Influence of diabetes on the reactivity of mesenteric microvessels to histamine, bradykinin and acetylcholine

Abstract

1 Noradrenaline (NA) evoked a vasoconstrictor response in rat mesenteric microvessels in situ, the latency and nature of which was analogous in normal and alloxan-diabetic animals. 2 Histamine and bradykinin (Bk) were capable of antagonizing the response to NA in normal but not in diabetic animals. In contrast, acetylcholine (ACh) was equally effective as an antagonist to NA in both groups of animals. 3 The altered responses to histamine and Bk were not associated with hyperglycaemia since fasting rendered the diabetic animals normoglycaemic and yet did not restore the reactivity of microvessels. Previous administration of insulin to diabetic animals corrected the impaired responses to histamine and Bk.4 A similar condition of impaired responses to histamine and Bk was produced in normal animals by the intravenous injection of 2-deoxyglucose although ACh remained fully active. 5 Apparently, the functional changes observed in the response to histamine or Bk, as antagonists of the vasoconstrictor reaction to NA, were not associated with a defective response of all smooth muscle. First, because ACh remained active in diabetic animals, and, second, because extravascular smooth muscles obtained from either normal or diabetic rats were equally relaxed by histamine or Bk in vitro.6 It is suggested that histamine and Bk antagonized the vasoconstrictor response of microvessels to NA through an action on lining endothelial cells resulting in increased vascular permeability and hyperosmolarity of extracellular fluids. 7 The process depended on the availability of insulin, and, therefore, might be affected by intracellular glucopaenia as occurring in diabetes. 8 Intracellular glucopaenia markedly affected other structures. Reduced atria rates were observed in diabetes, despite the fact that the isolated preparation responded normally to NA, ACh or tyramine. Partial substitution of glucose in the bathing fluid by 2-deoxyglucose or addition of NaF to the organ bath evoked similar changes in atria from normal animals.9 ACh which has little effect on vascular permeability must exert its vasodilator effects through mechanisms which are different from those influenced by the biochemical changes occurring in diabetes.

Influence of the vascular endothelium on agonist‐induced contractions and relaxations in rat aorta

“…It became relatively powerful when the endothelium had been removed, but with an Emax lower than that of noradrenaline. In contrast to angiotensin II, however, it was possible to demonstrate that histamine was capable of stimulating the release of EDRF confirming the results of other workers (Van de Voorde & Leusen, 1983;Fortes et al, 1983;Rapoport & Murad, 1983;Davies & Williams, 1984;Carrier et al, 1984). It thus seems possible that the differences in the responses of rubbed and intact preparations to histamine result from the reduced effectiveness of histamine on intact preparations due both to basal and to stimulated EDRF release.…”

Vascular reactivity in diabetes mellitus: role of the endothelial cell

“…Second, because a similar condition of impaired response to these agents is produced in normal animals by the intravenous injection of 2-deoxyglucose, the acute effects of which are the result of intracellular glucopaenia, secondary to inhibition of glucose utilization. Acetylcholine remains fully active in this situation (Fortes et al 1983). Increased vascular permeability, which leads to local and temporary changes in composition of extra-vascular fluid, is generally associated with the partial disconnection of endothelial cells along the intercellular junctions, resulting in the formation of gaps through which intravascular materials exude (Majno & Palade, 1961).…”

“…Accordingly, histamine and bradykinin must antagonize the vasoconstrictor effect of noradrenaline in microvessels through a different mechanism from acetylcholine. Local and temporary changes in composition of the interstitial fluid resulting from the effect of permeability-increasing factors might be relevant factors to explain such differences (Fortes, Garcia Leme & Scivoletto, 1983).…”

Pharmacological studies of human erectile tissue: characteristics of spontaneous contractions and alterations in α‐adrenoceptor responsiveness with age and disease in isolated tissues

“…For example, such alterations are among the contributing factors to the vascular complications of diabetes mellitus (Brody & Dixon;1964;Fortes et al, 1983;Factor et al, 1984;White & Carrier, 1986) and perhaps essential hypertension, coronary vasospasm, Raynaud's syndrome (van Zwieten, 1987;Vanhoutte, 1987;Hollenberg, 1987) and male impotentia as well (see below). However, despite recently demonstrated interspecies differences in vascular responsiveness to endogenous substances (Malomvolgyi et al, 1988), relatively little work has focused on the study of vascular pathophysiology utilizing human isolated tissue preparations (Docherty, 1987;Godfraind et al, 1988).…”