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European Journal of Heart Failure 2001 3(1):7-13; doi:10.1016/S1388-9842(00)00097-0
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© 2001 European Society of Cardiology

Enhanced Ca2+ -induced contractions and attenuated {alpha}-adrenoceptor responses in resistance arteries from rats with congestive heart failure

Anders Bergdahla, Stig Valdemarssona, Xiang-Ying Sunb, Thomas Hednerb and Lars Edvinssona,*

a Department of Internal Medicine, Lund University Lund, Sweden
b Department of Clinical Pharmacology, Gothenburg University Gothenburg, Sweden

* Corresponding author. Tel.: +46-46-171237; fax +46-46-184792. E-mail address: lars.edvinsson{at}med.lu.se (L. Edvinsson).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Aim: The aim of the present study was to examine the role of Ca2+ -mediated contractile responses in isolated mesenteric resistance arteries from rats with congestive heart failure (CHF).

Methods: Heart failure was induced by ligation of the left coronary artery. Rats exposed to the same surgical procedure except ligation served as controls (Sham). The following experiments were conducted: (1) passive increase in radial stretch (the length–tension relationship) in Ca2+ -free and in depolarizing high K+- solution; (2) the contractile responses to external application of Ca2+ and high K+ -solutions in the presence of nifedipine and phentolamine; and (3) a histological evaluation of CHF and Sham vessels.

Results: The length–tension induced response in Ca2+ -free buffer solution was significantly lower in arteries from CHF rats, starting at a very low tension (0.9 ± 0.2 mN/mm for heart failure and 1.7 ± 0.2 mN/mm for Sham). This difference, but at a higher degree of stretch, was also present in K+ -activated vessels. The external application of Ca2+ in K+ -depolarized vascular segments in the presence of phentolamine (1 µM) induced an enhanced contractile response in arteries from CHF rats compared with Sham (4.8 ± 0.3 mN/mm and 3.6 ± 0.6 mN/mm, respectively, P = 0.059). In the absence of phentolamine the reverse response was found (4.0 ± 0.4 mN/mm and 5.7 ± 0.3 mN/mm for CHF vs. Sham respectively, P = 0.035). Application of increasing concentrations of K+ -solution induced a stronger contractile response in Sham compared with CHF arteries (Sham 4.9 ± 0.4 and heart failure 4.0 ± 0.3, P = 0.04). Microscopic examination of vessels yielded no difference in gross morphology, media thickness or wall to lumen ratio between CHF and Sham arteries.

Conclusion: The results indicate an attenuation of {alpha}-adrenoceptors and a difference of Ca2+ -mediated vascular contractility in resistance arteries of congestive heart failure rats.

Key Words: Ca2+ • Congestive heart failure • {alpha}-Adrenoceptors

Received November 12, 1999; Revised May 11, 2000; Accepted June 8, 2000


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Congestive heart failure (CHF) is a clinical condition characterized by decreased cardiac output and increased vascular resistance. To compensate the failing heart and in order to restore systemic vascular blood flow, several vasoregulatory systems are activated. These include the renin–angiotensin–aldosterone system (RAAS) [1,2] and the activation of the sympathetic nervous system [3,4]. Further, augmented levels of endothelin-1 [5,6], arginine–vasopressin (AVP) [7,8] and atrial natriuretic peptide [9] have been reported. As the disease progresses, the vasoregulatory systems are even further activated and increased levels of vasoregulatory substances have been correlated to the degree of heart failure [2] and to prognosis [9,10].

The attenuated function of the vascular system in CHF is illustrated by reduced dilatory capacity after arterial occlusion. Thus, the hyperaemic peak blood flow was early reported to be decreased in CHF [11], a finding which has been confirmed later by other groups [12]. Moreover, while the response to endothelium-independent vasodilators like sodium-nitroprusside are preserved, ACh-mediated NO-induced vasodilatation is attenuated in humans with CHF [13,14]. The contractile response to noradrenaline in patients with CHF was earlier reported to be blunted [15]. Later many reports have shown the adrenoceptors to be attenuated (or ‘down-regulated’) in response to specific adrenoceptor-agonists. In the CHF rat model attenuation of both {alpha}1-adrenoceptor responses and {alpha}2-adrenoceptor-mediated responses have been reported [16–18].

The role of Ca2+ in cardiovascular regulation has almost exclusively been studied in the heart muscle in experimental models and in patients with heart failure. Adverse effects of Ca2+ have also been suggested, especially after ischaemic episodes in the heart, where an excessive cellular overload of Ca2+ after such an episode induces myocyte necrosis [19,20]. Less is known about the effects of Ca2+ at the vascular level in CHF. The use of calcium-antagonists has not yielded any positive results on mortality or morbidity in patient trials [21,22]. In fact a number of adverse effects have been noted, amlodipine being the sole exception, reported to reduce mortality in non-ischaemic dilated cardiomyopathy [23]. However, in this study, side-effects including orthostatic hypotension and oedema was more frequent in the amlodipine group as compared with placebo.

Thus, the impact of Ca2+ and Ca2+-homeostasis on vascular function in CHF has not been explored in detail and less is known about the Ca2+-dependent effects on vascular smooth muscle cell contractility per se in CHF. Furthermore, in man, a reduced contractile response to K+-induced contractions has been reported in patients with CHF [14]. In recent reports we have observed, non-consistent changes in the vascular contractile response after depolarization with potassium solutions (60 mM K+) in experimental CHF [18,24]. We have, therefore, in the present study analysed the passive and active length–tension relationship and the contractile response to increasing concentrations of K+- and Ca2+-solutions in rats suffering from CHF. In addition, the involvement of the {alpha}-adrenergic component following depolarization with K+-buffer solution was examined by use of phentolamine.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Experimental animals
Male Sprague–Dawley rats (ALAB; Sollentuna, Sweden) weighing 150–200 g at the time of operation, were used. The study was approved by the Committee of Ethics for Animal Experiments at Lund University Hospital and conformed with the Guide for Care and Use of Laboratory Animals published by the US National Institute of Health (NIH Publication No. 85-23, revised 1985).

2.2. Induction of congestive heart failure
During methohexital sodium anaesthesia (Brietal®, 60 mg/kg i.p., Eli Lilly, IN, USA) the rats were intubated and artificially ventilated. A left thoracotomy was performed, exposing the left ventricular wall. The left coronary artery was ligated by positioning a suture between the pulmonary artery out-flow tract and the left atrium. The rats were allowed to recover for 12 weeks before experiments. Half of the rats were sham-operated, i.e. they were subjected to the same surgical procedure but without coronary ligation. These rats served as controls. Approximately 20% of the rats died within 24 h after coronary ligation and less than 5% in the Sham group.

2.3. Evaluation of infarct size and determination of vessels morphology
To confirm the development of myocardial infarction in the operated animals a histological examination of the coronary ligated hearts was performed. The hearts were immersed into a 6% formalin solution. After fixation, the ventricular region was cut into four transverse slices and from each slice 10-µm-thin sections were stained with van Gieson dye for microscopic evaluation. The fibrotic area of the left ventricle was measured and related to the whole left ventricular circumference. Inclusion criteria of CHF rats was set to an infarct size comprising >30% of the left ventricular circumference [25]. In separate experiments, small mesenteric vessels were mounted and normalized and thereafter fixed in formalin before carefully dismounted. The vessels were cut in 10-µm-thin ring segments, stained and the morphology of the medial muscle layer and wall to lumen ratio was determined.

2.4. In vitro preparation
The animals were sacrificed under carbon dioxide anaesthesia, 12 weeks after coronary ligation. The intestinal tract was removed and kept in a cold physiological salt solution containing (in mM): NaCl 119; NaHCO3 15; KCl 4.6; MgCl2 1.2; NaH2PO4 1,2; CaCl2 1.5; glucose 5.5. The solution was continuously gassed with carbogen (5% CO2 in O2) to maintain a pH near 7.4. Segments from the second and third order branches of the superior mesenteric artery were carefully dissected. The dissected vessels were mounted in a Mulvany–Halpern myograph (model 600M, JP Trading, Aarhus, Denmark) allowing direct determination of the vessel wall force while the internal circumference was controlled [26]. After the temperature had reached 37°C, arteries were stretched radial to their optimal lumen diameter according to standard normalization procedures [26]. The contractile capacity of the vessels were initially examined by repetitive exposure to a potassium-rich (123 mM) buffer solution. Vessels were included if the contractions were reproducible and if the contraction did exceed 100 mmHg.

2.5. Length–tension relationship
After dissection, both CHF and Sham mesenteric arteries were placed in Ca2+-free buffer solution (substitution of Ca2+ in the above buffer solution for equimolar concentrations of EGTA (ethylene glycol-bis (β-amino ethyl ether) N,N,N',N'-tetraacetic acid) and left to rest overnight in the refrigerator (+6°C). The vessels were mounted and either maintained in Ca2+-free buffer solution or exposed to 123 mM K+ (Ca2+-containing) buffer solution. Passive length–tension measurements by radial stretch of the vessels were performed in both Ca2+-depleted and K+-activated vessels of CHF and Sham.

2.6. K+-induced contractile responses
Vessels were kept in normal physiological buffer solution and exposed to increasing concentrations of K+-buffer solution. After each exposure the vessels were washed repeatedly with standard NaCl buffer solution to regain resting tension. The concentrations of the K+-buffer solutions used were 10, 20, 30, 40, 63.5, 90 and 123 mM. Nifedipine (1 µM) were used to identify the influence of extracellular Ca2+ and phentolamine (1 µM) were added to inhibit the {alpha}-adrenergic component of the contraction.

2.7. Ca2+-induced contractions
Vessels were washed repeatedly with Ca2+-free buffer solution and 123 mM K+ calcium-free buffer solution until no contractions were obtained with the calcium-free K+-solution. Increasing concentrations (10 µM–0.15 M) of external Ca2+ were then added and the response recorded. Nifedipine and phentolamine (1 µM) were used as analogues to K+ experiments.

2.8. Drugs
The following drugs were used: nifedipine, phentolamine and EGTA, (Sigma Aldrich, St Louis, MO, USA). Experiments using nifedipine were performed in dim light conditions to avoid light-induced degradation.

2.9. Statistics
Statistical analysis were performed using the Mann–Whitney U-test in unpaired studies and Wilcoxon signed rank test in paired studies. P<0.05 was accepted as a statistically significant difference. If not otherwise stated, data are presented as mean±S.E.M. of six or more rats in each group of rats, respectively.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Induction of myocardial infarction and CHF status
Evaluation was made according to earlier reports [25]. The hearts showed post-infarction signs comprising fibrosis and enlargement of the left ventricle, as confirmed by microscopic evaluation. The infarct size in operated rats was 38.1±3.8% (mean±S.D.) of left ventricular circumference. Heart to body ratio was 0.47±0.1 and 0.34±0.05% in CHF and Sham, respectively (mean±S.D., P=0.008, n=8).

3.2. Normalization-induced contractions, morphology of vessel wall
Normalization of CHF and Sham mesenteric arteries yielded an internal circumference at 100 mmHg of 244±33 and 258±35 µm, respectively, (mean±S.D., n.s.). The initial K+-induced contractile responses after normalization were 4.2±0.2 mN/mm in CHF and 4.3±0.2 mN/mm in Sham (n.s). In the separate group of vessels used for histology examination, the diameter obtained after normalization was 247±27 µm in CHF and 270±16 µm in Sham (mean±S.D., n.s., n=5 in each group). Microscopic evaluation (40x magnification) of vessels fixed under normalized conditions and stained with van Gieson dye showed no difference in morphology, media thickness (CHF: 20.2±1.4 µm, Sham 19.6±1.2 µm) or media to lumen ratio (CHF 8.2±0.8 and Sham 7.2±0.2%).

3.3. Length-tension induced force in passive and K+-activated vessels
In Ca2+-free buffer solution the stretch of the mesenteric artery generated an increasing passive force in both CHF and Sham arteries. At a length of 250 µm from start (wires just touching each other) and at a tension of 0.9±0.2 mN/mm for CHF and 1.7±0.2 mN/mm for Sham, the passive force–tension curves diverged (Fig. 1a). This divergence was present up to 550 µm from the start corresponding to a tension of 18.6±4.8 mN/mm for CHF and 30.3±3.9 mN/mm for Sham. A similar difference was found in K+-depolarized vessels, starting at 400 µm from start, with a corresponding generated tension in CHF of 10.6±0.2 and Sham 14.1±1.3 mN/mm, Fig. 1b.


Figure 1
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  		Fig. 1 (a) The passive length–tension response curve of small mesenteric arteries in Ca2+-free buffer solution. The curves diverge at 250 µm from start of recording (e.g. wires just touching each other). (b) The active length tension curve in high K+ buffer solution (123 mM). A divergence is seen at high degrees of stretch. For numbers corresponding to the figures, see text. congestive heart failure (CHF); control-operated rats (Sham). Values represent mean±S.E.M.

 
3.4. K+-induced contractions
K+-buffer solution in increasing concentrations induced a rapid contractile response. In the presence of phentolamine (1 µM) there was no difference in contractile response between CHF and Sham arteries (Fig. 2a). In the absence of phentolamine CHF arteries responded with a lower contraction compared with Sham (Emax 4.0±0.3 and 4.9±0.4 mN/mm, P=0.04, Fig. 2b). In the presence of phentolamine (1 µM), nifedipine (1 µM) induced a stronger inhibition of the contractile response to CHF arteries compared with Sham (CHF: 1.8±0.4 mN/mm vs. Sham: 3.1±0.3 mN/mm, P=0.02, Fig. 2c).


Figure 2
Figure 2
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  		Fig. 2 Contractile response in congestive heart failure, CHF and control-operated Sham mesenteric arteries to increasing concentrations of K+ in (a) the presence of phentolamine (1 µM), (b) the absence of phentolamine and (c) in the presence of both phentolamine (1 µM) and nifedipine (1 µM). Values represents mean±S.E.M. *P<0.05 (Mann–Whitney U-test).

 
3.5. Ca2+-induced contractions
In Ca2+-free 123 mM K+-containing buffer solution, application of increasing concentrations of Ca2+ induced a strong contractile response in both CHF and Sham arteries. Contractile responses in the presence of phentolamine (1 µM) were 4.8±0.3 mN/mm in CHF and 3.6±0.6 mN/mm in Sham mesenteric arteries (P=0.059). The contractions were almost completely inhibited by nifedipine 1 µM or 0.1 µM (data not shown) with no difference at either concentration of nifedipine. In corresponding experiments but without phentolamine, Ca2+-induced a lower contractile response in CHF arteries compared with Sham (4.7±0.3 and 5.7±0.3 mN/mm, P=0.03). When comparing the effect of phentolamine within the CHF and the Sham groups, there was no difference in response to Ca2+ with or without phentolamine in CHF arteries (Fig. 3a) but a marked difference in contractile response to Ca2+ in the corresponding Sham group (P=0.02, Fig. 3b).


Figure 3
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  		Fig. 3 Contractile response to external application of Ca2+ in Ca2+-free K+ solution (123 mM). (a) Comparison of contractile response of CHF arteries in the absence and presence of phentolamine (1 µM) and (b) contractile response of Sham arteries in the absence and presence of phentolamine (1 µM). Values represent mean±S.E.M. *P<0.05 (Mann–Whitney U-test).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
The present study indicates a specific role for Ca2+-dependent vasoconstriction and supports earlier reports of attenuated {alpha}-adrenoceptor-mediated responses in CHF [14,15]. The isometric force generated by passive increase in diameter of Ca2+-depleted and K+-depolarized vessels was attenuated in CHF. Further, a reduced contractile response to K+-depolarization was obtained in CHF compared with Sham vessels in the absence of phentolamine but also a stronger effect of nifedipine in phentolamine-treated vessels; CHF arteries were inhibited to a greater extent by nifedipine compared with Sham. Furthermore, the direct effect of external application of Ca2+ was altered in CHF.

A lower contractile response in CHF as compared with Sham arteries was observed and phentolamine-inhibition had no effect on Ca2+-induced contraction in CHF arteries.

4.1. Length–tension-induced force in passive and K+-activated vessels
Due to reports of morphological rearrangements in vessels from patients with CHF [27,28] we expected an increased resting (passive) tension in the mesenteric small arteries of CHF rats. However, the reverse was noted. At the same degree of stretch and at a very low level of pressure, the generated force was lower in CHF arteries compared with Sham. The same was seen in K+-contracted vessels but at a much higher degree of tension. It has been shown in the experimental heart failure rat that 12 weeks are needed to alter vascular morphology [29]. Furthermore, in the same study, it was shown that conduit arteries of CHF rats had a reduced medial cross-sectional area while mesenteric and pulmonary resistance vessels showed an increase in external and internal diameter. The vessel-size, determined by normalization, did not differ between CHF and Sham arteries in this study. The results of our histological evaluation, although limited in number of arteries studied, did not reveal any difference in morphology, media thickness or wall to lumen ratio. Thus, the changes observed in these experiments supports the suggestion by Heeneman et al. [29] who proposed that the increased vascular resistance noted in CHF is mainly due to neurohumoral influences rather than rearrangement of the vessels structure. However, several mechanisms affecting the vascular resistance are involved in CHF such as increased concentration of Na+-ions in the vascular wall [30] and endothelial dysfunction [31].

4.2. K+-induced contractions
When stimulating the vessels with high K+-solution in the presence of phentolamine there was no difference in contractile responses between CHF and Sham. However, in the absence of phentolamine CHF-arteries responded with a lower contraction compared with Sham (Fig. 2b). A reduced number of both {alpha}1- and {alpha}2-adrenoceptors have been shown in the CHF rat [16,32] which may support these findings; the CHF arteries responding as if already inhibited with phentolamine (see also Fig. 3a). Interestingly, inhibition with both nifedipine and phentolamine induced a stronger inhibition in CHF as compared with Sham arteries. This may indicate an increased importance of Ca2+ in the vascular contractile response in CHF, either coupled to attenuated Ca2+-dependent contractile mechanisms or indirect, due to a reduced number of {alpha}-adrenoceptors. Since nifedipine inhibits mainly the L-type Ca2+-channels and ({alpha}-)?agonists stimulates both L-type and non-L-type Ca2+-channel mediated Ca2+-influx, besides increasing the sensitivity to contractile elements in the cell [33], the results obtained from the nifedipine experiments (Fig. 2c) may in part be explained by a reduced number of {alpha}-adrenoceptors, in accordance with the results discussed.

4.3. Ca2+-induced contractions
The results obtained by application of external Ca2+ in depolarized vessels indirectly supports the hypothesis of an attenuated {alpha}-adrenoceptor population. The contraction of CHF arteries did not differ in the presence or absence of phentolamine (Fig. 3a) while there was a marked decrease in Ca2+ contractility in the presence of phentolamine in Sham arteries (Fig. 3b). Interestingly, when inhibited by phentolamine, CHF responded with a stronger (P=0.059) contractile response as compared with Sham arteries. This result differ from the results discussed above and cannot be explained by an attenuated {alpha}-adrenoceptor-population. However, the presumed increase in contractile response of CHF arteries to external application of Ca2+ (in the presence of phentolamine) may represent a different mechanism related to the increased vascular resistance observed in CHF [34]. Alternatively, as has been shown in ischaemic cardiomyopathy, the intracellular myocardial ryanodine receptor, which releases Ca2+ from intracellular stores, is down regulated [19]. This might be the case also in the vascular system and the increased contractile response to external application may indicate an increased dependence on external Ca2+ in the vascular bed in CHF. A possible explanation to this result may also include a dysfunction of the endothelium which has been reported by several investigators [31]. A loss or diminished production of NO indefinitely leads to an increased vascular resistance which might correlate to the findings observed in these experiments.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
In conclusion, the present study has shown that differences in Ca2+-mediated responses occurs at the vascular level in CHF arteries which in part may be explained by an attenuated or reduced number of {alpha}-adrenoceptors in CHF and suggests a specific role for Ca2+-dependent vasoconstriction in CHF rats. This may represent a mechanism that contribute to the enhanced vascular resistance observed in CHF, independent of alterations in morphology.


   Acknowledgements
 
This study was supported by grants from the Swedish Medical Research Council (grant no. 5998).


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

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