Abstract
Diabetics have a higher risk of developing cerebral vasospasms (CVSP) than non‐diabetics. The addition of the ryanodine receptor (RyR) blocker dantrolene to standard therapies reduces vasospasms in non‐diabetics. Whether diabetics with CVSP also benefit from this drug, however, is unknown. We evaluated the effects of a 30‐min incubation with dantrolene (50 μM), nimodipine (50 nM), and both drugs in combination, on phenylephrine (PHE)‐induced contraction, and on acetylcholine (ACh)–induced relaxation in aortic rings from streptozotocin (STZ) diabetic rats. Age‐matched, non‐diabetic rats served as controls. The oxidative‐stress markers malondialdehyde (MDA) and 4‐hydroxyalkenal (4‐HAE) were also evaluated in the presence and absence of dantrolene and nimodipine. The combination of these two drugs acted synergistically to reduce the PHE‐induced contraction by 80% in both diabetics and controls. In contrast, it increased the Emax value for ACh‐induced relaxation (from 56.46 ± 5.14% to 96.21 ± 7.50 %; n=6, P < 0.05), and it decreased MDA +4‐HAE values in diabetic rats only. These results suggest that the combination of dantrolene and nimodipine benefits both diabetics and non‐diabetics by decreasing arterial tone synergistically.Support or Funding InformationSupported by NIH (MBRS‐RISE Grant R25GM061838), and NIMHD‐RCMI (Grant G12‐MD007600).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Highlights
Diabetic patients have a higher incidence of vascular complications and are more prone to developing cerebral vasospasms (CVSPs) than nondiabetics [1]
The etiology of CVSPs has not been determined, it has been associated with increased vascular tone due to persistent elevation of intracellular Ca2+ in vascular smooth muscle (VSM) [2, 3], which may be secondary to (1) increased extracellular Ca2+entry into the cell [4] or to (2) increased release of this ion from the sarcoplasmic reticulum (SR), which is mediated by the ryanodine receptors (RyRs) [5]
Unlike in nondiabetics, alterations in the status of endothelial nitric oxide synthase and inducible nitric oxide synthase characterize diabetic animal models and patients [10,11,12,13] and may contribute to increased vascular tone. These findings suggest that the pathophysiology of CVSP differs between diabetics and nondiabetics
Summary
Diabetic patients have a higher incidence of vascular complications and are more prone to developing cerebral vasospasms (CVSPs) than nondiabetics [1]. Unlike in nondiabetics, alterations in the status of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) characterize diabetic animal models and patients [10,11,12,13] and may contribute to increased vascular tone. These findings suggest that the pathophysiology of CVSP differs between diabetics and nondiabetics. The current treatment for this condition is similar for these two groups of patients, and includes the use of nimodipine, nicardipine, and other voltage-dependent L-type Ca2+ channel antagonists [1] These drugs are not completely effective in reducing CVSPs because Ca2+
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