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Browsing by Author "HUIDOBROTORO, JP"

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ADENOSINE 5'-TRIPHOSPHATE (ATP), THE NEUROTRANSMITTER IN THE PROSTATIC PORTION OF THE LONGITUDINAL MUSCLE LAYER OF THE RAT VAS-DEFERENS
(1994) DONOSO, MV; BATES, F; MONTIEL, J; HUIDOBROTORO, JP
Suramin (1-100 muM) and alpha,beta-methylene adenosine 5'-triphosphate (AMPCPP, 39 muM), antagonized the motor activity induced by exogenous adenosine 5'-triphosphate (ATP) but not exogenous noradrenaline (NA) in the longitudinal musculature of prostatic (P) and epididymal (E) segments of the rat vas deferens. Likewise, application of these drugs reduced the fast component of the nerve-stimulated contraction in response to a single transmural electrical pulse in E and P. Suramin also blocked in a concentration-dependent fashion, the contractile responses to trains of 1.5, 5, 15 or 30 Hz transmural electrical pulses in P, while it did not affect those in E. AMPCPP obliterated responses to trains of 1.5, 5, and 15 Hz in P, while reducing these responses in E to a significantly lesser extent. Present results strongly support that ATP is the motor transmitter in P, while in E, ATP and NA are likely the co-transmitters responsible for the motor tone.
AGE AND CASTRATION MODULATE THE INHIBITORY-ACTION OF NEUROPEPTIDE-Y ON NEUROTRANSMISSION IN THE RAT VAS-DEFERENS
(1991) BITRAN, M; TORRES, G; FOURNIER, A; STPIERRE, S; HUIDOBROTORO, JP
The potency of neuropeptide Y (NPY) to inhibit the electrically induced contractions of the epididymal half of the vas deferens diminishes markedly with age, being at least 20 times lower in the adult than in the 26-day-old rat. Castration sensitizes the epididymal segment to NPY in a testosterone-reversible manner. [Pro34]NPY was 3 times less potent than NPY in prepubertal rats and inactive in castrated adults, while NPY-(13-36) had no effect in either group. In the prostatic half, NPY and its analogs were active in rats from all ages studied; the order of potency being NPY > [Pro34]NPY > NPY-(13-36). The sensitivity of the prostatic segment from adult rats to NPY was unchanged by castration or testosterone replacement therapy. The NPY content of the ductus increases during development being higher in,the prostatic than in the epididymal half at all ages studied. Castration decreases the peptide content in the two segments and the effect is prevented by testosterone administration. The present investigation demonstrated that the effect of NPY on vas deferens neurotransmission is subject to regulation by sex steroids, which affects differently the response of the two segments of the ductus.
AGING DIFFERENTIALLY MODIFIES ARTERIAL SENSITIVITY TO ENDOTHELIN-1 AND 5-HYDROXYTRYPTAMINE - STUDIES IN DOG CORONARY-ARTERIES AND RAT ARTERIAL MESENTERIC BED
(1994) DONOSO, MV; FOURNIER, A; PESCHKE, H; FAUNDEZ, H; DOMENECH, R; HUIDOBROTORO, JP
The influence of age on vascular reactivity to endothelin-1 (ET-1) and 5-hydroxytryptamine (5-HT) was studied in coronary artery rings from dogs of 9 years of age or younger, and dogs older than 9 years. ET-1 caused concentration-dependent contractions that developed about 100% of the 70 mM KCl-induced tension in the younger dogs; those from older dogs did not generate more than 20%. In contrast, 5-HT developed only about 20% of the KCl-induced tension in rings from young dogs, whereas in the older animals, it developed up to 120% of the KCl tension. No significant difference in the tension developed by 70 mM KCl was noted between both groups of dogs. Mechanical denudation of the endothelial cell layer caused a modest, yet significant, leftward shift of the ET-1 and 5-HT concentration-response curves only in the younger dogs. N omega-Nitro-L-arginine (15 mu M) shifted the ET-1 concentration-response curves to the left in rings from both groups of dogs. Rings precontracted with 20 mM KCl relaxed in a concentration-dependent fashion with acetylcholine; its sensitivity was about threefold less in the older group of dogs. To validate the changes in Vascular reactivity with age, a parallel study was performed perfusing the arterial mesenteric bed of rats of 3, 7, and 30 weeks of age. In this experimental model, the efficacy of ET-1 significantly decreased with age and that of 5-HT was significantly increased. The vasomotor reactivity of noradrenaline was modestly affected by aging, whereas the acetylcholine-induced vasorelaxation was significantly reduced with age.
ASYMMETRIC DISTRIBUTION OF PURINERGIC AND ADRENERGIC NEUROTRANSMISSION COOPERATES IN THE MOTOR-ACTIVITY ALONG THE RAT VAS-DEFERENS
(1986) ROHDE, GC; VENEZIAN, E; HUIDOBROTORO, JP
The distribution of purinergic and adrenergic responses in the epididymal and prostatic segment of the rat vas deferens were studied in vitro. Prazosin antagonizes the twitch elicited by electrical stimulation mainly in the epididymal segment while .alpha.,.beta.-methyleneadenosine 5''-triphosphate (.alpha.,.beta.-mATP) preferentially inhibits the response of the prostatic segment. Using both prazosin plus .alpha.,.beta.-mATP, the response to field stimulation was completely inhibited. Concentration response curves revealed that adrenergic compounds elicited a greater contraction in the epididymal portion than in the prostatic end of the ductus. Purinergic compounds caused a contraction of greater magnitude in the prostatic portion. The results suggest that adrenergic and purinergic mechanisms are asymmetrically distributed along the vas deferens reflecting a gradient of adrenergic and purinergic receptors along the ductus.
BRADYKININ MODULATES THE RELEASE OF NORADRENALINE FROM VAS-DEFERENS NERVE-TERMINALS
(1991) LLONA, I; GALLEGUILLOS, X; BELMAR, J; HUIDOBROTORO, JP
To assess whether bradykinin influences the release of noradrenaline from the adrenergic varicosities of the vas deferens, tissues were loaded with 3H-noradrenaline. Upon electrical depolarization bradykinin increased in a concentration-dependent fashion, the overflow of tritium from the mouse or rat vas deferens. The 3H-overflow is dependent on the external Ca2+ concentration suggesting neuronal release of 3H-noradrenaline. The present results add evidence to the hypothesis that bradykinin modulates the release of noradrenaline from peripheral sympathetic nerve terminals via the activation of a presynaptic mechanism.
CENTRAL EFFECTS OF MORPHINE, LEVORPHANOL, ( - )-METHADONE AND THE OPIOID-LIKE PEPTIDES BETA-ENDORPHIN AND D-ALANINE2-METHIONINE ENKEPHALINAMIDE ON URINE VOLUME OUTFLOW AND ELECTROLYTES
(1981) HUIDOBROTORO, JP; HUIDOBRO, F
The intraventricular injection of 10-30 nmol of morphine, (-)-methadone or levorphanol caused a reduction in the volume of the urine output in rats previously hydrated with 0.5% NaCl. The decrease in urine outflow was associated with a dose-dependent reduction in the concentration of urine Na+ and K+. Two opioid-like peptides: .beta.-endorphin and D-alanine2 methionine enkephalinamide shared this morphine action. On a molar basis, .beta.-endorphin was about 100 times more potent than morphine to cause an equivalent antidiuresis. Naloxone injected i.p. antagonized the response of centrally administered morphine or .beta.-endorphin on urine formation and composition. (+)-Methadone or dextrorphan injected into the cerebral ventricles were considerably less active than their corresponding stereoisomers. N-methyl morphine injected i.p. was completely inactive up to doses that caused signs of toxicity; when injected into the lateral cerebral ventricles, it produced a decrease in the urine outflow and a reduction in the concentration of urine electrolytes. The pattern of changes in urine electrolytes produced by morphine and surrogates as well as the opioid-like peptides was in marked contrast to that caused by the i.p. administration of vasopressin. Whereas the i.p. administration of antidiuretic hormone caused oliguria and a large increase in the urine concentration of Na+ and K+, all the opiates produced at comparable antidiuresis a marked reduction in urine electrolytes. The opiates and the opioid-like peptides may selectively activate central opiate receptors to produce changes in urine formation and composition. Results are discussed in relation to probable central opiate mechanisms controlling the production and formation of urine.
CHARACTERIZATION OF KININ RECEPTORS MODULATING NEUROGENIC CONTRACTIONS OF THE MOUSE ISOLATED VAS-DEFERENS
(1995) MAAS, J; RAE, GA; HUIDOBROTORO, JP; CALIXTO, JB
1 This study analyses the receptors mediating the effects of bradykinin (BK) and analogues on neurogenic twitch contractions of the mouse isolated vas deferens evoked, in the presence of captopril (3 mu M), by electrical field stimulation with trains of 4 rectangular 0.5 ms pulses of supramaximal strength, delivered at a frequency of 10 Hz every 20 s.
CO-TRANSMISSION IN THE RAT VAS-DEFERENS - POSTJUNCTIONAL SYNERGISM OF NORADRENALINE AND ADENOSINE 5'-TRIPHOSPHATE
(1988) HUIDOBROTORO, JP; PARADA, S
In the isolated prostatic half of the rat vas deferens, joint application of noradrenaline (NA) and adenosine 5''-triphosphate (ATP) produced a contractile response whose magnitude was greatly larger than the addition of the tension generated by the application of each agent alone. The effect of ATP was mimicked by two non-hydrolyzable ATP analogs, but not by GTP, AMP or adenosine. In sympathectomized rats, ATP potentiated NA effects, increasing both the peak tension and the duration of the vas deferens contractile response. The synergism was concentration related. Prazosin antagonized the NA synergism but not the ATP response. Likewise, desensitization of the P2-purinoceptor blocked the ATP synergism without modifying the NA-induced contraction.
CORELEASE OF NEUROPEPTIDE-Y (NPY) AND NORADRENALINE FROM THE SYMPATHETIC-NERVE TERMINALS SUPPLYING THE RAT VAS-DEFERENS - INFLUENCE OF CALCIUM AND THE STIMULATION INTENSITY
(1992) TORRES, G; BITRAN, M; HUIDOBROTORO, JP
Epididymal (E) and prostatic (P) segments of the rat vas deferens were incubated with tritium-labeled noradrenaline (NA); upon transmural electrical stimulation for 20 or 60 s (70 V, 1 ms, 3-35 Hz), the outflow of immunoreactive neuropeptide Y (ir-NPY) and NA was detected in the superfusion media. Ir-NPY was detected only following trains of 35 Hz for 60 s in both E and P. In contrast, tritium was released in a graded fashion following trains of 3, 15 or 35 Hz stimulation for 60 s in E, whereas in P it reached a plateau at frequencies larger than 15 Hz. The outflow of tritium, under present conditions, was dependent on the duration of the stimuli, while the release of ir-NPY was only evoked with stimuli of 60 s duration. In the absence of external Ca2+, neurotransmission was blocked and co-release of ir-NPY and NA was prevented.
DEVELOPMENT OF TOLERANCE TO THE EXCITATORY EFFECT OF MORPHINE AND CROSS-TOLERANCE TO THE INHIBITORY-ACTION OF BETA-ENDORPHIN IN THE ISOLATED RAT VAS-DEFERENS
(1981) HUIDOBROTORO, JP; MIRANDA, H; HUIDOBRO, F
In the isolated rat vas deferens, morphine caused an increase in the neuromuscular twitch evoked by electrical stimulation. In rats chronically treated with morphine, the concentration of the opiate required to cause a 50% increase in the twitch was about 3 times larger than needed to elicit the same response in vasa from rats treated with a placebo. The simultaneous administration of naloxone plus morphine partially antagonized tolerance development by about 22%. Morphine tolerance was extended to other opiate-like alkaloids such as etonitazene and a derivative of azidomorphine (CAM). In contrast to the effects of morphine, .beta.-endorphin inhibited neuromuscular transmission. Vasa from rats chronically treated with morphine were about 10 times less sensitive to the inhibitory effect of .beta.-endorphin as compared to paired placebo-treated controls. Chronic naloxone treatment in conjunction with morphine significantly reduced the cross-opiate tolerance by 66%. Morphine may interact at 2 different sites in the nerve terminals of the rat vas deferens.
DIURETIC EFFECT OF BREMAZOCINE, A KAPPA-OPIOID WITH CENTRAL AND PERIPHERAL SITES OF ACTION
(1989) SALAS, SP; ROBLERO, J; URETA, H; HUIDOBROTORO, JP
Intracerebroventricular or i.p. injections of bremazocine produced a dose-dependent diuretic response and increased glomerular filtration rate in hydrated as well as in nonhydrated rats. The potency and magnitude of the bremazocine-induced diuresis were more pronounced in the nonhydrated group of rats. That bremazocine has a central component of action is deduced from the fact that 0.1 .mu.g of the opioid administered centrally caused a significant increase in urine output; proportionally, larger doses of bremazocine were required to produce the same diuretic effect when the drug was administered parenterally. Bremazocine did not change the total amount of urinary Na+ and K+ as compared to the saline controls; it increased significantly the free water clearance. The bremazocine-induced diuresis was antagonized in a competitive fashion by 10 mg/kg of naloxone giving further support to the notion that the mechanism of action of bremazocine involves activation of kappa-opioid receptors. Bremazocine injected i.v. to nonanesthetized rats increased mean systemic blood pressure in a dose-dependent manner; the pressor action of the opiate was blocked and prevented by 1 mg/kg of naloxone. In contrast, i.c.v. administration of bremazocine did not change mean systemic blood pressure but produced a dose-related increase in urine output. To determine whether in addition to a central site bremazocine also activates a renal mechanism, experiments were performed in the isolated perfused rat kidney. Bremazocine (0.15-2.5 .mu.M) caused a dose-dependent diurectic response and a significant rise in the perfusion pressure as well as in glomerular filtration rate. In contrast to the whole animal studies, in vitro administration of bremazocine resulted in a marked natriuresis and kaliuresis proportional to the dose. The renal effects were antagonized by naloxone, suggesting the existence of a local opiate renal mechanism. In conclusion, the present results demonstrate that in addition to a central site of action, bremazocine activates renal mechanisms to regulate water and electrolytes metabolism. The complexity of the pharmacology of opiates in the regulation of urine output may be related to this dual mechanism.
E-2078, A POTENT, SELECTIVE AND STABLE DYNORPHIN ANALOG WITH PREFERENTIAL ACTIVITY FOR THE KAPPA-OPIOID RECEPTOR SUBTYPE ON THE MOUSE VAS-DEFERENS NEUROEFFECTOR JUNCTION
(1991) VALENZUELA, R; TACHIBANA, S; HUIDOBROTORO, JP
The profile of opioid activity of E-2078, a synthetic stable dynorphin analog, was examined in the mouse vas deferens bioassay and compared to that of methionine enkephalin and nonpeptide kappa agonists in the absence and in the presence of selective antagonists for the mu-, kappa- and delta-opioid receptor subtypes. The inhibitory action of E-2078 and related kappa agonists was specifically and potently antagonized only by norbinaltorphimine, revealing the presence of kappa receptors in this tissue and the predominant kappa activity of E-2078.
EFFECT OF ENDOTHELIN ON TOTAL AND REGIONAL CORONARY RESISTANCE AND ON MYOCARDIAL-CONTRACTILITY
(1991) DOMENECH, R; MACHO, P; GONZALEZ, R; HUIDOBROTORO, JP
Endothelin is a 21-amino acid peptide produced by the endothelium and has a potent vasoconstrictor effect. Because of the importance of the endothelium on vasomotor regulation, we studied the effect of endothelin on total and regional coronary vascular resistance and on myocardial contractility in the intact heart of anesthetized dogs. Intracoronary administration of 2 to 80 pmol/kg of endothelin produced a dose-dependent increase in coronary resistance, ischaemic decrease in myocardial contractility and atrium-ventricular blockade. The increase in resistance was greater towards the outer layer of the left ventricular wall. When the coronaries were perfused at a constant rate and vasoconstriction was prevented with adenosine or nitroglycerine, endothelin did not produce inotropic changes. These results show that endothelin is a potent vasoconstrictor of the resistance coronary vessels, producing a redistribution of transmural blood flow and a decrease in myocardial contractility secondary to ischaemia.
EFFECT OF MORPHINE ON THE CLEARANCE OF ENDOGENOUS CREATININE AND BLOOD CLINICAL CHEMICALS IN THE RAT
(1979) HUIDOBRO, F; CROXATTO, R; HUIDOBROTORO, JP
The effect of morphine on urine and blood serum concentration of Na+, K+, Cl- and other chemicals was determined using Sprague Dawley rats, previously hydrated with 50 ml/kg of 0.5% NaCl to provoke an increased diuresis. Morphine caused about a 90% decrease in the urine concentration of Na+, K+ and Cl-. This reduction in the urine electrolyte excretion was associated with a small but significant increase in the concentration of the blood Na+ and Cl-. The anti-diuresis and the decrease in urine electrolytes caused by morphine was paralleled by a 50% reduction of the endogenous creatinine clearance. An acute dose of 7.5 mg/kg morphine i.p. did not alter the concentration of 13 other clinical blood chemicals with the exception of urea. After 18 h of morphine pellet implantation, a significant increase was found in the blood urea and in the activity of serum transaminases. Lactic dehydrogenases isoenzymes 1 and 2 were significantly increased in the blood of rats chronically administered with morphine.
EFFECTS OF BETA-ENDORPHIN AND D-ALANINE2 ENKEPHALINAMIDE ON URINE PRODUCTION AND URINARY ELECTROLYTES IN THE RAT
(1979) HUIDOBROTORO, JP; HUIDOBRO, F; CROXATTO, R
The intracerebro-ventricular administration of human .beta.-Endorphin (.beta.-EP, 0.1-3 .mu.g/rat) or D-alanine2 methionine enkephalinamide (D-ala, 0.3-30 .mu.g/rat) caused a dose dependent reduction in urine volume. The oliguria was associated with a decrease in the concentration of Na+ and K+ in the urine of rats previously hydrated by oral administration with 25 ml/kg tap water plus 50 ml/kg 0.5% NaCl. On a molar basis, .beta.-EP proved to be about 5-7 times more potent than D-ala. The effects caused by the peptides were antagonized by simultaneous i.p. administration of 1 mg/kg naloxone. In rats treated chronically with morphine, no cross-tolerance was demonstrated to the antidiuretic effect of .beta.-EP, but clear cross-tolerance was evident to the changes in urine electrolytes induced by .beta.-EP. Morphine and the opiate peptides may share a similar mechanism of action.
ENDOTHELIN REDUCES MICROVASCULAR BLOOD-FLOW BY ACTING ON ARTERIOLES AND VENULES OF THE HAMSTER-CHEEK POUCH
(1990) BORIC, MP; DONOSO, V; FOURNIER, A; STPIERRE, S; HUIDOBROTORO, JP
Superfusion of the cheek pouch with 0.1-10 nM endothelin (E) produced a concentration-related reduction in the clearance of 22Na+ used as an indicator of microvascular plasma flow. The median effective concentration was about 2 nM. The time course of E action was also concentration related. Superfusion with 10 nM E for 10 min caused a greater than 80% reduction in 22Na+ clearance; the rate at which the action of E started was significantly faster than the rate at which its action ended. Recovery did not exceed 70% even though the tissue was superfused with drug-free buffer for 90 min. The E-induced reduction in 22Na+ clearance was associated with vasoconstriction, as determined by intravital microscopy. Arterioles by 4th branching order were more sensitive to E action than arterioles of 1st or 2nd order; however, the constriction lasted considerably longer in the latter vessels. E-induced venular constriction followed a pattern analogous to that of arterioles of the same category, with the exception that the finer venules responded the least. Pretreatment of the cheek pouch with 300 nM nifedipine diminished but did not abolish the 1 nM E-induced reduction in 22Na+ clearance, and the recovery of clerance upon E washout was not accelerated by nifedipine.
ENDOTHELIN-1 (ET)-INDUCED MOBILIZATION OF INTRACELLULAR CA2+ STORES FROM THE SMOOTH-MUSCLE FACILITATES SYMPATHETIC COTRANSMISSION BY POTENTIATION OF ADENOSINE 5'-TRIPHOSPHATE (ATP) MOTOR-ACTIVITY - STUDIES IN THE RAT VAS-DEFERENS
(1992) DONOSO, MV; MONTES, CG; LEWIN, J; FOURNIER, A; CALIXTO, JB; HUIDOBROTORO, JP
Endothelin-1 (ET) enhances nerve-stimulated contractions in epididymal (E) and prostatic (P) halves of the rat vas deferens, in addition to raising the basal tone in E. Whereas the peak increase in basal tone occurs in about 30 s, the maximal enhancement of neuro-transmission is observed within 5 min. The latter effect is long lasting is maintained even after extensive tissue washout. Furthermore, ET potentiates, in a concentration-dependent fashion, the adenosine 5'-triphosphate (ATP) or the adenylylimido-diphosphate (AMP-PNP) but not the noradrenaline (NA)-induced motor activity. The ATP motor response is partially blocked in media without Ca2+ plus 0.1 mM EGTA or following tissue incubation in buffer containing 10-50 nM nifedipine. However, these procedures do not modify significantly the ET-induced potentiation of the ATP contractions. The ET-induced potentiation of the ATP motor response is not modified by tissue preincubation in Ca2+-free buffer plus 10-30-mu-m ryanodine or 5-20 mM caffeine. The ET-induced rise in E basal tension is significantly reduced in the absence of external Ca2+ or by nifedipine; ryanodine does not modify this effect. Surgical denervation of the tissues does not obliterate the ET-induced potentiation of the ATP motor responses nor the ET increase in E basal tension in tissues superfused in Ca2+-free media or buffer with 2.5 mM Ca2+. Endothelin-1 does not significantly modify the overflow of H-3-NA, following transmural electrical depolarization of tissue nerve terminals. Hoe 140 did not interfere with the ET activity.
EVIDENCE FOR MORPHINE AND MORPHINE-LIKE ALKALOID RESPONSES RESISTANT TO NALOXONE BLOCKADE IN THE RAT VAS-DEFERENS
(1979) MIRANDA, H; HUIDOBRO, F; HUIDOBROTORO, JP
The application of morphine or surrogates to the isolated rat was deferens maintained at 37.degree. C in Tyrode solution produced an increase in the electrically induced muscular twitch. Leucine enkephal in or D-2-D-Ala-Met enkephalinamide produced a dose-dependent inhibition of the muscular twitch. The effect of morphine and derivatives was not antagonized by naloxone, but the depression caused by the opiate pentapeptides or .beta.-endorphin was readily antagonized and reversed by naloxone. Tolerance developed to the in vitro effect of morphine; vasa deferentia obtained from tolerant-dependent rats were about 6 .times. less sensitive to the effect of morphine and about 5 .times. less sensitive to the depression caused by leucine enkephalin as compared to their respective paired, placebo implanted control rats.
EXCITATORY NEUROTENSIN RECEPTORS ON THE SMOOTH-MUSCLE OF THE RAT FUNDUS - POSSIBLE IMPLICATIONS IN GASTRIC-MOTILITY
(1985) HUIDOBROTORO, JP; KULLAK, A
Picomolar concentrations of neurotensin caused concentration-dependent contractions of the longitudinal musculature of the fundus of the rat stomach. The EC50 [concentration giving 50% effectiveness] of neurotensin was .apprx. 1.5 nM. On a molar basis neurotensin was about 5-10 times more potent than 5-hydroxytryptamine (5-HT) and .apprx. 80 times as active as acetylcholine in producing similar contractions. Studies with structurally related peptides indicated that whereas the carboxy terminal portion of neurotensin was essential for biological activity, a substantial part of its amino terminus end could be removed without affecting its potency. The EC50 for the neurotensin fragment 8-13 was identical to that of neurotensin, its 1-8 or 1-11 fragments were completely inactive. Tetrodotoxin did not modify the potency of neurotensin or structurally related analogs suggesting that the neurotensin receptor is probably located on the smooth muscle membrane. In addition, the potency of neurotensin in contracting the fundus was not modified by pretreatment with atropine, methysergide or diphenhydramine. Fade to the contractile response of neurotensin was followed by the development of tachyphylaxis; densensitization was concentration-dependent and characterized by a shift in the agonist concentration-response curve to the right and downwards. Desensitization with a priming concentration of neurotensin (.apprx. EC50) caused a substantial blockade of its excitability. There was cross-densensitization between neurotensin and the contractile activity of neurotensin 8-13 or xenopsin, but not with angiotensin II, bradykinin, substance P, acethylcholine, 5-HT or histamine. Pretreatment of the fundus strip with verapamil 0.3-1 .mu.M antagonized in a concentration-dependent fashion the neurotensin-induced contractions but not the muscular contractions caused by acetylcholine. Neurotensin activates a specific excitatory receptor probably located on the cell membrane of the smooth muscles of the rat fundus. This receptor is somehow related to a voltage-dependent Ca channel, sensitive to verapamil.
EXTRACELLULAR CALCIUM DEPENDENCE OF THE NEUROTENSIN-INDUCED RELAXATION OF INTESTINAL SMOOTH MUSCLES - STUDIES WITH CALCIUM-CHANNEL BLOCKERS AND BAY K-8644
(1987) KULLAK, A; DONOSO, MV; HUIDOBROTORO, JP
To investigate whether the neurotensin-induced relaxation of the rat duodenum and ileum is dependent on the external concentration of calcium, the effect of the neuropeptide was studied in isolated intestinal segments superfused with Tyrode solution containing no calcium, 1 or 2.5 mM Ca2+. The neurotensin-induced intestinal relaxation was reduced when the extracellular calcium concentration was lowered. In addition, the inhibitory effect of neurotensin was cancelled when the tissues were incubated in the presence of diltiazem, methoxyverapamil or nifedipine. BAY K-8644, a structural analog of nifedipine that functions as an agonist of the calcium channel, potentiated the neurotensin-induced smooth muscle relaxation. The facilitatory effect of BAY K-8644 was antagonized by nifedipine, indicating competition between the 2 dihydropyridines. Apamin, the K+ channel blocker, antagonized the neurotensin-induced visceral relaxation, displacing the concentration-response curve of the peptide to the right. Furthermore, apamin also blocked the effect of neurotensin when the neuropeptide was assayed in the presence of BAY K-8644. It is concluded that the smooth muscle relaxation induced by neurotensin is dependent on external calcium, suggesting that the activation of the neuropeptide receptor causes an influx of calcium which leads to the opening of K+ channels before smooth muscle relaxation is triggered.

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