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. 2018 Dec;156(6):2098-2107.
doi: 10.1016/j.jtcvs.2018.05.090. Epub 2018 Jun 8.

Enhanced coronary arteriolar contraction to vasopressin in patients with diabetes after cardiac surgery

Nicholas Sellke  1 , Alex Kuczmarski  1 , Isabella Lawandy  1 , Victoria L Cole  1 , Afshin Ehsan  1 , Arun K Singh  1 , Yuhong Liu  1 , Frank W Sellke  1 , Jun Feng  2
Affiliations

Enhanced coronary arteriolar contraction to vasopressin in patients with diabetes after cardiac surgery

Nicholas Sellke et al. J Thorac Cardiovasc Surg. 2018 Dec.

Abstract

Objective: Cardioplegic arrest (CP) and cardiopulmonary bypass (CPB) are associated with vasomotor dysfunction of coronary arterioles in patients with diabetes (DM) undergoing cardiac surgery. We hypothesized that DM may up-regulate vasopressin receptor expression and alter the contractile response of coronary arterioles to vasopressin in the setting of CP/CPB.

Methods: Right atrial tissue samples of patients with DM and without (ND) (n = 8 in each group) undergoing cardiac surgery were harvested before and after CP/CPB. The isolated coronary arterioles (80-150 μm) dissected from the harvested right atrial tissue samples were cannulated and pressurized (40 mm Hg) in a no-flow state. The changes in diameter were measured with video microscopy. The protein expression/localization of vasopressin 1A receptors (V1A) and vasopressin 1B receptors (V1B) in the atrial tissue were measured by immune-blotting and immunohistochemistry.

Results: The pre-CP/CPB contractile responses of the coronary arterioles to vasopressin were significantly increased post-CP/CPB in both the ND and DM groups. This effect was more pronounced in the vessels from patients in the DM group than that of vessels from patients in the ND group (P < .05). Vasopressin-induced contractile response of the coronary arterioles was inhibited in the presence of the specific V1A antagonist SR 49059 (10-7 M) in both ND and DM vessels (P < .05). The post-CP/CPB protein levels of V1A were significantly increased compared with pre-CP/CPB values in both the ND and DM groups (P < .05), whereas this increase was greater in DM than that of ND (P < .05). Immunohistochemistry staining further indicates that V1B were mainly expressed in the myocardium but not in vascular smooth muscle.

Conclusions: CP/CPB and DM are both associated with up-regulation in V1 receptor expression/localization in human myocardium. Vasopressin may induce coronary arteriolar constriction via V1A. This alteration may lead to increased coronary arteriolar spasm in patients with DM undergoing CP/CPB and cardiac surgery.

Keywords: cardioplegia; cardiopulmonary bypass; coronary arterioles; diabetes; microvascular reactivity; vasopressin.

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Conflict of interest statement

Disclosure: No potential conflicts of interest exist in the preparation of this manuscript

Figures

Figure 1.
Figure 1.
A, Dose-dependent contractile response of coronary arterioles to vasopressin (10−8-10−5M) from non-diabetic (ND) patients before cardoplegic ischemia and cardiopulmonary bypass (pre-CP/CPB-ND), post-CP/CPB-ND; and from diabetic patients (DM), pre-CP/CPB-DM and post-CP/CPB-DM. B, the bar graph showing the coronary arteriolar contractile response to vasopressin at 10−5M. *P<0.05 vs. pre-CP/CPB-ND, #P<0.05 vs. post-CP/CPB-ND; n = 8/group, mean ± SD.
Figure 1.
Figure 1.
A, Dose-dependent contractile response of coronary arterioles to vasopressin (10−8-10−5M) from non-diabetic (ND) patients before cardoplegic ischemia and cardiopulmonary bypass (pre-CP/CPB-ND), post-CP/CPB-ND; and from diabetic patients (DM), pre-CP/CPB-DM and post-CP/CPB-DM. B, the bar graph showing the coronary arteriolar contractile response to vasopressin at 10−5M. *P<0.05 vs. pre-CP/CPB-ND, #P<0.05 vs. post-CP/CPB-ND; n = 8/group, mean ± SD.
Figure 2.
Figure 2.
A, Dose-dependent contractile response of atrial coronary arterioles to vasopressin in the presence or absence of V1 receptor blocker SR490099 (10−7M) in the pre-CP/CPB-ND and the pre-CP/CPB-DM subgroups; B, the coronary arteriolar contractile response to vasopressin at 10−5M in the presence or absence of SR490099 (10−7M) in the pre-CP/CPB-ND and the pre-CP/CPB-DM subgroups; C, Dose-dependent contractile response of atrial coronary arterioles to vasopressin in the presence or absence of V1 receptor blocker SR490099 (10−7M) in the post-CP/CPB-ND and the post-CP/CPB-DM subgroups; D, the coronary arteriolar contractile response to vasopressin at 10−5M in the presence or absence of SR490099 in the post-CP/CPB-ND and the post-CP/CPB-DM subgroups;*P<0.05 vs. pre-CP/CPB-ND alone or #P <0.05 vs. pre-CP/CPB-DM alone, n = 6/group, mean ± SD.
Figure 2.
Figure 2.
A, Dose-dependent contractile response of atrial coronary arterioles to vasopressin in the presence or absence of V1 receptor blocker SR490099 (10−7M) in the pre-CP/CPB-ND and the pre-CP/CPB-DM subgroups; B, the coronary arteriolar contractile response to vasopressin at 10−5M in the presence or absence of SR490099 (10−7M) in the pre-CP/CPB-ND and the pre-CP/CPB-DM subgroups; C, Dose-dependent contractile response of atrial coronary arterioles to vasopressin in the presence or absence of V1 receptor blocker SR490099 (10−7M) in the post-CP/CPB-ND and the post-CP/CPB-DM subgroups; D, the coronary arteriolar contractile response to vasopressin at 10−5M in the presence or absence of SR490099 in the post-CP/CPB-ND and the post-CP/CPB-DM subgroups;*P<0.05 vs. pre-CP/CPB-ND alone or #P <0.05 vs. pre-CP/CPB-DM alone, n = 6/group, mean ± SD.
Figure 2.
Figure 2.
A, Dose-dependent contractile response of atrial coronary arterioles to vasopressin in the presence or absence of V1 receptor blocker SR490099 (10−7M) in the pre-CP/CPB-ND and the pre-CP/CPB-DM subgroups; B, the coronary arteriolar contractile response to vasopressin at 10−5M in the presence or absence of SR490099 (10−7M) in the pre-CP/CPB-ND and the pre-CP/CPB-DM subgroups; C, Dose-dependent contractile response of atrial coronary arterioles to vasopressin in the presence or absence of V1 receptor blocker SR490099 (10−7M) in the post-CP/CPB-ND and the post-CP/CPB-DM subgroups; D, the coronary arteriolar contractile response to vasopressin at 10−5M in the presence or absence of SR490099 in the post-CP/CPB-ND and the post-CP/CPB-DM subgroups;*P<0.05 vs. pre-CP/CPB-ND alone or #P <0.05 vs. pre-CP/CPB-DM alone, n = 6/group, mean ± SD.
Figure 2.
Figure 2.
A, Dose-dependent contractile response of atrial coronary arterioles to vasopressin in the presence or absence of V1 receptor blocker SR490099 (10−7M) in the pre-CP/CPB-ND and the pre-CP/CPB-DM subgroups; B, the coronary arteriolar contractile response to vasopressin at 10−5M in the presence or absence of SR490099 (10−7M) in the pre-CP/CPB-ND and the pre-CP/CPB-DM subgroups; C, Dose-dependent contractile response of atrial coronary arterioles to vasopressin in the presence or absence of V1 receptor blocker SR490099 (10−7M) in the post-CP/CPB-ND and the post-CP/CPB-DM subgroups; D, the coronary arteriolar contractile response to vasopressin at 10−5M in the presence or absence of SR490099 in the post-CP/CPB-ND and the post-CP/CPB-DM subgroups;*P<0.05 vs. pre-CP/CPB-ND alone or #P <0.05 vs. pre-CP/CPB-DM alone, n = 6/group, mean ± SD.
Figure 3.
Figure 3.
A and B, Representative immunoblots of atrial tissue lysates for V1A and V1B receptors, harvested from the diabetic (DM) and non-diabetic (ND) patients pre- and post-CP/CPB. C, Immunoblot quantification shows significantly increased V1A receptor expression post-CP/CPB-ND and post-CPB-DM; * P <0.05 vs. pre-CP/CPB-ND or preCP/CPB-DM, #P <0.05 vs. post-CP/CPB-ND; D, Immunoblot quantification shows significantly increased V1B receptor expression post-CP/CPB-DM, *P <0.05 vs. preCP/CPB-ND or pre-CP/CPB-DM, #P <0.05 vs. post-CP/CPB-ND, n = 6/group, mean ± SD.
Figure 3.
Figure 3.
A and B, Representative immunoblots of atrial tissue lysates for V1A and V1B receptors, harvested from the diabetic (DM) and non-diabetic (ND) patients pre- and post-CP/CPB. C, Immunoblot quantification shows significantly increased V1A receptor expression post-CP/CPB-ND and post-CPB-DM; * P <0.05 vs. pre-CP/CPB-ND or preCP/CPB-DM, #P <0.05 vs. post-CP/CPB-ND; D, Immunoblot quantification shows significantly increased V1B receptor expression post-CP/CPB-DM, *P <0.05 vs. preCP/CPB-ND or pre-CP/CPB-DM, #P <0.05 vs. post-CP/CPB-ND, n = 6/group, mean ± SD.
Figure 3.
Figure 3.
A and B, Representative immunoblots of atrial tissue lysates for V1A and V1B receptors, harvested from the diabetic (DM) and non-diabetic (ND) patients pre- and post-CP/CPB. C, Immunoblot quantification shows significantly increased V1A receptor expression post-CP/CPB-ND and post-CPB-DM; * P <0.05 vs. pre-CP/CPB-ND or preCP/CPB-DM, #P <0.05 vs. post-CP/CPB-ND; D, Immunoblot quantification shows significantly increased V1B receptor expression post-CP/CPB-DM, *P <0.05 vs. preCP/CPB-ND or pre-CP/CPB-DM, #P <0.05 vs. post-CP/CPB-ND, n = 6/group, mean ± SD.
Figure 4.
Figure 4.
A, Immunohistochemical image of V1A receptors in paraffin-embedded human atrial tissue slides from non-diabetic (ND) and diabetes (DM) patients. B, Densitometric analysis of signal intensities, C, Immunofluorescence staining of V1B receptors in the embedded human atrial tissue slides from the ND and DM patients before and after CP/CPB. D, Densitometric analysis of signal intensities. *P<0.05 vs. pre-CP/CP-DM, #P < 0.05 vs. post-CP/CPB-ND; n = 5/group, mean ± SD.
Figure 4.
Figure 4.
A, Immunohistochemical image of V1A receptors in paraffin-embedded human atrial tissue slides from non-diabetic (ND) and diabetes (DM) patients. B, Densitometric analysis of signal intensities, C, Immunofluorescence staining of V1B receptors in the embedded human atrial tissue slides from the ND and DM patients before and after CP/CPB. D, Densitometric analysis of signal intensities. *P<0.05 vs. pre-CP/CP-DM, #P < 0.05 vs. post-CP/CPB-ND; n = 5/group, mean ± SD.
Figure 4.
Figure 4.
A, Immunohistochemical image of V1A receptors in paraffin-embedded human atrial tissue slides from non-diabetic (ND) and diabetes (DM) patients. B, Densitometric analysis of signal intensities, C, Immunofluorescence staining of V1B receptors in the embedded human atrial tissue slides from the ND and DM patients before and after CP/CPB. D, Densitometric analysis of signal intensities. *P<0.05 vs. pre-CP/CP-DM, #P < 0.05 vs. post-CP/CPB-ND; n = 5/group, mean ± SD.
Figure 4.
Figure 4.
A, Immunohistochemical image of V1A receptors in paraffin-embedded human atrial tissue slides from non-diabetic (ND) and diabetes (DM) patients. B, Densitometric analysis of signal intensities, C, Immunofluorescence staining of V1B receptors in the embedded human atrial tissue slides from the ND and DM patients before and after CP/CPB. D, Densitometric analysis of signal intensities. *P<0.05 vs. pre-CP/CP-DM, #P < 0.05 vs. post-CP/CPB-ND; n = 5/group, mean ± SD.
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