V.Melih Altan

EFFECTS OF NON-INSULIN DEPENDENT DIABETES MELLITUS ON THE REACTIVITY OF HUMAN INTERNAL MAMMARY ARTERY AND HUMAN SAPHENOUS VEIN

The effects of non-insulin-dependent diabetes mellitus (NIDDM) were investigated on the reactivity of human internal mammary artery (IMA) and saphenous vein (SV) rings obtained from coronary artery patients (CAP) undergoing coronary artery bypass surgery. In the presence of endothelium, the maximal contractile response and sensitivity (pD2) of IMA or SV to NA and ET-1 significantly increased in CAP with NIDDM relative to CAP only (controls). Removal of the endothelium markedly and significantly enhanced the maximal contractile response and sensitivity of IMA or SV to NA in CAP only, but did not induce a significant alteration in CAP with NIDDM compared to that in the presence of endothelium. The maximal contractile response and sensitivity of diabetic vessels with or without endothelium to NA were similar to values of corresponding vessels without endothelium obtained from nondiabetic CAP. The maximum contractions developed by NA or ET-1 were much greater in SV than that determinated in the IMA. Acetylcholine (ACh) and histamine produced endothelium-dependent relaxations in precontracted IMA and these effects of ACh and histamine significantly decreased in CAP with NIDDM. Endothelium-dependent relaxations stimulated by ACh were more pronounced in IMA than that determinated in the SV. In precontracted SV, histamine induced marked contractions that were significantly greater in CAP with NIDDM relative to CAP only. Endothelium-independent relaxations of vessels to sodium nitroprusside (SNP) were not influenced by NIDDM. Data indicate that NIDDM causes a deficit in the vasorelaxant activity of endothelium, leading to an increase in contractility of human IMA and SV. Data also suggest that IMA can be a better choice of graft for coronary occlusive disease than SV, specially in patients with NIDDM.

The influence of diabetes on cardiac β-adrenoceptor subtypes

Despite the significant developments in the treatment of diabetes mellitus, diabetic patients still continue to suffer from cardiac complications. The increase of cardiac adrenergic drive may ultimately contribute to the development and progression of diabetic cardiomyopathy. β-Adrenoceptors play an important role in the regulation of heart function. However, responsiveness of diabetic heart to β-adrenoceptor agonist stimulation is diminished. The chronotropic responses mediated by β1-subtype, which is mainly responsible for cardiac effects of catecholamines are decreased in the atria of diabetic rats. The expression of cardiac β1-subtype is significantly decreased in diabetic rats as well. β2-Adrenoceptors also increase cardiac function. Although the expression of this subtype is slightly decreased in diabetic rat hearts, β2-mediated chronotropic responses are preserved. On the other hand, functional β3-adrenoceptor subtype was characterized in human heart. Interestingly, stimulation of cardiac β3-adrenoceptors, on the contrary of β1- and β2-subtypes, mediates negative inotropic effect in human ventricular muscle. Cardiac β3-adrenoceptors are upregulated in experimental diabetes as well as in human heart failure. These findings suggest that each β-adrenoceptor subtype may play an important role in the pathophysiology of diabetes-induced heart disease. However, it is still not known whether the changes in the expression and/or responsiveness of β-adrenoceptors are adaptive or maladaptive. Therefore, this review outlines the potential roles of these receptor subtypes in cardiac pathologies of diabetes.

Thyroid hormones mediated effect of insulin on alloxan diabetic rat atria

1. The influence of alloxan-induced diabetes was studied on spontaneously beating rat atria. Diabetic atria were found to have decreased rates, increased contractility and decreased responsiveness to both inotropic and chronotropic effects of isoprenaline. 2. Thyroid hormone levels were significantly reduced in diabetic animals. This revealed that the decrease in atrial beta-adrenergic responses was associated with a reduction in serum levels of thyroid hormones. 3. Insulin treatment of diabetic rats for 10 days corrected the changes observed in diabetic atria. Serum levels of thyroid hormones returned to normal following insulin treatment as well. 4. Administration of insulin to thyroidectomized-diabetic rats did not reverse the diabetes-induced changes suggesting that thyroid hormones are needed for insulin to normalize the alterations observed in diabetic atria.

Effects of L-arginine on blood pressure and metabolic changes in fructose-hypertensive rats.

In the present study, we examined the effects of chronic L-arginine treatment on plasma insulin levels and systolic blood pressure (SBP) in fructose-fed (F) rats. Fructose feeding resulted in hyperinsulinemia and elevated blood pressure when compared with that in controls (plasma insulin, 311.3+/-11.4 v control 164.4+/-11.8 pmol/L, P < .05; SBP, 135.4+/-4.2 v control 105.5+/-1.3 mm Hg, P < .05). L-arginine treatment of fructose-hypertensive rats prevented the development of hyperinsulinemia and hypertension (plasma insulin, 200.1+/-7.5 pmol/L; P < .05 compared with that in F rats; SBP, 108.0+/-0.9 mm Hg; P < .05 compared with F rats). However, treatment with L-arginine did not influence any of these parameters in control rats. Statistical analysis of the data of plasma insulin level and SBP, revealed a significant correlation between these two variables. On the other hand, L-arginine treatment of F rats prevented the increased glucose and insulin concentrations in response to oral glucose challenge. L-arginine treatment also prevented the decrease in insulin sensitivity of F rats. These results indicate that L-arginine treatment is able to prevent fructose-induced hypertension and hyperinsulinemia. Our data also suggest a strong relationship between hyperinsulinemia and hypertension in this hypertensive rat model. Therefore, the antihypertensive effect of L-arginine could be, at least in part, the result of the restoration of plasma insulin levels by its vasodilator ability to increase blood flow to insulin sensitive tissues.

The effects of chronic L-arginine treatment on vascular responsiveness of streptozotocin-diabetic rats

In this study, the protective effects of L-arginine treatment in vivo on vascular reactivity of streptozotocin (STZ)-induced 12-week-old diabetic rats were examined. Loss of weight, polydipsia, polyphagia, hyperglycemia, hypoinsulinemia, and elevated levels of plasma cholesterol and triglyceride were observed in diabetic rats. L-arginine treatment (1 mg/mL in drinking water) did not significantly affect these metabolic and biochemical abnormalities. Plasma malondialdehyde (MDA) levels in untreated diabetic rats were also significantly higher than untreated controls. However, L-arginine treatment prevented the increase in MDA level of plasma of diabetic rats. Contractile responses, but not sensitivity to noradrenaline (NA), were significantly increased in diabetic rats compared to controls. Treatment of diabetic rats with L-arginine completely prevented the increase in NA responses. Relaxation response to acetylcholine (ACh), but not to sodium nitroprusside (SNP), in diabetic aorta has been found to be significantly decreased as compared with controls. However, there were no significant differences in pD2 values of acetylcholine in either of the groups. L-arginine treatment increased the ACh responses to the control level. All effects of L-arginine on vascular reactivity were found to be specific for diabetic rats and not controls. These results suggest that functional abnormalities occurred in aorta from diabetic rat might at least in part result from L-arginine deficiency, and the lipid peroxidation-lowering effect of L-arginine may account for its protective effect on vascular reactivity of diabetic rats.

Decreased β-adrenergic responses of rat small intestine due to non-insulin-dependent diabetes

Abstract Relaxing responses to salbutamol of duodenum, jejunum and ileum isolated from alloxan-induced non-insulin-dependent diabetic rats were investigated by means of pharmacodynamic analysis using pD 2 (apparent receptor affinity) and α E (intrinsic activity) values. β-Adrenergic responses of these three intestinal parts of diabetic rats were found to be significantly decreased when compared to controls. The decreased responses may be attributable to a decrease in the number of β-adrenergic receptors. The gastro-intestinal manifestations reported in diabetic patients are possibly linked to the occurrence of a decrease in β-adrenergic receptors. Furthermore, this model seems to be useful for the investigations of gastro-intestinal complications resulting from non-insulin-dependent diabetes.

Decreased gastro-intestinal responses to salbutamol and serotonin in streptozotocin-induced diabetes: Improving effect of insulin in vivo and in vitro

1. Decreased gastro-intestinal responses to salbutamol (sal) and serotonin (5-HT) in experimental diabetes have been postulated. The present study was designed to investigate whether in vivo and in vitro insulin treatments improve the decreased gastro-intestinal responses. 2. In vivo insulin treatment (166.7 micrograms/kg/day i.p.) for 6 weeks is able to improve both decreased gastro-intestinal beta-adrenergic and serotonergic responses. 3. Insulin incubation in bathing medium for 4-5 hr enhances the decreased gastro-intestinal responses to sal, but not to 5-HT. 4. The above results strongly suggest that the improving effect of insulin on the gastro-intestinal beta-adrenergic responses is direct in nature. In contrast, the improving effect on insulin on the serotonergic responses occurs via an indirect mechanism.

Increased α1-adrenergic responsiveness of alloxan diabetic rat atria: effects of insulin therapy and thyroidectomy

1. Experimental models of diabetes are increasingly used for the investigation of cardiovascular complications as well as other complications due to diabetes mellitus. However, animal models have been used in relatively few studies on the myocardial alpha 1-adrenergic responses. Hence, this report describes the effect of alloxan-induced diabetes and insulin-treatment on the alpha 1-adrenergic responses of the isolated rat atria. 2. Alloxan-induced diabetes caused an increase in the alpha 1-adrenergic responses assessed in isolated spontaneously beating rat atria. Both pD2 and alpha E values for phenylephrine, an alpha 1-adrenergic agonist were increased in atria from rats with alloxan diabetes. 3. Insulin treatment (4 IU/kg/day, s.c.) for 10 days normalized the changes in diabetic rat atria. pD2 and alpha E values for phenylephrine were slightly lower than those from control rats. Serum levels of thyroid hormones returned to normal following insulin treatment as well. 4. The effect of insulin on the increased alpha 1-adrenergic responses of rat atria due to alloxan diabetes seems to be related to thyroid hormone metabolism, since thyroidectomy also changed the atrial parameters measured. 5. The finding obtained in this study suggest that experimentally-induced diabetes increases alpha 1-adrenergic sensitivity of the rat atria possibly due to an increased receptor affinity, but these changes can be reversed with insulin treatment.

The effect of vanadate on alloxan-diabetic rat atria

In this study, we examined the effect of vanadate treatment on cardiac changes recognized in diabetic rats. In addition, the possible contribution of thyroid hormones to vanadates effect on alloxan-diabetic atria was also investigated. Administration of alloxan to rats, as expected, resulted in hyperglycemia; hypoinsulinemia reduced thyroid hormone levels, decreased body weight and depressed cardiac function. Vanadate treatment of diabetic rats normalized blood glucose and serum thyroid hormone levels, neither were serum insulin levels of diabetic animals corrected after vanadate treatment. Vanadate treatment, however, did not affect the body weights of diabetic rats. Spontaneously-beating atria from diabetic rats were found to have decreased rates but increased forces of contractions compared with those from controls. On the other hand, the responsiveness of diabetic atria to both inotropic and chronotropic effects of isoprenaline was found to be decreased. Vanadate treatment resulted in the normalization of these alterations observed in diabetic atria. These results thus indicate that the normalizing effect of vanadate on diabetes-induced hypothyroidism may contribute to its effect in preventing cardiac changes observed at the early stage of diabetes.

The effects of chronic trimetazidine treatment on mechanical function and fatty acid oxidation in diabetic rat hearts

Clinical and experimental evidence suggest that increased rates of fatty acid oxidation in the myocardium result in impaired contractile function in both normal and diabetic hearts. Glucose utilization is decreased in type 1 diabetes, and fatty acid oxidation dominates for energy production at the expense of an increase in oxygen requirement. The objective of this study was to examine the effect of chronic treatment with trimetazidine (TMZ) on cardiac mechanical function and fatty acid oxidation in streptozocin (STZ)-diabetic rats. Spontaneously beating hearts from male Sprague-Dawley rats were subjected to a 60-minute aerobic perfusion period with a recirculating Krebs-Henseleit solution containing 11 mmol/L glucose, 100 muU/mL insulin, and 0.8 mmol/L palmitate prebound to 3% bovine serum albumin (BSA). Mechanical function of the hearts, as cardiac output x heart rate (in (mL/min).(beats/min).10-2), was deteriorated in diabetic (73 +/- 4) and TMZ-treated diabetic (61 +/- 7) groups compared with control (119 +/- 3) and TMZ-treated controls (131 +/- 6). TMZ treatment increased coronary flow in TMZ-treated control (23 +/- 1 mL/min) hearts compared with untreated controls (18 +/- 1 mL/min). The mRNA expression of 3-ketoacyl-CoA thiolase (3-KAT) was increased in diabetic hearts. The inhibitory effect of TMZ on fatty acid oxidation was not detected at 0.8 mmol/L palmitate in the perfusate. Addition of 1 mumol/L TMZ 30 min into the perfusion did not affect fatty acid oxidation rates, cardiac work, or coronary flow. Our results suggest that higher expression of 3-KAT in diabetic rats might require increased concentrations of TMZ for the inhibitory effect on fatty acid oxidation. A detailed kinetic analysis of 3-KAT using different concentrations of fatty acid will determine the fatty acid inhibitory concentration of TMZ in diabetic state where plasma fatty acid levels are increased.