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PubMed1975

The skeletal muscle response to the repeated administration of suxamethonium and its interaction with edrophonium in anaesthetised man.

Tetanic and single twitch contractions of the adductor pollicis muscle in man were recorded during repeated injections of suxamethonium (0.2 mg/kg or 0.1 mg/kg) every 15 minutes. 2 Tachyphylaxis to suxamethonium developed rapidly in every patient studied when single twitch contractions were observed but tetanic contractions later showed an increasingly prolonged recovery with repeated injections. 3 Edrophonium administered at the point of 50% recovery of the tetanic contractions in patients given suxamethonium (0.2 mg/kg) repeatedly first potentiated the blockade but when the tachyphylaxis had developed fully on the single twitch, usually after the third or fourth injection, the blockade of the tetanic contractions was reversed. 4 These findings indicate that the tachyphylaxis and the change in the nature of the blockade produced by suxamethonium in man take place at the same time and might be part of the same phenomenon.

Aged↗
PubMed1988

Homocysteic acid as a putative excitatory amino acid neurotransmitter: I. Postsynaptic characteristics at N-methyl-D-aspartate-type receptors on striatal cholinergic interneurons.

The actions of the stereoisomers of homocysteic acid (HCA) were characterized at N-methyl-D-aspartate (NMDA)-type receptors which mediate excitatory amino acid-evoked [3H]acetylcholine ([3H]ACh) release from striatal cholinergic interneurons. Like NMDA, L-HCA and D-HCA evoked the release of [3H]ACh formed from [3H]choline in striatal slices. The concentration-response curve for L-HCA was virtually superimposable on that for NMDA, yielding an equal EC50 value (56.1 microM) and maximal response. However, D-HCA was weaker, with an EC50 value of 81.1 microM, and an apparently smaller maximal response. L-HCA-evoked [3H]ACh release was inhibited by the same categories of compounds which inhibit NMDA-evoked [3H]ACh release: the divalent ion Mg2+ (IC50 = 25.8 microM); competitive NMDA antagonists 2-amino-7-phosphonoheptanoate (IC50 = 51.2 microM) and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (IC50 = 20.1 microM); and the dissociative anesthetics tiletamine (IC50 = 0.59 microM) and MK-801 (IC50 = 0.087 microM). Like NMDA, L-HCA produced a tachyphylaxis in this system. Tachyphylaxis to NMDA resulted in a decrease response to L-HCA, and conversely, tachyphylaxis to L-HCA resulted in a decrease response to NMDA. The results suggest that L-HCA is an agonist at the NMDA-type receptor and may represent an endogenous ligand for this excitatory amino acid receptor.

2-Amino-5-phosphonovalerate↗
PubMed1998

An audit of oestrogen implant hormone replacement therapy.

The aim of this review was to determine the factors that impact upon oestradiol levels in patients receiving oestradiol implants and to assess the relationship between symptom scores and oestradiol levels. In addition we sought to determine the incidence of tachyphylaxis (menopausal symptoms in spite of high oestradiol levels) among our patients, and to assess the degree of menstrual cycle control in the nonhysterectomized women receiving implant treatment. We undertook an audit of the medical records of 118 women who received 673 oestradiol implants (50 or 100 mg) over an 8-year period in the menopause clinics at Royal North Shore Hospital. Data on patient age, clinical diagnosis, symptom score, previous or subsequent hysterectomy, oestradiol implant dosage (50 mg or 100 mg), number of doses, oestradiol levels and concurrent testosterone implant insertion were recorded. We found that implant dosage (p<0.001) and implant number (p<0.001) were the factors that significantly impact upon oestradiol levels. Concomitant testosterone implant usage (p=0.74), patient age (p=0.14) and hysterectomy (p=0.57) did not have a statistically significant effect upon oestradiol levels. The incidence of tachyphylaxis was 1.7% (2 patients). There was no relationship between oestradiol levels and symptom scores (p=0.69). Oestradiol implant treatment, when administered on the basis of return of symptoms, without a strict target oestradiol level, results in a steady increase in baseline oestradiol levels. The dosage used and the number of implants received are important factors influencing oestradiol levels. The incidence of tachyphylaxis is low when patients are counselled regarding the lack of agreement between symptom scores and oestradiol levels.

Adult↗
PubMed1986

Effect of alpha, beta-methylene ATP on distal colonic and rectal motility--a possible involvement of P2-purinoceptors in pelvic nerve mediated non-adrenergic, non-cholinergic contraction.

The possible involvement of purinoceptors in the parasympathetic nervous control of large intestinal motility was investigated in cats anaesthetized with chloralose and treated with adrenolytics. Distal colonic and rectal motor responses to efferent pelvic nerve stimulation (PNS) and drugs injected close i.a., were recorded by a volumetric method. Single dose i.a. injections of alpha, beta-methylene ATP (mATP) induced colonic and rectal contractions which were resistant to atropine, hexamethonium and indomethacin, as well as to the nerve blocking agent tetrodotoxin. Repeated injections of mATP were followed by attenuated motor responses and eventually complete tachyphylaxis to the compound developed. In the presence of atropine, or a combination of hexamethonium and atropine, contractions elicited by PNS were inhibited during mATP tachyphylaxis. In contrast, prior to such anticholinergic drugs, or in the presence of hexamethonium alone, pelvic nerve mediated contractions persisted despite mATP tachyphylaxis, which did not affect the colonic and rectal contractions evoked by acetylcholine or histamine. The results suggest that P2-purinoceptors are involved in non-adrenergic, non-cholinergic large intestinal excitatory motor responses to PNS.

Adenosine Triphosphate↗
PubMed1978

Exogenous prostaglandins and gastric secretion in the cat.

1. In the conscious gastric fistula cate PGE2 was shown to produce dose-related inhibition of gastric acid and pepsin secreted in response to pentagastrin, histamine and insulin. 2. PGF2alpha had little effect on pentagastrin-stimulated gastric acid and pepsin secretion. 3PGF2 delayed the tachyphylaxis of gastric acid stimulated by pentagastrin and histamine, but not that stimulated by insulin. 4. Although not delaying tachyphylaxis of insulin stimulated acid, PGE2 delayed tachyphylaxis of insulin stimulated pepsin.

Animals↗
PubMed1977

The difference in effect of predosing with antiallergic compounds between the rat PCA model and the monkey asthma model. Comparison of the effects of PRD-92-Ea and disodium cromoglycate.

DSCG and PRD-92-Ea showed tachyphylaxis in the rat PCA test when a large intravenous dose (40 mg/kg of DSCG and 20 mg/kg of PRD-92-Ea) was given 30 min before administering intravenously the expected effective doses at the time of antigen challenge. This predosing led to a marked loss of effectiveness. Cross-reacting tachyphylaxis was also demonstrated in this model. Predosing rats with DSCG led to a great loss of effectiveness of a subsequent expected active dose of PRD-92-Ea and predosing with PRD-92-Ea had the same effect in preventing the antiallergic action of a subsequent dose of DSCG. The Rhesus monkey (Macaca mulatta) did not exhibit this phenomenon of tachyphylaxis. PRD-92-Ea and DSCG were given intravenously 30 min before and the same dose of 20 mg/kg repeated just before Ascaris suum challenge in the Rhesus monkey asthma model with no loss of their expected effectiveness.

Administration, Oral↗
PubMed1989

Antihypertensive effect of vasopressin withdrawal in young and adult spontaneously hypertensive rats.

The extent to which age influences the effect of prolonged intravenous infusion and withdrawal of arginine vasopressin (AVP) on blood pressure was investigated in spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto controls (WKY) of 6-, 10-, 14-, 18-, and 22-week age groups. The pressor response to AVP (20 ng/kg/min for 3 hours) was relatively well maintained in WKY but showed an age-dependent tachyphylaxis in SHR. After cessation of the infusion, arterial pressure of SHR fell in all age groups. In contrast, withdrawal of AVP in WKY resulted in little or no hypotensive response. Thus, a withdrawal-induced antihypertensive phenomenon (WAP) to AVP was specific to SHR. The magnitude of the WAP was significantly correlated with the level of initial blood pressure in SHR (r = -0.81, p less than 0.001). The magnitude of the tachyphylaxis during the AVP infusion was also correlated with the level of initial blood pressure in SHR (r = -0.66, p less than 0.001). Accordingly, a significant correlation was found between the magnitude of the WAP and the degree of tachyphylaxis to the pressor activity of AVP in SHR (r = 0.69, p less than 0.001). The significance of this is unknown, but it might mean that a common underlying mechanism existed in the expression of the tachyphylactic phenomenon and the WAP in SHR. Finally, an apparent enhancement in the baroreceptor reflex sensitivity was observed in both SHR and WKY during the infusion of AVP, but the magnitude of this enhancement appeared to be greater in SHR than in WKY.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Rapid development of renal resistance to low doses of synthetic bovine parathyroid hormone fragment 1-34. Dissociation of urinary cyclic adenosine monophosphate, phosphaturic, and calciuric responses.

The designing of parathyroid hormone (PTH)-renal dose-response studies in human beings is complicated by the possibility of rapid homologous receptor down-regulation, a phenomenon that is clearly shown to occur in vitro. Large amounts of PTH given to human subjects as serial injections or prolonged infusions cause decreased urinary 3',5'-cyclic adenosine monophosphate (cAMP) responses to subsequent PTH doses, but it is uncertain whether lower doses given over shorter periods similarly cause renal tachyphylaxis to PTH action. Thus, in seven water-loaded adults, we infused in ascending order 10, 30, 75, 150, and 300 U of synthetic bovine PTH fragment 1-34 (bPTH 1-34) per 70 kg body wt over 15 min on widely separated days ("separate day administration"). On another day, each subject received all five 15-min doses in ascending order at 75-min intervals ("single day administration"). Urine collection intervals were control, 0-30 min (including the PTH infusion), and 30-60 min. Peak nephrogenous cAMP (NcAMP, nmol/100 ml glomerular filtrate) response was linearly related to the dose of PTH (separate day study, r = 0.94, P less than 0.001; single day study, r = 0.88, P less than 0.001). However, the slope of NcAMP responses plotted against PTH dose for the single day study was only 36% of that derived from separate day administration of the same PTH doses (P less than 0.001). After only 40 U (10 + 30) of bPTH 1-34/70 kg, the NcAMP response to 75 U was reduced 44%, and the effect of 300 U/70 kg, when given as the last of the sequential single day infusions, was 64% less than the response to 300 U of bPTH 1-34 given alone (P less than 0.001). The phosphaturic response (fractional excretion of phosphorus, FEP [percent]) was also linearly related to bPTH 1-34 dose, but combined administration of the PTH infusions on one day increased FEP at each dose identically with the effects of separate day administration. A transient, dose-related, early hypercalciuric response to bPTH 1-34 also occurred, and was of equal magnitude in both protocols. These studies demonstrate that significant blunting of the NcAMP response to bPTH 1-34 occurs rapidly and follows brief exposure to relatively low doses of hormone. In contrast, there is no effect of recent PTH administration on the phosphaturic and early hypercalciuric actions of bPTH 1-34. This seeming dissociation of PTH effects makes unclear the physiologic importance of PTH-induced cAMP tachyphylaxis in the regulation of final PTH actions. In any case, studies of NcAMP responses in which the occurrence of tachyphylaxis would be undesirable should be designed to avoid prolonged or closely spaced administrations of the hormone.

Adult↗
PubMed1990

Implication of polymodal receptor activities in intraocular pressure elevation by neurogenic inflammation.

We studied, using anesthetized albino rabbits, whether polymodal receptors are responsible for rise in the intraocular pressure (IOP) caused by algesic substances, and also whether substance P (SP) is involved in this phenomenon. Intracameral administration of bradykinin (BK), SP, hypertonic saline, and hypertonic glucose caused an IOP rise. The IOP responses to BK and hypertonic saline were reduced by benoxinate, but aspirin reduced only the response to BK. Repeated applications of BK caused a decrease in subsequent responses (tachyphylaxis). These results are consistent with the characteristics of responses of polymodal receptors, and suggest that these IOP responses are produced by neurogenic inflammation. The IOP response to SP also showed tachyphylaxis, but after the tachyphylaxis to SP had been established, subsequent intracameral administration of BK still produced a marked rise in IOP. Moreover, the administration of SP into the posterior chamber, which is known to be the site of the blood-aqueous barrier, caused a much smaller rise in the IOP. These observations indicate that the IOP response to algesic substances might be caused by activation of the polymodal receptors, and that SP might not be a mediator in these responses.

Animals↗
PubMed1991

Antagonism of calcitonin gene-related peptide (CGRP) by human CGRP-(8-37): role of CGRP in internal anal sphincter relaxation.

We performed functional studies on the opossum internal anal sphincter (IAS) smooth muscle strips and receptor binding studies in the IAS smooth muscle membranes to examine the influence of: human calcitonin gene-related peptide (CGRP)-(8-37) on the fall in IAS tension caused by human CGRP I and CGRP II and on [125I]human CGRP I binding on the IAS smooth muscle membranes. We also compared the ability of [Tyr0]-rat CGRP 28-37 to displace the radioligand from the IAS membranes to that of human CGRP-(8-37). Human CGRP-(8-37) caused significant and dose-dependent right-ward shifts of the dose-response curves of both CGRP I and CGRP II on the IAS smooth muscle. The specific binding of [125I]human CGRP I to IAS smooth muscle membranes was time- and temperature-dependent. CGRP antagonists human CGRP-(8-37) and [Tyr0]-rat CGRP 28-37 and CGRP I and CGRP II caused dose-dependent displacement of the radioligand. Vasoactive intestinal polypeptide and calcitonin on the other hand had no significant effect on the radioligand binding. Tachyphylaxis and cross tachyphylaxis to the effects of CGRP I and CGRP II were observed. The CGRP antagonists and CGRP I and CGRP II tachyphylaxis failed to modify the fall in the IAS tension in response to neural stimulation by electrical field stimulation. From these studies we conclude: human CGRP-(8-37) and [Tyr0]-rat CGRP 28-37 may serve as potential antagonists of CGRP action; human CGRP I and CGRP II may act on the same receptor on the IAS smooth muscle; and CGRP may not play a significant role in the IAS relaxation in response to electrical field stimulation.

Anal Canal↗
PubMed1989

Formoterol, a new long-acting bronchodilator for inhalation.

The aim of this study was to evaluate if treatment with inhaled formoterol is appreciated by asthmatics and whether it causes tachyphylaxis. Twenty stable asthmatics were included in a randomized, double-blind, crossover study. They were treated for two weeks either with formoterol or salbutamol, with one week washout inbetween. They were given 12 micrograms formoterol or 200 micrograms salbutamol twice daily and instructed to use additional spray doses on demand. On a diary card they recorded the number of doses, asthma symptoms and peak expiratory flow rate (PEFR) before every dose. Forced expiratory volume in one second (FEV1) dose-response curves for salbutamol (total dose 1.3 mg) were performed before and after each treatment period to evaluate development of tachyphylaxis. There was a significant difference in favour of formoterol concerning symptoms, PEFR recordings, spray consumption, and preference. Fifteen patients preferred formoterol and two salbutamol. The dose-response curves before formoterol and before, as well as after salbutamol were almost identical. After formoterol the curve had changed; both basal and maximum values were higher than before. Thus, no evidence of tachyphylaxis was found, compared to the ordinary beta-stimulant treatment.

Administration, Inhalation↗
PubMed1981

[Effect of predosing with Y-12,141 on its antiallergic activity. --Studies on anti-allergic agents(IV)-- (author's transl)].

Y-12, 141 (0.1 approximately 0.3 mg/kg) given i.v. 1 min before the antigen challenge inhibited both the 48-hour passive cutaneous anaphylaxis (PCA) and active anaphylactic bronchoconstriction of rats mediated by IgE-like antibody. The anti-PCA activity of Y-12, 141 (0.3 mg/kg i.v.) given 1 min before the antigen challenge decreased significantly by predosing with Y-12, 141 (1 approximately 3 mg/kg i.v.) 60 min before the antigen challenge. The induction of tachyphylaxis in the PCA test appeared to depend on the doses in internal between predosing and second dosing. The anti-PCA activity of disodium cromoglycate (DSCG) at a dose of 1 mg/kg i.v. decreased significantly by predosing with DSCG (10 mg/kg i.v.) 30 min before the antigen challenge. Cross-tachyphylaxis between Y-12, 141 and DSCG was observed in the PCA test. The tachyphylaxis to Y-12, 141 was more readily induced in the PCA than in the bronchoconstriction. The inhibitory activity of Y-12, 141 (0.3 mg/kg i.v.) given 1 min before the antigen challenge in the PCA and bronchoconstriction was not affected by predosing with Y-12, 141 (1 mg/kg p.o. or s.c.) for 7 days.

Animals↗
PubMedDate not supplied

Chronic exposure to lidocaine does not alter flux through sodium channels in cultured neuronal cells.

BACKGROUND AND OBJECTIVES: Although tachyphylaxis to local anesthetics has been reported in the clinical literature for more than two decades, the molecular mechanism(s) remain unknown. The authors described an attempt to create an in vitro model for tachyphylaxis to local anesthetics using cultured neuronal cells. METHODS: Murine neuroblastoma cells (N1E115) and rat pheochromocytoma cells (PC-12) were grown in the presence or absence of lidocaine or tetrodotoxin for between 1 and 14 days. Thereafter, the authors tested flux through sodium channels by measuring total and tetrodotoxin-sensitive flux of 14C-labeled guanidinium (a ligand for the sodium channel) into the cells using the technique of Jacques et al. RESULTS: Chronic lidocaine or tetrodotoxin treatment caused no change relative to control cells in total or tetrodotoxin-sensitive guanidinium flux, or in the subsequent ability of lidocaine in the flux assay mixture to inhibit guanidinium flux. CONCLUSIONS: The authors concluded that chronic lidocaine or tetrodotoxin application did not produce changes in stimulated sodium channel activity or subsequent lidocaine susceptibility in this model. To the extent that this model simulated the clinical situation, mechanisms other than up-regulation of sodium channel number or maximal stimulated flux per channel may have been responsible for producing tachyphylaxis.

Animals↗
PubMed1997

The role of calcium in the desensitization of capsaicin responses in rat dorsal root ganglion neurons.

Capsaicin (Cap) is a pungent extract of the Capsicum pepper family, which activates nociceptive primary sensory neurons. Inward current and membrane potential responses of cultured neonatal rat dorsal root ganglion neurons to capsaicin were examined using whole-cell and perforated patch recording methods. The responses exhibited strong desensitization operationally classified as acute (diminished response during constant Cap exposure) and tachyphylaxis (diminished response to successive applications of Cap). Both acute desensitization and tachyphylaxis were greatly diminished by reductions in external Ca2+ concentration. Furthermore, chelation of intracellular Ca2+ by addition of either EGTA or bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid to the patch pipette attenuated both forms of desensitization even in normal Ca2+. Release of intracellular Ca2+ by caffeine triggered acute desensitization in the absence of extracellular Ca2+, and barium was found to effectively substitute for calcium in supporting desensitization. Cap activated inward current at an ED50 of 728 nM, exhibiting cooperativity (Hill coefficient, 2.2); however, both forms of desensitization were only weakly dependent on [Cap], suggesting a dissociation between activation of Cap-sensitive channels and desensitization. Removal of ATP and GTP from the intracellular solutions resulted in nearly complete tachyphylaxis even with intracellular Ca2+ buffered to low levels, whereas changes in nucleotide levels did not significantly alter the acute form of desensitization. These data suggest a key role for intracellular Ca2+ in desensitization of Cap responses, perhaps through Ca2+-dependent dephosphorylation at a locus that normally sustains Cap responsiveness via ATP-dependent phosphorylation. It also seems that the signaling mechanisms underlying the two forms of desensitization are not identical in detail.

Adenosine Triphosphate↗
PubMed1988

Actions of calcitonin gene-related peptide and tachykinins in relation to the contractile effects of capsaicin in the guinea-pig and rat heart in vitro.

1. The effects of calcitonin gene-related peptide (CGRP), neurokinin A (NKA), neuropeptide K (NPK) and substance P (SP) on contractility of the guinea-pig and rat heart were studied in vitro in relation to the response to capsaicin. 2. Human (h) CGRP alpha (alpha) and beta (beta) were equipotent in stimulating the contractile force and rate of the spontaneously beating guinea-pig right atrium. 3. Both NKA and NPK inhibited contractile force and rate in the guinea-pig atrium whilst a mainly negative chronotropic effect was observed in the whole heart. SP did not influence cardiac contractility. 4. Human CGRP alpha and beta mimicked the contractile effects of capsaicin in the guinea-pig atrium. In the whole heart preparation, hCGRP alpha and capsaicin increased heart rate whereas capsaicin also evoked an atropine-resistant inhibition of contractile force. The stimulatory effect of capsaicin on heart rate was absent after systemic capsaicin pretreatment, while the inhibition of ventricular contractile tension remained unchanged. 5. Extended incubation with hCGRP alpha or beta was associated with development of cross-tachyphylaxis between these two agents in the guinea-pig atrium. However, CGRP tachyphylaxis did not change the atrial response to noradrenaline, forskolin or NKA. The stimulatory effects of capsaicin on atrial contractility were absent after tachyphylaxis to hCGRP alpha or beta. 6. There was no detectable supersensitivity to the stimulatory effects of rat (r) CGRP alpha on the spontaneously beating atrium after capsaicin pretreatment of adult or neonatal rats. In conclusion the present data provide further evidence that the capsaicin-induced stimulation of atrial contractility is due to local release of CGRP.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1984

Capsaicin-induced stimulation of the guinea-pig atrium. Involvement of a novel sensory transmitter or a direct action on myocytes?

The mechanism underlying the positive inotropic and chronotropic effects of capsaicin were investigated using the spontaneously beating guinea-pig atrium in vitro. Capsaicin induced a long-lasting stimulatory effect (threshold dose 10(-9) M). Tetrodotoxin, phentolamine, 6-OHDA, mepyramine plus cimetidine, methysergide-, indomethacin-, somatostatin- or morphine pretreatment and local treatment with capsaicin on the vagal nerves did not reduce the capsaicin response, while it was abolished up to 1 month after systemic capsaicin pretreatment. The capsaicin response was subject to a rapid tachyphylaxis. During capsaicin tachyphylaxis, the positive inotropic and chronotropic effects of noradrenaline, serotonin and histamine were unchanged. Various neuropeptides were investigated with regard to cardiac activity. Physalaemin, eledoisin and somatostatin had negative inotropic and chronotropic effects. Substance P, bombesin, kassinin, CCK-8 or PHI (up to 10(-6)M of each) did not cause any detectable response on the guinea-pig auricle, while the substance P antagonist [D-Arg, D-Pro, D-Trp, Leu]SP induced a long-lasting stimulation of heart activity, VIP also stimulated the heart. Various adenyl compounds were also tested. Adenosine, AMP, ADP, ATP and beta-, gamma-methylene ATP had negative chronotropic and inotropic effects, while alpha-, beta-methylene ATP induced a stimulatory response. During alpha-, beta-methylene ATP tachyphylaxis, the auricles still responded to capsaicin. The inhibitory effects of adenosine and ATP analogues were antagonized by theophylline and 8-p-sulfophenyl theophylline. Capsaicin induced a small release of labelled nucleotides from 3(H)-adenine-prelabelled atria from control, but not from capsaicin-pretreated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1985

Calcitonin gene-related peptide (CGRP) and capsaicin-induced stimulation of heart contractile rate and force.

The effects of calcitonin gene-related peptide (CGRP) on guinea-pig heart contractility were investigated in vitro in relation to the response of capsaicin and noradrenaline (NA). Synthetic rat CGRP (greater than 10(-8) M) caused a long-lasting, positive inotropic and chronotropic effect on the spontaneously beating right atrium. The response to CGRP mimicked the effects of capsaicin and was resistant to beta-adrenoceptor blockade using metoprolol. Furthermore, CGRP did not change basal efflux or the release of 3H-NA induced by transmural nerve stimulation, suggesting an action independent of sympathetic mechanisms. Mepyramine and cimetidine did not reduce the response to CGRP. After tachyphylaxis to the effects of CGRP (5 X 10(-7) M) which developed within 15-20 min, the positive inotropic and chronotropic atrial response to capsaicin was abolished. The effects of NA, however, were not influenced by CGRP tachyphylaxis. In the isolated perfused whole heart, CGRP had more pronounced stimulatory effects on ventricular contractile rate than on force compared to NA. The CGRP response was resistant to metoprolol and still present in capsaicin-pretreated animals. Capsaicin caused a slight initial inhibition of ventricular contractility, which was followed by a marked stimulatory action. As for CGRP, the cardioexcitatory response to capsaicin was more pronounced on rate than on force. The stimulatory responses to capsaicin were absent 2 weeks after systemic capsaicin pretreatment. In conclusion, CGRP mimics the non-adrenergic, cardioexcitatory effects of capsaicin, and the capsaicin response is absent after CGRP tachyphylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Evidence for a capsaicin-sensitive vasomotor mechanism in the ventral medullary chemosensitive area of the cat.

The effects of capsaicin applied to the exposed ventral surface of the medulla were studied on the mean arterial blood pressure, heart rate, respiration and sympathetic efferent nerve activity in chloralose-urethane-anaesthetized cats. The application of capsaicin produced a marked increase in the mean arterial blood pressure and sympathetic nerve activity, but not in the heart rate. The "intermediate area" proved to be the most sensitive to capsaicin. Pressor responses could be elicited repeatedly; tachyphylaxis was not noted provided a time interval of 30 min elapsed between consecutive applications. Repeated applications of capsaicin at intervals of less than 30 min led to tachyphylaxis. However, pressor responses evoked by either topical application of glutamate or pentamethylene-tetrazole or bilateral carotid occlusion could invariably be demonstrated during this period of tachyphylaxis. Histological studies revealed the existence of a hitherto unrecognized termination of capsaicin-sensitive nerve endings within the ventral medullary chemosensitive area of the cat. The results provide both functional and morphological evidence for the presence of a capsaicin-sensitive vasomotor mechanism in the ventral medullary chemo-sensitive area of the cat. It is suggested that the pressor effects of capsaicin applied to the ventral medullary chemo-sensitive area may be mediated by an activation of capsaicin-sensitive primary sensory afferents terminating in this area. Accordingly, capsaicin-sensitive neuronal mechanisms located in the ventral medullary chemosensitive area may play an important role in the central nervous regulation of blood pressure.

Animals↗