wistar Kyoto rats (WKY). In WR and WKY, the rank order of agonist potency (R-PIA greater than NECA greater than adenosine) was compatible with the presence of adenosine A1-receptors. Whereas adenosine, NECA and R-PIA were equiactive in WR and WKY, they produced no or only slight changes in SHR. The left renal arteries of some WR were partially occluded to induce hypertension. R-PIA had the same effect in the tail arteries of these animals as in preparations obtained from sham-operated WR. The above results suggest that the subsensitivity of presynaptic A1-receptors in the blood vessels of SHR is genetically determined. This could contribute in vivo to enhanced transmitter release from terminals of perivascular nerves and subsequent increases in vascular resistance.

Adenosine↗

PubMed1989

Inhibition of cyclic adenosine-3',5'-monophosphate phosphodiesterase from vascular smooth muscle by rolipram analogues.

Rolipram [(R,S)-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone] has been shown to inhibit selectively the cAMP phosphodiesterase (PDE) of vascular smooth muscle. In order to further explore the structural requirements for selective PDE inhibition, we synthesized a series of rolipram derivatives differently substituted either at the pyrrolidinone or at the aromatic ring. Among these compounds, rolipram was the most active compound. Semirigid analogues were prepared and used for an evaluation of the active conformation of rolipram. Structural comparison with two other potent and chemically different smooth muscle cAMP-PDE inhibitors, trequinsin and Ro 20-1724, allows us to propose a first topological model of the smooth muscle cAMP-PDE pharmacophore.

3',5'-Cyclic-AMP Phosphodiesterases↗