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PubMed1990

Effect of age on contractile response to angiotensin II in rat aorta.

The effects of aging on contractile response to angiotensin II and tachyphylaxis to it were investigated using aortic strips from rats aged 1.5, 4 and 22 months. Whether the endothelium was present or not, the contractile response to angiotensin II was greater and tachyphylaxis to it was less in 1.5-month-old rats than in 4- and 22-month-old rats. The differences between 4- and 22-month-old rats were not significant. Removal of the endothelium enhanced angiotensin II-induced maximal contraction and depressed the tachyphylaxis, these endothelial effects being greater in 4- rather than in 1.5-month-old rats. When the contractile force of angiotensin II was adjusted to a similar level for 1.5- and 4-month-old rats, the endothelial effect on the tachyphylaxis was greater in the 4-month-old rats, but no significant difference was noted in the endothelial effect on the contractile force. These results suggest that during growth, the contractile response of rat aorta to angiotensin II decreases while the endothelial effect on it increases.

Acetylcholine↗
PubMed1987

Effects of capsaicin on nonadrenergic noncholinergic nerves in the guinea pig atria: role of calcitonin gene-related peptide as cardiac neurotransmitter.

Transmural nerve stimulation (TNS) in vitro produced positive chronotropic and inotropic responses in the spontaneously beating right atria and electrically driven left atria of guinea pigs, respectively. Both the positive responses of the atria were mediated not only by adrenergic but also by nonadrenergic noncholinergic (NANC) nerves. Numerous calcitonin gene-related peptide (CGRP)-like immunoreactive nerves were found in the sinus node and the muscle layers of both atria of guinea pigs. Exogenously applied CGRP produced positive chronotropic and inotropic responses in a dose-dependent manner. In both the right and left atria, capsaicin (10(-5) M) induced positive chronotropic and inotropic responses. The second application of capsaicin did not cause any responses in the atria, indicating a rapid development of tachyphylaxis. When the tissues developed tachyphylaxis to capsaicin, the intensity of CGRP-like immunoreactivity greatly decreased in the sinus node and in both atria. In the atria that developed tachyphylaxis to capsaicin, the positive chronotropic and inotropic responses to NANC nerve stimulation diminished markedly, but the responses to exogenous CGRP and those attributed to adrenergic nerves were not affected. These results suggest that CGRP is the neurotransmitter of intracardiac NANC nerves and that capsaicin produces positive chronotropic and inotropic responses through the release of CGRP from NANC nerves in the guinea pig atria. It is also suggested that capsaicin depletes endogenous CGRP, thereby accounting for the rapid development of tachyphylaxis to capsaicin and the marked and selective diminution of TNS-induced NANC responses following application of capsaicin.

Animals↗
PubMed1991

Ruthenium-red inhibits CGRP release by capsaicin and resiniferatoxin but not by ouabain, bradykinin or nicotine in guinea-pig heart: correlation with effects on cardiac contractility.

1. The possible influence of ruthenium-red (RR) on contractility and outflow of calcitonin gene-related peptide (CGRP)-like and neuropeptide Y (NPY)-like immunoreactivity (LI) from the heart of the guinea-pig induced by capsaicin, resiniferatoxin, nicotine, ouabain or bradykinin was studied in vitro. 2. In the isolated right atrium, exposure to capsaicin evoked an increase in contractile rate and tension simultaneously with an enhanced outflow of CGRP-LI, indicating release from the atria. Repeated administration of capsaicin induced tachyphylaxis. Incubation with RR markedly attenuated the capsaicin-evoked release of CGRP-LI while no clear-cut effects were seen on contractile tension or rate. 3. In the isolated whole heart, perfusion with capsaicin induced an increased outflow of CGRP-LI and stimulated heart rate, while a negative inotropic effect was observed. A second administration of capsaicin to the same preparations failed to influence the CGRP-LI outflow and in these experiments the positive chronotropic effect was absent while the negative inotropic action remained unchanged. Capsaicin-perfusion in the presence of RR failed to induce any increased outflow of CGRP-LI from the hearts or changes in contractile activity. However, after 1 h of rinsing with Tyrode solution repeated capsaicin perfusion in the absence of RR caused a clear-cut (60% of control) release of CGRP-LI and contractile responses were restored. 4. Perfusion with resiniferatoxin evoked a RR-sensitive, clear-cut increased CGRP-LI output without any effects on contractile force or heart rate. Repeated administration of resiniferatoxin induced tachyphylaxis with respect to outflow. Capsaicin perfusion after resiniferatoxin did not influence cardiac rate, force or CGRP-LI outflow suggesting development of cross-tachyphylaxis. 5. Perfusion with RR did not influence the outflow of CGRP-LI or contractility changes evoked by perfusion with nicotine, ouabain or bradykinin. In addition, the release of NPY-LI by nicotine remained unchanged in the presence of RR. Furthermore, the positive chronotropic effect of human CGRP alpha remained intact in the presence of RR. 6. It is concluded that RR selectively inhibits capsaicin- and resiniferatoxin-induced excitation of cardiac sensory nerves as revealed by inhibition of both CGRP-LI release and the cardiostimulatory action of capsaicin. RR also seems to protect the cardiac capsaicin-sensitive fibres from the development of tachyphylaxis to capsaicin. Finally, RR prevents the capsaicin-evoked negative inotropic effect which is not related to activation of sensory nerves.

Animals↗
PubMed1996

Investigation of the contributions of nitric oxide and prostaglandins to the actions of endothelins and sarafotoxin 6c in rat isolated perfused lungs.

1. The aims of the study were to assess the contribution of prostaglandins and nitric oxide (NO) to the effects of endothelin (ETs) and sarafotoxin 6c (SX6c) in perfused rat lungs. This was carried out by using indomethacin, a cyclo-oxygenase inhibitor and NG-nitro-L-arginine (L-NOARG), a NO synthase inhibitor. Responses were studied under basal perfusion conditions and in other experiments after the elevation of vascular tone with the thromboxane-mimetic, U46619. The sub-types of ET receptors involved were characterized by use of ET receptor antagonists and cross-tachyphylaxis. 2. Pulmonary perfusion pressure (PPP), lung weight and pulmonary inflation pressure (PIP), were continuously recorded. Although L-NOARG (100 microM) did not alter basal parameters it markedly augmented the vasoconstriction and lung weight increases induced by ET-1 (50-400 pmol) or SX6C (25-200 pmol) while vasoconstrictor responses to phenylephrine were not affected by L-NOARG. 3. L-NOARG markedly potentiated the bronchoconstriction induced by ET-1 or SX6C whereas it had no effect on responses to carbachol. 4. When vascular tone was elevated, low doses (1.25-40 pmol) of ET-1, ET-3 and SX6C produced falls in PPP. The vasodilator potencies were SX6C > ET-1 = ET-3. The ETA receptor antagonist, BQ123, did not affect these depressor responses whereas the mixed ETA/ETB antagonist, bosentan, blocked them. 5. Indomethacin (10 microM) partially inhibited vasodilator response to ET-1, whereas it had no effect on SX6C-induced vasodilation. 6. L-NOARG plus indomethacin completely blocked ET-1 induced vasodilation, whereas responses to SX6C were blocked by L-NOARG alone. 7. Repeated injections of submaximal doses of ET-1 or SX6C caused tachyphylaxis to vasodilator responses. Subsequent injections of SX6C or ET-1 did not elicit depressor responses showing cross tachyphylaxis had occurred. 8. These findings indicate that under basal conditions the pulmonary vasoconstrictor, lung weight and bronchoconstrictor responses to ET-1 and SX6C are attenuated by evoked release of nitric oxide (NO). When vascular tone was elevated, lower doses of ETs and SX6C produced vasodilatation. These vasodilator responses are indirect, those to SX6C being mediated via NO production, whereas those to ET-1 involve both NO and prostanoid(s). Tachyphylaxis and ET antagonist experiments indicate that the same receptor subtype is involved in mediating the vasodilatation and that this is of the ETB type located on the endothelium. However the post-receptor vasodilator events triggered by ET-1 or SX6C appear to be different.

Animals↗
PubMed1989

The hematologic effects of chronic administration of the monokines tumor necrosis factor, interleukin-1, and granulocyte-colony stimulating factor on bone marrow and circulation.

Monokines may contribute to the regulation of hematopoiesis and circulating numbers of leukocytes during chronic inflammation. The hematologic effects of daily intravenous injection of the recombinant monokines tumor necrosis factor (TNF), interleukin-1 (IL-1), and granulocyte-colony stimulating factor (G-CSF) were therefore studied in the bone marrow and circulation of rats over the course of a week. TNF induced daily neutrophilia and lymphopenia with no evidence of tachyphylaxis. TNF also induced a slight decrease in early myeloid forms in the marrow, but, more strikingly, induced a marked erythroid hyperplasia of late normoblasts, although no changes other than a slight reticulocytosis were noted in the peripheral red blood cell compartment. IL-1 also induced daily neutrophilia and lymphopenia with no evidence of tachyphylaxis. IL-1 differed from TNF in the induction of a significant myeloid hyperplasia and in the lack of any effect on the erythroid elements of the marrow. The lack of tachyphylaxis to the chronic administration of both TNF and IL-1 suggests that the mechanism of endotoxin-induced tachyphylaxis is not at the level of the effector cell response to these endogenous cytokines. G-CSF induced a biphasic peripheral neutrophilia first peaking on day one, reaching a nadir on day 4, and then rising progressively again until day 7. The low level of neutrophilia on day 4 is not due to marrow depletion of neutrophils secondary to the neutrophil releasing activity of G-CSF because the marrows of G-CSF-treated rats on both days 3 and 7 contained over twice the number of mature neutrophils as controls. Thus, the trough in the neutrophilia induced by G-CSF is postulated to be due to an as-yet unidentified negative feedback mechanism that inhibits neutrophil release from the marrow.

Animals↗
PubMedDate not supplied

Comparative effects of acetylcholine on the reptilian and mammalian aortae.

Responses of the lizard and the rabbit thoracic aortae to acetylcholine were studied. Acetylcholine (ACh) (10 nM-100 microM), carbachol (10 nM-50 microM) and PGF2 alpha (100 nM-100 microM) produced concentration-dependent contractions of the lizard thoracic aorta (LTA) with rapid tachyphylaxis. On the other hand, acetylcholine and carbachol relaxed the rabbit thoracic aorta (RTA) dose-dependently. There was no tachyphylaxis. Tachyphylaxis in the LTA was prevented by indomethacin (1 microM) or by rubbing the endothelium. Endothelial removal abolished ACh-induced relaxation of the RTA. Relaxation of the RTA and contractions of LTA were blocked by atropine, pirenzepine, acetoxy-N-methyl-piperidine methbromide (4-DAMP) and diltiazem. Removal of the endothelium rendered RTA insensitive to ACh. However, ACh-induced contractions of the LTA were not so influenced by removal of endothelial cells. It is concluded that the lizard thoracic aorta releases a metabolite of arachidonic acid that mediates tachyphylaxis. Relaxation of the RTA after ACh is mediated via the release of endothelium-dependent relaxing factor.

Acetylcholine↗
PubMed1988

Calcitonin gene-related peptide and tachykinins in relation to local sensory control of cardiac contractility and coronary vascular tone.

The possible role of peptides locally released from sensory nerves in the control of cardiac contractility and the coronary vascular tone was investigated in the present study. Immunohistochemical investigations revealed that calcitonin gene-related peptide (CGRP) -like immunoreactivity (-LI) was colocalized in sensory ganglia and in nerve fibres in the heart with substance P (SP) -LI. CGRP-LI was associated with myocardial cells, blood vessels and epicardia and endocardia in the atria while in the ventricles, CGRP-LI was mainly seen close to blood vessels and very few fibres were present in the myocardium. The level of CGRP-LI was three to four times higher in the right atria than in the ventricles. The tissue content of CGRP-LI was markedly reduced by systemic pretreatment with capsaicin, suggesting a sensory origin. Activation of capsaicin-sensitive cardiac C-fibres by K+, nicotine, bradykinin, ouabain and ischaemia was associated with a release of CGRP as indicated by an increased overflow from the isolated perfused guinea-pig heart. In addition, K+ and capsaicin induced the release of neurokinin A. Nicotine and K+ evoked the release of neuropeptide Y, which is present in sympathetic nerves. CGRP induced a prolongation of the action potential plateau phase in atrial myocytes, increased the velocity of relaxation and evoked positive chronotropic and inotropic effects. Capsaicin induced electrophysiological and contractile effects similar to those of CGRP. Furthermore, specific high affinity binding sites for CGRP were demonstrated in the rat heart and in the atrium CGRP stimulated adenylate cyclase activity. The capsaicin effects were abolished after systemic capsaicin pretreatment, which did not influence the stimulatory effects of CGRP or noradrenaline (NA), however. Repeated administration of CGRP to the same atrial preparation induced tachyphylaxis. After CGRP tachyphylaxis the stimulatory effects of capsaicin but not of NA were absent. The stimulatory actions of capsaicin on atrial contractility therefore seem to be evoked by CGRP. The inhibitory effects of capsaicin on ventricular contractility were not dependent on mediators released from capsaicin-sensitive sensory nerves. CGRP, SP and capsaicin induced coronary vasodilatation in the pig in vivo and in vitro. The vasodilatory effect of SP was subject to rapid tachyphylaxis and endothelium-dependent. Neither the CGRP- nor the capsaicin-induced relaxation was influenced by SP tachyphylaxis or removal of the endothelium. It is therefore suggested that CGRP is a more likely candidate than SP as a causative agent in the vasodilatory response seen upon activation of cardiac sensory nerves.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1993

Role of prostanoids in the regulation of central cholinergic receptor sensitivity.

Tachyphylaxis develops to the hypertensive response to central (i.c.v.) injection of carbachol in conscious rats. This pressor response exhibits tachyphylaxis if the injection is repeated within 8 hr of the first injection. Blockade of brain prostaglandin synthesis with indomethacin does not inhibit the pressor response to carbachol in naive rats, but eliminates the pressor response to carbachol when the muscarinic agonist is repeated within a few hours of the first injection. If the time interval is extended to permit return of the full response (i.e., 24 hr later), indomethacin no longer inhibits the pressor response. The related cyclooygenase inhibitor meclofenamate produced effects which were identical to those of indomethacin, but at approximately 10-fold higher doses. When shorter acting drugs (duration of action < 30 min), physostigmine or arecoline, were used according to the same paradigm, indomethacin was less effective at inhibiting the pressor response to the second injection, even when the two agonist injections were spaced only 30 min apart. The ability of indomethacin to enhance central muscarinic receptor tachyphylaxis was also observed in carbachol-induced hypothermia. The density of diencephalic muscarinic receptors was estimated by using N-[3H]methylscopolamine as a probe. Carbachol-induced a down-regulation of muscarinic receptors, and indomethacin increased the extent of this down regulation. These findings suggest that prostaglandins play a role in the development of tachyphylaxis to brain muscarinic receptor stimulation: activation of prostaglandin synthesis may decelerate the development of desensitization to muscarinic agonists.

Animals↗
PubMed1995

Structure-activity relationships of endothelin-1 analogues.

The importance of residues 9 and 10 for endothelin-1 (ET-1) biologic activity was assessed by studying the responses of the guinea pig ileum to [Ala9]-ET-1 and [Ala10]-ET-1. Both analogues induced relaxation followed by contraction. [Ala9]-ET-1 showed similar ED50 value and maximal response to those of ET-1, whereas [Ala10]-ET-1 had a larger ED50 value and was a partial agonist, as was IRL1620. ET-1 and [Ala10]-ET-1 induced similar degrees of tachyphylaxis, whereas [Ala9]-ET-1 induced very little tachyphylaxis, indicating that Lys9 is important for inducing tachyphylaxis. BQ-123, an ETA antagonist, did not inhibit the relaxation. It did inhibit [Ala9]-ET-1- and ET-1-induced contractions but not [Ala10]-ET-1- and IRL1620-induced contractions. Cross-tachyphylaxis and additivity studies indicated that [Ala9]-ET-1, like ET-1, acts at the ETA receptor, whereas [Ala10]-ET-1 behaved as an ETB receptor agonist, like sarafotoxin S6c. Therefore, the residue at position 10 plays a significant role in receptor activation and is a candidate for further exploration of receptor antagonism. FCE27037 (cyclo [D-Cys11-Cys15]-ET-1[8-21]) inhibited the contractile but not the relaxant component of the response induced by IRL1620. These results indicate that FCE27037 is a new ETB antagonist and a useful tool that can discriminate pharmacologically the functionally distinct ETB receptors present in the guinea pig ileum.

Animals↗
PubMed1994

Interrelation of coronary effects of atrial natriuretic peptide and the renin-angiotensin system in the isolated perfused rat heart.

The coronary vascular effect of atrial natriuretic peptide is controversial: Coronary vasodilator as well as constrictor effects have been reported. The controversy may originate from interference of atrial natriuretic peptide with the renin-angiotensin system and/or tachyphylaxis of the effect of atrial natriuretic peptide. The effect of alpha-human atrial natriuretic peptide bolus application on changes of coronary flow was examined in the isolated, constant-pressure perfused rat heart. Six groups were considered: (1) control group; groups in which the renin-angiotensin system was modulated by pretreatment with continuous infusion of: (2) angiotensin II, (3) the angiotensin converting enzyme inhibitor captopril (4) the angiotensin II receptor blocker saralasin; and groups in which tachyphylaxis was examined by pretreatment with ANP, (5) as continuous infusion and (6) as bolus application. First, in control hearts, dose-response curves were obtained for single ANP dosages of 1-100 nmol. The effect of high dosages (40 and 100 nmol) was biphasic, with an initial vasodilator and subsequent long-lasting vasoconstrictor component. Hearts in which coronary flow was reduced by approximately 18% through continuous angiotensin II infusion showed an enhanced early vasodilator response after ANP administration, whereas the vasoconstrictor effect was no longer observable. Angiotensin converting enzyme inhibition and angiotensin II receptor blockade reduced the vasodilator effect of ANP. In addition, saralasin nearly abolished ANP-induced vasoconstriction, whereas vasoconstriction was unaltered by pretreatment with captopril. Captopril or saralasin alone did not change coronary flow, heart rate and left ventricular developed pressure. In groups (5) and (6). ANP bolus application showed significantly reduced vasomotor activity. We conclude that in the isolated rat heart. ANP has a biphasic effect with early vasodilation and late vasoconstriction. Both effects can be modulated by inhibition of the renin-angiotensin system at different levels indicating that vasomotor ANP effects result from interaction of ANP with the local renin-angiotensin system. ANP effects can be markedly reduced by tachyphylaxis.

Angiotensin II↗
PubMed1976

A comparison of the effects of angiotensin II and heptapeptide on smooth muscle (vascular and uterine).

On the rabbit isolated aorta, dose-dependent contractions to both angiotensin II and heptapeptide ([des-Asp1]-angiotensin II) were obtained. The curves were parallel, and reached the same maximum level. On the rat isolated uterus, angiotensin II and the heptapeptide displayed non-parallel dose-response curves. Results obtained with angiotensin-analog antagonists and cross-tachyphylaxis experiments suggest that the heptapeptide and angiotensin II act, preferentially, on different populations of receptors in the uterus. The difference in action of indomethacin on recovery from tachyphylaxis to angiotensin II and heptapeptide on rat isolated aorta suggests that the mechanism of induction of tachyphylaxis by these two peptides may differ. SQ 20881, the angiotensin converting enzyme inhibitor, totally inhibited uterine responses to both decapeptide and nonapeptide, while slightly potentiating those to angiotensin II and heptapaptide. Indomethacin had no significant effect on uterine responses to either angiotensin II or the heptapeptide.

Angiotensin II↗
PubMed1985

Acute tolerance to clonidine hypotension and bradycardia in normotensive and hypertensive rats.

Tolerance to the antihypertensive effect of clonidine has been observed in humans but there are few studies showing either acute or chronic tolerance to clonidine hypotension in experimental animals. We determined whether tachyphylaxis to acute clonidine hypotension could be demonstrated in normotensive Sprague Dawley rats by i.v. injections of 2 repetitive clonidine doses of either 1.5, 3.0, 5.0, or 10.0 micrograms/kg, or in SHR rats by repeated intracerebroventricular injections of 1.5 or 3.0 micrograms/kg, while monitoring arterial blood pressure. Second doses of clonidine were given 30 minutes after recovery of arterial pressure from the first dose. At 3.0 micrograms/kg and greater, the hypotension produced by the second dose was at least 50% less than that elicited by the first dose. By contrast, no acute tachyphylaxis was observed to the decrease in tension caused by clonidine in the transmurally stimulated isolated guinea pig ileum after 2 repeated exposures to clonidine, with intervening wash, at concentrations between 5 X 10(-10) M to 5 X 10(-8) M. Also, no tachyphylaxis occurred to the initial hypertensive phase of clonidine in Sprague Dawley rats.

Animals↗
PubMedDate not supplied

Neurotensin-related peptides inhibit spontaneous longitudinal contractions of porcine distal jejunum.

The tridecapeptide neurotensin (NT) and its C-terminal homologs, including xenopsin (XP) and neuromedin N (NM-N), reduced the amplitude of spontaneous contractions in longitudinal smooth muscle strips from the porcine distal jejunum in vitro. The rank order of potency (IC50 in nM) was XP (0.1) greater than NT (0.9) approximately avian XP (1.0) greater than NM-N (1.6), which could not be explained on the basis of differential peptide degradation. Tachyphylaxis and cross-tachyphylaxis were observed after repeated NT and XP addition to muscle strips. The action of NT was mimicked by norepinephrine (NE), but not by opioid peptides, somatostatin, or vasoactive intestinal peptide. NE was nearly 100-fold less potent than NT and did not produce a state of tachyphylaxis to NT. The effects of NT and NE were unaltered by the neuronal conduction blocker tetrodotoxin (70 nM). However, the actions of NE, unlike those of NT, were reduced by the alpha-adrenoceptor blocker phentolamine (70 nM), the K(+)-channel blocker apamin (7 nM) and the Ca2(+)-channel blocker verapamil (0.7 microM). These results suggest that NT and related peptides, through a nonadrenergic mechanism, interact with smooth muscle receptors to modulate jejunoileal motor function in the pig.

Animals↗
PubMed1988

Trans-2-carboxy-3-pyrrolidineacetic acid (CPAA), a novel agonist at NMDA-type receptors.

Although 2-carboxy-3-pyrrolidineacetic acid (CPAA) analogs are associated with activity as agonists at kainate-type receptors, here we report that CPAA is an agonist at N-methyl-D-aspartic acid-type receptors. CPAA evoked the release of [3H]acetylcholine (ACh) from striatal slices with the same efficacy as NMDA, and an EC50 of 20.0 microM, compared to an EC50 of 45.8 microM for NMDA. CPAA-evoked [3H]ACh release was inhibited by CPP (IC50 = 5.1 microM), tiletamine (IC50 = 0.53 microM), MK-801 (IC50 = 0.12 microM), and MgCl2 (IC50 = 26 microM). CPAA produced a tachyphylaxis when applied continuously for 18 min or more, and a cross-tachyphylaxis to NMDA. Similarly, NMDA generated a cross-tachyphylaxis to CPAA. All of these data suggest that CPAA is an agonist at NMDA-type receptors.

Acetylcholine↗
PubMed1987

Multiple tachykinin pools in sensory nerve fibres in the rabbit iris.

A population of sensory nerve fibres in the rabbit iris is known to contain calcitonin gene-related peptide and tachykinins, such as substance P and neurokinin A. In the presence of atropine and guanethidine, the isolated iris sphincter responded to electrical stimulation with a contraction that could be abolished by tachykinin antagonists. Capsaicin, known to release tachykinins from sensory fibres, evoked a long-lasting tachykinin-mediated contraction of the iris sphincter. Repeated application of capsaicin led to tachyphylaxis, possibly reflecting depletion of releasable neuronal stores of tachykinins. At this stage, electrical stimulation failed to elicit contraction. The capacity of capsaicin to release neuropeptides from sensory fibres was confirmed by determination of substance P- and calcitonin gene-related peptide-like immunoreactivity in the incubation medium and in the iris tissue. The concentrations of substance P and calcitonin gene-related peptide in the iris after capsaicin exposure were reduced by about 25%. Like capsaicin, bradykinin evoked a tachykinin-mediated contraction and tachyphylaxis. However, after development of tachyphylaxis to bradykinin, electrical stimulation or exposure to capsaicin still evoked tachykinin-mediated contraction, albeit a reduced one compared with the response before bradykinin. Hence, capsaicin completely depletes tachykinin stores releasable by prolonged electrical stimulation, whereas bradykinin exhausts only a sequestered pool. The possibility that tachykinins occur in several releasable pools in sensory nerves was investigated in yet another way: the iris sphincter muscle was stimulated electrically once every 2.5 min over several hours. The contractile response diminished gradually.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Different responses to repeated applications of zingerone in behavioral studies, recordings from intact and cultured TG neurons, and from VR1 receptors.

When applied repetitively to the cornea, capsaicin, the pungent compound in hot pepper, causes an initial eye-wiping response that diminishes upon repeated exposure (tachyphylaxis). This diminution, however, is not observed upon repetitive application of its pungent analogue, zingerone, to the cornea or tongue. In addition, compared with capsaicin, the lingual application of zingerone produces a gustatory response with a shorter latency and duration. Because both the tongue and the cornea are innervated by the trigeminal nerve, and because zingerone and capsaicin are structurally related, it is not evident why the responses to these compounds should give such different behavioral and psychophysical endpoints. We have addressed this issue by measuring the neural responses from rat trigeminal ganglion neurons (TG) to repeated applications of zingerone applied to the cornea, from cultured rat TG neurons, and from cloned capsaicin receptors (VR1) expressed in Xenopus oocytes and then comparing these effects to those evoked by capsaicin. Extracellular recordings from the trigeminal ganglion revealed that the responses to repeated corneal applications of 30 mM zingerone show desensitization. Cultured TG neurons, and oocytes expressing VR1 receptors, were also desensitized by repeated applications of zingerone. Electrophysiological recordings revealed that these two vanilloids could activate the same receptor (VR1), currents in the same neuron, and crossdesensitize. The more rapid onset and shorter duration responses seen with zingerone (compared with capsaicin) provides a rationalization for its more rapid onset and shorter duration gustatory response. We attribute the different behavioral responses to periodic applications of these two agonists to two competing effects: one leading to sensitization, and the other to tachyphylaxis. Which of these dominates depends on the concentration, exposure time, and interstimulus interval. Consequently, whether or not zingerone will exhibit tachyphylaxis depends critically on the experimental conditions.

Animals↗
PubMed1984

Calcium pools in the contraction of arterial smooth muscle induced by several agonists.

After perfusing the vascular circuit of the mesenteric artery of the rat with a Ca-free solution for 20 min, extracellular Ca was depleted, and the vasoconstrictor effect of high K solutions was abolished, while the vasopressin response was reduced by 40%, serotonin by 30% and noradrenaline and adrenaline responses by about 20%. When the Ca-free perfusion was prolonged for 2 h or more, the vascular responses to the agonists were further reduced due to depletion of cellular Ca. Successive doses of each agonist injected at 1 min intervals showed a decline of the responses, that recovered when 4 min or more were allowed to pass after the last injection. This reversible desensitization or tachyphylaxis was rapidly abolished by Ca. Noradrenaline and adrenaline showed crossed tachyphylaxis, which depressed the responses to serotonin and vasopressin. Tachyphylaxis to serotonin and vasopressin did not depress the response to the other two agonists. These findings support the conclusion that not only do noradrenaline and adrenaline share a Ca pool, but that so do serotonin and vasopressin. These two agonists each require a separate Ca pool.

Animals↗
PubMed2005

Peroxynitrite elicits dysfunction of stereoselective s-nitrosocysteine recognition sites.

The aim of this study was to determine whether induction of tachyphylaxis to peroxynitrite (induced by giving 10 intravenous injections of a 10-micromol/kg dose) differentially affects the vasodilator responses elicited by systemic injections of the L- and D-isomers of S-nitrosocysteine (L-SNC and D-SNC), in pentobarbital-anesthetized rats. L- and D-SNC (12.5-200 nmol/kg, iv) elicited dose-dependent reductions in hindquarter, mesenteric, and renal vascular resistances. The L-SNC-induced vasodilator responses in the hindquarter and renal vascular beds were virtually abolished whereas the vasodilator responses in mesenteric bed were markedly diminished after administration of peroxynitrite. The D-SNC-induced vasodilator responses in the hindquarter and renal beds were slightly attenuated whereas the vasodilator responses in the mesenteric bed were not diminished after administration of peroxynitrite. The vasodilator responses elicited by the nitric oxide donor, MAHMA NONOate (5-50 nmol/kg, iv), were not attenuated by peroxynitrite. The finding that induction of tachyphylaxis to peroxynitrite diminishes the effects of L- and D-SNC but not MAHMA NONOate suggests that the stereoisomers exert their vasodilator effects by mechanisms other than their decomposition to nitric oxide. Moreover, the finding that induction of tachyphylaxis to peroxynitrite causes a more pronounced attenuation of the vasodilator effects of L- than D-SNC supports evidence that the stereoisomers differentially interact with stereoselective S-nitrosothiol recognition sites in the vasculature. Taken together, these novel results support the possibility that peroxynitrite diminishes the vasodilator potencies of L- and D-SNC by oxidation and/or nitration of amino acids in these recognition sites.

Animals↗