Synergistic Effects of Dantrolene and Nimodipine on the Phenylephrine-Induced Contraction and ACh-Induced Relaxation in Aortic Rings from Diabetic Rats.

Diabetics have a higher risk of developing cerebral vasospasms (CVSP) than nondiabetics. The addition of the ryanodine receptor (RyR) blocker dantrolene to standard therapies reduces vasospasms in nondiabetics. 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, nondiabetic 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 nondiabetics by decreasing arterial tone synergistically.

Simvastatin, atorvastatin, and pravastatin equally improve the hemodynamic status of diabetic rats.

AIM: To investigate if the effect of statins improving cardiovascular (CV) status of diabetics is drug-specific or class-dependent, and the underlying mechanisms involved. METHODS: We compared the results of daily administration over a four-week period of a low dose (10 mg/kg per day) of atorvastatin (AV), simvastatin (SV), and pravastatin (PV) on cardiac performance in diabetic rats. Echocardiographic variables were tested, as well as systolic blood pressure (SBP), acetylcholine (ACh)-induced relaxation, plasma cholesterol levels, and perivascular fibrosis. Malondialdehyde (MDA) and 4-hydroxyalkenal (4-HAE), and endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) protein levels were also measured in cardiac and aortic homogenates. RESULTS: In untreated diabetic rats, cholesterol levels were higher than in control rats (CT; n = 8, P < 0.05), and the low dose of statins used did not modify these levels. In diabetic rats, SBP was higher than in CT, and was significantly reduced by all three statins (n = 10, P < 0.05). Echocardiographic parameters (EF, SV, and COI) were all lower in untreated diabetic rats than in CT (n = 10, P < 0.05). These CV parameters were equally improved by all three statins. The maximal relaxation (EMax) induced by ACh in aortic ring from diabetic rats was also improved. Moreover, this relaxation was abolished by 1 mmol/L NG-nitro-L-arginine methyl ester, suggesting the involvement of a NO-dependent mechanism. CONCLUSION: AV, SV, and PV are equally effective in improving CV performance in diabetic rats. All tree statins decreased media thickness, perivascular fibrosis, and both MDA and 4-HAE in the aortas of diabetic rats, without affecting eNOS and iNOS protein levels. The observed hemodynamic benefits are cholesterol-independent. These benefits appear to be secondary to the improved endothelial function, and to the reduced vascular tone and remodeling that result from decreased oxidative stress.

Atorvastatin improves systolic function, but does not prevent the development of dilated cardiomyopathy in streptozotocin-induced diabetic rats.

BACKGROUND: Therapy with HMG-CoA reductase inhibitors (statins) has been associated with a significant reduction in the number of major cardiovascular (CV) events in diabetic patients. The mechanisms by which these drugs improve cardiac status remain unclear. We assessed the effects of atorvastatin (10 mg/kg/day) on CV function in streptozotocin (STZ)-induced diabetic rats. METHODS: Age-matched, nondiabetic rats were used as controls. Echocardiographic parameters, systolic blood pressure (SBP), endothelial-dependent relaxation, cardiac and vascular oxidative stress, perivascular fibrosis, and cholesterol levels were evaluated after a 4-week atorvastatin treatment period. RESULTS: In diabetic rats, SBP was higher than in controls. Atorvastatin decreased SBP in diabetic rats by 14% (n = 10, p < 0.05), and significantly increased stroke volume, ejection fraction, and cardiac output index. Whereas atorvastatin reduced left ventricular end systolic volume (LVESV) by 50% (p < 0.05), it failed to reduce left ventricular end diastolic volume (LVEDV). Total cholesterol was higher in diabetic rats than in controls and atorvastatin was ineffective in reducing cholesterol levels. The statin, however, decreased perivascular fibrosis and media thickness, and the markers of oxidative stress malondialdehyde (MDA) and 4-hidroxyalkenals (4-HAE) in aortic homogenates from diabetic rats. In addition, atorvastatin improved endothelial function by increasing the E MAX value of the acetylcholine-induced relaxation from 53.7 ± 4.1% in untreated diabetic to 82.1 ± 7.0% in treated diabetic rats (n = 10, p < 0.05). L-NAME fully abolished this improvement, suggesting that the increased vascular relaxation with atorvastatin is NO-dependent. CONCLUSIONS: Whereas atorvastatin does not reverse ventricular dilatation, it does have a positive hemodynamic effect on the CV system of diabetic rats. This hemodynamic benefit is independent of cholesterol levels, and is observed concomitantly with reduced oxidative stress, vascular remodeling, and improved endothelial function. Together, these results suggest that atorvastatin decreases the workload on the heart and improves systolic performance in type 1 diabetic rats by reducing oxidative stress, vascular tone, and systemic vascular resistance.

Daily administration of atorvastatin and simvastatin for one week improves cardiac function in type 1 diabetic rats.

Short-term administration of statins during the perioperative period has been suggested to improve cardiovascular (CV) outcomes in patients undergoing cardiac and vascular surgery. The effectiveness of this therapy, the optimal administration time and the statin best suited to improve cardiac performance under hyperglycemic conditions, however, are unknown. In this study, we compared the effects of 10 mg/kg/day simvastatin (SV), pravastatin (PV) and atorvastatin (AV), on the CV status of fully anesthetized streptozotocin-induced diabetic rats 4 weeks following diabetes induction. At this stage, cardiac function is compromised. The rats were anesthetized to mimic presurgical conditions. Cardiac status was evaluated twice by echocardiography, first 24 h after statin administration, and then after daily statin administration for 1 week. After 24 h of statin administration, CV parameters were not improved. Continued daily administration of SV and AV over a 1-week period, by contrast, significantly improved ejection fraction from 52.20 ± 2.33% before treatment to 64.89 ± 1.12% with AV and to 69.71 ± 2.30% with SV (n = 9, p < 0.05). The cardiac output index was also significantly improved from 51.13 ± 6.86 ml/min × 100 g body weight (BW) before treatment to 98.74 ± 13.78 ml/min × 100 g BW with AV and to 84.94 ± 8.64 ml/min × 100 g BW with SV. Only AV increased stroke volume from 0.50 ± 0.08 to 0.83 ± 0.13 ml (n = 9, p < 0.05). Unlike the other statins tested, PV provided no beneficial effects, regardless of the regimen of administration. Our results indicate that daily administration of AV and SV for 1 week enhances cardiac performance in fully anesthetized diabetic rats. This study of short-term statin administration may have strong clinical implications for improving perioperative outcomes in diabetic patients.

Diabetes alters cardiovascular responses to anaesthetic induction agents in STZ-diabetic rats.

BACKGROUND: People with diabetes are at increased risk of cardiovascular (CV) morbidity and mortality during surgery. The most appropriate anaesthetic induction agent for these patients is unknown. METHODS AND RESULTS: We assessed the CV effects of propofol, etomidate and ketamine in streptozotocin (65 mg/kg, IP) diabetic rats. In non-diabetic rats, none of these anaesthetics significantly modified cardiac output, heart rate or stroke volume, but ketamine increased systolic blood pressure (SBP) compared to etomidate and propofol (89.6 ± 2.4 mmHg, vs. 72.7 ± 3.0 and 75.4 ± 1.9; p < 0.05). In diabetic rats, by contrast, cardiac output was lower with ketamine (82.6 ± 14 ml/min) and etomidate (78.2 ± 15.8 ml/min) than with propofol (146 ± 21 ml/min, N = 8, p < 0.01). SBP, however, was higher in the propofol-treated group (93.3 ± 3.4 mmHg, p < 0.05). CONCLUSION: These results suggest that hyperglycaemia modifies CV responses to induction anaesthetics.

Differential regulation of the left and right coronary arteries of swine.

Coronary artery disease is one of the leading causes of myocardial infarction. Despite the predominant role of the coronary arteries in the induction of myocardial infarction, the precise contribution of each artery to this process is not well established. The present work evaluates the histological characteristics and functional properties of the left (LCA) and right (RCA) coronary arteries in swine in order to establish if the arteries are differentially regulated. To investigate this possibility, concentration-response curves for serotonin (5-HT, from 0.1 nmol/l to 100 micromol/l) and KCl (from 5 to 40 mmol/l) were performed on both arteries to determine the receptor-dependent and independent responses, respectively. The specific subtype of the 5-HT receptor involved in the contraction of both arteries was evaluated using DL-propranolol hydrochloride (5-HT1 and nonselective beta-adrenergic receptor antagonist) and ketanserine (5-HT2 antagonist) and immunohistochemical assays. The Emax from the 5-HT concentration-response curves was 24% higher in the LCA than in the RCA (n = 59, p < 0.05). EC50 values from both curves were also significantly different (LCA 0.150 +/- 0.005 micromol/l and RCA 0.171 +/- 0.010 micromol/l, n = 59, p < 0.05). Similarly, the Emax for KCl was 36% higher in the LCA than in the RCA (n = 9, p < 0.05), and the EC50 values also differed (LCA 15.30 +/- 0.06 mmol/l and RCA: 14.30 +/- 0.11 mol/l, n = 9, p < 0.05). Ketanserine reduced the Emax by 63% in the LCA and by 67% in the RCA. DL-propranolol hydrochloride decreased Emax by 24% in the LCA and by 26% in the RCA. The dry weight and media area were larger in the LCA than in the RCA (17%, n = 40, p < 0.05, and 3%, n = 40, p < 0.05, respectively). Immunohistochemical assay results reveal that the average density of 5-HT2A receptor subtype was also higher in the LCA (41.24 +/- 1.35) than in the RCA (18.49 +/- 1.14; n = 20, p < 0.05). Together, the findings of this study suggest that a differential physiological regulation exists between the LCA and RCA in swine. This differential regulation may have arisen as a mechanism for maintaining an adequate perfusion pressure in the wall of the left ventricle, favoring a greater oxygen delivery to match the increased oxygen demand of the left ventricle.

Statins decrease serotonin-induced contractions in coronary arteries of swine in vitro.

Recent evidence suggests that statins improve the status of patients with coronary artery disease not only by reducing cholesterol levels, but also by acting at the level of the endothelium-smooth muscle unit. Previous results from our laboratory showed that these drugs interact with the vascular wall by partially inhibiting calcium-dependent, agonist-induced contractions in rat aortas. To evaluate whether this effect is also extended to the coronary vasculature, we assessed the effect of statins on serotonin (5-HT) induced contractions of left and right coronary arteries of swine. Concentration-response curves for the 5-HT-induced contractions (from 0.1 nmol/l to 100 micromol/l) were calculated on rings from both coronaries in the presence and absence of either (5 micromol/l) pravastatin, mevastatin, simvastatin, lovastatin, or atorvastatin. After a 45-min incubation period, all statins significantly reduced the Emax for the 5-HT-induced contractions, ranging from 51.9 +/- 1.9% (simvastatin) to 15.9 +/- 2.0% (pravastatin) in the left coronary artery and from 48.8 +/- 2.0% (simvastatin) to 17.8 +/- 2.5% (pravastatin) in the right coronary artery. The EC50 values for the 5-HT-induced contractions were 0.150 +/- 0.005 micromol/l for the left coronary artery and 0.171 +/- 0.010 micromol/l for the right coronary artery. These values significantly changed after incubation with statins, ranging from 1.240 +/- 0.101 micromol/l (for simvastatin) to 0.081+/- 0.008 micromol/l (for pravastatin) in the left coronary artery and from 1.410 +/- 0.075 micromol/l (for simvastatin) to 0.084 +/- 0.008 micromol/l (for pravastatin) in the right coronary artery. This evidence supports the possibility that, beyond their lipid-lowering properties, statins may provide a beneficial effect in atherosclerotic patients by reducing the tone in the coronary vasculature, facilitating blood flow to the myocardium.