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Interact CardioVasc Thorac Surg 2005;4:232-237. doi:10.1510/icvts.2004.095505
© 2005 European Association of Cardio-Thoracic Surgery
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ESCVS article - Experimental

Ex-vivo effect of roxithromycin on human and rat arterial vasoactivity{star}

Marius Berman1,*, David Hasdai2, Ehud Raanani1, Georgios P. Georghiou1, Lina Kapustin3, Yelena Chepurko3, Bernardo A. Vidne1,3 and Edith Hochhauser3

1 Departments of Cardiothoracic Surgery, Rabin Medical Center, Beilinson Campus, Petach Tikva, Affiliated to Tel Aviv University, Tel Aviv, 49100 Israel
2 Departments of Cardiology, Rabin Medical Center. Affiliated to Tel Aviv University, Tel Aviv, Israel
3 Cardiac Research Laboratory, Felsenstein Center, Rabin Medical Center. Affiliated to Tel Aviv University, Tel Aviv, Israel

Received 30 July 2004; received in revised form 28 February 2005; accepted 1 March 2005

{star} Presented at the 53rd International Congress of the European Society for Cardiovascular Surgery, Ljubljana, Slovenia, June 2–5, 2004.

*Corresponding author. Tel.: +972-3-9376701; fax: +972-3-9240762.

E-mail address: mariusb{at}clalit.org.il (M. Berman), mariusby{at}yahoo.com (M. Berman).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Prior studies have suggested that inflammation and possibly bacterial infections play a role in atherogenesis and in the clinical pathogenesis of cardiovascular diseases. Treatment with the macrolide antibiotics has been associated with improved outcome from cardiovascular disease, although the mechanism through which they exert their effects may be unrelated to their antibiotic properties. Drugs that exert a vasodilator effect on arteries have been associated with attenuated atherogenesis and improved outcome from cardiovascular disease. Aim: To determine the effect of the macrolide, roxithromycin (RX), on arterial vasoactivity. Methods: Human internal mammary artery (IMA) and rat thoracic aorta (TA) rings were placed in organ chambers and contracted with norepinephrine (NE). Endothelial and smooth muscle integrity were assessed using acetylcholine (ACh) and nitroprusside (SNP), respectively. After restabilization, the rings were exposed to 10–6 M NE, followed by increasing concentrations of RX (10–7–10–4 M), then by 10–5 M SNP. The mechanism of RX action was tested in rats using solutions containing 10–6 M L-NAME, a nitric oxide synthase inhibitor; 10–6 M calcium ionophore (Ca), a calcium channel agonist; 10–6 M indomethacin (Indo), a prostaglandin inhibitor; 10–6 M glibenclamide (Glib), a membrenal ATP-sensitive-K+-channel inhibitor; 10–6 M 5-hydroxydecanoic acid (5-HD), a mitochondrial ATP-sensitive-K+-channel inhibitor. Results: Human IMAs and rat TAs exhibited similar contraction in response to NE and relaxation in response to RX, and ACh. RX-related relaxation was dose dependent (4.5±1 to 15±3%), similar to ACh, and lower than SNP. Relaxation was significantly reduced in the presence of Ca, L-NAME, and 5-HD (P<0.005). Glib and Indo had no effect on relaxation. Lower levels of relaxation in response to RX were observed in TAs without endothelium (P<0.005). Conclusions: RX exerts a mild endothelium-dependent vasodilatory effect mediated by calcium, mitochondrial K+-ATP channels and NO production, possibly explaining part of its mild salutary clinical effects.

Key Words: Atherosclerosis; Roxithromycin; Coronary disease; Macrolide; Endothelium


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The potential link between infectious agents, inflammation, atherosclerosis and coronary ischemic events has attracted much attention in recent years [1]. Chlamydia pneumoniae (CP), an intracellular pathogen, being a common cause of respiratory-tract infection, is one of the most likely candidates for such a link [2–4]. Assuming that targeted antibiotic treatment against CP may delay or prevent atherosclerosis and subsequent ischemic events, several groups assessed the efficacy of macrolide treatment; while some have reported a salutary effect [5,6], others have refuted such an effect [7–9]. Alternative mechanisms of action of the macrolides, unrelated to their antibiotic properties have been sought and proposed [10–12].

Drugs that exert a vasodilator effect on arteries have been associated with attenuated atherogenesis and improved outcome from cardiovascular disease. Thus, the macrolides may exert a beneficial effect on arterial vasomotor tone. The aim of this study was to assess the influence of the macrolide roxithromycin (RX) on human and rat arterial tone ex vivo.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Humans

Specimens of human internal mammary arteries (IMA) were obtained from 10 patients undergoing coronary bypass surgery. Approval to use discarded IMA tissue was granted by the hospital Human Ethics Committee. The surgeon, prior to positioning the anastomoses of the IMA graft, cut a segment about 10 mm long from the most distal part of the graft to which papaverine had already been administered. The specimen was placed in cold (4 °C) saline solution, and transported to the laboratory in less than 15 min. Specimens were divided into vascular rings (3 mm). The number of rings taken from each patient varied from two to four.

2.2. Rats

Animal care complied with the Principles of Laboratory Animal Care and the Guide for the Care and Use of Laboratory Animals. Approval for use of the thoracic aorta (TA) vessels was granted by the local IRB. To assess the RX mode of action, specimens of TA obtained from 40 Wistar rats weighing 250–300 g. Heparin (100 units/rat) was administered intraperitoneally. After 30 min the animals were anesthetized with diethyl ether. Their TA was rapidly excised and mounted on a stainless steel wire stirrups.

2.3. Technique

Fine wire stirrups were placed through each ring and attached to a force transducer for isometric tension recording (FT 0.3C Grass Force Displacement Transducer, Quincy, Mass., USA). The rings on stirrups were put into 20 ml water-jacketed glass organ bath chambers, filled with oxygenated Krebs-Henseleit solution (KH) (pH=7.4–7.5, 37 °C) continuously aerated with 95% O2/5% CO2. The solution was changed 3 times. After a stabilization period of 45 min, each ring was stretched progressively to a final resting tension of 2 g which was maintained throughout the experiment [13]. In the first part of the experiment, norepinephrine 10–6 M (NE) to evaluate contraction, acetylcholine 10–5 M (ACh), sodium nitroprusside 10–5 M (SNP) to evaluate endothelium dependent and non dependent relaxation, was administered for at least 5 min each to the organ bath to assess vascular integrity, with ACh and SNP assessing the integrity of the endothelium and smooth muscle layer, respectively. In the second part of the experiment, solutions were replaced. After re-stabilization, contraction was achieved with 10–6 M NE, followed by relaxation using graded concentrations of RX, 10–7 M to 10–4 M for about 5–10 min each until the response reached a plateau phase, and final relaxation was achieved using 10–5 M SNP. This Rx concentration was chosen as mentioned in the literature and as our preliminary studies produced a biological reaction. This part was done using both human IMAs and rat TAs. The experimental time protocol is presented in Fig. 1.



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  		Fig. 1. Experimental time protocol. After a stabilization period of 45 min, each ring was stretched progressively to a final resting tension of 2 g. In the first part of the experiment, NE 10–6 M, ACh 10–5 M, SNP 10–5 M were administered. In the second part of the experiment, solutions were replaced with new ones. After restabilization, 10–6 M NE, 10–7–10–4 M RX, followed by 10–5 M SNP, were added for 5 min each. This part was done using both IMA and TA. Experimental time protocol is presented.

 
Realizing that both human and animal arteries had similar responses to increasing concentrations of RX, we decided to investigate the mechanism of actions of RX in rat Tas, using solutions containing 10–6 M N-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor; 10–6 M calcium ionophore A23128 (Ca), a calcium channel agonist; 10–6 M indomethacin (Indo), a prostaglandin inhibitor; 10–6 M glibenclamide (Glib), a membrenal ATP-sensitive K+-channel inhibitor; 10–6 M 5-hydroxydecanoic acid (5-HD), a mitochondrial ATP-sensitive K+-channel inhibitor. Solutions containing (10–6 M each) KH, KH+ L-NAME, KH+ Ca, KH+ Indo, KH+ Glib, and KH+ 5-HD were added to the organ bath. After 45 min of stabilization, NE was added to all chambers until maximum contraction was achieved. Relaxation was then achieved using graded concentrations of RX until a plateau response, and final relaxation was achieved using SNP. RX, Indo, Glib and calcium ionophore were dissolved in 100 µl of DMSO. L-NAME and 5-HD were water soluble. Neither the vehicle (DMSO), nor the assessed agents had an effect on their own, on the vasoreactivity.

To determine the role of the endothelium in the vasodilator effect of RX, rat TAs were denuded of the endothelium, by mechanical abrasion. Loss of endothelial integrity was verified by a lack of a vasodilator response to ACh. After restabilization, the rings were exposed to cumulative concentrations of RX, as specified above.

2.4. Materials

All chemicals used during the experiments were purchased from Sigma Chemical Co. (St. Louis, USA).

2.5. Statistical analysis

Data are reported as mean±S.E.M. Maximal contractions were expressed as % contraction of the base line value. Relaxation is expressed as the percent decline in the maximal NE-evoked contraction. Unpaired Student's t-test was used to compare the percentage of contraction force or relaxation for each vasodilator. A P-value of less than 0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Physiological response

The extent of contraction and relaxation in the presence of the various drugs was found to be similar in human IMAs and rat TAs: NE (159±4.4% vs. 152±10%, respectively), ACh (4.5±1.3% vs. 5%±1%, respectively) and SNP (33±3.4% vs. 41±5%, respectively). Human IMAs and rat TAs attached to the stirrups manifested a spontaneous decline in tension within 210 min (3%). Relaxation in response to the elevated concentration of RX was dose-dependant (4.5±1 to 15±3%) in both human IMAs and rat TAs (Fig. 2). RX relaxation was similar to ACh and lower than SNP. Lower levels of relaxation in response to RX were observed in TAs without endothelium (P<0.005) (Fig. 3).



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  		Fig. 2. Relaxation of human IMA and rat TA in response to increasing concentrations of RX. Spontaneous decline of the different arteries is also presented to demonstrate the stability of the system prior to drug administration.

 


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  		Fig. 3. Graded concentrations of RX in rat TAs with and without endothelium.

 
RX mode of action was assessed only in rat TAs. Relaxation was significantly reduced in the presence of Ca, L-NAME, and 5-HD (P<0.005). Glib and Indo had no effect on relaxation (Fig. 4). The vehicle DMSO was tested in an organ bath and had no effect on vessel vasoactivity. Therefore, we concluded that the tested drugs were specific.



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  		Fig. 4. Relaxation of rat TAs in response to increasing concentrations of RX. Different groups were tested according to the organ bath solutions: KH, KH+ L-NAME, KH+ Ca, KH+ Indo, KH+ Glib; KH+ 5-HD.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The major finding of the current study was that RX is a direct endothelium-dependent vasodilator. This effect may be mediated by calcium, mitochondrial ATP-dependent K+-channels and NO production. These vasodilator properties of RX may possibly explain part of its mild salutary clinical effects.

A number of histopathologic, clinical and epidemiological studies have suggested that chronic infection with CP may play a contributory role in atherogenesis and the development of acute coronary events. Viable CP or its components have been identified in arterial plaques, and experimental studies have demonstrated that CP can replicate and maintain a low-grade infection in principal cellular components of atherosclerotic plaques, such as endothelial cells, arterial smooth muscle, and macrophages [3,4]. Infection can, through inflammatory mechanisms, lead to endothelial injury and the expression of adhesion molecules, plasminogen activator inhibitor-1, and tissue factor [14,15]. It may also result in the activation of inflammatory cells, the release of proinflammatory cytokines, and the production of oxygen free radicals, which in turn can affect the endothelial function [16]. The net result may be an increase in both the inflammatory activity and thrombogenic potential of the atheromatous plaques.

Several studies have been conducted in recent years, in order to assess whether antibiotic treatment with macrolides attenuate atherogenesis and improve the outcome of cardiovascular diseases. The favorable results with macro-lides include a 40% reduction in major cardiac events in patients with acute coronary syndromes [17], and an improvement of flow-mediated dilatation of brachial artery in coronary artery diseased patients [12]. Other studies [5,9,18] showed an immediate, but not sustained effect concerning cardiac ischemic death, myocardial infarction and severe recurrent ischemia. Yet another study showed that patients with high titers of CP, the macrolide RX reduced the rate of restenosis [19]. In Finland, treatment with clarithromycin reduced the risk of ischemic cardiovascular events in patients presenting with acute non-Q wave myocardial infarction or unstable angina pectoris [20]. Others have reported that in CP seropositive patients, no clinical benefit was observed after macrolide treatment [8].

These contradictory data regarding the efficacy of the macrolide treatment raises the question that a non-antimicrobial effect is the basis of macrolide action in atherosclerotic disease. It has been suggested that some of the favorable effects of antibiotics shown in clinical studies were due to the anti-inflammatory properties of these agents rather than their antimicrobial action [4,5,17]. Macrolide antibiotics have been shown to affect several pathways of the inflammatory process, such as the migration of inflammatory cells and the production of proinflammatory cytokines [21,22].

Drugs that exert a vasodilator effect on arteries have been associated with attenuated atherogenesis and improved outcome from cardiovascular disease. Mitsuyama et al. [23] found that the macrolide erythromycin increased constitutive NO synthase protein expression by human endothelial cells and enhanced NO release. Moreover, macrolide antibiotics appear to reduce superoxide production by activated leukocytes [24], which could result in a decrease of oxidative stress and an increase of the bio-availability of NO. The finding that there were no significant differences in the effect on flow mediated dilatation of the brachial artery and biochemical markers between patients with low and high CP antibody titers receiving the macrolide azithromycin [12], further suggests the non-antimicrobial action of the macrolides. A direct potassium channel effect of roxithromycin was suggested by Martin et al. [10], who demonstrated by the patch-clamp technique, the suppression of macrophage activity via the blockade of stretch-sensitive, large conductance potassium channels. Thus, we examined the vasoactive properties of the macrolide RX.

The adult dose administered orally is 300 mg/day but the actual effective blood level is smaller and estimated only, and we assessed an alternative, non-antibiotic mechanism for direct reaction of the RX on vessel vasoactivity. A concentration of 10–7 M–10–4 M of RX was chosen as mentioned in the literature and as indicated by the results of our study that this concentration resulted in relaxation [10].

In our study we observed dose-dependant arterial relaxation in response to RX that was significantly endothelium and no endothelium dependent. At 10–7 M–10–5 M the vasodilator effect was blocked by L-NAME (inhibiting endothelium release of NO) or partially blocked by 5HD, a mitochondrial ATP-sensitive K+-channel inhibitor or calcium ionophore and even augmented in the presence of indomethacin witch blocks the prostaglandins effect. At 10–4 M RX, the non-endothelium aspect of relaxation is dominant. Thus, some of the salutary clinical effects of RX may be attributed to its vasoactive properties. Its in vivo effect in atherosclerotic diseased patients, who have dysfunctional endothelium, may be attenuated. Our ex vivo studies in rat IMAs imply a complex mechanism involving several pathways, including NO production [25], mitochondrial ATP-dependent K+- channels [26], and calcium channels [11]. These findings indicate that RX influences the endothelium via NO production, opening the mitochondrial K-ATP channels and reducing calcium levels in the cytosol. In the presence of steady concentration of Indo (10–6 M) the relaxation effect of RX was dose dependent. Indo blocks the production of prostacyclin and in its presence the vasodilator effect of RX was not reduced but enhanced. Since Indo (prostagladin synthesis blocker) and Glib (a membranal ATP-sensitive K+-channel inhibitor did not reduce the relaxation properties of RX on the arteries, we conclude that prostaglandins and potassium membrane channels are not involved in RX-induced relaxation. Recently, PROVE-IT and ACES trials [27] found that patients administered antibiotics showed the same risk of cardiac events as those given placebo. The basis of these studies is an antibiotic mechanism (possible C. Pneumoniae), while our in vitro study is based on direct, modest vasoactive effect of the RX. Therefore, the extrapolation of our results to the clinical arena should be applied with caution.

In conclusion, our results indicate that RX has a favorable, vasodilator effect on arterial function, independent of its antimicrobial properties. Further studies are needed to clarify the clinical significance of our observation.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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