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PubMed2004

Effects of nicotine on cognitive deficits in schizophrenia.

Several lines of evidence suggest a pathophysiological role for nicotinic receptors in schizophrenia. Activation by nicotine alters physiological dysfunctions, such as eye movement and sensory gating abnormalities, but effects on neuropsychological performance are just beginning to be investigated. Nicotine-induced desensitization and the well-known tachyphylaxis of nicotinic receptors may confound such efforts. In all, 20 schizophrenics, 10 smokers, and 10 nonsmokers were assessed following the administration of nicotine gum and placebo gum. The Repeatable Battery for the Assessment of Neuropsychological Status was administered. Nicotine affected only the Attention Index; there were no effects on learning and memory, language, or visuospatial/constructional abilities. Attentional function was increased in nonsmokers, but decreased in nicotine-abstinent smokers after nicotine administration. The effects of nicotine in schizophrenia do not extend to all areas of cognition. Effects on attention may be severely limited by tachyphylaxis, such that decremented performance occurs in smokers, while modest effects may be achieved in nonsmokers.

Adult↗
PubMed1995

Cardiovascular effects of angiotensin-II in chickens.

1. Mature WL cockerels with permanent cannulae in brachial artery and vein were restrained in an isolated sling. Blood pressure (BP) and heart rate (HR) were continuously recorded. When the chickens were habituated to the sling, injections began. In each experiment the cockerels were injected intravenously 6 times at 6 min intervals. 2. In the first experiment 6 injections of 0.5 nmol[Aspl, Val5]ANG-II/kg body weight were given. 3. In the second experiment oxytocin (OT) antagonist ([d(CH2)5-O-Me-Tyr2,Thr4,Tyr9,Orn8]VT) at a dose of 2 nmol/kg, was injected for the first 3 and 0.5 nmol ANG-II/kg for the last 3 injections. Such OT-antagonist pretreatment completely abolishes the vasodepressor (VDP) response to neurohypophysial peptides in chickens. 4. Injections of ANG-II resulted in a biphasic effect on BP, an initial brief fall followed by a prolonged rise. During the hypotensive phase, tachycardia developed which turned into bradycardia as the hypertensive phase appeared. No tachyphylaxis of the VDP effect of ANG-II was evident with repeated injections. 5. OT-antagonist pretreatment had no effect on the VDP response to ANG-II. 6. These results suggest that, unlike relaxation of chicken aortic ring in in vitro preparations, there is no tachyphylaxis of the VDP response to ANG-II, in vivo. Furthermore, the neurohypophysial peptides are not involved in the VDP effect of ANG-II because pretreatment with an OT-antagonist had no effect on it. The baroreflex buffers the effects of ANG-II on vascular tone by affecting HR. 7. As ANG-II is secreted during hypovolaemia, the biphasic haemodynamic response peptides may have a compensatory role following volume contraction.

Angiotensin II↗
PubMed1986

Effects of ibuterol, a beta-2 adrenergic prodrug, on intraocular pressure.

Ibuterol, a prodrug of terbutaline, was approximately 100 times more potent than terbutaline in producing ocular hypotension in the treated eye of normal and sympathectomized (SX) rabbits. In normal rabbits, ibuterol produced no change in IOP of the contralateral eye whereas in unilaterally SX rabbits a rise in IOP occurred in the SX (contralateral) eye when the normal eye was treated with ibuterol. Ibuterol also suppressed ocular hypertension induced by water loading and delayed the IOP recovery rate although its onset of action was delayed. Aqueous flow was increased significantly at 1 hr after ibuterol in fluorophotometric studies in normal rabbits. Pretreatment with forskolin antagonized rather than enhanced ibuterol-induced ocular hypotension. Pretreatment with diclofenac failed to suppress the development of tachyphylaxis to the ocular hypotensive effect of ibuterol. Although ibuterol is an effective ocular hypotensive agent in rabbits, the effects of this agent on aqueous flow are complex and tachyphylaxis to the ocular hypotensive effect develops fairly rapidly.

Animals↗
PubMed1986

Prolonged infusion of suxamethonium in infants and children.

The neuromuscular blockade produced by a prolonged (greater than 90 min) continuous infusion of suxamethonium and measured with train-of-four stimulation was studied in 20 infants and 20 children during nitrous oxide and halothane in oxygen anaesthesia. The results were compared with a previous study in adults. Suxamethonium requirement was increased in infants and children. Mean peak infusion rates were 297 and 284 micrograms kg-1 min-1 in infants and children, compared with 134 micrograms kg-1 min-1 in adults. An initial tachyphylaxis was followed by bradyphylaxis, and the peak requirement occurred earlier in infants than in children and adults (40 v. 80-100 min). Phase II block developed during the tachyphylaxis. Recovery of neuromuscular activity commenced after stopping the infusion and was accelerated with neostigmine.

Child↗
PubMed1996

Protective effects of human urinary trypsin inhibitor against trypsin-induced relaxation in rat aorta.

OBJECTIVES: To investigate the vasodilatory responses induced by trypsin, and to determine the antitrypsin effects of human urinary trypsin inhibitor on blood vessels. DESIGN: Prospective, randomized, controlled study, with repeated measurements. SETTING: University research laboratory. INTERVENTIONS: The isometric tension of the aortic rings isolated from male Wistar rats was recorded. The vasodilatory responses to varying amounts of trypsin (0.01 to 10 U/mL) were examined under pretreatment with human urinary trypsin inhibitor (1 to 10 U/mL), chicken-egg-white trypsin inhibitor (0.1 to 10 mg/mL), N infinity-nitro-L-arginine (3 x 10(-5) M), and denudation of the endothelium. In addition, with the scanning electron microscopy, the endothelium of aorta was examined under treatment with trypsin alone (10 U/mL), and with trypsin plus human urinary trypsin inhibitor (10 U/mL each).4 MEASUREMENTS AND MAIN RESULTS: The addition of trypsin produced dose-dependent relaxation in aortic rings with an intact endothelium, which was abolished by denudation and treatment with N infinity-Nitro-L-arginine. Pretreatment with human urinary trypsin inhibitor and with chicken-egg-white trypsin inhibitor caused dose-dependent inhibition against trypsin-induced vasorelaxation. On the repeated trials of the response to trypsin, the responses gradually developed tachyphylaxis in control aortic rings, whereas no tachyphylaxis developed in rings pretreated with human urinary trypsin inhibitor (10 U/mL). Scanning electron microscopy demonstrated endothelial disruption in aorta exposed to trypsin alone, whereas the endothelium was intact in strips treated with trypsin plus human urinary trypsin inhibitor. CONCLUSIONS: The data indicate that relaxation induced by trypsin is attributable to nitric oxide released from the endothelium, and that human urinary trypsin inhibitor protects vessels against trypsin-induced endothelial injury. It appears that the clinical antishock effect of human urinary trypsin inhibitor is ascribable in part to its antitrypsin activity on the endothelium of vascular smooth muscle.

Animals↗
PubMed1997

Endothelin-B receptors in cerebral resistance arterioles and their functional significance after focal cerebral ischemia in cats.

In the cerebral circulation, endothelin-A receptor activation mediates marked prolonged vasoconstriction whereas endothelin-B (ETB) receptor activation effects dilation. In contrast to some peripheral vascular beds, ET(B) receptor-induced vasoconstriction has not yet been demonstrated in brain vessels. In this study in chloralose-anesthetized cats, with perivascular microapplications of ET(B) selective agonist (BQ-3020) and antagonist (BQ-788), we investigated whether ET(B) receptor-mediated constriction could be uncovered in cortical arterioles in vivo. In addition, we examined whether normal dilator response to ET(B) receptor activation is preserved in postischemic cerebral arterioles. The first microapplication of the selective ET(B) receptor agonist BQ-3020 (1 micromol/L) onto a pial cortical arteriole elicited marked dilation (caliber increased by 26.3 +/- 15.1% from preinjection baseline). A second application of BQ-3020 (10-minute interval) onto the same vessel failed to evoke any significant vasomotor response. Subsequent (third and fourth) adventitial microapplication of the ET(B) receptor agonist on the same arteriolar site effected a significant constriction of cerebral arterioles (-15.3 +/- 12.7% and -9.7 +/- 6.3% from preinjection baseline, respectively, at 20 and 30 minutes after the first application). The pial arterioles did not display tachyphylaxis to repeated applications of potassium (10 mmol/L). The perivascular application of the ET(B) receptor antagonist BQ-788 (0.001 to 1 micromol/L) had no effect on arteriolar caliber per se but blocked both BQ-3020-induced dilation (inhibitory concentration approximately 5 nmol/L) and vasoconstriction elicited by repeated activation of ET(B) receptors. After middle cerebral artery occlusion, most of the arterioles examined displayed a sustained dilation. The microapplication of BQ-3020 into the perivascular space surrounding postischemic dilated arterioles elicited a constriction of a similar magnitude to that induced by application of CSF (-17 +/- 7% and -17 +/- 7% from preinjection baseline, respectively). The adventitial microapplication of the ET(B) receptor antagonist (BQ-788, 0.1 micromol/L) on postocclusion dilated pial arterioles effected no change in the arteriolar caliber when compared with preinjection baseline. This BQ-788-induced response was significantly different from that induced by perivascular microinjection of CSF (P < 0.001, analysis of variance). These investigations indicate that (1) repeated activation of ET(B) receptors displays tachyphylaxis of the vasodilator response but also uncovers significant constriction of cerebral arterioles in vivo; (2) the ability of BQ-3020 to elicit dilation is lost within 30 minutes of induced focal ischemia; and (3) ET(B)-mediated contractile tone contributes in a small but significant manner in limiting postischemia dilation of cortical pial arterioles.

Animals↗
PubMedDate not supplied

Cardiovascular and behavioral actions of centrally administered cimetidine.

The cardiovascular and behavioral actions of cimetidine, injected into the lateral ventricle, were studied in conscious, freely moving rats. Cimetidine produced a dose-dependent pressor response accompanied by decreases in heart rate and increases in pulse pressure. At doses of 25-100 micrograms, cimetidine produced sedation; however, when 200 micrograms was injected, tremor was observed in all animals. If cimetidine was administered twice within 30 min to the same animal, tachyphylaxis in response to any of these actions was never evident. Although histamine produced similar pressor actions when administered intraventricularly, these effects were always subject to tachyphylaxis. The actions of cimetidine were not altered by central pretreatment with the H1 antagonist chlorpheniramine. A possible hypothesis of the central mechanism by which cimetidine produces these effects is discussed.

Animals↗
PubMed1990

Angiotensin II-induced [3H]adenosine release from in situ rat lung.

The purpose of the present study was to determine whether Ang II releases adenosine from the perfused rat lung. Rat lungs were perfused in situ with a physiological salt solution and were loaded with [3H]adenosine. The release of 3H from the perfused rat lung in response to intra-arterial injections of Ang II and other hormones was quantitated. Studies were conducted in both normal rats and in rats that had been nephrectomized before surgery to avoid exposure of the lungs to high levels of endogenous Ang II. Bolus doses of Ang II (10(-12)-10(-7) mol) increased the efflux of 3H from the lungs. Analysis of this effluent by thin-layer chromatography indicated that most of the Ang II-induced release of 3H was [3H]adenosine. The maximal response was usually obtained with 10(-9) mol, and higher doses (10(-8) and 10(-7) mol) mobilized less [3H]adenosine, which suggested tachyphylaxis. The effect of exogenous Ang II on [3H]adenosine release was greatly enhanced when activation of the endogenous renin-angiotensin system was prevented with prior nephrectomy. Infusion of the Ang II selective antagonist, (1-Sar-8-Ile)-Ang II, blocked Ang II-induced [3H]adenosine release. Neither norepinephrine, bradykinin, nor vasopressin consistently released adenosine. We conclude that (a) Ang II can induce the release of adenosine from the perfused rat lung, (b) this effect is receptor mediated, (c) this response is somewhat selective for Ang II, and (d) exposure to high levels of exogenous or endogenous Ang II causes tachyphylaxis so that Ang II-induced adenosine release is attenuated.

Adenosine↗
PubMed1992

Effects of endothelin-1 and endothelin-3 on the isolated guinea pig ileum: role of Na+ ions and endothelin receptor subtypes.

Endothelin (ET)-1 and ET-3 induced a biphasic effect (relaxation followed by contraction) in the isolated guinea pig ileum. The contractile but not the relaxant component of the responses was concentration dependent in the dose range studied. Neuronal mechanisms, cyclic guanosine monophosphate (GMP), and adenosine triphosphate (ATP)-dependent K+ channels do not seem to be involved in the relaxing effect of the two isopeptides, since that effect was not affected by either tetrodotoxin, methylene blue, or glibenclamide. Both ET-1 and ET-3 induced tachyphylaxis (homologous desensitization), which was not fully reversed after a 3-h resting period. The responses to both peptides were dependent on the Na+ gradient across the smooth muscle cells, as they were inhibited in low-Na+ medium and after treatment of the preparation with ouabain. Verapamil affected both the relaxant and the contractile components of the responses to the two isopeptides, whereas phorbol-12,13-dibutyrate affected mainly the contractile component. These results suggest that the voltage-operated channels are important for both components of the response induced by ET-1 and ET-3, and that protein kinase C may downregulate Ca2+ signalling. Cross-tachyphylaxis studies between ET-1 and ET-3 suggest the existence of at least two ET receptor subtypes in the guinea pig ileum.

Animals↗
PubMed1993

Two receptor subtypes are involved in the contractile component of the guinea pig ileum responses to endothelins.

Endothelin-1 (ET-1) and endothelin-3 (ET-3) induced a biphasic response (relaxation and contraction) in the guinea pig ileum. Short-term activation of protein kinase C (PKC) with phorbol 12,13-dibutyrate (PDBu) inhibited the contractile but not the relaxing component of the responses, as did H-7. Long-term pretreatment with PDBu reversed the short-term inhibition but did not affect the tachyphylaxis induced by ET-1. These results suggest that PKC contributes to ET-1 contraction but not to tachyphylaxis. The ETA antagonist BQ-123, at 34 nM, competitively inhibited ET-1 contraction, but at 340 nM the inhibition was noncompetitive. Dose-response curves for ET-1 relaxation were shifted to the left. For ET-3, BQ-123 (340 nM) only decreased the maximal contractile response of the dose-response curve without affecting the relaxation. We suggest that in this tissue there is one receptor for ET-1-induced contraction, which is competitively antagonized by BQ-123, and another one for ET-3-induced contraction, which is noncompetitively antagonized by BQ-123.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1994

Systemic and coronary hemodynamic effects of repetitive cocaine administration in conscious dogs.

The cardiovascular actions of cocaine are complex, and previous studies suggest that tachyphylaxis to the positive chronotropic and pressor effects of cocaine may develop after repetitive administration. We examined changes in systemic and coronary hemodynamics when single or multiple doses of intravenous (i.v.) cocaine were administered to conscious dogs. Dogs were chronically instrumented for measurement of aortic blood pressure (BP) and left ventricular pressure (LVP), LV dP/dtmax and dP/dt50, subendocardial segment length (%SS), diastolic coronary blood flow (CBF) velocity, and cardiac output (CO). Myocardial oxygen consumption was estimated by the pressure-work index (PWI). In one series of experiments, a single dose of cocaine (0.1, 0.2, 0.4, 0.8, or 1.6 mg/kg) was administered on 5 consecutive days in random fashion and peak changes in systemic and coronary hemodynamics were recorded. These doses were then randomly repeated in a second group of experiments with a 1-h interval between doses on the same day. Peak and steady-state changes in cardiovascular variables were recorded within and between each dose, respectively. In other experiments, higher doses of cocaine (0.8 or 1.6 mg/kg; separate groups) were administered four times at 1-h intervals in the same dogs and peak and steady-state changes in hemodynamics were determined. Cocaine caused dose-related increases in heart rate (HR), mean arterial pressure (MAP), LV systolic pressure (LVSP) and end-diastolic pressure (LVEDP), PWI, CO, and diastolic coronary vascular resistance and decreases in %SS when administered on different days. Cocaine also caused significant increases in baseline HR, MAP, LVSP, and PWI between doses given on the same day at 1-h intervals, but the absolute value of the peak response to cocaine of these hemodynamic parameters was independent of dosing regimen. These results were confirmed when we administered four doses of 0.8 mg/kg cocaine at 1-h intervals. The results indicate that baseline changes in systemic hemodynamic variables are a predominant feature of repetitive administration of lower doses of cocaine (< or = 0.8 mg/kg), but administration of higher doses of cocaine (> or = 8 mg/kg) at 1-h intervals caused tachyphylaxis to the hypertensive actions and myocardial oxygen consumption effects of cocaine.

Analysis of Variance↗
PubMed1998

Distinct endothelin-B receptors mediate the effects of sarafotoxin S6c and IRL1620 in the ileum.

In the guinea pig ileum, both sarafotoxin S6c (S6c) and IRL1620 induced a biphasic effect (relaxation and contraction). S6c induced strong tachyphylaxis of both components of the response, but IRL1620 induced tachyphylaxis mainly of the contractile component. Whereas the tissues rendered tachyphylactic to S6c did not respond to IRL1620, a normal biphasic response to S6c was observed in the tissues rendered tachyphylactic to IRL1620. In the presence of IRL1620, S6c could induce its biphasic effect, whereas in the presence of S6c, IRL1620 was ineffective. BQ-123, a specific ETA antagonist, did not affect the biphasic response induced by either agonist. PD145065, a potent ETA/ETB antagonist, was a competitive and a noncompetitive antagonist, respectively, of the contractile components of IRL1620 and S6c. RES-701-1, a specific ETB1 antagonist, inhibited both components of the response induced by IRL1620. However, it inhibited mainly the relaxant component induced by low doses of S6c. Apamin had different effects on endothelin-1 (ET-1), S6c, and IRL1620. Our results suggest that there are at least two distinct populations of ETB receptors mediating the biphasic response: the ETB1 receptor, sensitive to RES-701-1 and PD145065, and the ETB2 receptor, less sensitive to RES-701-1 and PD145065.

Animals↗
PubMed2005

Marked synergism between vasopressin and angiotensin II in a human isolated artery.

OBJECTIVE: To determine the direct contractile effects of angiotensin II (AII) and vasopressin (VP), and the effects of combinations of these agonists, in human isolated gastroepiploic arteries in vitro. DESIGN: Laboratory and clinical investigation. SETTING: University laboratory and hospital. SUBJECTS: Ring segments were prepared from gastroepiploic arteries obtained from 57 patients undergoing gastrectomy. Blood samples were obtained from ten patients after severe hemorrhage and from five healthy volunteers. INTERVENTIONS: Mechanical activity in the rings was assessed using a strain gauge. Plasma concentrations of AII and VP in the blood samples were measured using radioimmunoassay kits. MEASUREMENTS AND MAIN RESULTS: Both AII (1 or 10 ng/mL) and VP (100 or 500 pg/mL) produced concentration-dependent contractions in the rings. However, whereas VP produced reproducible sustained contractions, the contractile responses induced by multiple applications of AII showed marked desensitization (i.e., tachyphylaxis). Indeed, by the sixth application of either 1 ng/mL AII or 10 ng/mL AII, the contractile responses were <20% of the initial (control) response. During applications of AII after the sixth, the co-application of a low concentration of VP (100 pg/mL) fully restored the contractile response to AII in a clearly more-than-additive fashion. Similarly, the tachyphylaxis seen on AII application alone did not occur with repeated applications of an AII + norepinephrine mixture. In patients who had experienced hemorrhage, there were marked elevations of both AII and VP plasma concentrations, with values as high as 2.2 ng/mL and 550 pg/mL, respectively. CONCLUSION: These results indicate that there is a powerful synergism between the contractile effects of low-dose VP and AII in this human isolated artery. Moreover, the elevations of plasma AII and VP levels during hemorrhage suggest that this synergism may be both physiologically and clinically important in optimizing vasoconstriction and maintaining blood pressure in such critical states.

Adult↗
PubMed1989

The effects of salbutamol on blood pressure and heart rate in Large White and Pietrain-cross breeds of pig.

The effects of the beta 2-agonist salbutamol, on pig heart rate and blood pressure were evaluated at the expected commercially used concentration of 3 ppm in final feed, and at three times this level. Salbutamol was administered to pigs previously fed on control diet ('naive'), and in a second study to pigs fed 3 ppm salbutamol for 19 days ('acclimatized'). Heart rate and blood pressure were measured in conscious 30 kg pigs before (pre-ingestive), during (ingestive) and after ingestion (absorptive) of feed containing 3 or 9 ppm salbutamol. To assess any interaction with 'stress genotype' pigs, measurements were performed in Large White and Pietrain-cross breeds. The mean preingestive heart rates for the Large White and Pietrain-cross pigs were 127 and 109 beats/min, respectively. The corresponding figures for mean arterial blood pressure were 121 and 122 mmHg. The act of ingesting control feed caused heart rate to rise by 36-39% and blood pressure to increase by 17-27%. During the absorptive phase for 'naive' pigs fed 3 ppm salbutamol in the diet, blood pressure fell 5-11% and heart rate increased 20-24%, reflecting a classical baroreceptor mediated response. At 9 ppm the fall in blood pressure of 5-11% was similar to that at 3 ppm, while the rise in heart rate was larger at 31-38%. The magnitude of the changes at both 3 and 9 ppm was less than that evoked by the act of ingestion, with the exception of the heart rate response in Large Whites at 9 ppm, which was similar. The responses of the two breeds were comparable, indicating that salbutamol is unlikely to exacerbate the cardiovascular responses seen in potentially stress-susceptible pigs. The acute changes elicited by 3 ppm salbutamol during the absorptive phase in 'naive' pigs were abolished or substantially less in acclimatized pigs, implying a tachyphylaxis to the agonist's actions. This was confirmed by 9 ppm of salbutamol increasing heart rate of 'acclimatized' Large Whites to the same degree as 3 ppm in 'naive' counterparts. The desensitization in Pietrain-cross pigs was even more marked with no increase in heart rate produced by 9 ppm salbutamol following acclimatization. These data, combined with the rapid tachyphylaxis of response, indicate that salbutamol at the intended commercial inclusion of 3 ppm will not compromise the cardiovascular stability of the growing pig at rest.

Acclimatization↗
PubMed1979

Sodium nitroprusside as a hypotensive agent in intracranial aneurysm surgery.

Sodium nitroprusside (SNP) was used to induce hypotension during intracranial aneurysm surgery in 67 patients. The effects of SNP infusion (0.1 mg/ml) on blood pressure were rapid and it was easy to adjust blood pressure to desired levels in most patients. When SNP was stopped, the blood pressure returned instantly to the initial level. In eight patients an increase to about 25% or more above prehypotensive level was seen, counteracted in two patients by administration of small doses of halothane. There was a mean increase of 36% in heart rate. Total doses of SNP were 0.05--120 mg (mean: 10.8), corresponding to 0.08--6.8 micrograms/kg/min (mean: 1.9). No metabolic acidosis indicating cyanide intoxication was observed. Tachyphylaxis was seen in three patients, and SNP had to be discontinued in one. It is concluded that SNP gives a rapid and effective hypotension but tachyphylaxis and subsequent danger of cyanide intoxication exist. Therefore, in some cases SNP has to be replaced by or combined with some other hypotensive agent to achieve the desired effect. As there is a risk of impairment of cerebral autoregulation after the use of SNP, it is important to avoid sudden and prolonged blood pressure fluctuations, and to continue with controlled hyperventilation in the postoperative period to reduce the risk of brain oedema and high intracranial pressure.

Adolescent↗
PubMed1999

Influence of losartan and nicardipine on the contractile responses of human subcutaneous arteries and veins to angiotensin II.

In the human forearm vascular bed, the arterial constrictor effects of angiotensin II were found to be caused by an AT1-receptor mediated calcium influx, while the venous constrictor effects appeared to be independent of L-type calcium channels. In this study, we investigated the influences of the AT1-receptor antagonist losartan and the calcium channel blocker nicardipine on the angiotensin II-induced constriction of small isolated subcutaneous arteries and veins obtained from human mammary tissue. Subcutaneous arteries and veins were isolated from mammary tissue from 9 healthy women who underwent breast reduction surgery. Effects of angiotensin II (0.3 nM to 1 mM), losartan (0.1 mM) and nicardipine (0.1 mM) were investigated in a myograph set up. Identification of arteries and veins was confirmed histologically after the experiments. Drug effects were expressed relatively to the potassium-induced contraction. Angiotensin II concentration-dependently contracted arteries and veins by maximally 1.66 +/- 0.31 N/m and 0.43 +/- 0.08 N/m, respectively (P < 0.05). In arteries the angiotensin II were subject to a mild degree of tachyphylaxis: the Emax of the repetitive concentration-response curve (CRC) was reduced from 105 +/- 4% of the potassium-induced contraction to 84 +/- 6% (P < 0.05); the EC50 value was unchanged (P > 0.05). In veins no tachyphylaxis was observed. Losartan caused a rightward shift of the CRC of angiotensin II in arteries and veins (P < 0.05), and reduced the Emax in arteries from 105 +/- 4 to 85 +/- 9% (P < 0.05), but did not change the Emax in veins. Nicardipine significantly decreased the Emax in arteries and veins (to residual values of 10 +/- 2 and 20 +/- 4%, respectively, of the control values). In conclusion, the angiotensin II-induced constriction of human arteries and veins isolated from mammary tissue are AT1-receptor mediated and inhibited by losartan. The nearly complete inhibition by nicardipine indicates that the constrictor effects in both types of vessels are dependent on L-type calcium channels.

Acetylcholine↗
PubMed1974

The effect of ethacrynic acid on the guinea-pig and rat isolated vas deferens.

1 The effect of ethacrynic acid (EA) was studied on guinea-pig and rat vas deferens in vitro.2 EA contracted the guinea-pig but not the rat vas deferens in a dose-dependent manner (50-800 mug/ml). Tyramine caused contraction in 10 out of 18 guinea-pig vas deferens; EA caused contraction in 17 of the preparations which did not respond to tyramine. Repeated doses of EA produced tachyphylaxis, but there was no cross tachyphylaxis to tyramine.3 The contractions produced by EA were prevented by phentolamine or reserpine pretreatment and potentiated by cocaine. A low concentration of desipramine (3 ng/ml) potentiated and higher concentrations (0.6 and 3.0 mug/ml) inhibited the response of vas deferens to EA.4 Hexamethonium (100 mug/ml) or atropine (0.1 mug/ml) did not inhibit the effect of EA, excluding the nicotinic and muscarinic receptors as the sites of action.5 The effect of noradrenaline (NA) on the guinea-pig and rat vas deferens was enhanced by EA pretreatment, which may be due to inhibition of NA uptake.6 It is concluded that EA releases NA from guinea-pig vas deferens. The mechanism of release seems to be different from that of tyramine.

Animals↗
PubMed1975

Membrane potential changes induced by 5-hydroxytryptamine in the rabbit superior cervical ganglion.

1. Changes in resting membrane potential induced by 5-hydroxytryptamine (5-HT) have been measured in the excised ganglion by the sucrose-gap technique. 2. 5-HT produced a rapid depolarization, the threshold concentration for depolarization being around 10 muM. With concentrations of 100 muM or greater, repolarization began during the course of the superfusion; this was followed by prolonged tachyphylaxis. 3. Tachyphylaxis was largely avoided by making injections into the superfusion stream. Standard injections of 0.2 mumol 5-HT dissolved in 0.2 ml of Krebs solution were used routinely and could be given at 20-30 min intervals to evoke relatively constant responses. 4. The response to an injection consisted of a rapid depolarization, followed by a rapid repolarization and subsequent after-hyperpolarization. The threshold quantity for depolarization was around 0.01 mumol, while the ED50 estimated from 6 dose-response curves was 0.12 +/- 0.02 mumol (mean +/- s.e. mean). 5. Injections of 5-HT (0.2 mumol), choline (10 mumol) and acetylcholine (9.9 mumol) produced depolarizations of similar magnitude. 6. Monoamine oxidase inhibitors failed to alter substantially the amplitude of depolarizations to 5-HT. 7. 5-HT depolarizations were unaltered in amplitude when the impermeant anion benzenesulphonate was substituted for the chloride ion in Krebs solution, but were initially markedly reduced in amplitude in a sodium-deficient medium; some recovery of the response subsequently occurred. The depolarization which persisted in sodium-deficient solutions was much reduced or abolished when calcium ions were then removed from the superfusion medium. Removal of either calcium ions alone or potassium ions from the superfusion fluid did not reduce depolarization amplitude. 8. The after-hyperpolarization was abolished in sodium-deficient solutions, usually increased in potassium-free solutions, reduced or abolished by ouabain or nicotine, but unaffected by calcium free solutions. 9. A depolarizing action of 5-HT on presynaptic terminals in the ganglion appears probable.

Acetylcholine↗