Guinea-pig Aorta Research Articles

Functional characterization of three adenosine receptor types

1. The purpose of the present study was to classify adenosine receptors into A1 and A2 subtypes in a wide range of isolated tissues and cell types (rat adipocytes and atria, guinea-pig ileum and atria (A1); guinea-pig aorta, dog coronary artery and human platelets and neutrophils (A2)) using the R- and S-diastereoisomers of N-phenylisopropyladenosine (PIA), N-cyclopentyladenosine (CPA), the novel compound, N-[(1S,trans)-2-hydroxycyclopentyl]adenosine (GR79236), N-[(2-methylphenyl)methyl]adenosine (metrifudil), 2-(phenylamino)adenosine (CV1808), and 2[[2-[4-(2-carboxyethyl)phenyl]ethyl]amino]-N- ethylcarboxamidoadenosine (CGS21680); N-ethylcarboxamidoadenosine (NECA) was used as a standard. 2. Results obtained in all tissue preparations previously reported to contain A1-receptors could be described by a single rank order of agonist potency: CPA > or = GR79236, R-PIA > or = NECA >> S-PAI > or = metrifudil > or = CV1808, CGS21680. 3. In contrast, two distinct rank orders of agonist potency were observed in preparations previously reported to contain A2-receptors. In dog coronary artery, human neutrophils and platelets the rank order of potency was: CV1808, CGS21680 > or = NECA > R-PIA > or = metrifudil > or = CPA > GR79236 S-PIA. However, in guinea-pig aorta the rank order was: NECA > metrifudil > R-PIA, CPA > CV1808, GR79236 > or = S-PIA, CGS21680. 4. The results of this study are consistent with the existence of three types of adenosine receptor: A1-and two subtypes of A2-receptor. The receptor present in dog coronary artery, human platelets and neutrophils, probably corresponds to the A2a subtype, whilst that present in the guinea-pig aorta may be of the A2b subtype.

MECHANISMS OF TENSION DEVELOPMENT INDUCED BY MONENSIN IN GUINEA-PIG AORTA : EFFECTS OF VERAPAMIL, OUABAIN, PRAZOSIN AND GLIBENCLAMIDE

The influence of monensin (10 µmol/L) alone and in the presence of verapamil (3 µmol/L) or ouabain (1 mmol) and prazosin (1 µmol/L) or glibenclamide (10 µmol/L) were studied on the muscle tension of guinea pig aorta. Changes in tissue sodium, potassium and calcium ion contents of the aortic muscle produced by monensin in the presence of prazosin were evaluated. Monensin in normal Tyrode's solution containing prazosin caused an increase in the resting tension followed by a decrease and returned to normal values. Verapamil reduced the muscle tension induced by monensin. After ouabain, monensin induced sustained increase in the resting tension. Glibenclamide partially reversed the relaxant phase of monensin in presence of norepinephrine. The findings of the present study indicate that the contraction induced by monensin in guinea Pig aorta is due to the increased influx of calcium through voltage-dependent calcium Channels as well as through Na+ - Ca2+ exchange mechanisms. Monensin produced relaxation of guinea pig aorta in part through the increase in K+ permeability via opening of K+-ATP channels.

Role of endothelium in the responses to noradrenaline in normal and sensitized guinea-pig aorta.

1. The pharmacological reactivity of sensitized blood vessels has been less studied than that of the airways. Aorta rings were obtained from normal (non-sensitized) and actively sensitized guinea-pigs, and prepared for isometric recording of tension changes. 2. Noradrenaline (10 nM-0.1 mM), histamine (0.1 microM-0.1 mM) and KCl (10-100 mM) produced concentration-related contractions of normal tissues. Removal of endothelium resulted in a marked leftward and upward shift of the concentration-response curve for noradrenaline but it did not alter histamine- or KCl-induced responses. Pretreatment with L-NG-nitroarginine (L-NOARG, 30 microM), haemoglobin (5 microM) or ibuprofen (10 microM) enhanced noradrenaline-induced responses without affecting those to histamine or KCl. 3. Removal of endothelium or pretreatment with L-NOARG or ibuprofen did not alter agonist-induced responses in sensitized tissues. Acetylcholine (1 microM)-induced relaxation of the contraction produced by noradrenaline (1 microM) in intact rings was diminished in sensitized compared to normal tissues. 4. Neuronal uptake and release of [3H]-noradrenaline did not differ in normal and sensitized tissues. 5. Loss of the modulatory role of endothelium and other mechanisms may be involved in the hyperreactivity of sensitized guinea-pig aorta.

Activation of K + channel in vascular smooth muscles by cytochrome P450 metabolites of arachidonic acid

Arachidonic acid can be oxidatively metabolized by cytochrome P450 epoxygenase to four regioisomeric epoxyeichosatrienoic acids (5,6-; 8,9-; 11,12-; 14,15-EET), which exhibit vasorelaxant effects in vivo and in vitro with unknown mechanisms. In this study, the patch-clamp method was used to examine the effects of EETs on the Ca 2+-activated K + channel in cells from rabbit portal vein, rat caudal artery, guinea pig aorta and porcine coronary artery. In all four cell types, EETs in the bath activated the K + channel in cell-attached patches by increasing the single channel open-state probability. Potencies of the four EETs did not differ significantly for each cell type. The concentrations for doubling open-state probability were 0.1 μM in portal vein and coronary artery, 0.3–1 μM in aorta and 1–3 μM in caudal artery. In caudal artery cells, K + channel activation by 3 μM 5,6,- and 1 μM 11,12-EET was blocked and reversed by glyburide at 0.5 μM. In aorta, coronary artery, and caudal artery cells, micromolar EETs induced a dose-dependent and reversible augmentation of whole-cell K + current by 50–120% and a 5–12 mV hyperpolarization. EETs on the cytosolic side of inside-out patches produced little or no potentiation of K + channels, implying an interaction of receptor-mediated nature. Thus, EETs may promote vasolidation by functioning as endogenous K + channel openers.

Effects of ouabain on muscle tension and intracellular Ca 2+ level in guinea-pig aorta

The effects of ouabain on muscle tension and the intracellular Ca 2+ level ([Ca 2+] i) were examined in guinea-pig aorta loaded with fura-2. Ouabain caused a gradual and sustained increase in both [Ca 2+] i and muscle tension. There was a positive correlation between these two parameters. In Ca 2+-free solution, ouabain did not affect either [Ca 2+] i or muscle tension, suggesting that the ouabain-induced increase in [Ca 2+] i was not due to Ca 2+ release from storage sites. The ouabain-induced increase in [Ca 2+] i and muscle tension was inhibited by Ni 2+, which inhibits the Na +/Ca 2+ exchanger, but not by verapamil. Furthermore, anionic and cationic amphiphiles were used as modulators of the Na +/Ca 2+ exchanger. Sodium dodecyl sulfate accelerated the responses to ouabain, whereas dodecyltrimethylammonium bromide inhibited them. These results suggest that in the guinea-pig aorta, ouabain induces contraction by increasing the Ca 2+ influx through the Na +/Ca 2+ exchanger on the plasma membrane, but not through verapamil-sensitive Ca 2+ channels.

Pharmacological evidence for distinct endothelin receptors in guinea-pig bronchus and aorta.

The ETA receptor antagonist, BQ-123 (1 microM) potently antagonized endothelin-1 (ET-1) concentration-response curves in guinea-pig aorta (pKB = 7.1). However, 10 microM BQ-123 was without effect on ET-1-induced contractions in guinea-pig bronchus. The ETB-selective agonist, sarafotoxin S6c did not contract the aorta but was a potent and effective contractile agonist in the bronchus. BQ-123 (10 microM) was without effect on sarafotoxin S6c-induced contractions in the bronchus. These data provide evidence for distinct endothelin receptors in guinea-pig aorta and bronchus, which appear to be predominantly of the ETA and non-ETA, perhaps ETB, subtypes, respectively.

Comparison of the Relaxing Effects of Cicletanine and Cromakalim on Vascular Smooth Muscle

Cicletanine inhibited the spontaneous activity of portal vein preparations (rat, guinea pig, and rabbit) and that produced by norepinephrine or an increase in external K+ concentration to 20 mmol/L in seven types of vascular smooth muscle preparation (portal vein of rat, guinea pig, and rabbit; aorta of rat and guinea pig; and iliac artery and ear artery of rabbit). The cicletanine EC50 was approximately 10(-4) mol/L. Contractions produced by K+ = 80 mmol/L were also inhibited by cicletanine in most preparations. Only in aortic strips of rat and guinea pig and in rabbit iliac artery were the concentration-response relationships for cicletanine shifted to the right, yielding EC50 values of approximately 3 x 10(-4) mol/L. In contrast, the inhibitory effects of the potassium channel opener cromakalim (BRL 34915) were completely abolished during K+ = 80 mmol/L treatment in all preparations. The inhibitory effect of cromakalim under the other test conditions (above) was completely antagonized by application of glibenclamide, 10(-5) mol/L, whereas this treatment had only negligible effects on cicletanine inhibition in most preparations. The results indicate that a potassium channel opening effect does not contribute significantly to the inhibitory effect of cicletanine on vascular smooth muscle.

Vascular actions of thrombin receptor peptide.

We have examined the action of the thrombin receptor-derived polypeptide, S42FLLRNPNDKYEPF55 (TRP 42-55), in rat and guinea pig aortic rings and helical arterial strips, and we have compared the actions of the peptide with those of thrombin. In rat preparations, both TRP 42-55 and thrombin caused a concentration-dependent endothelium-dependent relaxation that was blocked by N omega-nitro-L-arginine methyl ester; the relaxation response of the intact rat aortic strip preparation to concentrations of the peptide in the range 30-60 micrograms/mL (17-34 microM) was equivalent to the response to 0.03-0.1 U/mL of thrombin (about 0.3-0.9 nM), yielding a potency ratio (TRP 42-55:thrombin) of about 38,000:1. In contrast with the complete desensitization of thrombin-treated rat aortic preparations to a second administration of the enzyme, the rat aortic tissue was not desensitized by repeated exposures to TRP 42-55 and remained responsive to the peptide even after treatment of the tissue by thrombin. In contrast with the rat aortic tissue, in either intact or endothelium-free guinea pig aortic preparations both TRP 42-55 and thrombin caused a concentration-dependent endothelium-independent contraction. The contractile action of 60 micrograms/mL of receptor peptide (34 microM) in guinea pig aortic strip preparations was equivalent to the contractile action of 0.1-0.3 U/mL thrombin (0.9-3 nM), yielding a potency ratio of about 17,000:1. In guinea pig aortic preparations with an intact endothelium that were precontracted with noradrenaline, neither thrombin nor TRP42-55 caused relaxation, whereas substance P did so.(ABSTRACT TRUNCATED AT 250 WORDS)

Relative agonist potencies of C 2-substituted analogues of adenosine: Evidence for adenosine A 2B receptors in the guinea pig aorta

Nine C 2-substituted adenosine analogues that are potent and selective for the A 2-adenosine receptor were tested for their ability to induce relaxations of the guinea pig aorta. Compounds tested were 2-phenylethoxyadenosine (PEA), 2-phenylethoxy-5′- N-ethylcarboxamidoadenosine (PENECA), 2-cyclohexylethoxyadenosine (CEA), 2-fluorophenylethoxyadenosine (FPEA), 2-methoxyphenylethoxyadenosine (MPEA), 2-naphthylethoxyadenosine (NEA), 2-phenylaminoadenosine (CV-1808), 2-phenylethylaminoadenosine (PEAA) and 2-carboxyethylphenethylamino-5′-N-ethylcarboxamidoadenosine (CGS21680). The responses to these agents were compared to those of three standard adenosine receptor agonists, 5′-N-ethylcarboxamidoadenosine (NECA), N 6-cyclohexyladenosine (CHA) and R-N 6-phenylisopropyladenosine (R-PIA). The C 2-ethoxyadenosine analogues were 30- to 140-fold less potent than NECA and the C 2-amino-substituted analogues were 250 to 1000-fold less potent than NECA at inducing relaxations of the guinea pig aorta. All of the analogues were also less potent than the A 1-selective agonist R-PIA. However, only responses to NECA were competitively antagonized by the non-selective adenosine receptor antagonist 8-phenyltheophylline (8-PT), pK B=6.83±0.05. The results suggest that the C 2-substituted analogues produce relaxations of the guinea pig aorta through a combination of actions at A 2-adenosine receptors and at xanthine resistant sites. The lack of potency of these analogues at activating the xanthine sensitive A 2-receptors in the guinea pig aorta suggests that these adenosine receptors may be of the A 2b-subtype.

Evidence that the apparent complexity of receptor antagonism by angiotensin II analogues is due to a reversible and syntopic action.

1. The interactions between angiotensin II (AII), two non-peptide antagonists DuP 753 and IMI, and eight peptide analogues of AII were investigated on the rabbit isolated aorta assay. DuP 753 and IMI behaved as simple competitive antagonists (pKB values 8.4 and 6.8, respectively). To different degrees, all the AII-peptide analogue interactions failed to meet the basic criteria for simple competition. In addition to rightward shift, the most significant feature was a concentration-dependent saturable depression of the upper asymptote of the AII concentration-effect curves. 2. 'Washout' and combined dose-ratio analysis experiments, in which DuP 753 was used as a reference antagonist, indicated that the profile of peptide antagonism was solely due to a reversible and syntopic action at the AII receptor. 3. By use of an operational model of agonism (Black & Leff, 1983) as a starting point, it was possible to account for the data with a new model which describes reversible receptor occupancy and occupied receptor-determined, saturable reduction in the efficacy of AII. Model-fitting gave estimates of pKB values for the peptide analogues and agonist affinity and efficacy parameters for AII. 4. The model was successfully tested by applying it to qualitatively similar results obtained in a cross-tissue analysis on guinea-pig aorta, ileum and stomach. 5. A 'molecular' interpretation of the efficacy changes, based on the concepts of receptor internalisation and expression, is offered.

Evidence that adenosine receptors in the dog left atrium are not of the typical A 1 or A 2 adenosine receptor subtypes

The adenosine receptors from the isolated dog left atrium were characterized using the non-selective agonists 5′-N-ethyl-carboxamidoadenosine (NECA) and adenosine, the A 1-selective agonist N 6-R-phenylisopropyladenosine (R-PIA), and the A 2 adenosine receptor agonist C 2-naphthylethoxyadenosine (NEA). The potency order of the agonists in the dog left atrium was NECA > adenosine > R-PIA = NEA. This potency order was the same as that found in the guinea pig aorta (A 2) but different from that in the guinea pig left atrium (A 1). In the guinea pig left atrium the potency order was NECA > R-PIA > adenosine ⪢ NEA. The negative inotropic responses to NECA in the dog left atrium were antagonised by the non-selective antagonist 8-phenyltheophylline (8-PT) and the A 1-selective antagonists 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) and N 6-endonorbornan -2-yl-9-methyladenine (N-0861), giving pK B values of 6.3, 7.3 and 5.1, respectively. These values are significantly different from those estimates determined in either the guinea pig left atrium or guinea pig aorta. The potency order of the agonists and the relatively low potencies of the A 1-selective antagonists suggests that the adenosine receptors in the dog left atrium are not of the classical A 1 adenosine receptor subclass and may instead be more closely related to the A 2 adenosine receptor.

O-171 - Thapsigargin-induced relaxation in guinea pig aorta through EDRF production

O-171 - Thapsigargin-induced relaxation in guinea pig aorta through EDRF production

Pituitary adenylate cyclase activating peptide (PACAP) in guinea-pig lung: distribution and dilatory effects

The lower airways of guinea-pigs were analyzed for pituitary adenylate cyclase activating peptide (PACAP) using immunocytochemistry. In the trachea a moderate supply of PACAP-immunoreactive nerve fibers occurred around smooth muscle bundles, glands and small blood vessels. In the lung, PACAP-immunoreactive nerve fibers were distributed around small glands and bronchi. A rich supply of PACAP immunoreactive nerve fibers was found around blood vessels in the lungs. PACAP-suppressed smooth muscle responses were analysed using isolated circular segments of trachea, pulmonary arteries and aorta of guinea-pigs. In both airways and arteries PACAP caused a concentration-dependent relaxation of precontracted segments. The maximal relaxation effects were more pronounced in the airways than in the arteries while the order of potency was aorta > pulmonary artery > trachea. The effect of PACAP was compared to those of acetylcholine (ACh) and vasoactive intestinal peptide (VIP). In the pulmonary artery the vasomotor responses expressed as maximal dilatation had the order: ACh > VIP = PACAP while the order of potency was PACAP = VIP > ACh . In the trachea, PACAP was slightly more potent than VIP. The relaxatory responses to PACAP in the trachea and the intrapulmonary arteries were unaffected by pretreatment with atropine, prazosin, yohimbine, propranolol, mepyramine, cimetidine and Spantide. Removal of the endothelium abolished PACAP-induced vascular relaxation. Conceivably, PACAP-containing nerve fibers play a role in the regulation of airway resistance and local blood flow.

Involvement of Ca2+ influx-induced Ca2+ release in contractions of intact vascular smooth muscles.

Application of Ca2+ (0.1-2.5 mM) to guinea pig aortas incubated in Ca(2+)-free isotonic KCl solution induced a contraction (Ca contraction), a part of which depended on preloading the intracellular stores with Ca2+ and which was sensitive to 3 x 10(-5) M ryanodine. Because 45Ca2+ influx from the external fluid upon the addition of Ca2+ was not modified either by the state of filling of the Ca2+ store or by the presence of ryanodine, the ryanodine-sensitive component of the contraction could be attributed to the Ca2+ influx-induced Ca2+ release from the Ca2+ store. Supporting the possibility of involvement of Ca(2+)-induced Ca2+ release, the Ca contraction due to 0.1 mM Ca2+ was enhanced either by decreasing Mg2+ in the medium or by low temperature. The ratio of the ryanodine-sensitive fraction in the Ca contraction was inversely related to the concentration of Ca2+ added and also to the extent of 45Ca2+ influx. When the Ca2+ influx was decreased by verapamil or cadmium, the ratio of ryanodine-sensitive fraction increased. On the contrary, an increase of Ca2+ influx by CGP-28392 decreased the ratio. These results suggest that Ca2+ influx at a physiological level triggers Ca2+ release from the Ca2+ store, resulting in the amplification of contractile force.

Differences Between Rat and Guinea Pig Aorta in Postreceptor Mechanisms of α1-Adrenoceptors

The relative importance of different postreceptor mechanisms associated with alpha 1-adrenoceptor activation in guinea pig aorta and rat aorta was compared. In both tissues, a concentration-dependent correlation was observed between contractile responses produced by high concentrations of norepinephrine (NE) and inositol-1-phosphate (IP1) accumulation. Blockade of Ca2+ entry through voltage-dependent membrane channels by nifedipine had no inhibitory action on NE-induced contractile responses in guinea pig aorta, but significantly inhibited NE-induced contractile responses in rat aorta. Nifedipine had no major effect on NE-induced IP1 accumulation in either tissue. A medium with no Ca2+ inhibited NE-induced contractile responses and IP1 accumulation in guinea pig aorta, but had a more marked effect on contractile responses and IP1 accumulation in rat aorta. The combination of a high concentration of nifedipine and a medium with no Ca2+ almost completely inhibited NE-induced contractile responses and IP1 accumulation in both tissues. Exposure to EGTA also virtually completely inhibited NE-induced contractile response and IP1 accumulation in both tissues. Significant 45Ca2+ entry was stimulated in rat aorta by NE, and this entry was completely blocked by nifedipine. No significant 45Ca2+ entry was stimulated by NE in guinea pig aorta. We conclude that the most important postreceptor event linked to alpha 1-adrenoceptor stimulation in guinea pig aorta is activation of the phosphatidylinositol pathway, whereas in rat aorta Ca2+ entry through voltage-dependent membrane channels is as important as activation of the phosphatidylinositol pathway. We also conclude that activation of the phosphatidylinositol pathway in both tissues is critically dependent on the presence of a small amount of Ca2+, which may enter from the external medium.

Effect of pressure overload on cardiac Ca2+ antagonist binding sites of guinea pig. Comparison with the adaptational response of the hypertrophied rat heart.

The aim was to determine if the adaptational process of the cardiac calcium channel to pressure overload observed in rat heart also occurs in species characterised by a higher sensitivity to external calcium than in the rat. This adaptation occurs via a maintained density of dihydropyridine receptors and calcium current in hypertrophied rat heart. The guinea pig was chosen and the dissociation constant (Kd), association and dissociation rate constants (k+1,k-1), and maximal number (Bmax) of the dihydropyridine receptors were measured through binding of [3H]PN 200-110 to crude sarcolemma fractions from control and hypertrophied guinea pig left ventricle. Hypertrophy of the left ventricle was obtained by stenosis of the abdominal aorta in guinea pigs. Hypertrophy reached at least 50% in 15% of the surviving animals. No significant differences in the binding of [3H]PN 200-110 to the dihydropyridine receptor were observed between control and hypertrophied left ventricle microsomal preparations: Kd = 1.59(SEM 0.22) and 1.17(0.36) nM; Bmax = 225(18) and 213(4) fmol.mg-1 of protein; k-1 = 2.30(0.26) and 2.00(0.13) min-1 x 10(-2); k+1 = 3.8(0.7) and 3.5(0.3) nM-1.min-1 x 10(-2) respectively. In guinea pig as in rat, the total number of dihydropyridine receptors per left ventricle increased proportionately to the hypertrophy. This is consistent with an unchanged density of the cardiac Ca2+ channels in the hypertrophied guinea pig heart as previously shown in hypertrophied rat heart.

Angiotensin II-induced increase in slowly exchanging 45Ca2+ in relation to contractile responses of rat and guinea-pig aorta

To gain more information about sources of activator Ca2+ involved in the contraction of rat and guinea-pig aorta evoked by angiotensin II and their sensitivity to Ca2+ entry blockers, measurement of slowly exchanging 45Ca2+ was established. A more physiological procedure was used, replacing La(3+)- and EGTA-containing solutions by a normal Ca(2+)-containing buffer. It was demonstrated that the angiotensin II-induced increase in slowly exchanging 45Ca2+ in rat aorta was incompletely (by approximately 60%-70%) inhibited by the organic Ca2+ entry blockers nifedipine, verapamil and diltiazem and by other Ca2+ entry blocking compounds like CoCl2 and chlorpromazine. 8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8) was able to inhibit the angiotensin II-induced increase in 45Ca2+ content completely, but this may be an intracellular storage effects. By contrast, the organic Ca2+ entry blockers completely inhibited that part of the angiotensin II-induced contraction of rat aorta which was dependent upon extracellular Ca2+. In guinea-pig aorta, the increase in 45Ca2+ content elicited by angiotensin II could be completely suppressed by all compounds under study. The results of these experiments correlated well with data from the functional experiments in guinea-pig aorta. In both preparations the release of Ca2+ from a rapidly as well as a slowly exchanging intracellular pool appears to contribute to the contractile response elicited by angiotensin II.

Verapamil analog with restricted molecular flexibility

Three analogues with restricted flexibility were designed to study the active conformation of verapamil during interaction with the slow calcium channel. Thus cis- and trans-1-(3,4-dimethoxyphenyl)-4-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N- methylamino]-r-1-cyclohexanecarbonitrile (5a and 5b), and 4-(3,4-dimethoxyphenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-4-cyanopiper idine, in which the verapamil structure is inserted into a cyclohexane or piperidine ring, were synthesized. Conformational analysis was performed with NMR and theoretical methods, and slow calcium channel antagonism was tested on guinea pig aorta strips. The compounds are some 100 times less potent than the parent compound even if they are able to reach conformations that are quite close to the lowest energy conformation proposed for verapamil and similar compounds. It appears that the flexibility to rotate around the bond between the quaternary atom and the adjacent methylene, a property which is lost in compounds 5a, 5b, and 6, is a major requisite for the calcium antagonism of verapamil.

Roles of neuropeptide Y and noradrenaline in sympathetic neurotransmission to the thoracic vena cava and aorta of guinea-pigs

The roles of neuropeptide Y (NPY) and noradrenaline (NA) in sympathetic neurotransmission to large arteries and veins were studied in vitro using the thoracic portions of the aorta and inferior vena cava from guinea-pigs. Both vessels are densely innervated by axons containing NA and NPY. Repetitive transmural stimulation at 2–30 Hz produced contractions of the aorta, which were abolished by prazosin. NPY did not have significant postsynaptic or presynaptic effects on vascular tone of the aorta. Transmural stimulation of the vena cava produced long-lasting contractions which were enhanced by α- and β-adrenoceptor antagonists, and were blocked by guanethidine. Precontracted venae cavae responded to sympathetic stimulation with β-adrenoceptor-mediated relaxation, followed by contraction. α-Adrenoceptor blockade delayed the onset of neurogenic contractions. NPY was a potent contractile agent of the vena cava (EC 50 ∼ 1.5 · 10 −8 M). A high concentration (3 · 10 −6 M) of NPY, or the specific NPY Y 1 receptor agonist, [Leu 31,Pro 34]NPY, caused parallel, and reversible, desensitization of contractions produced by sympathetic nerve stimulation, and by low concentrations of exogenous NPY. This provides good evidence that NPY is the mediator of the non-adrenergic sympathetic contractions of the vena cava. Furthermore, these results demonstrate that differential location or coupling of postsynaptic receptors for NA and NPY in the aorta and vena cava, leads to differential participation by these substances in sympathetic vasomotor responses. This is likely to be related to the different functions of these two parts of the systemic circulation.

Comparative study of postsynaptic α-adrenoceptors in aorta obtained from human and other mammalian species

The alpha-adrenoceptor populations in aortic strips from humans, rats, guinea-pigs and rabbits were investigated in vitro, using specific agonists and antagonists. In rabbit and human preparations the activities of the two agonists tested, noradrenaline and methoxamine, were competitively antagonized by prazosin, whereas in the other animal species prazosin showed a competitive antagonism for methoxamine induced contraction, but an uncompetitive behaviour against noradrenaline. The alpha 2-selective agonists B-HT 920 and detomidine did not elicit any effect on aortic strips up to 10(-3) M. On the basis of these results, alpha 1-receptors seem to represent an homogeneous population in human and rabbit aortae, but not in rat and guinea-pig tissues. On the other hand, the contractile response of noradrenaline and methoxamine on aortic strips from the four animal species examined cannot be ascribed to the activation of postsynaptic alpha 2-receptors. Moreover we present preliminary evidence that rat and guinea-pig aortae do not contain a clear subdivision in alpha 1a- and alpha 1b-receptors.