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Department of Physiology, School of Pharmacy and Biochemistry, University of Buenos Aires, IQUIMEFA-CONICET, Argentina.
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(Received 15 January 2004;
accepted after revision 26 February 2004; first published online 16 March 2004)
Corresponding author A. L. Fellet Department of Physiology, school of Pharmacy and Biochemistry, University of Buenos Aires, (1113) Jun'n 956, 7° Piso Buenos Aires, Argentina. Email: afellet{at}huemul.ffyb.uba.ar
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Introduction |
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It has been proposed that NO participates in the modulation of sympathetic and parasympathetic neurotransmission in different tissues. Several studies have shown that NO plays a role in cholinergic modulation of automaticity in isolated myocytes (Han et al. 1994; Iadecola et al. 1994; Koss, 1997) and that it also participates in vagal control of HR in intact animals (Conlon et al. 1996; Elvan et al. 1997). However, little is known about the chronotropic effects of NO in the heart. We have recently reported that acute NOS inhibition with L-NAME induces an increase in MAP accompanied by tachycardia in complete autonomic-blocked (CAB) anaesthetized rats. The addition of L-NAME in isolated atria, in an equivalent dose used in in vivo experiments, did not affect either chronotropic or inotropic effects. Thus, the L-NAME-induced tachycardia, observed in vivo, might not be due to a direct action of the inhibitor on the pacemaker (Fellet et al. 2003). Alterations in thyroid and adrenal status, in secretions of vasoactive substances (Nagayama et al. 1998; Dillmann, 2002; Lee et al. 2002), as well as physical factors such as shear stress might be involved in this positive chronotropic response (Iadecola et al. 1994).
It is also known that thyroid disorders are associated with changes not only in vascular function but also in autonomic regulation of the cardiovascular system (Foley et al. 2001). Recent evidence suggests that NO participates in the regulation of thyroid function. It is possible that NO is one of the factors that plays a role in the regulation of thyroid vascularity and blood flow (Colin et al. 1995). These findings have confirmed the existence of a functional relationship between thyrocytes and endothelial cells and thus with the NO pathway (Lesley et al. 2000).
Considering the importance of NO and hormonal systems in cardiovascular homeostasis, the aim of the present study was to examine whether the thyroid and adrenal glands are involved in the pressor and chronotropic responses induced by inhibition of the NO pathway with L-NAME in animals without the influence of the autonomic nervous system.
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Methods |
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Male Sprague-Dawley rats (weight, 230–260 g) from the breeding laboratories of the School of Veterinary Science (University of Buenos Aires, Argentina) were used in each experimental group throughout all experiments.
Rats were housed in a humidity- and temperature-controlled environment with an automatic 12 h light–12 h dark cycle. Rats were fed with standard rat chow from Nutriments Purina (Buenos Aires, Argentina) and tap water ad libitum up to the day of the experiments. Animals were used in compliance with the research animal use guidelines of the American Heart Association.
Rats were anaesthetized with urethane (1.0 g (kg body weight)–1I.P., Sigma Chemical Co, St Louis, MO, USA]. Anaesthesia was maintained with a supplemental intraperitoneal dose throughout the experiment. A tracheotomy was performed and an endotracheal tube (3.5 or 4 mm i.d., Portex) was inserted 4 cm into the trachea and secured. After performing the tracheotomy, a polyethylene cannula was inserted into the right and left femoral vein for infusion of phenylephrine (PE) and administration of drugs, respectively. MAP was measured directly with a cannula inserted in the right femoral artery and connected to a pressure transducer. The blood pressure signal was continuously measured with a Statham P23 ID pressure transducer (Gould Instruments, Cleveland, OH, USA) and recorded with a polygraph (Physiograph E & M Co Inc., Houston, TX, USA). HR was derived from the pulsatile pressor signal via tachographic beat-to-beat conversion with a tachograph preamplifier (Coulbourn Instruments, Inc., tachometer S77-26, PA, USA). Body temperature was monitored with a rectal probe and was maintained at 37.0 ± 0.5 °C with heating lamps to avoid the influence of temperature on cardiovascular parameters during the experiments.
Labtech Notebook program (Laboratory Technologies, Wilmington, MA, USA) was used for data acquisition.
Experimental design
The rats were divided into five groups. (1) Group L: rats (n= 9) were studied after CAB and intravenous bolus (7.5 mg kg–1 of L-NAME. (2) Group PE: rats (n= 9) were studied after CAB and an intravenous bolus (6 µg kg–1) of PE. This group was used to verify the specificity of the chronotropic response to acute administration of L-NAME. (3) Group TX: rats (n= 9) were studied after thyroidectomy and CAB. (4) Group L-TX: rats (n= 9) were studied after thyroidectomy, CAB and intravenous bolus (7.5 mg kg–1) of L-NAME. After the trachea was exposed, the parathyroid glands were dissected from the thyroid gland under a stereoscope microscope and re-implanted into the surrounding neck muscles. The thyroid gland was carefully dissected, to avoid injury to the laryngeal nerves, and then completely excised. Thyroidectomy was performed about 120 min before L-NAME injection. (4) Group L-AX: rats (n= 9) were studied after bilateral adrenalectomy, CAB and intravenous bolus (7.5 mg kg–1) of L-NAME. A ventral midline incision was made, and the adrenals were exposed by gentle displacement of the kidneys toward the midline. For adrenalectomy, each adrenal gland and its surrounding fat were excised. Then, the body wall was sutured and the skin closed with wound clips. Adrenalectomy was performed about 120 min before injection of L-NAME. This group was used to remove the ß-adrenergic effect of catecholamines on the chronotropic response to acute L-NAME administration.
All groups of anaesthetized rats were studied after CAB induced by hexamethonium (10 mg kg–1I.V., Sigma) and bilateral vagotomy at the supraclavicular level. The administration of hexamethonium was repeated every 20 min to ensure complete blockade of ganglionic transmission during the experiments. A continuous intravenous infusion of PE (4–6 mg kg–1 min–1I.V.) was given during the experiment to maintain MAP and HR in the basal range (Vargas et al. 1990; Pegoraro et al. 1992).
The L-NAME bolus was administered after 40 min of PE infusion in L, L-AX and L-TX groups, while at the same time, a PE bolus was injected in the PE group. The pressor and the chronotropic responses were assessed when the maximal response to acute L-NAME or PE administration were observed.
Plasma triiodothyronine (T3), thyroxine (T4) and thyrotropin (TSH) levels were measured in L and L-TX groups, 5 min before and 30 min after L-NAME injection. Plasma T3 and T4 levels were measured with a sensitive radioimmunoassay (RIA) (Britton et al. 1975). Rat plasma TSH concentrations were determined by RIA using the kits provided by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (Bethesda, USA). Results were expressed in terms of rat thyroid stimulating hormone standard (rTSH-RP-2). Intra and interassay coefficients of variation for TSH were 8.7% and 13.4%, respectively.
Measurement of NOS activity
The catalytic NOS activity was evaluated in thyroidectomized and CAB rats (TX) without L-NAME treatment. Animals with only CAB were used as a control group (C). NOS activity was measured by the NADPH-diaphorase (NADPH-d) histochemical method (Stuehr et al. 1991; Vincent & Kimura, 1992) in the TX group at the same period of time after thyroidectomy in which we evaluated the pressor and chronotropic responses induced by L-NAME in L-TX group.
All rats were decapitated and atria, ventricles and thoracic aorta were immediately removed and fixed with 4% paraformaldehyde in 0.1 M phosphate-buffered saline (PBS) at pH 7.4, according to the method of Rothe et al. (1998). The tissues were cryoprotected with sucrose, and frozen, 15-µm sections were cut on a cryostat and mounted on gelatin-coated glass slides. Sections were then mounted in PBS–glycerol (1:3 by volume). Observation, optical density (OD) measurement and photography were carried out on a Zeiss Axiophot microscope. In all cases, special care was taken to fix and process control and experimental tissues simultaneously. To avoid technical variations in the tissue staining, the time and temperature of incubation with the reaction mixture were carefully controlled and the samples were randomly processed. The NADPH-d-stained cells from the different groups were measured by using a computerized image analyser (Kontron-Zeiss Vidas). The mean of each OD value resulted from the measurement of OD in different tissue areas of the same section and different sections of the same organ. Each set of OD measurements was performed blindly and under similar conditions of light, gain, offset and magnification.
Statistics
Data are presented as the mean ±S.E.M. Analysis of variance (ANOVA) followed by Bonferroni test was used for multiple comparisons. In some cases, an unpaired Student's t test was used to evaluate the changes of haemodynamic parameters induced by L-NAME administration in each group. The 5% probability level was used as a criterion for significance. The software Prism (Graph Pad Software, San Diego, CA, USA) was used for statistical analysis.
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Results |
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The maximal pressor and chronotropic responses to administration of L-NAME were compared, in all cases, with the average for 5 min before the injection. These pre-injection MAP and HR values in L group were compared with L-TX group (L: MAP, 85 ± 3, HR, 374 ± 7; L-TX: MAP, 84 ± 4, HR, 398 ± 13). These parameters were stable at this time. The pressor response induced by L-NAME administration reached the peak value 5 min after the injection in both groups (Fig. 1). L-NAME bolus increased MAP in L and L-TX groups (to 123 ± 5 and 124 ± 2, respectively, P < 0.0001 versus basal values for both). The MAP rise was of similar magnitude in both groups (Fig. 1A and B). L-NAME administration induced a tachycardic effect after complete autonomic blockade. The maximum tachycardic effect was reached about 30 min after intravenous L-NAME administration in L group, whereas this effect in L-TX group was observed at about 6 min after the L-NAME bolus (408 ± 8 and 413 ± 12, respectively, P < 0.0001 versus basal values for both). Thyroidectomy attenuated the chronotropic response induced by L-NAME in L-TX group (Fig. 2A and B).
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Despite the fact that the PE group exhibited the same change in MAP (
MAP) as the L group (MAP: PE, 45 ± 5 mmHg; L, 38 ± 3 mmHg, P= n.s.), administration of PE did not modify HR compared with basal values (Before PE, HR, 365 ± 14 beats min–1 after PE: HR, 370 ± 16 beats min–1,P= n.s.).
The plasma levels of T3 (ng ml–1) and T4 (µg dl–1) as well as TSH (ng ml–1) concentration in L and L-TX groups 5 min before and 30 min after administration of L-NAME are shown in Fig. 3. Thyroidectomy in L-TX group by itself decreased the circulating levels of T3 but it had no effect on the plasma levels of T4 and TSH. Moreover, when L-NAME is administered, similar levels of circulating T4 and TSH were observed in both groups, meanwhile plasma levels of T3 decreased in L group.
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Figure 4 shows that NOS activity was similar in the ventricles of the rats of the TX compared to the C group (OD: TX, 0.127 ± 0.036; C, 0.108 ± 0.041, P= n.s., n= 9). By contrast, the enzyme activity in the cardiac atria was greater in TX than in C (OD: TX, 0.199 ± 0.017; C, 0.114 ± 0.003, P < 0.01, n= 9). The NOS activity in endothelium (E) and smooth muscle (M) of the thoracic aorta is shown in Fig. 5. Endothelium and muscle staining were more intense in sections of the aorta from TX than C rats (OD values for TX: E, 0.082 ± 0.005*; M, 0.115 ± 0.004**; OD values for C: E, 0.064 ± 0.004; M, 0.099 ± 0.003; *P < 0.01, **P < 0.001, TX versus C; n= 9 for both groups).
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Discussion |
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MAP and HR were similar in all groups of animals at the beginning of the experiments, reflecting similar haemodynamic conditions before autonomic blockade. Regarding the pressor response, we observed that L-NAME induced a similar increase in MAP in L, L-AX and L-TX groups. Additionally, L-NAME induced a tachycardic response associated with this rise in MAP. This tachycardia was not observed when a similar increase in MAP was induced by a bolus of PE, confirming that the increase in HR induced by L-NAME administration is not related to the enhancement of arterial blood pressure.
It is well known that adrenal catecholamines are involved in the regulation of arterial blood pressure and intrinsic HR. The effect of NO on the catecholamine secretion is controversial. Nagayama et al. (1998) reported that NO may play an inhibitory role in the regulation of adrenal catecholamine secretion, meanwhile, others claim that NO has no effect on this secretion (Breslow et al. 1992, 1993). The results of this research have shown that bilateral adrenalectomy did not have any effect on the L-NAME-induced pressor and chronotropic responses in CAB rats. L-AX group would not be suitable to test the role of adrenal catecholamines given that the animals were treated with ganglion blocker plus PE. However, this group allowed us to rule out the involvement of the ß-adrenergic actions of epinephrine on the L-NAME-induced tachycardia. Our findings show that adrenal catecholamines do not participate in either the pressor or tachycardic effects induced by inhibition of the L-arginine–NO pathway in our experimental conditions.
As cardiovascular function is also modulated by the thyroid system, changes in thyroid status markedly influence cardiac contractile and electrical activity. The predominant route by which thyroid hormones affects cardiac function is by exerting a direct effect in cardiac myocytes through binding to thyroid hormone nuclear receptor isoforms (Yen, 2001). In addition, several studies suggest that specific ion channel proteins in the sinus atrial node exert control of HR. Some of these channels, such as the sodium–calcium exchanger protein, the L-type and T-type calcium channel, the ryanodine channel, voltage-gated potassium channel and ß-adrenergic receptors are targets for thyroid hormone action (Pachucki et al. 1999; Dillmann, 2002). However, the intrinsic chronotropic effect and the alterations of electrical conductivity mediated by the thyroid hormone signalling system remain to be clarified (Schwarz et al. 1995; Koss, 1997).
In this study, we showed that thyroidectomy by itself reduced the plasma levels of T3 in the L-TX group; meanwhile no changes in the levels of T4 and TSH were observed. Furthermore, a decrease in plasma T3 levels was observed after L-NAME administration in the L group but not in the L-TX group. These results suggest that L-NAME treatment might not be able to further reduce the plasma levels of T3 in the L-TX group. Given the plasma half-life of thyroid hormones, it is difficult to explain the reduction of T3 plasma levels in the L group after L-NAME administration. However, given that the major pathway for the production of T3 is via 5'- deiodination of the outer ring of T4 by deiodinases (Gereben et al. 2000), this system might be altered by inhibition of NO pathway.
On the other hand, when the autonomic nervous system was blocked, thyroidectomy did not modify the L-NAME-induced pressor response but attenuated the L-NAME-induced tachycardia. Our data show that the increase of HR after L-NAME treatment depends on a certain basal T3 level. Previous reports have shown that in chronic models of hypothyroidism for 6 weeks, NOS activity increased in both ventricles but decreased in the aorta (Quesada et al. 2002). However, in our experimental conditions, CAB animals with functional a NO system (TX group) showed an increase of NOS activity in the atria but not in the ventricles 150 min after thyroidectomy. Therefore, this finding has allowed us to postulate that the decrease of the plasma T3 levels may be one of the stimuli for the rise of NOS activity observed in the atria. Given that the different NOS isoforms (Cadenas et al. 2001; Carreras et al. 2001) are expressed not only in the cardiomyocytes but also in the vascular and endocardial endothelium of the atria, we cannot ignore the effects induced by an increased release of vasoactive substances and/or mechanical forces due to haemodynamic changes that could affect venous return (Iadecola et al. 1994). Previous reports support the possibility that the renin–angiotensin system is activated during chronic L-NAME administration (Lee et al. 2002); however, there is no evidence that L-NAME activates renin secretion in acute experimental conditions in CAB animals. Therefore, the L-NAME-induced tachycardia cannot be due to the cardiac effect of angiotensin. We assume that the chronotropic response induced by inhibition of the NO system with L-NAME would involve the thyroid gland in CAB animals. In addition, we showed that plasma TSH levels were unchanged after thyroidectomy and inhibition of NO system in the L and L-TX groups. This original profile after thyroidectomy could be explained taking into account the low severity and short duration of this experimental hypothyroidism. Drvota et al. (1995) have demonstrated the presence of functional thyrotropin receptor in cardiac muscle and postulated that TSH would have direct cardiac actions. Our results suggest that thyrotropin is not involved in L-NAME-induced tachycardia in our experimental conditions.
Given that the abnormalities in vascular function in thyroid disorders are important (Vargas et al. 1995; Ojamaa et al. 1996; McAllister et al. 1998), we have also studied the NOS activity in the large vessels (thoracic aorta). The higher NOS activity observed in endothelium and smooth muscle in the aorta of the animals without thyroid gland (TX group), suggest that the thyroid gland influences not only the cardiac NO system but also the vascular NO pathway. Several reports have shown an increased systemic vascular resistence in a chronic model of hypothyroidism (Hermenegildo et al. 2002; Donnini et al. 2003). The findings observed in our acute model of thyroidectomy, suggest that typical vascular changes of hypothyroidism would seem to be inversely correlated with L-arginine–NO system. The rise of aortic NOS activity might represent a compensatory mechanism, playing a protective role in maintaining blood flow.
In summary, we have been able to show that the pressor effect of L-NAME is independent of autonomic influences, adrenal and thyroid glands and it is probably due to a direct vasoconstrictor effect caused by the decrease of vascular NO synthesis. Moreover, inhibition of NO system in CAB rats, with baroreflex response to the rise in MAP blunted, induces a positive chronotropic effect. Acute thyroidectomy (TX group), would be associated with an overproduction of atrial NO and with the attenuation of the L-NAME-induced chronotropic response. This study has demonstrated for the first time that in heart without autonomic influences, thyroid hormones modulate intrinsic heart rate through a mechanism that involves, at least in part, the NO pathway.
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