1 This study investigated the responsiveness to vasoconstrictor agents (including endothelin-1, ET-1) of aortic rings from rats with two-week streptozotocin (STZ, 60mgkg-', i.v.)-induced diabetes and vehicletreated control rats. The basal tension was 10g, which was estimated to be more physiological than the tension of 1-2 g that has been previously used for most studies of aortic rings from diabetic rats. 2 Maximum responses to ET-1 (0.13-18 nM), KCl (2-20mM) or CaCl2 (1OpM-10mM) were reduced in aortae from STZ-treated rats compared to those from control rats. Such reductions were still evident after removal of the endothelium. 3 Responses to noradrenaline (NA, 0.1 nM-26pM) of aortae from STZ-treated rats were not significantly different from responses of aortae of control rats.4 Removal of endothelium resulted in a significant reduction in the EC50 values for NA of rings from both STZ-treated rats (6.90 + 0.13 and 8.17 + 0.35 (-logM) with and without endothelium, respectively, n = 5) and control rats (6.90 + 0.15 and 8.37 + 0.44 (-logM) with and without endothelium, respectively, n= 5).5 In calcium-free medium (with 1 mm EGTA), responses to NA and ET-1 were reduced compared with those in normal Krebs solution and maximum responses were less in rings from STZ-treated compared with control rats. 6 Indomethacin (5,UM) did not prevent the reduced maximum responsiveness to ET-1 in rings from STZ-treated rats compared with those from controls. 7 This study indicates that changes in vascular responsiveness to ET-1, KCI and CaCl2 (but not NA) occur in aortae of two-week STZ-treated rats. The endothelium does not appear to play a major role in mediating changes in responsiveness to ET-1.

1. Dose-response curves were obtained to bolus injections of 5-hydroxytryptamine (5-HT) in Krebs'-perfused hindquarters of male Wistar rats. Vasoconstrictor responses to 5-HT (5.7-363 nmol/kg) were significantly attenuated in hindquarters of alloxan-treated 14 day diabetic rats compared with non-diabetics. 2. Infusion of the thromboxane A2 (TxA2)-mimetic U46619 (317 and 31.7, but not 3.17 nmol/L) significantly potentiated vasoconstrictor responses to 5-HT in Krebs'-perfused hindquarters of non-diabetic and diabetic rats. The degree of potentiation was similar for both groups. 3. In Krebs'-perfused hindquarters of non-diabetic rats, infusion of the alpha 1-adrenoceptor agonist methoxamine (8.96 mumol/L, which caused a rise in perfusion pressure intermediate in magnitude to that produced by infusion of 31.7 and 317 nmol/L U46619) did not significantly affect responses to bolus injections of 5-HT. 4. The same concentration of methoxamine did not cause a significant potentiation of vasoconstrictor responses to 5-HT (except for the two highest 5-HT doses, 182 and 363 nmol/kg) in hindquarters of diabetic rats. This potentiation was significantly less than that due to 317 nmol/L U46619, although there was no significant difference between the rise in basal perfusion pressures produced by these concentrations of methoxamine and U46619. 5. Infusion of the TxA2 receptor antagonist AH23848 (111 nmol/L) inhibited the potentiating effect of U46619 (317 nmol/L) on responses to 5-HT in both non-diabetic and diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

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1. The effects of ATP, the stable ATP analogues alpha,beta-methylene ATP (alpha,beta-mATP), 2-methylthioATP (2meSATP) and adenosine tetraphosphate (ATP4), the pyrimidine nucleotide uridine 5'-triphosphate (UTP) and the alpha1-adrenoceptor agonist phenylephrine were examined on the isolated perfused uterine vasculature of dioestrous, oestradiol-treated, dexamethasone-treated and late-pregnant guinea-pigs. 2. The alpha1-adrenoceptor agonist phenylephrine elicited concentration-dependent vasoconstriction from preparations of perfused uterine vasculature from dioestrous, estradiol-treated and late-pregnant guinea-pigs. The mean maximal response to phenylephrine was unaffected by treatment of dioestrus guinea-pigs with oestradiol or dexamethasone, but was reduced in preparations from late-pregnant animals. 3. In perfused uterine arteries from dioestrous animals, the pyrimidine UTP, but not ATP4 and ATP, elicited vasoconstrictor responses. In preparations from oestradiol-treated animals, all three agonists elicited vasoconstriction, with a rank order of potency of ATP4 = UTP >> ATP, whereas in preparations from late-pregnant animals this order of potency was ATP4 >> UTP = ATP. In preparations from dexamethasone-treated animals, the vasoconstriction was similar to that seen in dioestrous animals. Vasoconstrictor responses to ATP4 were significantly greater in preparations of uterine vasculature from oestradiol-treated and pregnant animals than in preparations from dioestrous animals or dexamethasone-treated animals. 4. In preparations from dioestrous, oestradiol-treated, pregnant and dexamethasone-treated animals, alpha,beta-mATP was approximately two to three orders of magnitude more potent than 2meSATP. Compared with preparations from dioestrous animals, the maximal responses to alpha,beta-mATP were significantly greater in tissues from oestradiol-treated and pregnant animals. In preparations from dioestrous animals, the P2 purinoceptor antagonist suramin (100 micro mol/L) inhibited the responses to alpha,beta-mATP, but not those to ATP4. 5. The present study has demonstrated that pregnancy, but not the steroid treatment of dioestrous guinea-pigs with oestradiol or dexamethasone, reduces the sensitivity of the guinea-pig isolated perfused uterine vasculature to phenylephrine. In contrast, preparations from pregnant or oestradiol-treated guinea-pigs respond to ATP4 and to alpha,beta-mATP with significantly greater constrictions than those of dioestrous or dexamethasone-treated animals. These data indicate that the sensitivity of the uterine vasculature to adrenoceptor and purinoceptor agonists is differentially regulated by oestradiol and pregnancy, but not by the synthetic glucocorticoid dexamethasone.

This paper attempts to provide a short review of the evidence for: 1. Increased platelet production of thromboxane A2 and reduced vascular production of prostacyclin in the human and also animal models of diabetes. 2. Reduced depressor responsiveness to arachidonic acid of anaesthetized alloxan- and streptozotocin-induced diabetic rats. 3. Enhanced constrictor responsiveness to arachidonic acid in blood-perfused hindquarters of alloxan-induced diabetic rats. 4. Potentiation by the thromboxane A2-mimetic, U46619, of constrictor responses to 5-hydroxytryptamine in Krebs'-perfused hindquarters and kidneys of both control and alloxan-induced diabetic rats. 5. Alterations during diabetes in production of, and responsiveness to, eicosanoids may contribute to the cardiovascular changes which occur in this disease.