Impaired Contraction and Endothelium-Dependent Relaxation in Isolated Resistance Vessels from Patients with Insulin-Dependent Diabetes Mellitus

Abstract

1. An increase in capillary blood flow and pressure has been implicated in the pathogenesis of diabetic microangiopathy. Abnormal vascular reactivity of the resistance vasculature may play a contributory role by permitting alterations in regional haemodynamics. 2. We have studied the contractile behavior of isolated resistance arteries from normotensive patients with insulin-dependent diabetes mellitus and non-diabetic matched control subjects. Contractile responses to potassium (123 mmol/l), noradrenaline (10(-8) to 3 x 10(-5) mol/l) and angiotensin II (10(-11) to 3 x 10(-8) mol/l) were recorded. Relaxation studies were performed in maximally contracted vessels using acetylcholine (10(-8) to 10(-5) mol/l) and bradykinin (10(-9) to 10(-6) mol/l) (endothelium-dependent) and sodium nitroprusside (10(-9) to 10(-5) mol/l) (endothelium-independent). 3. The maximal contractile responses to potassium (P < 0.05), noradrenaline (P < 0.01) and angiotensin II (P < 0.01) were depressed in diabetic patients. Relaxation to acetylcholine was impaired (P < 0.05), but was normal with bradykinin and sodium nitroprusside. 4. These results suggest that there may be a defect in the endothelial cell acetylcholine receptor excitation-coupling in diabetes mellitus rather than a decreased ability to synthesize and release endothelium-derived relaxing factor. Impaired contraction and endothelium-dependent relaxation of resistance arteries in diabetic patients may contribute to the development of diabetic microangiopathy by causing an increase in tissue blood flow, a rise in capillary pressure and, as a result, an increase in vascular permeability.

Impaired endothelium‐dependent relaxation in isolated resistance arteries of spontaneously diabetic rats

“…Moreover, a study of insulin-treated STZ-induced diabetic rats, showed that insulin did not prevent enhanced contractility to NA, although it did prevent impaired endothelium-dependent relaxation to ACh (Taylor et al, 1994a). These findings contrast with those from human studies, which have shown resistance arteries from insulin dependent diabetis mellitus (IDDM) patients without complications other than background retinopathy, display impaired contractile responses to NA, and impaired endothelium-dependent relaxation to ACh (McNally et al, 1994); furthermore, resistance arteries from healthy volunteers exposed to increasing concentrations of insulin show decreased contractile response to NA in a dose-dependent manner (McNally et al, 1995). Thus, the altered reactivity found with chemically induced diabetes may depend on the vascular effect of streptozotocin per se.…”

“…Thus, impaired relaxation responses to an endothelium-dependent vasodilator, acetylcholine, have been demonstrated in the large blood vessels of animals with experimentally induced diabetes (Oyama et al, 1986;Kamata et al, 1989;Tesfamariam et al, 1990;Mayhan et al, 1991). Similarly, defective endothelium-dependent relaxation has been demonstrated in the smooth muscle of the corpora cavernosa in diabetic man (de Tejada et al, 1989), and isolated subcutaneous resistance arteries from juvenile onset insulin-dependent diabetics (McNally et al, 1994). Other studies have demonstrated that acetylcholine relaxation response attenuation of diabetic rabbit aorta and normal rabbit aorta exposed to elevated glucose in vitro is restored with a cyclo-oxygenase inhibitor, suggesting a release of a vasoconstricting prostanoid in diabetes (Tesfamariam et al, 1990;Tesfamariam 1994).…”

Endothelial dysfunction in diabetes

“…Impaired ACh-induced relaxation with normal responses to bradykinin has been reported in isolated resistance vessels from patients with type I diabetes (McNally et al, 1994), in the forearm circulation of type II diabetes patients (Gazis et al, 1999) and in mesenteric and hindlimb arteries of streptozotocin (STZ)-rats (Lash & Bohlen, 1991;Taylor et al, 1995), suggesting an abnormality at the level of the G-proteins. However, several other studies found equally suppressed responses to di erent endothelium-dependent agonists (Heygate et al, 1995;Fulton et al, 1996;Costa e Forti & Fonteles, 1998;Mayhan & Patel, 1995;1998;Mayhan, 1997) or impaired relaxation to the calcium-ionophore A23187 (Oyama et al, 1986;Durante et al, 1988;Cameron & Cotter, 1992;Fukao et al, 1997), making a disturbance of receptors or receptor-coupled mechanisms unlikely as a common mechanism of endothelial dysfunction.…”

The effect of insulin on the vascular reactivity of isolated resistance arteries taken from healthy volunteers

“…Drury et al [33] reported that the vascular response to angiotensin II was increased in IDDM patients without microvascular complications. However, impaired vascular responses to angiotensin II have been shown in patients with diabetes [15,35]. Recently, Wamback and Lui [36] demonstrated that insulin attenuated the vasoconstrictor response to a variety of agonists, including noradrenaline, serotonin and potassium chloride in rat mesenteric arterioles, suggesting that the action of insulin on vascular reactivity is not specific for a given receptor system.…”