Cardiovascular responses to intrathecal dopamine receptor agonists after spinal transection in conscious rats.

OBJECTIVE: The cardiovascular responses to transient intrathecal administration of dopamine agonists were studied daily in chronically prepared rats that had been spinally transected or were sham operated. The goals were (1) to determine the group differences in evoked heart rate and arterial pressure responses and (2) to determine, within the transected group, whether or not the long term responses could be dissociated. The hypothesis tested is that cord transection releases a tonic inhibition of cardiovascular responsiveness independently of the mechanism of receptor hypersensitivity. METHODS: Changes in mean aortic blood pressure and heart rate induced by intrathecal administration of the mixed D1/D2 dopamine receptor agonist apomorphine (150 nmol per rat) were measured in conscious rats during a 10 d experimental period following spinal transection. RESULTS: Complete spinal transection did not affect aortic pressure but increased basal heart rate values by about 33% with respect to normal rats (p < 0.001). When apomorphine was injected caudally to the section (at T9-T10) but not rostrally (at T2-T4), it induced a 50% greater and an 800% more long lasting decrease in mean aortic pressure and a 230% greater and 70% more long lasting decrease in heart rate in spinal than in sham operated rats. These increases in cardiovascular responses were corroborated by a leftward shift of the apomorphine dose-response curves. They were also found after intrathecal administration of highly selective D1 and D2 receptor agonists fenoldopam (50 nmol per rat) and quinpirole (150 nmol per rat), and were specifically blocked by intrathecal haloperidol (27 nmol per rat), a non-selective dopamine antagonist. CONCLUSIONS: Complete spinal transection induces different increases in hypotensive and bradycardic responses to the stimulation of caudally located spinal dopamine receptors which could be due to the destruction of a tonically inhibiting spinal system rather than to hypersensitivity of the dopamine receptors.

Central dopaminergic origin of bromocriptine induced tachycardia in normotensive rats.

OBJECTIVES: This study was undertaken to investigate the mechanism of the tachycardic effect of bromocriptine, a specific dopamine D-2 receptor agonist, which is not abolished, as previously reported, by intravenous domperidone, a selective dopamine D-2 antagonist unable to cross the blood brain barrier. Two hypotheses were tested: (1) that the increase in heart rate after intravenous treatment with bromocriptine could be related to central dopamine receptor stimulation and (2) that it could be induced by a release of adrenaline from the adrenal medulla. METHODS: Changes in mean aortic pressure and heart rate, induced by treatment with 150 micrograms.kg-1 bromocriptine intravenously, were measured in conscious or anaesthetised normal or adrenalectomised rats submitted to various pretreatments. RESULTS: In conscious intact rats, intravenous bromocriptine decreased mean aortic pressure (-11 (SEM1) mm Hg) and increased heart rate (62(12)) beats.min-1). Both effects were prevented by intravenous pretreatment (0.3 mg.kg-1) with dopamine D-2 receptor antagonists able to cross the blood brain barrier, such as haloperidol, sulpiride, and metoclopramide. In anaesthetised rats, domperidone (50 and 20 micrograms.kg-1) given via a lateral cerebral ventricle abolished the bromocriptine induced tachycardia without affecting the hypotensive response. Both effects were unchanged after bilateral adrenalectomy but were completely abolished by intravenous haloperidol pretreatment (0.3 mg.kg-1) in conscious adrenalectomised rats. CONCLUSIONS: These results suggest that in anaesthetised and conscious normotensive rats, the bromocriptine induced tachycardia is not related to a release of adrenaline from the adrenal medulla but could be elicited by central dopamine D-2 receptor stimulation through a possible increase in cardiac sympathetic tone.

Na+/H+ exchange and osmotic shrinkage in isolated trout hepatocytes

The ability of rainbow trout liver cells to regulate their intracellular pH (pHi) was studied using two methods on hepatocytes isolated by collagenase digestion: (i) by monitoring pHi with the fluorescent dye BCECF-AM, and (ii) by measuring the amiloride-sensitive uptake of 22Na, which represents Na+/H+ exchange. In low-Na+ medium (¾16mmoll-1), Na+ uptake was reduced by approximately 70% in the presence of amiloride derivatives (DMA or MPA, 10(-4)moll-1). Changing separately either the extracellular pH (pHe) or the intracellular pH (pHi, clamped by treating the cells with nigericin in the presence of 140mmoll-1 K+) between 6 and 8 induced an increase in the rate of Na+ uptake when pHe was raised or when pHi was reduced. When transferred to hypertonic medium, hepatocytes shrank to nearly 72% of their initial volume, and thereafter a slow and partial regulatory volume increase phase was observed, with an increase in the amiloride-sensitive rate of Na+ uptake and an increase in intracellular pH. As DIDS-sensitive Cl- uptake was concomitantly enhanced, it is suggested that hypertonic stress activates Na+/H+ and Cl-/HCO3- exchange.

Blunted pressor responsiveness to intravenous quinpirole in conscious, chronic spinal cord-transected rats: peripheral vs. spinal mechanisms.

Intravenous quinpirole (1 mg/kg) in conscious rats with chronic spinal cord transection (at T5-T7) induced an initial pressor effect, which was significantly reduced in both magnitude and duration compared with that in sham-operated rats, which was then followed by a long-lasting depressor effect. To distinguish the spinal and/or peripheral origin of this phenomenon, conscious, spinal cord-transected rats were also pretreated with either intravenous (0. 5 mg/kg), intrathecal (40 microg/kg) or combined intravenous and intrathecal domperidone, a dopamine D(2) receptor antagonist that does not cross the blood-brain barrier. Intravenous pretreatment with domperidone enhanced, but did not completely restore, the pressor effect of quinpirole, and had no effect upon the depressor component. However, both the depressor component and the reduction of the pressor effect induced by spinal section were fully abolished by intrathecal or combined intrathecal and intravenous domperidone. Quinpirole-induced changes in mean aortic pressure were also fully abolished by intravenous pretreatment with metoclopramide (5 mg/kg). Neither the pressor nor the bradycardiac response to intravenous phenylephrine differed between sham-operated and spinal rats. These results suggest that the blunted pressor response to quinpirole after spinal cord transection is related to an enhanced spinal dopamine D(2) receptor-mediated depressor effect rather than to hypersensitivity of peripheral dopamine D(2) receptors or vascular hyporesponsiveness to alpha(1)-adrenoceptor stimulation. Thus, in conscious intact rats, the prominent central pressor effect of quinpirole seems to oppose, not only a peripheral sympathoinhibitory depressor effect, as previously thought, but also a spinal depressor effect.

Involvement of spinal dopamine receptors in mediation of the hypotensive and bradycardic effects of systemic quinpirole in anaesthetised rats.

This study examined the involvement of spinal dopamine D2 receptors in the cardiovascular effects induced by intravenous administration of the selective dopamine D2 receptor agonist quinpirole, as has been previously reported for the hypotensive action of systemic bromocriptine. In normotensive pentobartitone-anaesthetised rats, intravenous injection of quinpirole (25 to 1000 microg/kg) decreased mean aortic pressure and heart rate in a dose-related manner. The intravenous (0.5 mg/kg) or intrathecal (40 microg/rat at T9-T10) pretreatment with domperidone, a dopamine D2 receptor antagonist that does not cross the blood-brain barrier, significantly reduced the maximal hypotensive and bradycardic responses to intravenous quinpirole (1000 microg/kg). In contrast, the latter effects were fully abolished either by intravenous metoclopramide (5 mg/kg) or combined pretreatment with intravenous and intrathecal domperidone. In addition, when injected intrathecally at the T9-T10 level of the spinal cord, quinpirole (7.7 to 61.4 microg/rat) also produced dose-dependent depressor and bradycardic effects which could be blocked by intrathecal, but not intravenous, domperidone pretreatment. This suggests that, in anaesthetised normotensive rats, the hypotensive and bradycardic responses to intravenous quinpirole are fully mediated by dopamine D2 receptors, some of which are located in the peripheral circulation and some of which are located within the spinal cord. The latter finding is novel, suggesting that partial spinal mediation may not be peculiar to bromocriptine, as was previously thought. Rather, partial spinal mediation may be common to most dopamine D2 receptor agonists.

Cardiovascular responses to intrathecal dopamine receptor agonists in conscious DOCA-salt hypertensive rats.

Previous studies have demonstrated that in conscious deoxycorticosterone acetate (DOCA)-salt hypertensive rats, the hypotensive action of intravenous (i.v.) bromocriptine, a selective dopamine D2 receptor agonist, was mediated partly by peripheral and partly by spinal dopamine D2 receptor stimulation, and that this effect was greater and longer-lasting than that in uninephrectomized control rats. To determine whether this amplification results partly from a putative spinal hypersensitivity phenomenon, cardiovascular responses to intrathecal (i.t.) administration of apomorphine and quinpirole were studied in conscious, 4-week DOCA-salt hypertensive rats and compared with those in uninephrectomized control rats. In both groups, upper thoracic (T2-T4) i.t. injections of apomorphine (9.1, 45.5 and 91.1 microg/rat) induced immediate and dose-dependent decreases in mean aortic pressure (MAP) and heart rate (HR), while i.t. quinpirole (38.4 microg/rat) induced only bradycardia. Neither magnitude nor duration of these responses was enhanced in DOCA-salt hypertensive rats when compared to control rats. In DOCA-salt hypertensive rats, apomorphine-induced hypotension and bradycardia remained unaffected by i.v. (500 microg/kg) pretreatment with domperidone, a selective dopamine D2 receptor antagonist that does not cross the blood-brain barrier. However, i.t. (40 microg/rat at T2-T4) pretreatment with domperidone significantly reduced apomorphine-induced hypotension, but fully suppressed bradycardia elicited by either apomorphine or quinpirole. These results demonstrated that in conscious DOCA-salt hypertensive rats, intrathecally-injected apomorphine or quinpirole decreased MAP and/or HR through a spinal D2 dopaminergic mechanism, as previously demonstrated in normotensive intact rats. Since both magnitude and duration of these responses were unchanged with respect to uninephrectomized control rats, enhancement of the hypotensive effect of intravenously-administered bromocriptine in DOCA-salt hypertensive rats does not appear to involve spinal dopamine D2 receptors.

Hypotensive action of bromocriptine in the DOCA-salt hypertensive rat: contribution of spinal dopamine receptors.

To assess the role of spinal dopamine receptors in mediation of hypotension induced by systemic administration of the dopamine D2 receptor agonist, bromocriptine, conscious deoxycorticosterone acetate (DOCA)-salt hypertensive rats were pretreated with either intravenous (i.v.; 500 micrograms/kg) or intrathecal (i.t.; 40 micrograms/rat at T9-T10) domperidone, a selective dopamine D2 receptor antagonist that does not cross the blood-brain barrier. In DOCA-salt hypertensive rats, i.v. administration of a sub-maximal dose of bromocriptine (150 micrograms/kg) induced a significant decrease in mean aortic pressure (MAP) which was greater and longer lasting than that in uninephrectomized control rats. Intravenous or i.t. pretreatment with domperidone reduced partially, but significantly, the hypotensive effect of bromocriptine (reduction of about 57% and 45% of the maximal effect, respectively). The remaining responses observed during the 60 min postinjection period were still statistically significant as compared with vehicle injection. In contrast, the bromocriptine-induced hypotension was fully abolished by i.v. pretreatment with metoclopramide (300 micrograms/kg), a dopamine D2 receptor antagonist that crosses the blood-brain barrier, or by combined pretreatment with i.v. and i.t. domperidone. These results suggest that, in DOCA-salt hypertensive rats, the hypotension induced by i.v. bromocriptine is mediated partly through a peripheral D2 dopaminergic mechanism and partly through stimulation of spinal dopamine D2 receptors, has been demonstrated in conscious normotensive rats.

Effects of long-term pretreatment with isoproterenol on inotropic responsiveness to alpha-adrenoceptor stimulation: study in isolated perfused rat hearts.

The effects of chronic pretreatment with isoproterenol (5 mg kg(-1)) daily for 10 days on cardiac alpha-adrenergic responsiveness in Langendorff heart preparations were investigated. Isoproterenol pretreatment caused cardiac hypertrophy (29%) as shown by a significant increase in the ratio of ventricular dry weight to body weight. In preparations from isoproterenol-pretreated rats, both maximum increases in left ventricular systolic pressure and heart rate elicited by isoproterenol (10(-12) to 10(-4) M) were significantly reduced (the isoproterenol concentration producing 50% of the maximum positive inotropic and chronotropic responses was enhanced almost 32- and 4-fold, respectively), while the positive inotropic response to phenylephrine (10(-12) to 10(-4) M) was significantly enhanced (the phenylephrine concentration producing 50% of the maximum positive inotropic effect was reduced almost 100-fold), compared with saline-pretreated rats. In preparations from both groups, phenylephrine infusion induced non-significant changes in heart rate and its positive inotropic response was reduced in the presence of propranolol (10(-7) M) in the perfusion medium. Even under beta-adrenoceptor blockade, the curve for the phenylephrine-induced positive inotropic effect remained shifted upward after isoproterenol pretreatment. Chronic isoproterenol pretreatment induces the expected cardiac beta-adrenoceptor desensitization while simultaneously enhancing the positive inotropic responsiveness to phenylephrine in Langendorff heart preparations. These findings support the hypothesis that cardiac alpha1-adrenoceptor stimulation may contribute to the maintenance of myocardial function under conditions in which beta-adrenoceptor function is compromised.

Influence of a multideficient diet from northeastern Brazil on resting blood pressure and baroreflex sensitivity in conscious, freely moving rats.

The "regional basic diet" or RBD is a multideficient diet (providing 8% protein) which is known to produce dietary deficiencies in some populations in northeastern Brazil. The present study investigated the effects of RBD-induced malnutrition on resting blood pressure and baroreflex sensitivity in conscious rats. Malnourished rats were obtained by feeding dams the RBD during mating and pregnancy (RBD-1 group) or during nursing and a 10-day period after weaning (RBD-2 group). At 90 days of age, only RBD-2 rats weighed significantly (P<0.001) less than control rats born to dams fed a standard commercial diet (23% protein) during pregnancy and nursing. Baseline mean arterial pressure and heart rate of both RBD-1 and RBD-2 rats were comparable to those of controls. The slopes for both reflex bradycardia and tachycardia (bpm/mmHg) induced by intravenous phenylephrine and sodium nitroprusside, respectively, were unchanged in either RBD-1 (-2.08 +/- 0.11 and -3.10 +/- 0.43, respectively) or RBD-2 (-2.32 +/- 0.30 and -3.73 +/- 0.53, respectively) rats, when compared to controls (-2.09 +/- 0.10 and -3.17 +/- 0.33, respectively). This study shows that, after a prolonged period of nutritional recovery, the patterns of resting blood pressure and baroreflex sensitivity of both pre- and postnatally malnourished rats were similar to those of controls. The decreased body weight and the tendency to increased reflex tachycardia in RBD-2 rats may suggest that this type of maternal malnutrition during lactation is more critical than during pregnancy.

(-)-α-Bisabolol inhibits preferentially electromechanical coupling on rat isolated arteries.

Previous findings enable us to hypothesize that (-)-α-bisabolol acts as inhibitor of voltage-dependent Ca(2+) channels in smooth muscle. The current study was aimed at consolidating such hypothesis through the recording of isometric tension, measurement of intracellular Ca(2+) as well as discovery of channel target using in silico analysis. In rat aortic rings, (-)-α-bisabolol (1-1000 µM) relaxed KCl- and phenylephrine-elicited contractions, but the IC50 differed significantly (22.8 [17.6-27.7] and 200.7 [120.4-334.6] µM, respectively). The relaxation of phenylephrine contractions remained unaffected by l-NAME, indomethacin, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, tetraethylammonium, glibenclamide or KT-5720. Under Ca(2+)-free conditions, (-)-α-bisabolol did not alter the contractions evoked by phenylephrine or caffeine whereas it reduced those evoked by CaCl2 in KCl-, but not in PHE-stimulated preparations. Furthermore, it did not significantly alter the contractions evoked by phorbol 12,13-dibutyrate or induced by the extracellular Ca(2+) restoration in cyclopiazonic acid-treated preparations. In mesenteric rings loaded with Fluo-4 AM, (-)-α-bisabolol blunted the tension and the cytosolic levels of Ca(2+) in response to K(+) but not to norepinephrine. Silico docking analysis of the Cavß2a subunit of voltage-dependent Ca(2+) channel indicated putative docking sites for (-)-α-bisabolol. These findings reinforce the ability of (-)-α-bisabolol to inhibit preferentially contractile responses evoked by Ca(2+) influx through voltage-dependent Ca(2+) channels.

Chemical composition, antinociceptive and anti-inflammatory effects in rodents of the essential oil of Peperomia serpens (Sw.) Loud.

ETHNOPHARMACOLOGICAL RELEVANCE: Peperomia serpens (Piperaceae), popularly known as "carrapatinho", is an epiphyte herbaceous liana grown wild on different host trees in the Amazon rainforest. Its leaves are largely used in Brazilian folk medicine to treat inflammation, pain and asthma. AIM OF THE STUDY: This study investigated the effects of essential oil of Peperomia serpens (EOPs) in standard rodent models of pain and inflammation. MATERIALS AND METHODS: The antinociceptive activity was evaluated using chemical (acetic acid and formalin) and thermal (hot plate) models of nociception in mice whereas the anti-inflammatory activity was evaluated by carrageenan- and dextran-induced paw edema tests in rats croton oil-induced ear edema, as well as cell migration, rolling and adhesion induced by carrageenan in mice. Additionally, phytochemical analysis of the EOPs has been also performed. RESULTS: Chemical composition of the EOPs was analyzed by gas chromatography and mass spectrometry (GC/MS). Twenty-four compounds, representing 89.6% of total oil, were identified. (E)-Nerolidol (38.0%), ledol (27.1%), α-humulene (11.5%), (E)-caryophyllene (4.0%) and α-eudesmol (2.7%) were found to be the major constituents of the oil. Oral pretreatment with EOPs (62.5-500 mg/kg) significantly reduced the writhing number evoked by acetic acid injection, with an ED(50) value of 188.8 mg/kg that was used thereafter in all tests. EOPs had no significant effect on hot plate test but reduced the licking time in both phases of the formalin test, an effect that was not significantly altered by naloxone (0.4 mg/kg, s.c.). EOPs inhibited the edema formation induced by carrageenan and dextran in rats. In mice, EOPs inhibited the edema formation by croton oil as well as the leukocyte and neutrophil migration, the rolling and the adhesion of leukocytes. CONCLUSIONS: These data show for the first time that EOPs has a significant and peripheral antinociceptive effect that seems unrelated to interaction with the opioid system. EOPs also displays a significant anti-inflammatory effect in acute inflammation models. This effect seems to be related to components which inhibit the production of several inflammatory mediators. These results support the widespread use of Peperomia serpens in popular medicine to treat inflammation and pain.

Effects of K+channels inhibitors on the cholinergic relaxation of the isolated aorta of adult offspring rats exposed to maternal diabetes.

Vascular disease has importance in chronic diabetes mellitus but long-term impact of maternal diabetes (MD) on vascular function in the offspring is poorly investigated. This study aimed to examine the alterations produced by MD in K (+) channels activity on endothelium-dependent aortic relaxation induced by acetylcholine (ACh) in adult offspring rats. Diabetes mellitus was induced in female Wistar rats by streptozotocin (STZ; 42 mg/kg, i. p.) injected on the 7 (th) day of pregnancy. Body weights of offspring rats from diabetic mothers (O-DR) were significantly lesser than those of offspring rats from control mothers (O-CR). At 120 days of age, triglyceride but not glucose and cholesterol level was significantly higher in O-DR than in O-CR. In aortic preparations from O-DR, norepinephrine (NE)-induced contractions were significantly higher than those observed in O-CR. In aortic preparations from O-DR precontracted with NE (1 muM), vasorelaxant response to either ACh (0.1, 1 and 10 muM) or sodium nitroprusside (0.1, 1 and 10 nM) was significantly reduced when compared to O-CR. In both groups, vasorelaxant responses to ACh were reduced in the presence of tetraethylamonium chloride and 4-aminopyridine. However, pretreatment with glybenclamide reduced vasorelaxant effects of lowest concentration (0.1 muM) of ACh only in preparations from O-CR. Our results suggest a reduced K (+)(ATP) activity in the cholinergic relaxation of aortic rings of adult offspring born to STZ-diabetic mothers.

Vasorelaxant effects of the monoterpenic phenol isomers, carvacrol and thymol, on rat isolated aorta.

Various essential oils are rich in carvacrol, a monoterpenic phenol isomeric with thymol. This study was undertaken to assess the vasorelaxant effects of thymol and carvacrol in rat isolated aorta and the putative mechanisms underlying these effects. Thymol and carvacrol produced a concentration-dependent relaxation on the aortic ring preparations pre-contracted using KCl (IC(50) value of 64.40 +/- 4.41 and 78.80 +/- 11.91 microm, respectively) or using phenylephrine (PHE, 0.1 microm) (IC(50) value of 106.40 +/- 11.37 and 145.40 +/- 6.07 microm, respectively) and inhibited the concentration-response curves of aortic rings to PHE or KCl. In Ca(2+)-free medium with ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid (2 mm), thymol and carvacrol both at 1000 microm completely abolished the phasic component of PHE-induced endothelium-containing ring contractions. At 400 microm, thymol and carvacrol significantly reduced the CaCl(2)-induced contractions in Ca(2+)-free medium. Furthermore, both thymol and carvacrol (300 and 1000 microm) significantly reduced the contraction evoked by phorbol dibutyrate (1 microm), an activator of protein kinase C. Magnitude of this inhibitory effect was enhanced in the presence of the Ca2+ pump inhibitor, thapsigargin (1 microm). At 1000 microm, neither thymol nor carvacrol altered the resting potential of vascular smooth muscle cells. In conclusion, thymol and carvacrol induced an endothelium-independent relaxation in rat isolated aorta, an effect that seems mediated through some mechanisms probably involving a transduction pathway between Ca(2+) release from sarcoplasmic reticulum and/or regulation of the Ca2+ sensitivity of the contractile system. Moreover, it's conceivable that thymol and carvacrol, at low concentrations, block the Ca(2+) influx through the membrane.

Croton sonderianus essential oil samples distinctly affect rat airway smooth muscle.

Plants of the genus Croton have been used extensively in the northeast of Brazil for treating various clinical conditions. Previous studies have demonstrated that the essential oil of some specimens of Croton sp. have a relaxing effect on tracheal smooth muscle. Our study aimed to characterize the effects of Croton sonderianus essential oil samples, collected at 1:00 pm (EO-13) and 9:00 pm (EO-21), on rat tracheal smooth muscle. The two samples were submitted to gas chromatography (GC) and mass spectrometry (MS) analysis to identify their components. Rat tracheal smooth muscle strips were used to assess the biological activity. The major constituents of EO-21 were: spathulenol (18.32%), beta-caryophyllene (14.58%) and caryophyllene oxide (8.54%) and the major constituents of EO-13 were bicyclogermacrene (16.29%), beta-phellandrene (15.42%) and beta-caryophyllene (13.82%). These samples showed an antispasmodic effect on tracheal smooth muscle strips pre-contracted with high K+ concentration (80 mM) or with acetylcholine. EO-21 increased baseline tonus while EO-13 provoked a decrease. These results demonstrated that EO-13 and EO-21 have different chemical composition and showed myorelaxant activity. In conclusion, EO-13 and EO-21 may have potential therapeutic use in the treatment of bronchospasm.

Role of capsaicin-sensitive sensory nerves in mediation of the cardiovascular effects of the essential oil of croton zehntneri leaves in anaesthetized rats.

The essential oil of Croton zehntneri Pax et Hoffm. (EOCZ) contains anethole (42%) and estragole (46%), two isomers that share some chemical structural similarities with capsaicin. The present study investigated the cardiovascular effects of EOCZ and the role of capsaicin-sensitive sensory nerve fibres in the mediation of these effects in anaesthetized rats. 2. Intravenous bolus injection of EOCZ (1-20 mg/kg) elicited dose-dependent hypotension and bradycardia that were immediate and transient. Similar responses were also observed with anethole and estragole (both at 10 mg/kg). After cervical bivagotomy or perineural treatment of both cervical vagus nerves with capsaicin (250 mg/mL) to selectively block the conduction of sensory C-fibres, both cardiovascular responses to EOCZ (10 mg/kg) were abolished. 3. Like capsaicin, an epigastric retrograde intra-arterial injection of EOCZ (10 mg/kg, i.a.) into the femoral artery elicited a monophasic hypotensive response. This reflex response was blocked by either neonatal pretreatment with capsaicin (50 mg/kg, s.c.) or intrathecal injection of the substance P receptor antagonist RP 67580 (7.8 nmol, at the spinal level L5-L6), suggesting that it is mediated exclusively by substance P-containing primary afferent fibres. 4. The cardiovascular responses to EOCZ (10 mg/kg, i.v.) were also significantly reduced by the selective vallinoid TPRV1 receptor antagonist capsazepine (1 mg/kg, i.v.). 5. It is concluded that i.v. administration of EOCZ in anaesthetized rats elicits a capsaicin-like bradycardic and depressor reflex, which appears to be mediated by the activation of vallinoid TPRV1 receptors located on vagal sensory nerves. Like capsaicin, i.a. injection of EOCZ induces a spinally mediated sensory reflex.

Essential oil of croton nepetaefolius and its main constituent, 1,8-cineole, block excitability of rat sciatic nerve in vitro.

1. The effects of the essential oil of Croton nepetaefolius (EOCN) and its major constituent, 1,8-cineole, on the compound action potential (CAP) of nerve were investigated. 2. Experiments were performed in sciatic nerves dissected from Wistar rats, mounted in a moist chamber and stimulated at a frequency of 0.2 Hz, with electric pulses of 100 micros duration at 20-40 V. Evoked CAP were displayed on an oscilloscope and recorded on a computer. The CAP control parameters were as follows: peak-to-peak amplitude 8.1 +/- 0.6 mV (n = 15); conduction velocity 83.3 +/- 4.2 m/s (n = 15); chronaxie 58.0 +/- 6.8 msec (n = 6); and rheobase 2.8 +/- 0.1 V (n = 6). 3. Lower concentrations of EOCN (100 and 300 microg/mL) and 1,8-cineole (153 and 307 microg/mL; i.e. 1 and 2 mmol/L, respectively) had no significant effects on CAP control parameters throughout the entire recording period. However, at the end of 180 min exposure of the nerve to the drug, peak-to-peak amplitude was significantly (P < 0.05) reduced to 27.4 +/- 6.7 and 1.7 +/- 0.8% of control values by 500 and 1000 microg/mL EOCN, respectively (n = 6), and to 76.5 +/- 4.4, 70.0 +/- 3.9 and 14.8 +/- 4.1% of control values by 614, 920 and 1227 microg/mL (i.e. 4, 6 and 8 mmol/L) 1,8-cineole, respectively (n = 6). Regarding conduction velocity, at the end of the 180 min exposure period, this parameter was significantly reduced to 85.8 +/- 7.3 and 48.7 +/- 12.3% (n = 6) of control values by 500 and 1000 microg/mL EOCN, respectively, and to 86.4 +/- 4.5 and 76.1 +/- 5.2% (n = 6) by 920 and 1227 microg/mL 1,8-cineole, respectively. Chronaxie and rheobase were significantly increased by the higher concentrations of both EOCN and 1,8-cineole. 4. It is concluded that EOCN and its main constituent 1,8-cineole block nerve excitability in a concentration-dependent manner, an effect that was totally reversible with 1,8-cineole but not with EOCN. This suggests that other constituents of EOCN, in addition to 1,8-cineole, may contribute to the mediation of this effect of EOCN.

Central bromocriptine-induced tachycardia is reversed to bradycardia in conscious, deoxycorticosterone acetate-salt hypertensive rats.

A central dopaminergic origin has been demonstrated for the bromocriptine-induced tachycardia in conscious, normotensive rats. The present study investigated the effect of bromocriptine on heart rate and the principal site of action of this agonist in conscious, deoxycorticosterone acetate-salt hypertensive rats, in which altered central dopaminergic activity has been previously reported. Intravenous administration of bromocriptine (150 microg/kg) increased heart rate (49+/-5 beats/min.) in uninephrectomized control rats, while it induced a significant bradycardia (50+/-6 beats/min.) in deoxycorticosterone acetate-salt hypertensive rats. In the latter animals, intravenous (500 microg/kg) or intrathecal (40 microg/rat at T9-T10) pretreatment with domperidone, a selective dopamine D2 receptor antagonist that does not cross the blood-brain barrier, reduced partially, but significantly, the bradycardiac responses to bromocriptine (reduction of about 44% and 48% of the maximal effect, respectively). In contrast, the bromocriptine-induced bradycardia was fully abolished by intravenous pretreatment with metoclopramide (300 microg/kg), a dopamine D2 receptor antagonist that crosses the blood-brain barrier, or by combined pretreatment with intravenous and intrathecal domperidone. These results indicate that, in deoxycorticosterone acetate-salt hypertensive rats, bromocriptine decreases rather than increases heart rate, an effect that is mediated partly through a peripheral D2 dopaminergic mechanism and partly through stimulation of spinal dopamine D2 receptors. They further support the concept that, in normotensive, conscious rats, the central tachycardia of bromocriptine appears to predominate and to mask the bradycardia of this agonist at both peripheral and spinal dopamine D2 receptors.

Increase in the hypotensive effect of bromocriptine induced by spinal transection in rats: contribution of spinal dopamine receptors.

Intravenous (i.v.) administration of bromocriptine (150 micrograms/kg) in conscious normotensive rats with chronic spinal cord transection (at T5-T7), pretreated or not with i.v. propranolol (0.5 mg/kg), induced significant decreases in mean arterial blood pressure (MAP) which were greater and longer lasting than those in intact rats (-15 to -20 as compared with -10 mm Hg) for 8 days after transection. To assess the spinal and/or peripheral origin of this phenomenon, rats were also pretreated with either i.v. (0.3 mg/kg) or intrathecal (i.t.; 93 nmol/rat; at T9-T10) administration of domperidone, a selective dopamine (DA)2 receptor antagonist incapable of crossing the blood-brain barrier (BBB) freely. The increase in hypotension induced by spinal section was suppressed by i.t. but not by i.v. domperidone. In intact rats, bromocriptine elicited an increase in heart rate (HR; approximately 50 beats/min more), which was prevented by i.v. propranolol treatment. In spinal cord-transected rats, however, it had a significant bradycardic effect (approximately 50 beats/min less), which was antagonized by i.t.-administered domperidone. These results suggest that enhancement of the hypotensive effects induced by systemic administration of bromocriptine after a complete thoracic spinal transection is fully mediated by spinal DA2 receptors. This finding may help explain the increased orthostatic hypotension induced by DA receptor agonists in Parkinsonian patients with spinal lesions.

Contribution of spinal dopamine receptors to the hypotensive action of bromocriptine in rats.

Bromocriptine, a dopamine (DA) receptor agonist, has been reported to have hypotensive effects in anesthetized and conscious normotensive rats but its mechanism of action is still not fully understood. Therefore, we studied the changes in mean arterial blood pressure (MAP) and heart rate (HR) elicited by an intravenous (i.v.) administration of bromocriptine (150 micrograms/kg), in either pentobarbital-anesthetized or conscious normotensive rats, pretreated with either i.v. (0.3 mg/kg) or intrathecal (i.t.) (93 nmol) domperidone, a DA receptor antagonist that does not cross the blood-brain barrier. In these preparations, i.v. administration of bromocriptine elicited dose-dependent decreases in MAP and rises in HR. The hypotensive effect was antagonized partially by i.t. and fully by i.v. domperidone. However, the latter compound did not modify the tachycardia, which could be blocked by propranolol (0.5 mg/kg i.v.). In rats pretreated with the latter beta-adrenoceptor antagonist, bromocriptine produced only a decrease in blood pressure that was inhibited by i.v. and i.t. domperidone. These results suggest that, in anesthetized and conscious normotensive rats, the hypotension induced by systemic administration of bromocriptine is fully mediated by DA2 dopamine receptors, which are located partly within the spinal cord and partly in the peripheral circulation.