INTRODUCTION
Cardiovascular disease is leading cause of death among Indians with important risk factors such as hyperlipidemia and diabetes.[12] It has been reported that endothelial dysfunction is characteristic features of diabetes and atherosclerosis, which further leads to impaired vasodilation, increased oxidative stress, inflammation, leukocyte adhesion and hyperpermeability, and endothelial cell senescence and finally responsible for the cardiovascular disease.[3456] Restoration of blood flow is exigent to maintain normal physiology of ischemic myocardium.[7] However, reperfusion after a prolonged period of ischemia induces ischemic reperfusion injury (I/R).[7] Moreover, controlled reperfusion is to prevent the further injury through briefs episodes of reperfusion and ischemia at the onset of reperfusion work against the ischemia-reperfusion injury is termed as ischemic postconditioning (IPOC).[8] It is already documented that both ischemic preconditioning (IPC) and IPOC induce threshold potential of myocardium to phosphorylation of PI-3K/Akt and its downstream mediators GSK-3β.[9]
Diabetes modulates cardioprotective potential of IPC and IPOC by impairment of PI-3k/Akt, STAT-3 signaling pathway.[910] It has been reported that diabetes mellitus abolished the cardioprotective potential of IPC through activation of GSK-3β and decreased of Nitric Oxide generation (NO).[91112]
Atrial natriuretic peptide (ANP) is a 28 amino acid residue isolated from rat and human atrial tissue.[1314] Natriuretic peptide exhibit natriuretic, diuretic, vasodilating and maintain the blood volume and blood pressure.[15] It has been also reported that ANP attenuates endoplasmic stress in experimental animal model.[16] Perfusion of ANP has been reported to induce the cardioprotection prior to reperfusion and at the time of reperfusion against the ischemic reperfusion injury.[17] It is interesting to note that ANP induce the cardioprotection by activating the PI-3K/Akt/Bad/Bcl2 signaling and nitric oxide (NO)-dependent mechanism against ischemic-reperfusion injury.[1718] Additionally, It has been reported that low plasma level of ANP is an independent risk factor for diabetes.[19] Therefore, the present study has been design to elucidate the role of ANP in abrogated cardioprotective effect of IPOC in diabetic rat.
METHODS
The experimental protocol was approved by Institutional Animal Ethical Committee (GLAIPR/CPCSEA/IAEC/2015/P.Col/R05) meeting was held on January 28, 2015, to approve animals used in this study. Thirty-six Wistar rats weighed (200–250g) of either sex. Six animals in each six groups were used in this study.
Drugs and chemicals
Alloxan monohydrate (120 mg/kg) (Sigma Aldrich, Bangalore, India) was dissolved in distilled water, and a single-dose used for hyperglycemia.[20] ANP (0.1 μM/L) (Sigma Aldrich, Bengaluru, India) and L-NAME (Nω-Nitro-L-arginine methyl ester hydrochloride) (100 μM/L) (Sigma Aldrich, Bangalore, India) were dissolved in Krebs–Henseleit solution (K-H) (Central Drug House, New Delhi, India).[21] All other analytical grade regents were always freshly prepared before use.
Induction of experimental diabetes mellitus
Experimentally, diabetes mellitus was induced in Wistar rat using single dose of Alloxan monohydrate (120 mg/kg; i.p.).[20] Serum glucose was estimated after 1 week of administration of alloxan monohydrate using ultraviolet (UV) spectrophotometer at 505 nm by using an enzymatic kit (Spam diagnostics Ltd., Surat, India). Serum glucose level (equal/more than 185 mg/dl) was considered as hyperglycemic. The animals were used for the experimental protocol after 6 weeks from given alloxan.
Isolated rat heart preparation
Heart from heparinized rats (500 IU, i. p.) were quickly excised and instantly mounted on Lagendorff's apparatus.[22] The heart was enclosed by a double-walled jacket, maintained temperature at 37°C. The isolated heart preparation was perfused retrogradely at a constant pressure of 80 mmHg, with Krebs–Henseleit (K-H) Buffer (Nacl 118 mM; Kcl 4.7 mM; Cacl2 2.5 mM; MgSO4.7H2O 1.2 mM; NaHCO325 mM; KH2PO41.2 mM; Glucose 11 mM) (Central Drug House, New Delhi, India). After 10 min of stabilization, 30 min of global ischemia was produced by blocking the inflow of K-H buffer solution. IPOC was induced by a brief episode of reperfusion and ischemia at onset of 120 min of reperfusion.[823] Coronary effluent was collected before ischemia, immediate and at 5 min for the estimation of lactate dehydrogenase (LDH), Creatine kinase-MB (CK-MB), and nitrite.[2425]
Assessment of myocardial injury
Myocardial infarct size was measured by triphenyltetrazolium chloride (TTC) staining technique.[26] The assessment of LDH and CK-MB were estimated using commercially available kits (Span Diagnostics Ltd. Surat, India), expressed in international per liter (IU/L).[2728]
Assessment of myocardial infarct size
The heart was removed from Langendorff's apparatus and put overnight at −4°C temp. Frozen ventricles were sliced into 1–2 mm thickness uniformly. The slices were incubated in TTC at 1% w/v at 37°C in 0.2M tris-chloride buffer for 30 min.[2529] The normal myocardium slice was stained brick red expressed as a normal, while the infarct portion remained unstained. The volume method was used for the estimation of myocardial infarct size.[30]
Nitrite estimation
Nitrite is a stable, highly reactive nitrogen intermediate formed by the breakdown of NO.[12] Nitrite concentrations used to conclude levels of NO production.[313233] Nitrite release in coronary effluent was estimated.[34] Greiss regent 0.5ml (1:1 solution of 1% sulfanilamide in 5% phosphoric acid and 0.1% N-(1-Naphthyl) ethylenediamine dihydrochloride in water) was mixed with 0.5 ml of coronary effluent. Nitrite estimation measured at 550 nm using UV spectrophotometer. Nitrite concentration was calibrated by reading of standard solution of sodium nitrite in K-H buffer.
Experimental protocol
A diagrammatic presentation of the experimental protocol is shown in Figure 1. In all groups, the isolated rat heart was perfused with K-H solution and allowed to stabilize for 10 min.
;)
Figure 1: Diagrammatic representation of experimental protocol. S, I, R, ANP, L-NAME Denotes Stabilization, Ischemia, Reperfusion, Atrial Natriuretic Peptide, Nω-Nitro-L-arginine methyl ester hydrochloride
- Group 1 (Sham Control; n = 6) – Isolated heart was perfused with K-H buffer solution, constantly for 200 min without subjecting to global ischemia
- Group 2 (Ischemia-Reperfusion Control; n = 6) – Stabilized for 10 min after that, isolated rat heart was subjected to 30 min global ischemia followed by 120 min reperfusion
- Group 3 (IPOC; n = 6) – After 10 min of stabilization, the heart was subjected to 30 min global ischemia followed four cycles of IPOC, comprises 5 min reperfusion and 5 min ischemia further followed by 120 min reperfusion
- Group 4 (IPOC in Diabetic Rat; n = 6) – After 10 min stabilization, isolated heart from diabetic rat subjected to 30 min of global ischemia followed by IPOC as described earlier in group 3
- Group 5 (IPOC in ANP (0.1μM/L) perfuse diabetic rat heart; n = 6) – After stabilization, isolated heart from diabetic rat was subjected to 30 min. of global ischemia followed by 5 min reperfusion, perfused by ANP (0.1 μM/L) at the onset of 120 min reperfusion
- Group 6 (IPOC in L-NAME (100 μM/L) and ANP (0.1 μM/L) perfused diabetic rat heart; n = 6) – At stabilization L-NAME (100 μM/L) perfused, heart was subjected to 30 min ischemia followed by 5 min reperfusion perfused with ANP (0.1 μM/L) and L-NAME (100 μM/L) at onset of 120 min reperfusion.
Statistical analysis
All data were expressed as mean ± standard deviation. Statistical analysis was performed using Graph pad software. Values were statistically analyzed by (ANOVA) followed by Turkey's t-test. P <0.005 was considered to be statistically significant.
RESULTS
Effect of alloxan monohydrate on serum glucose
The Alloxan monohydrate (120mg/kg; i.p.) was administered once to each animal during experimental protocol, significantly enhanced serum glucose as compared to normal control [Figure 2].
Figure 2: Effect of single dose of Alloxan Monohydrate on serum glucose level. Values are expressed as mean ± S.E.M. *= P < 0.05 as compared to control animals
Effect of ischemic postconditioning and pharmacological interventions on myocardial infarct size
Global ischemia for 30 min followed by 120 min of reperfusion significantly increased the myocardial infract size as compared to sham control. Four episodes of IPOC significantly attenuated I/R-induced increase in myocardial infract size in normal rat heart.
However, IPOC failed to reduce the myocardial infarct size in diabetic rat heart. Moreover, IPOC reduced in myocardial infract size restored by ANP (0.1μM/L) perfusion in diabetic rat heart. Moreover, perfusion with L-NAME (100μM/L) modulates the ANP postconditioning in diabetic rat heart [Figure 3].
Figure 3: Effect of ANP (0.1μM/L) and L-NAME (100μM/L) on ischemia reperfusion infarct size in isolated diabetic rat heart. The values are expressed as mean ± S.E.M. a=P < 0.05 vs. Sham Control, b= P < 0.05 vs. I/R Control, c= P < 0.05 vs. IPOC in normal rat heart, d= P < 0.05 vs. IPOC in normal rat heart e=P < 0.05 vs. diabetic rat heart
Effect of ischemic postconditioning and pharmacological interventions on the release of lactate dehydrogenase
Global ischemia for 30 min followed by 120 min of reperfusion markedly increased the release of LDH as compared to sham control. Four brief episodes of IPOC significantly attenuated ischemia-reperfusion induced increase in the release of LDH in normal rat heart. Despite it, IPOC failed to reduce LDH in diabetic rat heart. Moreover, IPOC-induced decrease in the release of LDH was significantly restored in ANP (0.1μM/L) perfused heart in diabetic rat heart. However, perfusion with L-NAME (100μM/L) modulates the ANP postconditioning to reduce in the release LDH of diabetic rat heart [Figure 4].
Figure 4: Effect of perfusion of ANP (0.1μM/L) and L-NAME (100μM/L) on I/R induced release of lactate dehydrogenase (LDH). Perfusion of L-NAME (100μM/L) increase release of lactate dehydrogenase (LDH) in diabetic rat heart. The values are expressed as mean ± S.E.M. a=P < 0.05 vs. Sham Control, b=P < 0.05 I/R Control, c= P < 0.05 vs. IPOC in normal rat heart, d=P < 0.05 vs. IPOC in normal rat heart e=P < 0.05 vs. diabetic rat heart
Effect of ischemic postconditioning and pharmacological interventions on the release of creatine kinase-MB
Global ischemia for 30 min followed by 120 min of reperfusion markedly increased the release of CK-MB as compared to sham control. Four episodes of IPOC considerably decreased, I/R-induced increase in the release of CK-MB in normal rat heart. Despite it, IPOC failed to reduce CK-MB in diabetic rat heart. Moreover, IPOC-induced decrease in the release of CK-MB was significantly restored in ANP (0.1 μM/L) perfused rat heart. However, perfusion with L-NAME (100 μM/L) modulates the ANP postconditioning considerably to reduce in the release CK-MB of diabetic rat heart [Figure 5].
Figure 5: Effect of perfusion of eNOS inhibitors L- NAME (100μM/L) and ANP (0.1μM/L) on I/R induced release of CK-MB. Perfusion of L- NAME (100μM/L) increase release of creatine kinase-MB (CK-MB) in diabetic rat heart. The values are expressed as mean ± a=P < 0.05 vs. Sham Control, b=P < 0.05 I/R Control, c= P < 0.05 vs. IPOC in normal rat heart, d=P < 0.05 vs. IPOC in normal rat heart e=P < 0.05 vs. diabetic rat heart
Effect of ischemic postconditioning and treatment with atrial natriuretic peptide release of nitrite
Four episodes of IPOC significantly increased the release of nitrite into coronary effluent in normal, as compared to I/R group but not in isolated heart preparation from diabetic rat. Perfusion of ANP (0.1μM/L) significantly increased the release of nitrite in diabetic rat heart. However, perfusion with L-NAME (100μM/L) modulates the ANP postconditioning to reduce the release of nitrite in diabetic rat heart [Figure 6].
Figure 6: Effect of perfusion of eNOS inhibitor L-NAME (100μM/L) and ANP (0.1μM/L) on I/R induced release of nitrite. Perfusion of L-NAME decrease release of nitrite in diabetic rat heart. The values are expressed as mean ± a=P < 0.05 vs. Sham Control, b=P < 0.05 I/R Control, c= P < 0.05 vs. IPOC in normal rat heart, d=P < 0.05 vs. IPOC in normal rat heart e=P < 0.05 vs. diabetic rat control
DISCUSSION
Postconditioning, i.e., four briefs episodes of reperfusion and ischemia-induced cardioprotection in normal rat in terms of decrease in the infarct size, GK-MB, and LDH. These cardioprotective results are supported by the other studies.[103536] However, the cardioprotective effect of IPOC was significantly modulated in the diabetic rat, our results supported earlier published studies.[1035]
In our present study, perfusion of ANP significantly restored the attenuated effect of IPOC in diabetic rat myocardium in the terms of decreasing the myocardial infarct size, CK-MB and LDH. IPOC induces the cardioprotection by activating the PI3K/Akt pathway and endothelial nitric oxide (eNOS).[3637] Probably, attenuated cardioprotective effect of IPOC in diabetic heart may be due to decrease releases of NO. So that NO responsible for the IPOC-induced cardioprotection.[38]
In the present study, diabetes has been induced by the administration of alloxan monohydrate considerably enhance the glucose level. Glucose analysis is demonstrated the difference between normal and diabetic heart. Phosphorylation of eNOS helps to secrete the NO in heart.[39] whether secretion of NO decrease in diabetic rat heart this showed that cardioprotection of diabetic rat heart decrease due to phosphorylation of eNOS getting low, increase in the eNOS activate the survival kinase PI3K/Akt pathway.[40] At the time of ischemia NO produced through nitrite by xanthine oxidoreductase may help in opening of mitochondrial potassium ATP sensitive channel (mito KATP), act as end effectors.[41424344] Diabetes is shown to inhibit prosurvival kinase which inactivate the Akt and that reduce the phosphorylation of eNOS by which secretion of NO decrease and opening of mitochondrial permeability transport pore (MPTP) increase.[36454647] Opening of MPTP is the most crucial point from which place induction of I/R proceed myocardial damage.[4849]
ANP is naturally occurring 28 amino acid peptide which is bind to NPRA, which is a membrane-associated guanylyl cyclase receptor.[1550] NPRAis partially soluble guanylyl cyclase receptor, a receptor for nitric oxide (NO). Perfusion of the ANP induced the cardioprotection by activating the PKG and mito KATPchannel and Reperfusion injury salvage kinase pathway (RISK), i.e., PI3K/AKT.[17]
It has been reported that diabetes mellitus decrease the level of ANP.[19] In our study, perfusion of L-NAME along with ANP, significantly attenuated ANP-induced myocardial protection in terms of infarct size, CK-MB, LDH, and nitric oxide in coronary effluent on the basis of the above discussion it may be concluded the ANP-induced postconditioning, showed cardioprotection against the I/R injury in diabetic rat heart through NO pathway.
CONCLUSION
As per the above discussion, it may be concluded ANP restores the attenuated cardioprotection in diabetic rat heart. This observed cardioprotection is due to increase release of NO in coronary flow. Our data indicate the perfusion of ANP along with postconditioning protects the myocardium against the ischemia-reperfusion injury in diabetic rat heart. Therefore, ANP could be a therapeutic intervention for the management of ischemic reperfusion injury.
Limitations
Although the current findings are obliging with some limitation, Western blot of an ANP could not be conduct because of a limited institutional fund.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgments and statement of contribution
GG is thankful to GLA University. All the authors contributed equally to this work. H. N. Y. and V. V. developed this concept. G. G. performed the experiment in laboratory and V. V., A. G., and J. K. G. carried out the analysis of the results and GG prepared the manuscript.
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