Central cholinergic blockade reduces the pressor response to L-glutamate into the rostral ventrolateral medullary pressor area

Injections of the excitatory amino acid L-glutamate (L-glu) into the rostral ventrolateral medulla (RVLM) directly activate the sympathetic nervous system and increase mean arterial pressure (MAP). A previous study showed that lesions of the anteroventral third ventricle region in the forebrain reduced the pressor response to L-glu into the RVLM. In the present study we investigated the effects produced by injections of atropine (cholinergic antagonist) into the lateral ventricle (LV) on the pressor responses produced by L-ghl into the RVLM. Male Holtzman rats (280-320 g, n=5 to 12/group) with stainless steel cannulas implanted into the RVLM, LV or 4th ventricle (4th V) were used. MAP and heart rate (HR) were recorded in unanesthetized rats. After saline into the LV, injections of L-glu (5 nmol/100 nl) into the RVLM increased MAP (51 +/- 4 mm Hg) without changes in HR. Atropine (4 nmol/1 PI) injected into the LV reduced the pressor responses to L-glu into the RVLM (36 +/- 5 mm Hg), However, atropine at the same dose into the 4th V or directly into the RVLM did not modify the pressor responses to L-glu into the RVLM (45 +/- 2 and 49 +/- 4 mm Hg, respectively, vs. control: 50 +/- 4mmHg). Central cholinergic blockade did not affect baro and chemoreflex nor the basal MAP and HR. The results suggest that cholinergic mechanisms probably from forebrain facilitate or modulate the pressor responses to L-glu into the RVLM. The mechanism is activated by acetylcholine in the forebrain, however, the neurotransmitter released in the RVLM to facilitate the effects of glutamate is not acetylcholine. (C) 2007 Elsevier B.V. All rights reserved.

Lesions in the central amygdala impair sodium intake induced by the blockade of the lateral parabrachial nucleus

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Serotonergic receptor blockade in the lateral parabrachial nucleus: Different effects on hypertonic and isotonic NaCl intake

Hypertonic NaCl intake is produced by serotonin receptor antagonism in the lateral parabrachial nucleus (LPBN) of dehydrated rats or in rats pretreated with a mineralocorticoid, for example deoxycorticosterone (DOCA), that receive an intracerebroventricular injection (icv) of angiotensin II (ang II). The objective of the present work was to find out whether these two mechanisms are also involved with isotonic NaCl intake. Serotonin receptor blockade by methysergide in the LPBN (4 mu g/0.2 mu l bilaterally) had no effect on 0.15 M NaCl (methysergide: 19.3 +/- 5.2 ml/60 min; vehicle: 19.3 +/- 4.2 ml/60 min; n=7) or water (methysergide: 3.4 +/- 1.4 ml/ 60 min; vehicle 2.2 +/- 0.6 ml/60 min) intake induced by systemic diuretic furosemide combined with low dose of captopril (Furo/Cap). Methysergide treatment 4 days later in the same animals produced the expected enhancement in the 0.3 M NaCl intake induced by Furo/Cap (methysergide: 16.6 +/- 3.5 ml/60 min; vehicle: 6.6 +/- 1.5 ml/60 min). Similar result was obtained when another group was tested first with 0.3 M NaCl and later with 0.15 M NaCl. Isotonic NaCl intake induced by icv ang II was however enhanced by prior DOCA treatment. A de novo hypertonic NaCl intake was produced in another group by the same combined treatment. The results suggest that a facilitatory mechanism like the mineralocorticoid/ang II synergy may enhance NaCl solution intake at different levels of tonicity, while the action of an inhibitory mechanism, like the LPBN serotonergic system, is restricted to the ingestion at hypertonic levels. (c) 2007 Elsevier B.V. All rights reserved.

AT(1) receptor blockade in the lateral parabrachial nucleus reduces the effects of muscimol on sodium intake

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Reduction of crotoxin-induced neuromuscular blockade by gamma radiation

A comparative study between crotoxin and gamma irradiated crotoxin was performed on the indirectly evoked twitches and tetani of sciatic nerve-extensor digitorum longus muscle of rats. Crotoxin (3 to 14 mu g/ml) decreased the amplitude of twitches and induced a slight tetanic fade, and irradiated crotoxin did not significantly affect either twitch amplitude or tetanic tension. Since gamma radiation reduced the neurotoxicity of crotoxin it may be useful for the production of anticrotalic serum. (C) 1998 Elsevier B.V. Ltd. All rights reserved.

Effects of indoramin in rat vas deferens and aorta: concomitant alpha(1)-adrenoceptor and neuronal uptake blockade

1 the actions of the alpha(1)-adrenoceptor antagonist indoramin have been examined against the contractions induced by noradrenaline in the rat vas deferens and aorta taking into account a putative neuronal uptake blocking activity of this antagonist which could. result in self-cancelling actions.2 Indoramin behaved as a simple competitive antagonist of the contractions induced by noradrenaline in the vas deferens and aorta yielding pA(2) values of 7.38 +/- 0.05 (slope = 0.98 +/- 0.03) and 6.78 +/- 0.14 (slope = 1.08 +/- 0.06), respectively.3 When the experiments were repeated in the presence of cocaine (6 mu M) the potency (pA(2)) of indoramin in antagonizing the contractions of the vas deferens to noradrenaline was increased to 8.72 +/- 0.07 (slope = 1.10 +/- 0.05) while its potency remained unchanged in the aorta (pA(2) = 6.69 +/- 0.12; slope = 1.04 +/- 0.05).4 In denervated vas deferens, indoramin antagonized the contractions to noradrenaline with a potency similar to that found in the presence of cocaine (8.79 +/- 0.07; slope = 1.09 +/- 0.06).5 It is suggested that indoramin blocks alpha(1)-adrenoceptors and neuronal uptake in rat vas deferens resulting in Schild plots with slopes not different from unity even in the absence of selective inhibition of neuronal uptake. As a major consequence of this double mechanism of action, the pA(2) values for this antagonist are underestimated when calculated in situations where the neuronal uptake is active, yielding spurious pK(B) values.

Investigation of the Effects of a1-Adrenoceptor Antagonism and L-Type Calcium Channel Blockade on Ejaculation and Vas Deferens and Seminal Vesicle Contractility In Vitro

Introduction. Premature ejaculation is one of the most common male sexual dysfunctions. Current pharmacological treatments involve reduction in penile sensitivity by local anesthetics or increase of ejaculatory threshold by selective serotonin reuptake inhibitors. a1-Adrenoceptors (a1-ARs) and L-type calcium channels are expressed in the smooth muscles of the male reproductive tract, and their activations play an important role in the physiological events involved in the seminal emission phase of ejaculation.Aim. To evaluate if the inhibition of the contractility of the vas deferens and seminal vesicle by alpha(1)-AR antagonism or the L-type calcium channel blockade can delay ejaculation.Methods. The effects of the alpha(1)-AR antagonist tamsulosin and of the L-type calcium channel blockers, nifedipine and (S)-(+)-niguldipine, on contractions induced by norepinephrine in the rat vas deferens and seminal vesicles in vitro and on the ejaculation latency of male rats in behavioral mating tests were evaluated.Main Outcome Measure. Tension development of vas deferens and seminal vesicles in response to norepinephrine in vitro and behavioral mating parameters were quantified.Results. Tension development of vas deferens and seminal vesicle to alpha(1)-AR activation was significantly inhibited by tamsulosin, nifedipine, and (S)-(+)-niguldipine. Tamsulosin displayed insurmountable antagonism of contractions induced by norepinephrine in the rat vas deferens and seminal vesicle. Ejaculation latency of male rats was not modified by tamsulosin, nifedipine, or (S)-(+)-niguldipine; however, both the number and weight of the seminal plugs recovered from female rats mated with male rats treated with tamsulosin were significantly reduced.Conclusion. Seminal emission impairment by inhibition of vas deferens or seminal vesicle contractility by L-type calcium channel blockade or alpha(1)-AR antagonism is not able to delay the ejaculation. de Almeida Kiguti LR and Pupo AS. Investigation of the effects of alpha(1)-adrenoceptor antagonism and L-type calcium channel blockade on ejaculation and vas deferens and seminal vesicle contractility in vitro. J Sex Med 2012; 9: 159-168.

CENTRAL ANGIOTENSIN-CONVERTING ENZYME-BLOCKADE AND THIRST

1. The effect of lisinopril, a potent inhibitor of angiotensin converting enzyme (ACE), injected into the medial preoptic area (MPOA) on water intake was investigated in male Holtzman rats (200-250 g).2. Injection of lisinopril (2 mug/mul) into the MPOA abolished the water intake induced by subcutaneous (sc) injection of isoprenaline (100%) and water deprivation (90%) and drastically reduced the water intake induced by sc injection of polyethyleneglycol (60%). A small reduction of water intake induced by lisinopril was also observed 90 and 120 min after sc hypertonic saline (N = 10 for each group).3. These results suggest that central ACE activation, particularly in the MPOA, plays an important role in the dipsogenic responses induced by the agents studied.

Vascular effects of long-term propranolol administration after chronic nitric oxide blockade

Long-term propranolol treatment reduces arterial blood pressure in hypertensive individuals mainly by reducing peripheral vascular resistance, but mechanisms underlying their vasodilatory effect remain poorly investigated. This study aimed to investigate whether long-term propranolol administration ameliorates the impairment of relaxing responses of aorta and mesenteric artery from rats made hypertensive by chronic nitric oxide (NO) deficiency, and underlying mechanisms mediating this phenomenon. Male Wistar rats were treated with N-omega-Nitro-L-arginine methyl ester (L-NAME; 20 mg/rat/day) for four weeks. DL-Propranolol (30 mg/rat/day) was given concomitantly to L-NAME in the drinking water. Treatment with L-NAME markedly increased blood pressure, an effect largely attenuated by DL-propranolol. In phenylephrine-precontracted aortic rings, the reduction of relaxing responses for acetylcholine (0.001-10 mu M) in L-NAME group was not modified by DL-propranolol, whereas in mesenteric rings the impairment of acetylcholine-induced relaxation by L-NAME was significantly attenuated by DL-propranolol. In mesenteric rings precontracted with KCl (80 MM), DL-propranolol failed to attenuate the impairment of acetylcholine-induced relaxation by L-NAME. The contractile responses to extracellular CaCl2 (1-10 mM) were increased in L-NAME group, and co-treatment with DL-propranolol reduced this response in both preparations in most Ca2+ concentrations used. The NO2/NO3 plasma levels and superoxide dismutase (SOD) activity were reduced in L-NAME-treated rats, both of which were significantly prevented by DL-propranolol. In conclusion, propranolol-induced amplification of the relaxation to acetylcholine in mesenteric arteries from L-NAME-treated rats is sensitive to depolarization. Additional mechanisms involving blockade of Ca2+ entry in the vascular smooth muscle and increase in NO bioavailability contributes to beneficial effects of long-term propranolol treatment. (C) 2007 Elsevier B.V. All rights reserved.