Asaad, A., Kakey, I., Awez, D., Mhamadsalih, M. (2023). In vitro study of the relaxant effect of doxazosin in the activity of smooth muscles in isolated goat renal artery. , 37(4), 781-788. doi: 10.33899/ijvs.2023.136609.2597
Aveen M. Asaad; Ismail S. Kakey; Dawan J. Awez; Mehri M. Mhamadsalih. "In vitro study of the relaxant effect of doxazosin in the activity of smooth muscles in isolated goat renal artery". , 37, 4, 2023, 781-788. doi: 10.33899/ijvs.2023.136609.2597
Asaad, A., Kakey, I., Awez, D., Mhamadsalih, M. (2023). 'In vitro study of the relaxant effect of doxazosin in the activity of smooth muscles in isolated goat renal artery', , 37(4), pp. 781-788. doi: 10.33899/ijvs.2023.136609.2597
Asaad, A., Kakey, I., Awez, D., Mhamadsalih, M. In vitro study of the relaxant effect of doxazosin in the activity of smooth muscles in isolated goat renal artery. , 2023; 37(4): 781-788. doi: 10.33899/ijvs.2023.136609.2597

In vitro study of the relaxant effect of doxazosin in the activity of smooth muscles in isolated goat renal artery

Iraqi Journal of Veterinary Sciences
Article 2, Volume 37, Issue 4, October 2023, Pages 781-788    PDF (945.24 K)
Document Type: Research Paper
DOI: 10.33899/ijvs.2023.136609.2597
Authors
Aveen M. Asaad* 1; Ismail S. Kakey* 2; Dawan J. Awez* 3; Mehri M. Mhamadsalih* 1
1Department of Medical Laboratory Technology, Koya Technical Institute, Erbil Polytechnic University, Erbil, Iraq
2Department of Biology, College of Science and Health, Koya University, Erbil, Iraq
3Department of Surgery, College of Medicine, Koya University, Erbil, Iraq
Abstract
Doxazosin is a competitive, short-acting, selective alpha 1-adrenoceptor antagonist. Selective alpha 1-blockers dilate blood vessels in the veins and arteries. The specificity for alpha-adrenoreceptors causes the smooth muscle of the blood vessels to relax. The findings of the recording and analysis demonstrate that doxazosin generates an endothelium-dependent relaxation of renal artery rings that had been pre-contracted with a high amount of KCl (60 mM) or phenylephrine (PE) (10-5 M). Additionally, doxazosin shows strong inhibitory effects on PE and weaker effects on contractions induced by KCl. Pre-incubating renal artery rings with 4-aminopyridine (4-AP), indomethacin, potassium (K+) channels blocker (TEA), barium chloride (BaCl2), prostaglandin I2 (PGI2) inhibitor (Indomethacin), and nitric oxide (NO) synthase inhibitor (L-Name), significantly affects the relaxation brought on by doxazosin. Contrarily, neither glibenclamide (GLIB) nor clotrimazole, show any effect on the relaxation caused by doxazosin. Doxazosin’s role suggests that a Ca++ channel-blocking mechanism has a relaxing impact on the smooth muscles of the renal artery. The relaxing effect of doxazosin is thus concluded from these findings to involve both potassium and calcium channels, potentially through the blockage of KV, KCa, KIr, endothelium/NO, PGI2, and voltage-dependent calcium channels.

Highlights
  1. Isolation renal artery from freshly slaughtered goat in Koya slaughter house.
  2. The vascular reactivity in isolated renal artery recorded by organ bath.
  3. Different doses of doxazosin have relaxant effect in the goat isolated renal artery precontracted by PE and KCl.
  4. The vasorelaxation effect of doxazosin is mediated via enhancement of opening potassium channel.
Keywords
Doxazosin; Renal artery; Smooth muscle activity
Full Text

Introduction

 

Doxazosin is a competitive, short-acting, selective alpha1-adrenoceptor antagonist (1). It is the second alpha1-blocker approved by the Food and Drug Administration (FDA) for the treatment of symptomatic Benign Prostatic Hyperplasia (BPH) (2,3). Selective alpha1-blockers act as vasodilators, both on arteries and veins. The specificity of alpha-adrenoreceptors is that it induces relaxation of the vascular smooth muscle (4,5). Also, the selective alpha1A,1D-adrenergic receptor antagonist improves stone passage rates in patients with distal ureteral stones (6,7). Various a1-AR antagonists that are available in clinics, e.g., alfuzosin, doxazosin, tamsulosin, and silodosin, exhibit inhibitory effects on contractions in isolated ureters of a variety of species (8-10), including humans (11,12). Results obtained from randomized controlled trials suggest that a1-AR antagonists may be used in patients to facilitate the passage of ureter stones (13,14). Doxazosin treatment in rats increased blood flow to the bladder and reduced the severity of the response to partial outlet obstruction (15). Alpha-blockers in MET have a proven role to promote stone passage and reduce the need for minimally invasive surgery for distal ureteral stones (16). Medical expulsive therapy (MET) is defined as the use of medication to facilitate ureteral stone passage before surgical intervention. The two classes of medications generally accepted for use as medical expulsive therapy are alpha-blockers and calcium channel blockers (17). Currently, the two most common drug classes used in medical expulsive therapy are calcium channel blockers and α1- adrenoceptor antagonists, and both are thought to act by inducing relaxation of the smooth muscle in the most common location of stone formation, the distal ureters, and the pelvic-ureteric junction in order to allow stone passage to the bladder (18). The α1- receptor antagonists inhibit basal tone and decrease peristaltic frequency and amplitude. Consequently, intraurethral pressure might decrease and fluid transport might increase, according to some studies (19). Recent studies implicated the α -adrenoceptor as the mediator of prostate smooth muscle contraction (3).

This current study aims to provide a helpful guide to further understand the underlining mechanisms of doxazosin vascular actions, and its use as medication or stone passing by testing it on a goat’s renal smooth muscle cells with emphases on the role of endothelium/NO, PGI2 and EET, Ca++ and K+ channels in its relaxant effects.

 

Materials and methods

 

Ethical approve

Renal artery samples collected from freshly slaughtered goat in Koya slaughter house in Koya city, Iraq. The technique and research methodology of the research approved by Koya technical institute/ Erbil polytechnic university. Of course, we did not any experimental animals in this research. By approval letter with no. 4161 in 20/10/2022.

 

Goat renal artery

This research was carried out at Health and Science Research Centre, Koya University. Forty male goats' renal arteries are employed throughout this investigation, and after they are slaughtered and weighed nearly 20kg with the age ranging 12-18 months, at Koya slaughterhouse, their kidneys are promptly collected. Then, they were submerged in a freshly made Kreb's solution at 37°C, the which has a pH of 7.4, and is exposed to the air with 95% O2 and 5% CO2 (17). The stock solution of doxazosin (Abcam, UK, ab120754), was prepared by dissolving 0.4515 gm of doxazosin in 1 ml of 0.9% NaCl. The solution was kept in the refrigerator and warmed to 37°C just before use. From the stock solution, the necessary serial dilution was made using a 0.9% NaCl solution.

 

Renal artery preparation

 The isolated renal artery was cleared of adhering fat and blood. Then, the dissected artery was cut into several rings (2-4 mm) in length and kept in the physiological saline before starting the experiments. To evaluate the vascular reactivity in the isolated renal artery (20). To measure the isometric tension of the isolated renal artery rings, two stainless steel wires were carefully inserted into the lumen of the artery rings; one of them was attached to a glass organ bath, and the other wire was connected to a force transducer, coupled to the trans bridge amplifier, and operated by an AD Instrument Power Lab 26T Data Acquisition system with a computer running LabChart Version8 chart software.

 

Data record by organ bath

The temperature of the organ bath was fixed to 37°C before the experiment started, and it was filled with double-distilled water (60-90 min), followed by the addition of (10 ml) of Kreb’s solution (in mM/L: 118 NaCl, 4.7 KCl, 25 NaHCO3, 1.2 KH2PO4, 1.2 MgSO4, 2.4 CaCl2, 11 Glucose, and 0.03 EDTA) or Free Calcium Kreb's solution to each organ bath channel (18,21). The preparation was oxygenated continuously with (95% O2 and 5% CO2). As for temperature of the solution inside the organ bath, it was maintained at 37 °C by circulating water through a water jacket from a circulating water bath set at 37 °C (Thermo circulator LabTech DAIHAN LABTECH CO., LTD.). The primary tension was set at (2 gm) weight. Renal artery rings were given 1 to 1.5 hours to equilibrate, with buffer solution changes every (15 min). KCl was used to ensure the prepared artery segments' functional integrity (60 mM) (22), and a standard percentage contractile response was employed with the largest contraction produced being taken into account. After the maximum contraction by KCl was reached to plateau, the renal artery rings were washed and restabilized at the optimum tension for at least (30 min) before applying any vasoactive substances (23). Constructing concentration-response curves (CRCs) for PE (1 10-5 M) and KCl (60 mM) against induced contraction was done after tension had isometrically stabilized before the studies could begin.

 

Experimental procedure

The experimental process entails observing the normal mechanical activity of the smooth muscles in the renal arteries and examining the effects of potassium chloride (KCl), phenylephrine (PE), and free Ca++ Kreb's solution on the smooth muscles in the renal arteries of goats. Then, the role of endothelial nitric oxide (NO), prostaglandin I2 (PGI2), and EET in the association with vasorelaxation induced by different doses of the doxazosin (1×10-3 -10-8 M) was studied, then followed by incubating intact renal artery rings for (10 min) separately with each of NO synthase inhibitor (L-Name (3×10-4 M)), PGI2 inhibitor (Indomethacin (3×10-5 M)) and EET (Clotrimazole (3×10-5 M)) and contracted with PE (1×10-5 M). Also, the roles of Potassium channels (K+ channel) and calcium channels (Ca++ channel) in the development of vasorelaxation induced by different doses of doxazosin (1×10-3 - 10-8 M), were also studied by preincubating the renal artery rings separately with each of the following potassium channel blockers, KCa channel blocker (TEA (1 mM)), KATP channel blocker (GLIB (1×10-5 M)), KIR channel blocker (BaCl2 (1mM)) and KV channel blocker (4-AP (1 mM)), and contracted with PE (1×10-5 M). Then, in the free Ca++ solution, the a1-AR antagonist doxazosin, Doxa. 1×10-5 and 3×10-5 M, were used to test the role of the Ca++ channels.

 

Statistical analysis

The data of this study were expressed as M±SE. The effective mean concentrations (IC50 and EC50) were presented as geometric means with (95% confidence intervals) and the potency values were described as the negative logarithms (-log IC50 = pIC50 and -logEC50 = pEC50) of the mean of individual values for each tissue. Two-way analysis of variance (Two-way ANOVA) (24), backed by Sidak's multiple comparisons test, was used to compare the means of the two groups, and non-linear regression was employed to analyze the concentration-response curve. A Probability of less than 0.05 (p˂ 0.05) was considered statistically significant, in all figures and tables, the symbols *, **, ***, and **** indicate that the difference between means is significant at 0.05, 0.01, 0.001, and ˂ 0.0001 levels, respectively. GraphPad Prism software for Windows, version 7.04, was used to construct all the graphs, calculations, and statistical analyses (GraphPad Software, USA). The maximal amplitude response obtained in concentration effects for the relaxant substance was referred to as the maximum effect of relaxation (Emax.) (18).

 

Results

 

Effect of doxazosin on renal artery rings

The doxazosin (1×10-8 - 1×10 -3 M) exerts a relaxing action on contractions produced by KCl and PE, with the PE having a stronger relaxing effect (10-5 M) compared to its relaxing impact on precontracted renal artery rings treated with KCl (60 mM) (Figure 1). The pIC50, (Log IC50 of CI 95%) and Emax are shown in (Table1). Doxazosin produced a highly effective inhibitory action on PE-and KCl-induced contractions in renal artery rings with a pIC50 of 7.72 mg/mL, (Log IC50 of CI 95% between -8.027 to -7.342) and 7.879 mg/mL (Log IC50 of CI 95% between - 8.199 to -7.479), respectively. The Emax (%) ring contractions in the renal arteries caused by PE dropped to only 96.245 ± 3.566 %, while in renal artery rings precontracted with KCl, the increased contraction tone showed that the relaxation response was reduced. 86.8 ± 4.203%.

 

 

 

Figure 1: Cumulative dose-response curve of the effects of doxazosin on PE (10-5) and KCl (60mM) precontracted renal artery rings. Left panel: lines represent 4 parameters logistic curve, which calculate the variable, pIC50 and Emax

 

Table 1: The pIC50, Log IC50 of CI 95%, and Emax (%) ± SEM for the effects of doxazosin on PE- and KCl precontracted renal artery rings

 

Parameters

Doxazosin + PE

Doxazosin + KCl

pIC50

7.72

7.879

Log IC50 of CI 95%

-8.027 to -7.432

-8.199 to -7.479

Emax (%) Mean±SE

96.245±3.566

86.8 ±4.203

pIC50: Potency value, Log IC50 of CI 95%: Geometric mean with 95% confident interval, Emax: Maximum effect of relaxation

 

Role of potassium channel in the vasorelaxant effect of doxazosin

The rings have been preincubated for 10 minutes separately with: TEA (1mM), Glib (10-5), BaCl2 (1mM), and 4-AP (1mM), which are the blockers of KCa, KATP, KIR, and KV channels, to study the involvement of potassium channels in the vasorelaxant effect of doxazosin in the renal artery rings. They were observed to have relaxing effects. Dose-response curves for doxazosin's effects on PE-induced contractions and its pre-incubation with potassium channel blockers are displayed in (Figures 2, 3, 4, and 5). Pre-treatment of renal artery rings with Glib remained unaltered, while 4-AP and TEA revealed a slight shift to the right and BaCl2 significantly shifted to the right. doxazosin concentrations (10-8 to 10-3 M) caused a potent relaxation on PE (10 -5M) precontracted the goat renal artery rings. Table2 shows, the pIC50, (LogIC50 of CI 95%) and Emax for the effect of K+ channel inhibitors on the relaxant response to doxazosin in the rings. Pre-treatment of renal artery rings with 4-AP, TEA, and BaCl2 significantly reduced the relaxation, with pIC50 7.107±0.2629 mg/ml, 6.884±0.1504 and 6.606±0.1527 (LogIC50 of CI 95% between -7.916 to -5.993, -7.227 to -6.471 and -7.028 to -6.327), and also, it reduced the percentage of relaxation to 73.13± 2.083 %, 91.939±1.948 and 81.897±1.024, compared to the control, which was 96.245±2.566 %.

 

 

 

Figure 2: Cumulative dose-response curves of the vasorelaxant effects of Doxa. On control and preincubated renal artery rings with 4AP (1mM), precontracted with PE (1×10-5 M). Left panel: lines represent 4 parameters logistic curve which calculate the variable, pIC50 and Emax.

 

 

 

Figure 3: Cumulative dose-response curves of the vasorelaxant effects of doxazosin on control and preincubated renal artery rings with BaCl2 (1mM), precontracted with PE (1×10-5 M). Left panel: lines represent 4 parameters logistic curve, which calculate the variable, pIC50 and Emax.

 

 

 

Figure 4: Cumulative dose-response curves for the vasorelaxant effects of doxazosin on control and preincubated renal artery rings with TEA (1mM), precontracted with PE (1×10-5 M). Left panel: lines represent 4 parameters logistic curve, which calculate the variable, pIC50 and Emax.

 

 

 

Figure 5: Cumulative dose-response curves for the vasorelaxant effects of doxazosin on control and preincubated renal artery rings with Glib (1mM), precontracted with PE (1×10-5 M). Left panel: lines represent 4 parameters logistic curve, which calculate the variable, pIC50 and Emax.

 

Role of endothelium/NO, PGI2, and EET in the vasorelaxant effect of doxazosin

Comparing renal artery rings preincubated with L-Name and slightly with Indomethacin to control rings, the percentage of relaxation, pIC50, and (LogIC50 of CI 95%) for the doxazosin-induced relaxant response were very significant (Figures 6, 7 and 8), with pIC50 5.935 M, and (LogIC50 of CI 95% between -6.387 to -5.476) and 6.814M (withLogIC50 of CI 95% between -7.267 to -6.245) and Emax were 84.412±0.888 and 70.95±1.555, respectively. Although pre-treatments with Clotrimazole seemed to no effect on the relaxation brought on by doxazosin (Table 2).

 

 

 

Figure 6: Cumulative dose-response curve for the vasorelaxant effects of doxazosin on control and preincubated renal artery rings with L-Name (3 ×10-5 M), precontracted with PE (10-5 M). Left panel: lines represent 4 parameters logistic curve, which calculate the variable, pIC50 and Emax.

 

 

 

Figure 7: Cumulative dose -response curve for the vasorelaxant effects of doxazosin on control and preincubated renal artery rings with Indomethacin (3×10-5 M), precontracted with PE (10-5 M). Left panel: lines represent 4 parameters logistic curve which calculate the variable, pIC50 and Emax.

 

 

 

Figure 8: Cumulative dose -response curve for the vasorelaxant effects of doxazosin on control and preincubated renal artery rings with Clotrimazole (3×10-4 M), precontracted with PE (10-5 M). Left panel: lines represent 4 parameters logistic curve which calculate the variable, pIC50 and Emax.

 

Table 2: The pIC50, Log IC50 of CI 95%, and Emax (%) ± SEM for the effects of doxazosin after incubation of renal artery with K+ channel blockers, clotrimazole, indomethacin, and L-Name

 

Groups

No.

pIC50

LogIC50 of CI 95%

Emax (%) Mean ± SE

Control

4

7.72±0.1268

-8.027 to -7.342

96.245±2.566

TEA

4

6.884±0.1504

-7.227 to -6.471

91.939±1.948**

Glib

4

7.067±0.1714

-7.57 to -6.568

76.97±2.04

BaCl2

6

6.606±0.1527

-7.018 to -6.317

81.897±1.024***

4AP

5

7.107±0.2629

-7.916 to -5.993

73.13±2.085*

Clotrimazole

4

6.618±0.138

-7.012 to -6.152

82.312±0.953

Indomethacin

6

6.814±0.1891

-7.267 to -6.2445

70.95±1.555***

L-Name

6

5.935±0.1741

-6.387 to-5.476

84.412±0.888***

pIC50: Potency value, Log IC50 of CI 95%: Geometric mean with 95% confident interval, Emax: Maximum effect of relaxation

 

Role of Ca2+ channels in doxazosin: The vasorelaxant effect of CaCl2-induced contraction

Both doxazosin dosages (1×10-5 and 3×10-5 M) produced highly significant (P<0.0001) vasoconstriction effects on CaCl2-induced dose-dependent contraction in renal artery rings pre-incubated with doxazosin as compared to the control (Figure 9). The pEC50, (LogEC50 of CI 95%) and the maximum contraction are shown in (Table3). Both doxazosin doses (1×10-5 and 3×10-5 M) showed highly significant effects on CaCl2 contracted goat artery rings with pEC50 2.386 M (LogEC50 of CI 95% between -2.609 to -2.13) and 2.845 M (LogEC50 of CI 95% between -3.112 to -2.56), along with the greatest contraction (62.155 ± 5.499) and (53.346 ± 3.183), respectively.

 

 

 

Figure 9: Cumulative dose-response curves of CaCl2 in renal artery rings pre-incubated with different doses of doxazosin (1×10-5 mg/ml - 3×10-5 mg/ml). Left panel: lines represent 4 parameters logistic curve, which calculate the variable, pEC50 and Emax.

 

Table 3: The pEC50 (Log EC50 of CI 95%) and Emax (%) ± SEM for the effects of doxazosin and Nifedipine on preincubated renal artery rings with CaCl2

 

Parameters

Control

Doxazosin

0.01 M

0.03 M

No.

6

6

6

pEC50

3.442±0.2037

2.386±0.1107

2.845±0.1296

LogEC50 of CI 95%

-4.074 to -2.827

-2.609 to -2.13

-3.112 to -2.56

Emax (%) Mean ± SE

+61.402±2.318

62.155±5.499 ****

53.346±3.186****

pEC50: Potency value, Log EC50 of CI 95%: Geometric mean with 95% confident interval, Emax: Maximum effect of relaxation

 

Discussion

 

Effect of doxazosin's vasorelaxant on isolated renal artery rings

 This study is the first in-depth examination of how doxazosin relaxes the renal artery in a concentration-dependent approach. Several scientific studies examined the use of a1 A/D-selective alpha-blockers and demonstrated their advantages in improving stone removal. A recent study revealed that doxazosin produced a significant increase in maximum urinary flow rate (1). Doxazosin is a clinically effective α-adrenergic antagonist used in the treatment of symptomatic benign prostatic hyperplasia (BPH). Notwithstanding, the major therapeutic effect of the agent is believed to occur on the smooth muscle components of the prostate by reducing prostatic urethral resistance and thus improving emptying (15,25). The results of this study showed that doxazosin added cumulatively had a more relaxing effect on contractions brought on by PE than by KCl. With KCl-induced vasoconstriction, doxazosin's vasorelaxant effects became less effective. The constriction brought on by PE reduced the doxazosin-induced vasodilation, which is supported by Nickel (26), which states the effective phenylephrine concentration for a rabbit. Therefore, phenylephrine promotes maximal contraction and was chosen as the effective concentration used in the experiment. Karadeniz (27) showed that when PE binds to a1A-adrenoceptors, Phospholipase C is activated, which releases the second messenger IP3 and causes the release of calcium ions from IP3-sensitive stores. When calcium ions rise, there is a subsequent increase in [Ca2+]i as a result of Ca2+ being released from Ca2+-sensitive Ca2+ pools and increased Ca2+ entry through L-type.

 

The role of potassium channels in the doxazosin relaxing action

Pre-treatment of renal artery rings with potassium channel blockers, 4-AP, TEA, and BaCl2 showed significant enhancement in the vasorelaxant effect of doxazosin, while there were no changes in the vasorelaxation effect of doxazosin in pre-treated with Glib. The finding of the study disagrees with Eckert (28), which stated that TEA and BaCl2 did not affect biochanin-A-induced relaxation in the goat coronary arterial rings. While Brede (18) and Kumar (29) revealed that 4-AP has significant enhancement in renal artery relaxation. In addition, Novakovic (30) stated that BaCl2 has a significant effect on broncho dilators. Doxazosin's dose-dependent vasodilation with 4-AP, TEA, and BaCl2 was statistically proven in the current study's findings. These results demonstrate that the vasodilatory effects of doxazosin are mediated via a negative function of KV, KCa, and KIr channels.

 

The effect of doxazosin on relaxation is influenced by NO, PGI2, and EET    

Renal artery rings were pre-incubated with L-Name, indomethacin, or clotrimazole to investigate the roles of endothelium/NO, PGI2, and EET, the three key enzymes responsible for the release of relaxant substances in the vascular beds. The impact of doxazosin was then assessed. According to the current study's findings, doxazosin causes vasodilation in precontracted renal artery rings with PE, which is mediated by indomethacin, L-Name, but not by Clotrimazole. Otherwise, Clotrimazole has a significant effect when preincubated by herbal medicine, which acts as an alpha blocker (31,32). In addition, Hassan (33) revealed the role of PGI2, as a potent vasodilator substance, which mediated through activation of Adenylate Cyclase in VSMCs. Furthermore, the result of our study can be supported by Valero (34) and Kwon (35), which found that after treatment with L-NAME, the vasorelaxant effect was significantly diminished and relaxations on the endothelium-denuded rings were nearly entirely eliminated. We demonstrate a specific beneficial effect of doxazosin on endothelium-dependent vasodilation. This may be due to a direct effect on NO levels both by increasing nitric oxide synthase (NOS) activity, thus potentially enhancing NO synthesis, and also by reducing NO degradation. Conversely, the endothelial function may have been enhanced by the reduction in blood pressure per se rather than a specific action of doxazosin (36).

 

Role of Ca++ channel blockers in doxazosin relaxant effect

In the study, doxazosin considerably increased the rate of relaxation in renal artery rings. The smooth muscle is effectively relaxed by α1A-adrenoceptor blockers and Ca++ channel blockers. Doxazosin inhibits α-1A/1D receptors in the ureter and bladder, which prevents calcium from entering the cell and relaxes smooth muscle cells (37,38). Alpha antagonists, calcium channel blockers, and steroids have been demonstrated to improve the time to the ejection of distal ureteral stones in adults in several recent researches (39,40). Researchers have demonstrated that Ca++ channels allow the passage of extracellular calcium into the cell, restoring normal levels of ureteral peristalsis. Troxel (41) using human caliceal rings that demonstrate how calcium channel blockers can suppress the upper urinary tract's naturally occurring phasic-rhythmic activity. While α-1 adrenergic blockers decreased ureter muscle tone, calcium channel blockers decreased the degree of smooth muscle contractions and reduced ureter spasm (42,43).

 

Conclusion

 

The results of the current study revealed that different doses of doxazosin have relaxant actions in the goat isolated renal artery precontracted by PE and KCl. These effects may be countable for their uses as vasodilators and uses as medications for stone passing. Also, we can say the results is the first observation of this drug in the renal artery. Doxazosin also blocks potassium and calcium channels, possibly by inhibiting KV, KCa, KIr, endothelium /NO, PGI2, and voltage-dependent calcium channels. With these findings, we came to the conclusion that doxazosin can be utilized as a MET for ureteric stones.

 

Acknowledgment

 

We acknowledge all laboratory staffs at Health and Science Research Centre, Koya University that helped us to undertake this study, and all veterinarian staff in slaughter house.

 

Conflict of interest

 

No conflict of interest to declare

References
  1. Kumar VL, Dewan S. Alpha adrenergic blockers in the treatment of benign hyperplasia of the prostate. Int Urology Nephrol. 2000;32:67-71. DOI: 1023/a:1007108201320
  2. Lepor H. The evolution of alpha-blockers for the treatment of benign prostatic hyperplasia. Rev Urol. 2006;8:S3. [available at]
  3. Lepor H. Alpha blockers for the treatment of benign prostatic hyperplasia. Rev Urol. 2007;9:181. [available at]
  4. Kaplan M. Alpha-blockers in the treatment of hypertension. Nefrologia. 2000;20:35. [available at]
  5. Ali IH, Abdullah QH, Al-Habib OA. Bronchodilator activity of ethyl acetate extract of Nigella sativa, Iraqi J Vet Sci. 2021;35(1):145-149. DOI: 33899/ijvs.2020.126455.1333
  6. Dellabella M, Milanese G, Muzzonigro G. Efficacy of tamsulosin in the medical management of juxtavesical ureteral stones. J Urol. 2003;170:2202-2205. DOI: 1097/01.ju.0000096050.22281.a7
  7. Nakada SY, Coyle TL, Ankem MK, Moon TD, Jerde TJ. Doxazosin relaxes ureteral smooth muscle and inhibits epinephrine-induced ureteral contractility in vitro. Urol. 2007;70(4):817-21. DOI: 1016/j.urology.2007.06.002
  8. Kobayashi S, Tomiyama Y, Hoyano Y, Yamazaki Y, Kusama H, Itoh Y, Kubota Y, Kohri K. Gene expressions and mechanical functions of α1-adrenoceptor subtypes in mouse ureter. World J Urol. 2009;27:775-780. DOI: 1007/s00345-009-0396-y
  9. Kobayashi S, Tomiyama Y, Hoyano Y, Yamazaki Y, Kusama H, Itoh Y, KubotaY, Sasaki S, Kohri K. Mechanical function and gene expression of α1-adrenoceptor subtypes in dog intravesical ureter. Urol. 2009;74:458-462. DOI: 1016/j.urology.2009.01.009
  10. Villa L, Buono R, Fossati N, Rigatti P, Montorsi F, Benigni F, Hedlund P. Effects by silodosin on the partially obstructed rat ureter in vivo and on human and rat isolated ureters. Br J Pharmacol. 2013;169:230-238. DOI: 1111/bph.12123
  11. Rajpathy J, Aswathaman K, Sinha M, Subramani S, Gopalakrishnan G, Kekre NS. An in vitro study on human ureteric smooth muscle with α1-adrenoceptor subtype blocker, tamsulosin. BJU Int. 2008;102:1743-1745. DOI: 1111/j.1464-410X.2008.08022.x
  12. Sasaki S, Tomiyama Y, Kobayashi S, Kojima Y, Kubota Y, Kohri K. Characterization of α1-adrenoceptor subtypes mediating contraction in human isolated ureters. Urol. 2011;77(3):762e13-e17. DOI: 1016/j.urology.2010.09.034
  13. Hollingsworth JM, Rogers MA, Kaufman SR, Bradford TJ, Saint S, Wei JT, Hollenbeck BK. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet. 2006;368(9542):1171-9. DOI: 1016/S0140-6736(06)69474-9
  14. Seitz C, Liatsikos E, Porpiglia F, Tiselius HG, Zwergel U. Medical therapy to facilitate the passage of stones: What is the evidence?. Eur Urol. 2009;56(3):455-71. DOI: 1016/j.eururo.2009.06.012
  15. Das AK, Leggett RE, Whitbeck C, Eagen G, Levin RM. Effect of doxazosin on rat urinary bladder function after partial outlet obstruction. Neurourol Urodyn. 2002;21(2):160-6. DOI: 1002/nau.10045
  16. Çelik S, Akdeniz F, Yildirim MA, Bozkurt O, Bulut MG, Hacihasanoglu ML, Demir O. Tadalafil versus alpha blockers (alfuzosin, doxazosin, tamsulosin and silodosin) as medical expulsive therapy for< 10 mm distal and proximal ureteral stones. Arch Ital Urol Androl. 2018;90(2):117-22. DOI: 4081/aiua.2018.2.117
  17. Al-Zuhairy MT. Using T cell lymphokines of hyperimmunized chickens with Salmonella pullorum to protect layer hens against Salmonella pullorum Iraqi J Vet Sci. 2022;36(I):223-227). DOI: 10.33899/ijvs.2022.136020.2555
  18. Brede CM, Hollingsworth JM, Wolf JS. Medical expulsive therapy (MET) for ureteral calculi in the real world: targeted education increases use of MET and improves patient outcomes. J Urol. 2009;181(4S):520. DOI: 1016/S0022-5347(09)61468-3
  19. Asaad AM, Kakey IS. The relaxant effect of tamsulosin in the vascular reactivity of goat isolated renal artery. J Appl Res. 2019;4(2):106-19. DOI: 24017/science.2019.ICHMS.11
  20. Campschroer T, Zhu X, Vernooij RW, Lock TM. α‐blockers as medical expulsive therapy for ureteric stones: A cochrane systematic review. BJU Int. 2018;122(6):932-45. DOI: 1002/14651858.CD008509.pub3
  21. Al-Habib OA, Shekha MS. Vasorelaxant effect of aqueous extract of Crataegus azarolus aronia and quercetin on isolated albino rat’s thoracic aorta. J Duhok Univ. 2010;13:1-9. [available at]
  22. Shin IW, Sohn JT, Kim HJ, Kim C, Lee HK, Chang KC, Chung YK. Etomidate attenuates phenylephrine-induced contraction in isolated rat aorta. Can J Anaesth. 2005;52(9):927-34. DOI: 1007/BF03022053
  23. Qu Z, Zhang J, Gao W, Chen H, Guo H, Wang T, Li H, Liu C. Vasorelaxant effects of Cerebralcare Granule® are mediated by NO/cGMP pathway, potassium channel opening and calcium channel blockade in isolated rat thoracic aorta. J Ethnopharmacol. 2014;155(1):572-9. DOI: 1016/j.jep.2014.05.062
  24. Mahmood MB. A comparison between ketamine-xylazine and ketamine-midazolam or all of them to induce balance anesthesia in rabbits. Iraqi J Vet Sci. 2022;36(2):499-506. DOI: 33899/ijvs.2021.130618.1852 
  25. Ahmed AH, Maulood IM. The roles of potassium channels in contractile response to urotensin-II in mercury chloride induced endothelial dysfunction in rat aorta. Iran J Vet Res. 2018;19(3):208. [available at]
  26. Nickel JC, Sander S, Moon TD. A meta‐analysis of the vascular‐related safety profile and efficacy of α‐adrenergic blockers for symptoms related to benign prostatic hyperplasia. Int J Clin Pract. 2008;62(10):1547-59. DOI: 1111/j.1742-1241.2008.01880.x
  27. Karadeniz A, Pişkin İ, Eşsiz D, Altintaş L. Relaxation responses of trigonal smooth muscle from rabbit by alpha 1-adrenoceptor antagonists alfuzosin, doxazosin and tamsulosin. Acta Vet Brno. 2008;77(1):81-88. DOI: 2754/avb200877010081
  28. Eckert RE, Karsten AJ, Utz J, Ziegler M. Regulation of renal artery smooth muscle tone by α 1-adrenoceptors: Role of voltage-gated calcium channels and intracellular calcium stores. Urol Res. 2000;28:122-7. DOI: 1007/s002400050149
  29. Kumar T, Sharma M, Rana A, Lingaraju MC, Parida S, Kumar D, Singh TU. Biochanin-A elicits relaxation in coronary artery of goat through different mechanisms. Res Vet Sci. 2020;131:206-14. DOI: 1016/j.rvsc.2020.05.003
  30. Novakovic A, Pavlovic M, Milojevic P, Stojanovic I, Nenezic D, Jovic M, Ugresic N, Kanjuh V, Yang Q, He GW. Different potassium channels are involved in relaxation of rat renal artery induced by P 1075. Basic Clin Pharmacol Toxicol. 2012;111(1):24-30. DOI: 1111/j.1742-7843.2011.00855.x
  31. Asaad A, Ibraheem I. The vasorelaxant effect of Adiantum capillus-veneries extract in the vascular activity of goat’s isolated renal artery. Polytech J. 2022;12(1):67-78. [available at]
  32. Ahangari F, Farshbaf‐Khalili A, Javadzadeh Y, Adibpour M, Sadeghzadeh Oskouei B. Comparing the effectiveness of Salvia officinalis, clotrimazole and their combination on vulvovaginal candidiasis: A randomized, controlled clinical trial. J Obstet Gynaecol Res. 2019;45(4):897-907. DOI: 1111/jog.13918
  33. Hassan NA, Abdelfattah MA, Mandour YM, El-Shazly AM, Sobeh M, Mahmoud MF. Vasorelaxant effects of Syzygium samarangense (Blume) Merr. and LM perry extract are mediated by NO/cGMP pathway in isolated rat thoracic aorta. Pharmaceuticals. 2022;15(11):1349. DOI: 3390/ph15111349
  34. Valero MS, Nuñez S, Les F, Castro M, Gómez-Rincón C, Arruebo MP, Plaza MÁ, Köhler R, López V. The potential role of everlasting flower (Helichrysum stoechas Moench) as an antihypertensive agent: Vasorelaxant effects in the rat aorta. Antioxidants. 2022;11(6):1092. DOI: 3390/antiox11061092
  35. Kwon J, Choi YI, Jo HJ, Lee SH, Lee HK, Kim H, Moon JY, Jung SJ. The role of prostaglandin E1 as a pain mediator through facilitation of hyperpolarization-activated cyclic nucleotide-gated channel 2 via the EP2 receptor in trigeminal ganglion neurons of mice. Int J Mol Sci. 2021;22(24):13534. DOI: 3390/ijms222413534
  36. Courtney CH, McCance DR, Atkinson AB, Bassett J, Ennis CN, Sheridan B, Bell PM. Effect of the alpha-adrenergic blocker, doxazosin, on endothelial function and insulin action. Metabolism. 2003;52(9):1147-52. DOI: 1016/S0026-0495(03)00190-2
  37. Davenport K, Timoney AG, Keeley FX. A comparative in vitro study to determine the beneficial effect of calcium‐channel and α1‐adrenoceptor antagonism on human ureteric activity. BJU Int. 2006;98(3):651-5. DOI: 1111/j.1464-410X.2006.06346.x
  38. Sigala S, Dellabella M, Milanese G, Fornari S, Faccoli S, Palazzolo F, Peroni A, Mirabella G, Cunico SC, Spano P, Muzzonigro G. Evidence for the presence of α1 adrenoceptor subtypes in the human ureter. Neurourol Urodyn. 2005;24(2):142-8. DOI: 1002/nau.20097
  39. Aydogdu O, Burgu B, Gucuk A, Suer E, Soygur T. Effectiveness of doxazosin in treatment of distal ureteral stones in children. J Urol. 2009;182(6):2880-4. DOI: 1016/j.juro.2009.08.061
  40. Bhagat TS, Solanki P, Bhagat R, Gupta S. To study and evaluate the efficacy of alpha 1 a-d receptors antagonist tamsulosin. Santosh Univ J Health Sci. 2019;5(1):35-39. DOI: 18231/j.sujhs.2019.009 
  41. Troxel SA, Jones AW, Magliola L, Benson JS. Physiologic effect of nifedipine and tamsulosin on contractility of distal ureter. J Endourol. 2006;20(8):565-8. DOI: 1089/end.2006.20.565
  42. Omran MO, Bendary LA, Ibrahim DE, Kamel MA. Urolithiasis updated management guidelines in lower ureters. Eur J Mol Clin Med. 2021;8(3):4383-91. [available at]
  43. Srivastava VP, Pandey CP, Raza MA, Agarwal KK, Chauhan C. Effectiveness of alpha blockers+ corticosteroids in expulsion of ureteric stones: A clinical observation. Int J Med Sci Public Health. 2014;3(6):693-6. DOI: 5455/ijmsph.2014.180320143
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