High glucose-enhanced acetylcholine stimulated CGMP masks impaired vascular reactivity in tail arteries from short-term hyperglycemic rats.

UNLABELLED: Impaired vascular endothelium-dependent relaxation and augmented contractile responses have been reported in several models of long-term hyperglycemia. However, the effects of short-term ambient hyperglycemia are poorly understood. Since oxidative stress has been implicated as a contributor to impaired vascular function, we investigated the following: AIMS: (1) the effects of high glucose exposure in vitro (7-10 days) on vascular relaxation to acetylcholine (Ach) and contractility to norepinephrine (NE) and KCl; (2) if NO-dependent cGMP generation is affected under these conditions; and (3) aortic redox status. METHODS: Non-diabetic rat tail artery rings were incubated in normal (5mM) (control NG) or high (20 mM) glucose buffer (control HG). Vascular responses to Ach, NE and KCl were compared to those of streptozotocin (SZ) diabetic animals in the same buffers (diabetic NG, diabetic HG). Ach-stimulated cGMP levels were quantitated as an indirect assessment of endothelial nitric oxide (NO) production and oxidative stress evaluated by measuring vascular glutathione and oxidized glutathione. RESULTS: Rings from diabetic rats in NG showed impaired relaxation to Ach (P = 0.002) but relaxed normally, when maintained in HG. Similarly, contractile responses to NE were attenuated in diabetic rings in NG but similar to controls in HG. HG markedly augmented maximal contraction to KCl compared to control and diabetic vessels in NG (P < 0.0001). Diabetic vessels in a hyperosmolar, but normoglycemic, milieu respond like those in HG. In vitro, HG for 2 hours changed neither relaxation nor contractile responses to NE and KCl in control rings. Basal cGMP levels were lower in aortae from diabetic animals pre-incubated in NG than in HG/LG or in control rings in NG (P < 0.05). cGMP responses to Ach were exaggerated in diabetic vessels in HG (P = 0.035 vs. control NG, P = 0.043 vs. diabetic NG) but not different between control and diabetic rings in NG. Vessels from diabetic animals had lower levels of GISH (P < 0.0001) and higher levels of GSSG (P < 0.0001) indicating oxidative stress. CONCLUSIONS: Our data indicate that endothelium-dependent relaxation is altered early in the diabetic state and that increased NO responses may compensate for augmented oxidative stress but the lack of effect of short-term exposure of normal vessels to HG suggests that short-term hyperglycemia per se does not cause abnormal vascular responses.

Augmentation of the inotropic response to insulin in diabetic rat hearts.

Insulin participates in the modulation of myocardial function, but its inotropic action in diabetes mellitus is not fully clear. In the present study, we examined contractile responses to insulin in left-ventricular papillary muscles and ventricular myocytes isolated from hearts of normal or short-term (5-7 days) streptozotocin-induced (65 mg/kg) diabetic rats. Mechanical properties of papillary muscles and ventricular myocytes were evaluated using a force transducer and an edge-detector, respectively. Contractile properties of papillary muscles or cardiac myocytes, electrically stimulated at 0.5 Hz, were analyzed in terms of peak tension development (PTD) or peak twitch amplitude (PTA), time-to-peak contraction (TPT) and time-to-90% relaxation (RT90). Intracellular Ca2+ transients were measured as fura-2 fluorescence intensity change (deltaFFI). Insulin (1-500 nM) had no effect on PTD in normal myocardium, whereas it produced a positive inotropic response in preparations from diabetic animals, with a maximal increase of 11%. Insulin did not modify TPT or RT90 in either group. Further studies revealed that insulin enhanced cell shortening in diabetic but not normal myocytes, with a maximal increase of 21%. Consistent with its action on the mechanical properties of papillary muscles and cardiac myocytes, insulin also induced a dose-dependent increase in the intracellular Ca2+ transient in diabetic but not normal myocytes. Collectively, these data suggest that the myocardial contractile response to insulin may be altered in diabetes.

Difficult-to-treat hypertensive populations: focus on African-Americans and people with type 2 diabetes.

The awareness, treatment, and control of hypertension has risen steadily over the past three decades, until the early 1990s. However, blood pressure control to < 140/90 mmHg is attained in fewer than 25% of all hypertensive patients and fewer than 50% of drug-treated hypertensive patients, except for white women. Two special populations, African-Americans and diabetics, share several important attributes. First, they both have a high prevalence of hypertension, including stage 3 hypertension (as defined by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of Hypertension VI: > or =180/110 mmHg), relative to other subgroups. African-Americans have an approximate 8% prevalence of stage 3 hypertension, and elevated systolic blood pressure is highly prevalent among diabetic people, particularly older African-American women. Second, both groups have high levels of blood-pressure-related target-organ damage, which contributes to their inordinately high absolute risk for cardiovascular disease complications (i.e. stroke, congestive heart failure, renal failure) at a given level of blood pressure. Moreover, the reduced natriuretic capacity common to each group contributes to the attenuated efficacy of antihypertensive drug monotherapy, particularly for drug classes other than diuretics and calcium antagonists. These two special populations are also typically salt-sensitive, an intermediate blood pressure phenotype that raises blood pressure medication requirements. This phenomenon has been associated with an attenuation in the normal nocturnal fall in blood pressure. The high absolute risk for cardiovascular disease among diabetics led to the formulation of more aggressive treatment recommendations for antihypertensive drug therapy. In diabetics, blood pressure therapy is initiated at blood pressures > or = 130/85 mmHg, and treatment goals are at least to this level, unless proteinuria is > or = 1g/day (in which case the goals are < 125/75 mmHg). The more aggressive treatment targets for diabetics will not be reached with most currently available single antihypertensive agents in many African-Americans. While at best only 50-60% of hypertensive patients can be controlled with single drug therapy, that percentage falls dramatically in persons with stage 3 hypertension and renal insufficiency, thereby necessitating the use of combination drug therapy. Treatment alone is not enough; treatment to goal blood pressure is an essential first step towards optimal target-organ protection. While circulating levels of renin are suppressed, in general, in these special populations, each group manifests an inordinate burden of blood-pressure-related target-organ damage that has been linked to excessive levels of angiotensin II or a reduced bradykinin and nitric oxide tissue effect. The renin-angiotensin-aldo-sterone-kinin system is therefore an attractive therapeutic target that might conceivably provide target-organ protection over and above that attributable solely to lowering the blood pressure.

Diabetic vascular disease and hypertension.

There is increasing evidence that essential hypertension is associated with a panoply of metabolic abnormalities. Included in these abnormalities are insulin resistance, dyslipidemia, enhanced coagulation, and decreased fibrinolytic activity, microalbuminuria, and platelet abnormalities and endothelial dysfunction. Visceral obesity appears to be the most common and predictive underlying factor for all of these metabolic abnormalities accompanying hypertension as well as increased cardiovascular disease (CVD) risk. As the prevalence of obesity is increasing, there is cause for concern that CVD increases will parallel this risk factor, particularly in especially high-risk populations, such as African-American women. Other important risk factors, such as increased oxidative stress, may require special therapeutic strategies, including the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin blockers as cornerstones of antihypertensive drug therapy.

Altered inotropic response to IGF-I in diabetic rat heart: influence of intracellular Ca2+ and NO.

Normally, insulin-like growth factor I (IGF-I) exerts positive effects on cardiac growth and myocardial contractility, but resistance to its action has been reported in diabetes. This study was designed to determine whether IGF-I-induced myocardial contractile action is altered in diabetes as a result of an intrinsic alteration of contractile properties at the cellular level. Contractile responses to IGF-I were examined in left ventricular papillary muscles and ventricular myocytes from normal and short-term (5-7 days) streptozotocin-induced diabetic rats. Mechanical properties of muscles and myocytes were evaluated using a force transducer and an edge detector, respectively. Preparations were electrically stimulated at 0.5 Hz, and contractile properties analyzed include peak tension development (PTD) or peak twitch amplitude (PTA), time to peak contraction/shortening, and time to 90% relaxation/relengthening. Intracellular Ca2+ transients were measured as fura 2 fluorescence intensity changes. IGF-I (1-500 ng/ml) caused a dose-dependent increase in PTD and PTA in preparations from normal but not diabetic animals. IGF-I did not alter time to peak contraction/shortening or time to 90% relaxation/relengthening. Pretreatment with the NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (100 microM) attenuated IGF-I-induced increases in PTD in normal myocardium but unmasked a positive inotropic action in diabetic animals. Pretreatment with Nomega-nitro-L-arginine methyl ester blocked IGF-I-induced increases in PTA in single myocytes. Consistent with its inotropic actions on muscles and myocytes, IGF-I induced a dose-dependent increase in Ca2+ transients in normal but not diabetic myocytes. These results suggest that the IGF-I-induced inotropic response is depressed in diabetes because of an intrinsic alteration at the myocyte level. Mechanisms underlying this alteration in IGF-I-induced myocardial response may be related to changes in intracellular Ca2+ and/or NO production in diabetes.

Renin-angiotensin-aldosterone-kinin system influences on diabetic vascular disease and cardiomyopathy.

Diabetes mellitus is associated with an inordinately high risk of virtually all manifestations of cardiovascular-renal disease including atherosclerotic coronary and peripheral vascular disease, congestive heart failure, stroke, nephropathy, and cardiomyopathy unassociated with coronary heart disease. Abnormalities in the renin-angiotensin-aldosterone-kinin (RAAK) cascade have been implicated in the pathogenesis and clinical expression of these cardiovascular-renal sequelae. Thus, pharmacological modulation of the RAAK system is an attractive therapeutic target in diabetes mellitus. Indeed, emerging data from human clinical studies appear to confirm this thesis.