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PubMed2005

In vivo analysis of chronic phosphodiesterase-5 inhibition with sildenafil in penile erectile tissues: no tachyphylaxis effect.

PURPOSE: Conflicting information exists regarding the long-term efficacy of phosphodiesterase-5 (PDE5) inhibitor therapy for erectile dysfunction, particularly in regard to whether therapeutic resistance occurs. We investigated the erectile response, and cavernous PDE5 expression and activity after continuous long-term administration of sildenafil at verified therapeutic plasma concentrations, applying an in vivo rat model of age related erectile dysfunction. MATERIALS AND METHODS: Male Fisher 344 young (4 months old) and aged (19 months old) rats (National Institute of Aging, Bethesda, Maryland) were injected with sildenafil mesylate (20 mg/kg) or saline subcutaneously every 8 hours for 3 weeks. After a 10 to 18-hour washout period electrical stimulation of the cavernous nerve was performed to assess penile erection. Penes were excised to measure PDE5 protein expression and activity, and blood was collected for sildenafil measurement. Responses were compared with those determined 30 minutes after a single sildenafil injection. RESULTS: Chronic sildenafil treatment increased the detumescence phase in young and aged rats (p <0.05), although aged rats showed a greater increase than young rats. Baseline cavernous PDE5 expression and activity were greater in aged vs young rats (p <0.05). After chronic sildenafil treatment cavernous PDE5 expression was increased in young (p <0.05) but not in aged rats. Chronic and acute sildenafil treatment similarly inhibited PDE5 activity in the penis of young and aged rats (p <0.05), coincident with its free plasma concentrations equivalent to clinically therapeutic ranges. CONCLUSIONS: Pharmacological PDE5 inhibitor therapy with sildenafil chronically does not result in treatment resistance. Rather, therapeutic efficacy is maintained and apparently more pronounced with erectile impairment than with normal erectile ability.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1992

Effect of histamine treatment on dopamine tachyphylaxis of canine tracheal smooth muscle.

In order to understand how histamine-sensitized airways may react to exogenous dopamine, we investigated the effect of histamine treatment on the dopamine-induced contractions of canine tracheal smooth muscle. The results showed that preconstricting muscle strips with histamine (10(-6) M to 10(-4) M) not only increased the amplitude of dopamine-induced contraction, but also lowered the concentration of dopamine required to provoke contraction from 10(-4) M to 10(-6) M. In muscle strips desensitized by repeated challenges of 10(-3) M dopamine, a 15-min treatment with 10(-4) M histamine transiently restored the response. The restored contractions were decreased by the dopaminergic antagonist, domperidone, and the alpha 2-adrenoceptor antagonist, yohimbine, and increased by the beta 1-adrenoceptor antagonist, atenolol. It is concluded that in addition to its role in mediating airway constriction, histamine can promote and enhance the contractile response of canine tracheal smooth muscle to dopamine. Histamine treatment restored the dopamine response of desensitized tracheal muscle with resensitization of the adrenoceptors.

Animals↗
PubMed1984

[Anti-inflammatory effect and tachyphylaxis of systemic and combined systemic-topical treatment with corticosteroids in the pyrexal erythema test].

On account of clinical experience as well as experimental findings, we noticed subsiding anti-inflammatory and antiproliferative effects of topical corticosteroids after regularly repeated application. Following four-day's oral therapy with methylprednisolone 40 mg daily, the pyrexal erythema test did not reveal any decrease of anti-inflammatory effect in six volunteers. The efficacy of this therapy was similar to that of occlusive topical therapy with 0.25% desoxymethasone ointment. The anti-inflammatory effect of systemic steroid treatment could even be slightly increased by additional topical steroid therapy.

Administration, Topical↗
PubMed1986

Angiotensin II-induced tachyphylactic constrictions in isolated and perfused canine mesenteric arteries.

The stainless steel cannula inserting method was used to investigate the effects of angiotensin II on isolated and perfused dog mesenteric arteries with and without indomethacin treatment, or with and without intraluminal saponin-treatment which removed the endothelium. In non-treated preparations, angiotensin II was intraluminally administered repetitively at 10, 20, 30 or 60 min inervals. Each period of angiotensin II causes tachyphylaxis. The order of degree of tachyphylaxis was 10 greater than 20 greater than 30 greater than 60 min intervals. Relatively large doses much readily caused tachyphylaxis. Tachyphylaxis was not affected by phentolamine-treatment preparations. In indomethacin (5 mg)-treated preparations, the angiotensin II-induced tachyphylaxis was significantly less than that in non-treated ones. In small doses of angiotensin II, tachyphylaxis did not appear in the majority of cases in indomethacin-treated preparations. In deendothelial preparations which were induced by intraluminal administration of saponin (1 and 3 mg), the tachyphylaxis was induced similar to non-saponin treated preparations. It is concluded that prostaglandin may partially participate in induction of angiotensin-induced tachyphylaxis, the prostaglandin may be synthesized in the inside of vasculature, and a large dose of angiotensin II induces tachyphylaxis unrelated to production of prostaglandin.

Angiotensin II↗
PubMed1997

Angiotensin II induces a tachyphylactic calcium response in the rabbit afferent arteriole.

The influence of repeated administration of angiotensin II (AII) on smooth muscle calcium concentration ([Ca2+]i) was studied in isolated rabbit renal afferent arterioles loaded with the calcium-sensitive fluorescent probe Fura-2. [Ca2+]i was evaluated in the proximal and distal parts of the afferent arterioles. AII (10(-8) M) increased the [Ca2+]i in both these regions. A second administration of AII, however, did not elicit any response in [Ca2+]i. The response to noradrenaline administration at the end of the experiment was not affected, i.e. there was no fading or cross-desensitization. Since this desensitization was specific for AII, it was of the tachyphylaxis type. Increasing doses of AII (10(-11)-10(-8) M) did not reverse the tachyphylaxis. However, in the proximal part, pretreatment with the voltage-sensitive calcium channel blocker nifedipine (10(-6) M) blunted the tachyphylactic effect of a second administration of AII. When L-arginine (L-Arg) was administered to the bath solution, thus activating the NO system, the development of tachyphylaxis was suppressed in the proximal region. Pretreatment with the protein kinase C (PKC) inhibitor chelerythrine (10(-6) M) did not affect the tachyphylaxis. We conclude that the calcium response to AII in the isolated rabbit afferent arteriole shows tachyphylaxis. This tachyphylaxis cannot be reversed by applying increasing doses of AII (10(-11)-10(-8) M). PKC does not seem to be involved in the tachyphylactic phenomenon in this preparation. It was also found that nifedipine and NO reduced the tachyphylaxis.

Alkaloids↗
PubMed1989

Temperature-dependent specific desensitization in the rat anococcygeus muscle to angiotensin II.

The effect of angiotensin II (A II) on isolated rat anococcygeus muscle was investigated. A II, when used submaximally (4 X 10(-9) mol/l), produced a rapid contraction of the rat anococcygeus muscle. However, a profound tachyphylaxis developed with repeated administrations. This tachyphylaxis is specific in nature, since the tissue responded normally to noradrenaline even after the establishment of a complete tachyphylaxis to the peptide. Incubation with phentolamine or indometacin had no effect on the A II-induced tachyphylaxis. On the other hand, a marked prevention of tachyphylaxis was obtained by lowering the bath temperature to 31 or 25 degrees C. These results indicate that neither noradrenaline nor prostaglandin release participate in the development of tachyphylaxis to A II in rat anococcygeus muscle, and this tachyphylaxis can be prevented by lowering the temperature of the bath solution.

Angiotensin II↗
PubMed2004

Homologous desensitization of calcitonin gene-related peptide-induced relaxation in rat intramural coronary arteries.

We investigated the type of desensitization of calcitonin gene-related peptide (CGRP)-induced responses in rat isolated intramural coronary arteries using isometric myograph and FURA-2 technique. In coronary arteries precontracted with 9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F2alpha (U46619), development of tachyphylaxis to CGRP is characterized by significant attenuation of CGRP-induced maximal reduction in the tension and [Ca2+](i) during the second CGRP concentration-response curve; however, there was no further reduction in the CGRP-induced maximum relaxation during the third CGRP concentration-response curve. There was no sign of tachyphylaxis to CGRP when CGRP concentration-response curves were recorded in 36 mM K+-depolarized coronary arteries contrary to the results obtained in 300 nM U46619-precontracted coronary arteries. Preincubation with colchicine did not prevent the development of tachyphylaxis to CGRP in U46619-precontracted coronary arteries, indicating no role for endocytosis. Development of tachyphylaxis to CGRP was completely abolished by preincubating the coronary arteries with 1 microM RO 31-8220, indicating a role for protein kinases. Pre-exposure of the coronary arteries to isoprenaline or forskolin did not attenuate the CGRP-induced relaxation in these vessels, indicating that the cAMP-protein kinase A (PKA) pathway is not involved. Like CGRP, the coronary arteries developed tachyphylaxis toward isoprenaline during the second exposure. However, there was no sign of tachyphylaxis to either forskolin or dibutyryl cAMP (dbcAMP) during the second exposure. In conclusion, these results suggest that development of tachyphylaxis to CGRP in U46619-precontracted coronary is related to CGRP receptor-mediated activation of protein kinase.

Animals↗
PubMed1989

Studies on the mechanism of action of the bipyridine milrinone on the heart.

Milrinone is a positive inotropic and vasodilator agent when tested in experimental animals and in human heart-failure patients. It is generally believed that milrinone acts by inhibiting phosphodiesterase IV, thus increasing cyclic AMP, [Ca++]i and cardiac contractile force and relaxation. Maximal force produced by milrinone is greater when single-dose response curves are compared to cumulative dose-response curves. In vitro, milrinone produces a tachyphylaxis, the extent of which is both dose- and time-dependent. Recovery of tachyphylaxis is both dose- and time-dependent and is not influenced by inhibitors of protein or RNA synthesis. There is a specific cross-tachyphylaxis between milrinone and amrinone, theophylline, papaverine, and Bay K8644. This tachyphylaxis may explain the low maximal contractile response of the cumulative dose-response observed in isolated tissues. Milrinone increased cyclic AMP in dog and guinea pig cardiac muscle. As previously shown by Endoh et al., milrinone in low doses produced a biphasic effect on cyclic AMP. The early increase (first 60-70 s) in cyclic AMP shows a good correlation with contractile force changes. If cyclic AMP is determined at maximal contractile force this correlation was poor. Here we also present instances where the increase in cyclic AMP after milrinone (determined at maximal effect) does not correlate with the contractile response. The cross-tachyphylaxis of milrinone with Bay K8644 suggests that milrinone has an action on the sarcolemmal Ca++ channels. Bay K8644 suppresses the positive inotropic effect of catecholamines by 50%, but not the cyclic AMP response. The inotropic effect of milrinone, in contrast to norepinephrine is highly sensitive to [Ca++]0, stimulation rate, and [K+]0. In this respect milrinone behaves more like Bay K8644. We postulate that the main inotropic action of milrinone is due to a sarcolemmal effect. The early cyclic AMP production described could be in the sarcolemmal compartment and this may explain some of the similarities of milrinone's actions with those of Bay K8644. The tachyphylaxis observed with the inotropic effect of milrinone does not extend to the decreases in relaxation time. This and other findings to be discussed suggest that the positive inotropic and reduction in relaxation time by milrinone depend on different mechanisms, possibly through differential compartmentalization of cyclic AMP.

Animals↗
PubMed1998

Thoracic spinal neuron responses to repeated myocardial ischemia and epicardial bradykinin.

Bradykinin has been strongly implicated as a mediator of cardiac nociception. During coronary artery occlusion, the content of bradykinin in coronary sinus blood increases. In non-cardiac tissues nociception to bradykinin exhibits tachyphylaxis, however, this phenomenon has not been rigorously studied in the heart. This raises the question that repeated coronary occlusions may also result in tachyphylaxis, thereby reducing cardiac sensation on subsequent ischemic stimulation. We therefore examined the hypothesis that repetitive episodes of myocardial ischemia and of epicardial application of bradykinin demonstrate tachyphylaxis. Mongrel cats were anesthetized with alpha-chloralose and heart rate, arterial pressure, and thoracic spinal neuron firing rate were recorded during 60 s of anterior descending coronary occlusion or local epicardial application of bradykinin (10 microM). Neurons were identified by cutaneous receptive fields in the left shoulder area. Sixty-one of 93 neurons tested responded with an increase in firing rate to coronary artery occlusion only (n=24), bradykinin only (n=19) or to both (n=18). On repetitive coronary occlusion, 14 of 25 neurons demonstrated tachyphylaxis compared to 12 of 15 tested with bradykinin (p<0.05). Similar responses were observed in thoracic spinal neurons that projected to the brain. In neurons demonstrating tachyphylaxis, dorsal cervical cold block partially restored the neuronal activation to coronary occlusion but not to bradykinin. We conclude, based on neuronal responses to repetitive stimuli, that afferent spinal responses to coronary occlusion and bradykinin are different. These data suggest that bradykinin is not the sole mediator of myocardial ischemic pain. The tachyphylaxis to repeated coronary artery occlusions may contribute to the clinical phenomenon of silent myocardial ischemia.

Animals↗
PubMed1993

Actions of norepinephrine and angiotensin II on aortic rings of adult and aged normotensive and hypertensive rats.

Development of desensitization to physiologic concentration of norepinephrine (NE 10(-9) M) and its effects on angiotensin II (AII) tachyphylaxis in the aortic rings of adult and aged normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were investigated. Aortic rings of all animals developed desensitization to 10(-9) M NE and tachyphylaxis to AII (10(-9)-10(-6) M). In normotensive WKY, the response to NE and AII was not affected by age, whereas in SHR desensitization to NE and tachyphylaxis to AII were significantly more marked in aged animals. The desensitization to 10(-9) M NE appeared to be homologous because this physiologic concentration of NA significantly attenuated tachyphylaxis to AII (for concentrations of 10(-8)-10(-6) M) in the aortic rings of both adult and aged WKY. Tachyphylaxis to AII was not affected by 10(-9) M NE in either adult or aged SHR, however. These data support our previous finding of similar attenuation of AII tachyphylaxis by NE in aortic rings of normotensive Sprague-Dawley rats, and indicate that absence of such attenuation in SHR; the latter finding could reflect a probable lesion in the interactive pathways of these two vasoconstrictors in hypertensive rats.

Aging↗
PubMed1982

The effects of substance P and met5-enkephalin in dog ileum.

Substance P initiated tonic contraction of dog ileum when administered in doses from 1 pg to 20 micrograms intraarterially (ED50 = 67 ng). Low doses acted to excite cholinergic postganglionic neurones since atropine or tetrodotoxin (TTX) increased the ED50 of substance P about 25-fold, while hexamethonium and local field stimulation had only a small effect to increase the ED50. Also atropine and tetrodotoxin effects were not additive. Higher doses apparently acted to stimulate smooth muscle directly, but no evidence was obtained that local field stimulation could release substance P to act on smooth muscle. Substance P tachyphylaxis prevented substance P actions on cholinergic nerves, but it did not affect responses to intraaterial acetylcholine or block distal inhibition from proximal distention or field stimulation. Met-enkephalin given intraarterially, was also excitatory in doses from 1 ng to 20 micrograms; the amplitude of tonic and phasic contractions produced was significantly decreased by TTX and atropine but was not diminished by hexamethonium or substance P tachyphylaxis. Partial tachyphylaxis to met-enkephalin was produced but was not diminished by hexamethonium or substance P tachyphylaxis. Partial tachyphylaxis to met-enkephalin was produced without affecting the ED50 for substance P. We conclude that substance P acts in small amounts on receptors in myenteric nerves to release acetylcholine by a mechanism, presumably involving postganglionic cholinergic nerves, while met-enkephalin also apparently may act at least in part through a similar TTX- and atropine-sensitive mechanism. These peptides also caused activation of other receptors, probably on smooth muscle by noncholinergic. TTX-insensitive mechanisms. Also the receptors for each peptide which are located on nerves were distinct and independent since tachyphylaxis could be produced to each without affecting the response to the other.

Acetylcholine↗
PubMed1999

Activation of spinal wide dynamic range neurons by intracutaneous microinjection of nicotine.

Nicotine evokes pain in the skin and oral mucosa and excites a subpopulation of cutaneous nociceptors, but little is known about the central transmission of chemogenic pain. We have investigated the responses of lumbar spinal wide dynamic range (WDR)-type dorsal horn neurons to intracutaneous (ic) microinjection of nicotine in pentobarbital-anesthetized rats. Nearly all (97%) units responded to nicotine microinjected ic (1 microl) into the low-threshold region of the hind-paw mechanosensitive receptive field in a concentration-related manner (0.01-10%). Responses to repeated injections of 10% nicotine exhibited tachyphylaxis at 5-, 10-, and 15-min interstimulus intervals. Significant tachyphylaxis was not seen with 1% nicotine. All nicotine-responsive units tested (n = 30) also responded to ic histamine (1 microl, 3%) and did not exhibit tachyphylaxis to repeated histamine. However, there was significant cross-tachyphylaxis of nicotine to histamine. Thus 5 min after ic nicotine, histamine-evoked responses were attenuated significantly compared with the initial histamine-evoked response prior to nicotine, with partial recovery over the ensuing 15 min. Neuronal excitation by ic nicotine was not mediated by histamine H1 receptors because ic injection of the H1 receptor antagonist, cetirizine, had no effect on ic nicotine-evoked responses, whereas it significantly attenuated ic histamine-evoked responses in the same neurons. The lowest-threshold portion of cutaneous receptive fields showed a significant expansion in area at 20 min after ic nicotine 10%, indicative of sensitization. Responses to 1% nicotine were significantly reduced after ic injection of the nicotinic antagonist, mecamylamine (0.1% ic), with no recovery over the ensuing 40-60 min. These data indicate that nicotine ic excites spinal WDR neurons, partly via neuronal nicotinic acetylcholine receptors that are presumably expressed in cutaneous nociceptor terminals. Repeated injections of high concentrations of nicotine led to tachyphylaxis and cross-tachyphylaxis with histamine, possibly relevant to peripheral analgesic effects of nicotine.

Action Potentials↗
PubMed2001

Acute sensitization by NGF of the response of small-diameter sensory neurons to capsaicin.

We investigated acute sensitization by nerve growth factor (NGF) of the response of small-diameter (<30 microm) dissociated dorsal root ganglion (DRG) cells to brief repeated puffs of capsaicin as a model for thermal hyperalgesia induced by NGF. We have previously shown that placing NGF in the bath after an initial puff of capsaicin can completely overcome the tachyphylaxis normally observed in response to a second puff 10 min later, and this response is often substantially larger than the first. If tachyphylaxis is abolished by carrying out the experiment in Ca2+-free solution, NGF still elicits potentiation of the second puff. However, the amount of potentiation is considerably less than that observed when tachyphylaxis also takes place. Thus it is concluded that NGF has two effects: overcoming tachyphylaxis and potentiation. With three puffs of capsaicin separated by 10 min, we have found that the potentiation established after 10 min exposure to NGF is no longer evident 10 min after removal of NGF. In Ca2+-free solution the potentiation can last up to 1 h after removal of NGF. These results suggest that the initial behavioral sensitization elicited by NGF could result from a direct effect on the sensory neuron but that its later components most likely involve other mechanisms. We have also investigated the contribution of various second-messenger pathways in these actions of NGF by treating the cells with blockers of MAP kinase (PD98059), protein kinase A (PKA; PKAI14-22, H89), and PKC (Bisindolylmaleimide I). Surprisingly, PD98059, which previously has been shown to diminish the enhancement of capsaicin responses of dissociated neurons when exposed to NGF for several days, had no effect on the acute response to NGF; nor did the PKC inhibitor. However, PKA inhibitors reduced the capsaicin response of the cells to NGF (as determined from the NGF effect on tachyphylaxis). Consistent with these findings we confirmed that forskolin, a PKA activator, enhances the effect of NGF on the capsaicin response. The percentage of small cells sensitized by NGF under these conditions, as determined by its ability to reduce tachyphylaxis, was 64%. This suggests that about two-thirds of DRG cells <30 microm and sensitive to capsaicin express a functional trkA receptor.

Animals↗