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Ann Thorac Surg 2002;73:516-522
© 2002 The Society of Thoracic Surgeons

Original article: cardiovascular

Interaction between vasodilators and vasopressin in internal mammary artery and clinical significance

Wei Wei, MDa, H. Storm Floten, MDa, Guo-Wei He, MD, PhD*a,b

a Cardiovascular Research, Starr Academic Center, Providence Heart Institute, Department of Surgery, Oregon Health Sciences University, Portland, Oregon, USA
b Division of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China

Accepted for publication September 19, 2001.

* Address reprint requests to Dr He, Department of Surgery, The Chinese University of Hong Kong, Block B, 5A, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China
e-mail: gwhe{at}cuhk.edu.hk


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Arginine vasopressin (AVP) has recently been demonstrated as an alternative in the treatment of severe refractory vasodilatation in coronary artery bypass grafting. However, AVP may be a spasmogen for graft spasm. We compared the in vitro antispastic effect among calcium-channel antagonists (nifedipine, diltiazem, and verapamil), nitroglycerin, and the highly selective AVP (V1) receptor antagonist [1-deaminopenicillamine, 4-valine, 8-D-arginine] vasopressin.

Methods. Human internal mammary artery segments (n = 218) were studied in organ baths. The inhibitory effects of the above vasodilators on AVP-mediated contraction were studied in two ways: relaxation with AVP precontraction and depression of the AVP-induced contraction after pretreatment with vasodilators.

Results. All three calcium-channel antagonists caused limited relaxation (18.3% ± 5.4% for nifedipine, n = 11; 22.2% ± 3.8% for verapamil, n = 10; and 26.2% ± 7.5% for diltiazem, n = 9). The plasma concentration of calcium-channel antagonists had no significant depression effect on the AVP-induced contraction. In contrast, [1-deaminopenicillamine, 4-valine, 8-D-arginine] vasopressin caused full (100%, n = 11) and nitroglycerin caused nearly full (93% ± 3%, n = 10) relaxation. Pretreatment with [1-deaminopenicillamine, 4-valine, 8-D-arginine] vasopressin (10-8, 10-7, or 10-6 mol/L, respectively) significantly increased the effective concentration for 50% of the AVP-induced contraction (10-8.6 ± 100.1 mol/L, p = 0.009; 10-7.8 ± 100.07 mol/L, p = 0.000; or 10-6.9 ± 100.11 mol/L, p = 0.000 versus the control, 10-9.24 ± 100.16 mol/L). However, nitroglycerin only slightly depressed the AVP-induced contraction.

Conclusions. [1-Deaminopenicillamine, 4-valine, 8-D-arginine] vasopressin may provide specific antispastic effect in either prophylaxis or treatment of the AVP-related vasospasm in the internal mammary artery. Nitroglycerin may be effective in treatment but has little effect on prophylaxis. Use of calcium-channel antagonists may have little benefit in AVP-related vasospasm.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Recently, arginine vasopressin (AVP) has been determined to be an effective alternative to catecholamines in the treatment of severe refractory vasodilatory shock [1, 2], which can occur unpredictably in coronary artery bypass grafting (CABG) perioperatively [3]. Arginine vasopressin can produce a marked pressor effect and successfully overcome catecholamine resistance in some vasodilatory shocks, such as those induced by milrinone during CABG [2]. However, as a neuropeptide and one of the most potent coronary constrictors [4], AVP has a great propensity to cause potential vasospasm in coronary bypass conduits. First, AVP can evoke potent constriction of vascular smooth muscle mainly through V1 receptor [5] and therefore cause cardiac ischemia by dramatically reducing coronary blood flow [6]. Second, even at low concentrations, AVP can facilitate sympathetic neurotransmission and promote constrictor effects of norepinephrine in human saphenous veins used as coronary grafts [5]. Moreover, significantly higher plasma concentrations of endogenous vasopressin secreted during cardiopulmonary bypass has been measured in patients undergoing CABG than in patients having other open-heart operations [7]. All these factors may play a synergistic effect when exogenous AVP is added in evoking coronary bypass graft spasm.

The internal mammary artery (IMA) has been unanimously accepted as the choice for arterial grafts for CABG in most institutions because of its superiority of long-term patency compared with the saphenous vein [8]. However, vasospasm occurs in the IMA during CABG as mentioned above, and AVP may be one of the spasmogens. Therefore, pharmacologic strategies to treat potential AVP-mediated contraction in the human IMA may be clinically important.

Three different types of calcium-channel antagonists (CCA; nifedipine, verapamil, and diltiazem as the prototype of dihydropyridine, phenylalkylanine, and benzothiazepine, respectively) have been widely used to treat hypertension, angina pectoris, and vasospasm. In addition, nitroglycerin (NTG) is frequently used to treat patients suffering from coronary artery disease as it dilates epicardial conductance arteries, increases collateral blood flow to ischemic myocardium, and decreases left ventricular preload [9]. However, the effects of CCA and NTG on the AVP-mediated vasoconstriction or spasm in the human IMA have not been systematically studied. This study was designed to examine the effects of CCA (nifedipine, verapamil, and diltiazem), NTG, and the highly selective V1 receptor antagonist [1-deaminopenicillamine, 4-valine, 8-D-arginine] vasopressin (dPVDAVP) on AVP-mediated contraction in human IMA.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
General
Human IMA segments (n = 218) were collected from 60 patients undergoing CABG (Table 1). Approval to use the discarded IMA tissues was given by the Institutional Review Board, Providence St. Vincent Hospital, Portland, Oregon. Any discarded IMA segments were collected and placed in a container with oxygenated physiologic solution (Krebs solution) maintained at 4°C and transferred to the laboratory immediately. The IMA was transferred into a glass dish and carefully dissected out from its surrounding connective tissue. The IMA was cut into 3-mm-long rings and suspended on wires in organ baths for isometric recording of tension [10, 11]. The number of rings taken from each patient varied from 4 to 6. Each IMA ring was set up in a 25-mL bath that contained modified Krebs solution of the following composition (in mmol/L): Na+, 144; K+, 5.9; Ca2+, 2.5; Mg2+, 1.2; Cl-, 128.7; HCO3-, 25; SO42-, 1.2; H2PO4-, 1.2; and glucose, 11. The solution was continuously aerated with 95% oxygen and 5% carbon dioxide at 37°C.


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  		Table 1. Clinical Characteristics of 60 Patients Undergoing Internal Mammary Artery Graft Operation

 
Organ bath techniques
A technique that allowed for vascular rings to normalize to a physiologic pressure in the organ bath was used in this study. The vascular rings were set at a pressure comparable with that used in the in vivo situation. The details of the technique have been published before and repeatedly used in our in vitro studies for human vessels [12–15]. In brief, two parallel stainless-steel wires were introduced through the lumen of the IMA ring. The lower hook was fixed to a micrometer-adjustable support leg and the upper to an isometric force transducer (model FT03, Grass Instrument Company, Quincy, MA) to record changes in isometric force, which was amplified and recorded on a polygraph chart recorder (model 79H, Grass Instrument Company). The rings were stretched up in progressive steps to determine the length-tension curve for each ring. A computer iterative fitting program (Vastand 2.1; Yang-Hui He, Princeton, NJ) was used to determine the exponential line, pressure, and the internal diameter. When the transmural pressure on the rings reached 100 mm Hg, as determined from their own length-tension curves, the stretch-up procedure was stopped, and the rings were released to 90% of their internal circumference at 100 mm Hg. This degree of passive tension was then maintained throughout the experiment. After the normalization procedure, the IMA rings were equilibrated for at least 45 minutes.

In this study, the endothelium was intentionally preserved by cautiously dissecting and mounting the rings because endothelium plays a modulating role in the contractility of arterial grafts. We previously found that this technique allowed for experiments to be carried out with an intact endothelium, as determined by the functional relaxation response to acetylcholine or calcium ionophore in human arteries [11].

Protocol
Human IMA rings from the same patient were randomly assigned to different groups to maximally reduce the possible influence to the results because of multiple rings from the same patient allocated in a certain group of experiments.

Relaxation
In this study, the effective concentrations that produced 10% to 90% of the maximal contraction with AVP (EC10 to EC90) were determined from the logistic curve-fitting equation in the IMA rings (n = 12). Arginine vasopressin at 10-8.5 mol/L (approximately EC70) was used to precontract rings in relaxation studies, and cumulative concentration-relaxation curves to CCA, NTG, and dPVDAVP were then established. Only one concentration-relaxation curve was obtained from each IMA ring. From our pilot experiments, the contraction induced by AVP was not sustained in a stable enough manner for long periods (4 to 5 hours); therefore, in each experiment, one ring from the same patient was contracted with AVP as a time control and the other rings from the same patient were contracted with AVP and then used to establish the concentration-relaxation curves for CCA and dPVDAVP in 20-minute intervals. In addition, the relaxing effect of dPVDAVP on K+ (25 mmol/L) -induced contraction was also studied. Concentration-relaxation curves for dPVDAVP (10-12 to 10-6.5 mol/L) were then established in the IMA rings (n = 7).

Depression of contraction by pretreatment with calcium-channel antagonists, nitroglycerin, and [1-deaminopenicillamine, 4-valine, 8--arginine] vasopressin
After equilibration, K+ (100 mmol/L) was added into the organ bath, and the contraction force was recorded. The rings were then repeatedly washed with Krebs solution to restore the baseline tension. To determine whether pretreatment of CCA, NTG, and dPVDAVP would alter the contraction response to AVP, cumulative concentration-contraction curves were established in the IMA rings. Only one concentration-contraction curve was obtained from each IMA ring. The contraction was expressed as a percentage of the maximal contraction force induced by 100 mmol/L K+.

Effect of calcium-channel antagonists
Four rings taken from the same patient were incubated for 20 minutes with nifedipine (20 nmol/L, 200 nmol/L, 30 µmol/L, or vehicle [1% ethanol], n = 7 in each group), or verapamil (20 nmol/L, 200 nmol/L, 30 µmol/L, or vehicle, n = 7 in each group), or diltiazem (60 nmol/L, 600 nmol/L, 30 µmol/L, or vehicle, n = 7 in each group), respectively. Those concentrations (20 to 200 nmol/L for nifedipine; 0.2 to 2 µmol/L for verapamil; 60 to 600 nmol/L for diltiazem) were chosen because they are similar to the optimal therapeutic free plasma concentration reached clinically [16], and the supraclinical concentration (30 µmol/L), which can be reached for topical treatment during operation, was chosen to study the possible maximal inhibitory effect. Concentration-contraction curves to AVP (10-12 to 10-6.5 mol/L) were then established.

Effect of nitroglycerin
Four rings taken from each of 7 patients were respectively incubated for 10 minutes with 0.1 µmol/L, 1 µmol/L, 30 µmol/L, or vehicle of NTG. In these concentrations, 0.1 and 1 µmol/L of NTG are relevant to the optimal therapeutic free plasma concentrations reached clinically [17]. Cumulative concentration-contraction curves to AVP (10-12 to 10-6.5 mol/L) were then established.

Effect of [1-deaminopenicillamine, 4-valine, 8--arginine] vasopressin
Regarding the therapeutic plasma concentration of the selective AVP antagonist dPVDAVP, because there are no clinical reports available, the concentrations of dPVDAVP at 10 nmol/L, 100 nmol/L, and 1 µmol/L were used to study the effect on the AVP-mediated contraction. Four rings from each of 6 patients were respectively incubated for 20 minutes with 10 nmol/L, 100 nmol/L, 1 µmol/L, or vehicle of dPVDAVP. Cumulative concentration-contraction curves to AVP (10-12 to 10-6.5 mol/L) were then established.

Data analysis
The sensitivity of both vasoconstrictors and vasodilators was expressed as EC50, the effective concentration that caused 50% of maximal contraction or relaxation. The EC50 was determined from each concentration-contraction (or relaxation) curve by a logistic, curve-fitting equation:

where E is response, M is maximal contraction or relaxation, A is concentration, K is EC50 concentration, and P is the slope factor [18]. A computerized program was used for the curve fitting.

In this study, all values were expressed as mean ± SEM. Statistical comparisons of the percentage relaxation or contraction under different treatments were tested by two-way analysis of variance (ANOVA) with repeated measures, followed by post hoc Scheffe test to detect the individual difference. The EC50 and maximal response values were compared by one-way ANOVA followed by post hoc Scheffe test. A p value less than 0.05 was considered significant.

Drugs
All drugs used in this study were purchased from Sigma Chemical Company (St. Louis, MO), except NTG, which was from Abbott Laboratories (North Chicago, IL). All solutions were freshly made before use. Nitroglycerin, nifedipine, and verapamil were protected from light. Nifedipine was dissolved in ethanol to 10-2 mol/L. The other drugs were dissolved in distilled water.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Resting vessel measurements
The mean internal diameter of the IMA rings (n = 218) at an equivalent transmural pressure of 100 mm Hg was 2.7 ± 0.04 mm, as determined from the normalization procedure [18]. When the IMA rings were set at 90% of the diameter at 100 mm Hg, the equivalent transmural pressure was 67.7 ± 0.5 mm Hg, and the resting force was 4.7 ± 0.1 g.

Relaxing effect of calcium-channel antagonists, nitroglycerin, and [1-deaminopenicillamine, 4-valine, 8--arginine] vasopressin on the internal mammary artery rings contracted by arginine vasopressin
The maximal relaxation caused by CCA is shown in Table 2. The values were normalized by the time control. In contrast to the limited relaxation, full or nearly full maximal relaxation (also normalized by the time control) was induced by dPVDAVP and NTG, respectively. The relaxant effect of dPVDAVP or NTG on the AVP-mediated contraction was significantly greater than that of CCA (p = 0.000, two-way ANOVA; Fig 1). In the IMA rings precontracted with AVP, the EC50 values are shown in Table 2. In five rings from nifedipine, two from diltiazem, and one from verapamil groups, the EC50 values could not be calculated from the logistic curve-fitting equation. There were no significant differences regarding EC50 among CCA, NTG, and dPVDAVP groups (p > 0.05, ANOVA; Table 2; Fig 1). In addition, dPVDAVP (10-12 to 10-6.5 mol/L) only induced 9.6% ± 1.7% of maximal relaxation in the IMA rings precontracted with K+ (25 mmol/L, n = 7).


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  		Table 2. Maximal Relaxation and Effective Concentration Causing 50% Maximal Relaxation for Calcium-Channel Antagonists, Nitroglycerin, and [1-Deaminopenicillamine, 4-Valine, 8-D-Arginine] Vasopressin in Human Internal Mammary Artery Ringsa

 


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  		Fig 1. (A) Mean concentration (-log10 mol/L)-relaxation (% reversal of arginine vasopressin [10-8.5 mol/L]-induced contraction) curves for five relaxant agents in the human internal mammary artery (n = 11 for nifedipine [NIF], n = 10 for verapamil [VER], n = 9 for diltiazem [DIL], n = 10 for nitroglycerin [NTG], and n = 11 for selective V1 receptor antagonist [dPVDAVP]). The rings were taken from 9 to 11 patients in each group. (B) Mean concentration (-log10 mol/L)-relaxation (% reversal of 25 mmol/L K+-induced contraction) curve for dPVDAVP. Values are expressed as mean ± standard error of the mean. (*p = 0.000 versus dPVDAVP; two-way analysis of variance.)

 
Depression of contraction by pretreatment with calcium-channel antagonists, nitroglycerin, and [1-deaminopenicillamine, 4-valine, 8--arginine] vasopressin
Effect of calcium-channel antagonists
Pretreatment with nifedipine or verapamil (20 nmol/L, 200 nmol/L, or 30 µmol/L), or diltiazem (60 nmol/L, 600 nmol/L, or 30 µmol/L) did not change the maximal contraction (p > 0.05 versus control, 1-way ANOVA; Fig 2; Table 3). With regard to the EC50, only nifedipine at 30 µmol/L marginally increased the EC50 value for the AVP-mediated contraction (10-8.84 ± 100.07 mol/L versus 10-9.15 ± 100.94 lmol/L in control, p = 0.049, one-way ANOVA and Scheffe F test; Table 3).



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  		Fig 2. Mean concentration (-log10 mol/L)-contraction (percentage of 100 mmol/L K+-induced contraction) curves for three calcium-channel antagonists: nifedipine (NIF; A), verapamil (VER; B), and diltiazem (DIL; C). Four rings from each of 7 patients were randomly allocated to different treatments for each calcium-channel antagonist. Calcium-channel antagonists were added into organ baths 20 minutes before the start of AVP contraction. Values are expressed as mean ± standard error of the mean (maximal contraction, p = 0.749 for nifedipine [A], p = 0.062 for verapamil [B], and p = 0.504 for diltiazem [C]; one-way analysis of variance). No significant difference was found among the four curves of each drug by two-way analysis of variance.

 

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  		Table 3. Inhibitory Effect of Relaxant Agents on Maximal Contraction and Effective Concentration Causing 50% Maximal Contraction to Vasopressin in Human Internal Mammary Artery Ringsa

 
Effect of nitroglycerin
Pretreatment with NTG (10-7, 10-6, or 10-4.5 mol/L) did not significantly change the maximal contraction and EC50 values for the AVP-mediated contraction (p > 0.05 versus control, ANOVA; Table 3; Fig 3). Only NTG at 10-6 mol/L significantly depressed the AVP-induced contraction at 10-10 mol/L from 15% ± 6.4% (control) to 0.5% ± 0.3% (p = 0.04; 95% confidence interval, 0.5% to 28.5%; one-way ANOVA; Fig 3).



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  		Fig 3. Mean concentration (-log10 mol/L)-contraction (percentage of 100 mmol/L K+-induced contraction) curves for nitroglycerin (NTG). Four rings from each of 7 patients were randomly allocated to four groups. Nitroglycerin (10-7, 10-6, 10-4.5 mol/L, or vehicle) was added 10 minutes before the start of arginine vasopressin (AVP) contraction. Values are expressed as mean ± standard error of the mean. (*p = 0.04 for nitroglycerin [10-6 mol/L] versus control; p = 0.394 for nitroglycerin among the four curves by one-way analysis of variance.)

 
Effect of [1-deaminopenicillamine, 4-valine, 8--arginine] vasopressin
Pretreatment with dPVDAVP did not significantly change the AVP-mediated maximal contraction (p > 0.05 versus control, one-way ANOVA; Table 3). However, regarding the EC50, pretreatment with dPVDAVP at 10-8 mol/L increased the EC50 from 10-9.24 ± 100.16 mol/L (control) to 10-8.6 ± 100.1 mol/L (p = 0.009), whereas the EC50 was increased by dPVDAVP at 10-7 mol/L to 10-7.8 ± 100.07 mol/L (p = 0.000). In addition, pretreatment with dPVDAVP at 10-6 mol/L increased the EC50 to 10-6.86 ± 100.12 mol/L (p = 0.000; Table 3; Fig 4). Furthermore, the contractile response curves in dPVDAVP groups of 10-7 and 10-6 mol/L were significantly changed (p = 0.035 for 10-7 mol/L; 95% confidence interval, 100.03 to 100.86 mol/L; p = 0.000 for 10-6 mol/L; 95% confidence interval, 100.31 to 101.14 mol/L versus control; two-way ANOVA; Fig 4).



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  		Fig 4. Mean concentration (-log10 mol/L)-contraction (percentage of 100 mmol/L K+-induced contraction) curves for the selective V1 receptor antagonist [1-deaminopenicillamine, 4-valine, 8-D-arginine] vasopressin (dPVDAVP). Four rings from each of 6 patients were allocated to four groups. [1-Deaminopenicillamine, 4-valine, 8-D-arginine] vasopressin (10-8, 10-7, 10-6 mol/L, or vehicle) was added into the organ bath 20 minutes before the start of arginine vasopressin (AVP) contraction. Values are expressed as mean ± standard error of the mean. (*p < 0.05, **p < 0.001 versus control curve; one-way analysis of variance; p = 0.491 for dPVDAVP [10-8 mol/L], *p = 0.035 for dPVDAVP [10-7 mol/L], **p = 0.000 for dPVDAVP [10-6 mol/L] versus control; by two-way analysis of variance.)

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
The present study demonstrated that (1) CCA had limited effect on AVP-mediated contraction in human IMA; (2) NTG almost fully abolished the AVP contraction, but it has little depressing effect when used before the AVP-mediated contraction; and (3) dPVDAVP completely relaxed the AVP-mediated contraction and had a potent and specific depressing effect on the AVP-mediated contraction when used as a prophylactic agent.

In our previous studies we found that CCA had a potent spasmolytic effect on the vasoconstriction through the voltage-operated channels, such as in the K+-induced vasoconstriction [10, 12], but had little relaxant effect on the contraction through the receptor-opened channels, such as in the norepinephrine-induced, U46619-induced, or endothelin-induced contraction [10, 13, 14]. It has been found that AVP exerts smooth muscle contraction mainly through the V1 receptor [5, 19], and the inward calcium current was mainly through the receptor-operated calcium-permeable channel, which was possibly controlled by the intracellular enzymatic pathways and second messenger systems [20]. Regarding human vessels, AVP-mediated contraction in the mesenteric artery [21] and the saphenous vein [5] was reportedly not affected by nifedipine, indicating that voltage-operated channels (L-type calcium channels) may not be involved in these vessels. However, in the present study, we found in the human IMA, that three representative prototypes of CCA (nifedipine, verapamil, and diltiazem) had approximately one fifth of full relaxation on AVP-mediated contraction. In addition, the sensitivity of the IMA to AVP was decreased after nifedipine pretreatment at 10-4.5 mol/L (EC50 increased 2.1-fold higher, p = 0.049). This indicates that the L-type calcium channel may be partially involved in the AVP-mediated contraction in human IMA. The mechanism may be explained by a recent study [22] that demonstrated that calcium antagonists (nifedipine and nicardipine) only partly inhibited the inward calcium current through the block of L-type calcium channels in rat aortic smooth muscle [22]. Our results imply that CCA only have a marginal effect in the clinical setting in inhibition of the AVP-mediated vasoconstriction.

As a nitrovasodilator, NTG exerts its relaxing effect on vessels through the release of nitric oxide, which then triggers the rapid sequestration of initially raised Ca2+ from the smooth muscle cells by stimulating the initiation and rise of cyclic guanosine 5'-monophosphate in smooth muscle cells [23]. The potent spasmolytic effect of NTG against U46619, endothelin, potassium, and phenylephrine has been demonstrated repeatedly in our previous studies [10, 13, 14]. In the present study, we found that AVP-mediated vasoconstriction in human IMA was abolished by NTG. However, pretreatment with NTG was observed to have no depressing effect on AVP-mediated contraction. Similar results indicating that NTG had no prophylactic effect against vasoconstrictors have been observed in our previous studies [10, 14] as well as in the studies by others [24]. This phenomenon has been characterized as tachyphylaxis (NTG tolerance). The mechanisms responsible for the NTG tolerance are usually classified into two categories: one is pseudotolerance [25], which may be caused by the neurohumoral mechanism opposing nitric oxide–mediated vascular relaxation, and the other is true tolerance [24, 26]. In the present study, human IMA rings were studied in the organ bath, and therefore pseudotolerance may be excluded. Regarding true tolerance, two main reasons may be responsible. First, because of the short duration of the effect of NTG (1 to 4 minutes), the short-term increase in cyclic guanosine 5'-monophosphate may well be terminated before the increase in Ca2+ entry current by the vasoconstrictor stimulus [10]. Second, pretreatment with NTG in the organ bath may predispose rapid tolerance, perhaps mainly owing to the rapid development of impaired bioconversion of NTG to 1,2-dinitroglycerin (1,2-GDN) in human IMA [26].

Endogenous AVP has recently been accepted as one of contributing factors in essential hypertension in African-Americans [27], and the selective V1 receptor antagonist is now regarded as a potential antihypertension agent because it has significant hypotensive effect in hypertensive blacks [28]. The present study found that dPVDAVP, a highly selective V1 receptor antagonist, abolished the contraction in human IMA rings precontracted with AVP. Moreover, preincubation with dPVDAVP had a dramatically depressing effect on AVP-mediated contraction with respect to significantly decreased sensitivity (increased EC50; Table 3; Fig 4). This strongly indicates that dPVDAVP is a potent antagonist of AVP. Our observation is in agreement with other reports [19]. In addition, the present study also found that K+-induced contraction was only slightly relaxed by dPVDAVP (10-12 to 10-4.5 mol/L), which suggests the selective effect of dPVDAVP.

At this stage, the strategy to use specific AVP antagonists has not been established regarding the indication of administration. This is because of the complexity of the clinical situation between the use of AVP to treat vasodilatory shock and the concern that AVP may contract arterial grafts. However, the present study provides a scientific basis for future establishment of such indication.

In conclusion, AVP-mediated vasoconstriction in human IMA is only marginally engaged through the voltage-operated channels (L-type calcium channels) but acts mainly through receptor-opened channels. Thus, the use of CCA might have limited effects on AVP-related vasospasm. Selective V1 receptor antagonists may provide potent and specific spasmolytic effects in either prophylaxis or treatment. Nitroglycerin may be effective in treatment but has little effect on prophylaxis. These results may have important clinical implications in AVP-related perioperative vasospasm in human IMA.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
The work described in this paper was supported by the Providence St. Vincent Medical Foundation, Portland, OR, and grants from the Research Grants Council of the Hong Kong Special Administrative Region (Project Nos. CUHK7246/99 M and CUHK4127/01 M), China. The technical assistance of the surgical team and of Kay McCantz and other nurses in the Cardiac Operating Room, Providence St. Vincent Hospital, are gratefully acknowledged. Doctor Wei is on a Starr-He international Postdoctoral Fellowship established by the Providence St. Vincent Medical Foundation.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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