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Nebivolol and carvedilol induce NO-dependent coronary vasodilatation that is unlikely to be mediated by extracellular ATP in the isolated guinea pig heart

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Nebivolol and carvedilol induce NO-dependent coronary vasodilatation that is unlikely to be mediated by extracellular ATP in the isolated guinea pig heart

Valery I. Kozlovski, Magdalena Lomnicka, Stefan Chlopicki

Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University Medical College, Grzegórzecka 16, PL 31-531 Kraków, Poland

Correspondence:Stefan Chlopicki, e-mail: s.chlopicki@cyfronet.krakow.pl

Abstract:

In contrast to classical b-adrenoreceptor antagonists, nebivolol and carvedilol possess endothelium-dependent vasorelaxant properties. It has been proposed that nebivolol and carvedilol activate microvascular endothelium into producing NO by the release of extracellular ATP and subsequent stimulation of endothelial P receptors.

Here we tested this hypothesis in the coronary circulation of the isolated guinea pig heart. We analyzed the role of NO in the coronary vasodilatation induced by nebivolol and carvedilol as well as a possible involvement of extracellular ATP in these responses.

Nebivolol and carvedilol (3–30 × 10`$M) induced a concentration-dependent coronary vasodilatation that was inhibited by NO-synthase inhibitor, L-NAME (10`"M). In contrast to nebivolol and carvedilol, neither atenolol nor labetalol acted as a coronary vasodilator. Vasodilatation induced by nebivolol and carvedilol was affected neither by the Preceptor antagonist, 8-sulfophenyl theophylline (8-SPT, 10`#M), nor by the P receptor antagonist, suramin (10`#M).

On the other hand, ATP-induced coronary vasodilatation (0.3–10 × 10`$M) was strongly inhibited by L-NAME (10`"M), partially inhibited by 8-SPT (10`#M), while suramin (10`#M) had a minor effect.

In conclusion, in the isolated guinea pig heart nebivolol and carvedilol, but not their classical counterparts (atenolol, labelatol), act as NO-dependent coronary vasodilators. It seems unlikely that this response is mediated by the release of extracellular ATP.

Key words:

b-adrenoreceptor antagonist, nebivolol, carvedilol, nitric oxide, ATP, coronary endothelium.

Abbrevations: 5-HT – 5-hydroxytryptamine, L-NAME – N/- nitro-L-arginine methyl ester; NO – nitric oxide; NOS – nitric oxide synthase; 8-SPT – 8-sulfophenyl theophylline

Introduction

Recent evidence suggests that the third generation of b-adrenoreceptor antagonists with ancillary vasodila-

tor properties (nebivolol and carvedilol) possess supe- rior clinical efficacy as compared to the classical, se- lective or non-selective, b-adrenoreceptor antagonists [13, 17, 28, 35].

Superior cardiovascular protection afforded by novel b-adrenolytics seems to be related not to their b-blocking properties, but rather to their ability to re- lease and/or preserve endothelial NO. Importantly, endothelial pleiotropic activity of nebivolol or carve- dilol is not shared by other b-adrenolytics. Indeed,

Pharmacological Reports 2006, 58, suppl., 103–110 ISSN 1734-1140

Copyright © 2006 by Institute ofPharmacology Polish Academy ofSciences

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Moreover, long-term treatment with nebivolol – but not with atenolol – reversed endothelial dysfunction in arterial hypertension both in experimental models as well as in patients [9, 22, 24, 25, 34].

Carvedilol, unlike nebivolol, is a non-selective b-adrenoreceptor antagonists with a1-receptor block- ing properties. Nevertheless, similarly to nebivolol, carvedilol reversed endothelial dysfunction in experi- mental models as well as in patients with coronary ar- tery disease [6, 23, 24]. Interestingly, unlike other b-adrenolytics, both nebivolol and carvedilol in- creased insulin sensitivity [17, 28] and this effect could also be related to their ancillary endothelial mechanism of action. Accordingly, the third generation of b-adrenoreceptor antagonists including nebivolol and carvedilol represents a distinct pharmacological entity as compared with other b-adrenoreceptor an- tagonists. Still the mechanism of their pleiotropic vaso- protective action is far from understood.

It has been suggested in numerous studies that the unique antioxidant properties of nebivolol and carve- dilol [8, 11, 26, 33, 36] and their better direct scav- enging abilities towards the reactive oxygen species (ROS), particularly towards hydroxyl radical, may be responsible for their beneficial cardiovascular action.

Recently, we have excluded this notion by showing similar ROS scavenging properties of numerous b-adrenoreceptor antagonists [32]. It has also been suggested that the direct endothelial action of nebivo- lol is mediated by b2adrenoceptors [2], b3-adrenoce- ptors [14] or by serotonin 5-HT1A receptors [18].

Again, the involvement of these receptors in coronary vasodilatation induced by nebivolol was not con- firmed in our study [9]. On the other hand, demonstra- tion of the effects of nebivolol on inositol phosphate metabolism [27] and on NOS coupling [25] suggest an intracellular, rather than a receptor-dependent, mechanism of the endothelial action of nebivolol.

An interesting concept of the mechanism of the en- dothelial action of the third generation b-adrenorece- ptor antagonists have been put forward recently by Kalinowski et al. [19]. Authors suggested that vaso- dilatation induced by nebivolol and carvedilol in- volves the release of extracellular ATP and subse- quent stimulation of NO production by P2Yendothe- lial receptors [19]. Here we tested this hypothesis in the coronary circulation of the isolated guinea pig

extracellular ATP in this response.

Materials and Methods

Langendorff preparation of the guinea pig heart

The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health, and the experimen- tal procedures used in the present study were ap- proved by the local Animal Research Committee.

The details of the method are described elsewhere [5]. Briefly, guinea pigs of both sex and with a body weight of 300–400 g were anaesthetised with pento- barbital (30–40 mg/kg body weight). Their hearts were isolated, washed in ice-cold saline, and mounted in Langendorff apparatus by Hugo Sachs Electronics (HSE). Guinea pig hearts were perfused retrogradely through the aorta under a constant perfusion pressure of 60 mmHg with Krebs-Henseleit buffer of the fol- lowing composition (mM): NaCl 118, KCl 4.7, CaCl2 2.52, MgSO4 1.64, NaHCO3 24.88, KH2P04 1.18, glucose 5.55, sodium pyruvate 2.0, equilibrated with 95% O2+ 5% CO2at 37oC in an oxygenator with ro- tating disc (HSE). The hearts were paced with 273 impulses per min. through two platinum electrodes placed in the right atrium. Left ventricular pressure (LVP) was measured using a fluid-filled balloon in- serted into the left ventricle and connected to a pres- sure transducer (Isotec HSE). The end diastolic pres- sure was adjusted to be less than 10 mmHg. The dP/dtmaxand dP/dtminvalues were calculated from the LVP signal by an analogue differentiation amplifier (DIF module HSE). The values of LVP, dP/dtmaxand dP/dtminwere used to control the quality of the prepa- ration and only those hearts with acceptable LVP, and dP/dt parameters were used for the experiments.

Coronary flow (CF) was monitored by an Ultrasonic flowmeter (HSE). LVP, dP/dtmax, dP/dtmin and CF were calibrated once a day before the experiment and then continuously displayed throughout the experi- ment, and finally analysed using a specially-designed software (PSCF, Igel, Poland).

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Protocol of experiments

The isolated heart of the guinea pig was equilibrated at a perfusion pressure of 50 mmHg for about 10 min, after which the pressure was adjusted to 60 mmHg. At that pressure the heart was further equilibrated for 10–15 min. before the beginning of the experiment.

The heart was used for the experiment only if the fol- lowing criteria were fulfilled: (i) basal coronary flow (CF) was 7–20 ml/min, (ii) the increase in CF to bolus injection of 300 pmoles of acetylcholine was > 2 ml/min.

Nebivolol, carvedilol (3–30 × 10–6M), atenolol, la- betalol (3 × 10–5M), ATP (0.3–30 × 10–6M), adeno- sine (1–10 × 10–6M) were given as intracoronary in- fusions (duration of 1 min.) into the coronary circula- tion of the isolated guinea pig.

To study the contribution of nitric oxide and purine receptors in nebivolol-, carvedilol-, ATP- or adeno- sine-induced coronary vasodilatation, these responses were induced in the absence, or in the presence of cor- responding pharmacological antagonists: nonselective NOS inhibitor, L-NAME (10–4M), purine P1-receptor antagonist, 8-sulfophenyl theophylline (8-SPT, 10–5M)

or purine P2-receptor antagonist, suramin (10–5 M).

All inhibitors were infused for at least 15 min before eliciting the response.

Carvedilol and nebivolol were dissolved in a mix- ture of DMSO and water (v/v 1 : 1) or in DMSO alone (when used at the highest concentration of 3 × 10–5M).

Atenolol, labetalol, ATP and adenosine were dis- solved in water. The rate of infusion was adjusted to the value of basal coronary flow and never exceeded 1% of coronary flow. Infusion of DMSO alone slightly increased coronary flow by 1.03 ± 0.11 ml/min.

The duration of an experiment never exceeded three hours, and for this period the quality of preparation of the isolated guinea pig heart stayed mostly un- changed.

Statistical methods

Results are presented as mean ± SEM. Paired t-test were used for evaluation of the differences before and after addition of the antagonists. A value of p < 0.05 was accepted as being significant.

Coronary vasodilatation by b-adrenoreceptor antagonists

Valery I. Kozlovski et al.

Fig. 1. A.Original tracing of an experiment in the isolated guinea pig heart showing coronary flow response to nebivolol (3 ´ 10`#M) and lack of response to atenolol (3 ´ 10`#M). Coronary flow response to bradykinin (3 ´ 10`'M) is shown for comparison. B. Original tracing of an experi- ment showing coronary flow response to carvedilol and a lack of response to phentolamine or labetalol (each drug at a concentration of 3 ´ 10`#M)

A B

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Results

In the isolated guinea pig heart basal coronary flow was 9.39 ± 0.29 ml/min. Nebivolol as well as carvedilol (3–30 × 10–6 M) induced concentration-dependent coronary vasodilatation. In contrast, atenolol (3 × 10–5M)

and labetalol (3 × 10–5 M) did not induce coronary vasodilatation (Fig. 1, 2). Phentolamine (Fig. 1) and prazosin (data now shown) also did not act as vasodi- lators in this preparation.

In the presence of the NO-synthase inhibitor L-NAME (10–4M), the coronary vasodilator response induced by nebivolol and by carvedilol was signifi-

Fig. 2Effect of L-NAME (10`"M) on coronary vasodilatation induced by nebivolol (A) and carvedilol(B) in the isolated guinea pig heart. Data are expressed as increase in coronary flow (ml/min). Results are mean ± SEM (n = 3–7)

Fig. 3.Effect of L-NAME (10`"M)(A) and 8-SPT (10`#M)(B) on coronary vasodilatation induced by ATP. Data are expressed as increase in coronary flow (ml/min). Results are mean ± SEM (n = 3–5)

A B

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cantly inhibited (Fig. 2). In the presence of L-NAME (10–4M) vasodilatation induced by ATP was also in- hibited (Fig. 3A).

P1 receptor antagonist 8-SPT (10–5 M) (Fig. 3B) partially inhibited the vasorelaxant response to ATP (Fig. 3B) or that to adenosine (for adenosine 10–6 M the response was 14.3 ± 1.7 and 4.1 ± 1.1 ml/min, and for adenosine 3 ´ 10–6 M it was 16.6 ± 3.6 and 10.0 ± 0.7 ml/min, before and after 8-SPT, respec- tively, p < 0.05). On the other hand, 8-SPT (10–5M) had no effect on vasodilatation induced by nebivolol or carvedilol (Fig. 4). Moreover, suramin (10–5 M) had an effect on ATP-induced vasodilatation (for ATP, 3 ´ 10–6 M the response was 7.0 ± 2.0 and 5.5 ± 1.2 ml/min, for ATP 10–6 M the response was 9.0 ± 2.1 and 6.4 ± 1.8 ml/min, before and after su- ramin, respectively, p < 0.05). However, suramin did not modify the nebivolol- and carvedilol-induced re- sponses (Fig. 4).

Discussion

The third generation of b-adrenoreceptor antagonists with vasodilator properties such as nebivolol and

carvedilol appears to possess superior clinical effi- cacy as compared to classical b-adrenoreceptor an- tagonists [13, 17, 28, 35]. The vasoprotective proper- ties of nebivolol and carvedilol may be related to their endothelial action i.e. to their ability to release NO and/or to reverse endothelial dysfunction [9, 22, 24, 25, 34]. Recently it has been proposed that the vasore- laxant effect of nebivolol and carvedilol may be re- lated to the release of extracellular ATP and subse- quent stimulation of endothelial P2 receptors [19].

Here we demonstrated that nebivolol and carvedilol induced NO-dependent coronary vasodilatation, but the involvement of extracellular ATP in this response seems to us unlikely. Indeed, in our hands ATP- induced vasodilatation was dependent largely on NO, but was mediated in major part by P1receptors. Sur- prisingly, P2 receptors played a minor role in the response to ATP in this preparation. These results sug- gest that in the isolated guinea pig heart ATP-induced coronary vasodilatation is mediated mainly by adeno- sine formedvia the extracellular conversion of ATP to adenosine as also demonstrated previously [12]. Of course, in many other types of vascular preparations, ATP induced NO-dependent vasodilatation is medi- ated by endothelial P2 receptors [15,19,29]. Further- more, adenosine-induced vasodilatation, which was

Coronary vasodilatation by b-adrenoreceptor antagonists

Valery I. Kozlovski et al.

Fig. 4.Lack of effect of 8-SPT (10`#M) and suramin (10`#M) on coronary vasodilatation induced by nebivolol (10`#M)(A) and carvedilol (10`#M)(B). Data are expressed as increase in coronary flow (ml/min). Results are mean ± SEM (n = 3–5)

A B

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less, neither the P1-receptor antagonist 8-SPT, nor the P2-receptor antagonist suramin, inhibited vasodilator response induced by nebivolol or carvedilol in the iso- lated guinea pig heart. Accordingly, our crude phar- macological analysis seems to exclude the possibility that the release of extracellular ATP by nebivolol or carvedilol is involved in NO-dependent coronary vasodilation induced by these agents, at least in the coronary circulation of the guinea pig. These results do not preclude the possibility that ATP is released by nebivolol or carvedilol. We did not measure the changes in ATP levels in the coronary effluent after nebivolol and carvedilol administration as it was done previously in renal microcirculation [19]. This is cer- tainly a limitation of our study.

Previously we excluded the involvement of the b-adrenoreceptor and serotonin 5-HT1Areceptors in coronary vasodilator response to nebivolol in the iso- lated guinea pig heart [9]. Carvedilol-induced re- sponse was also not blocked by nadolol (data now shown). Moreover, as we questioned the significance of the b3-adrenoreceptor in the regulation of coronary flow in the isolated guinea pig heart [21], the contri- bution of these receptors to vasodilator response of nebivolol or carvedilol in this preparation also seems unlikely. It is worthwhile adding that the non- selective b- and a-adrenoreceptor antagonist labeta- lol, as well as thea-adrenoreceptor antagonists phen- tolamine and prazosin, did not induce vasodilatation in this preparation. Accordingly, it seems that the ne- bivolol- and carvedilol-induced NO-dependent re- sponse is not mediated by adrenergic receptors.

On the other hand it is likely that the NO- dependent vasodilatation induced by nebivolol and carvedilol reported here and previously [1, 4, 7, 10, 19, 27, 31, 32] may be a receptor-independent phe- nomenon. Equal vasodilator activity of both stereoi- somers of nebivolol, as well as the high lipophilic na- ture of both drugs, seem to support such a hypothesis [4]. Indeed, it has been suggested that nebivolol- induced NO-dependent vasodilatation is mediated by stimulation of the inositol phoshate metabolism [27].

Nebivolol is also able to prevent endothelial NOS un- coupling [25]. Still the intracellular target of nebivolol as well as of carvedilol is not known and it is not clear if both drugs share the same intracellular mechanism of action. Interestingly, it was recently suggested that

Endothelial dysfunction was identified as a prog- nostic factor in atherothrombosis, so its reversal by therapeutic strategies may limit the risk of cardiovas- cular events [3]. It is important to note that both carvedilol and nebivolol that showed NO-releasing properties in our experimental set-up reversed endo- thelial dysfunction in patients with cardiovascular dis- eases [24, 34]. Therefore it is possible that the endo- thelial NO-releasing properties of carvedilol and ne- bivolol demonstrated in our work are relevant to the clinically important differences in the profile of action of nebivolol and carvedilol as compared to classical b-adrenolytics.

In conclusion, in the isolated guinea pig heart, the third generation of b-adrenoreceptor antagonists in- cluding nebivolol and carvedilol in contrast to their classical counterparts (atenolol, labetalol) induce NO-dependent coronary vasodilatation. It seems un- likely that this response is causally linked to the re- lease of extracellular ATP and subsequent NO release by P2receptors, as suggested previously.

Acknowledgment.

This work was supported by the Polish Ministry of Science and Higher Education (grants no. P05A/003/25 and PBZ-KBN-101/T09/2003), and by NATO Collaborative Linkage Grant No 980826. Professor Stefan Chlopicki is the recipient of a Professorial grant from the Foundation for Polish Science (SP/04/04).

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Received:

December 11, 2006; in revised form: December 28, 2006.

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