The diabetic heart: A review of the lifework of Sophie Maria Koltai.

It is well known that cardiovascular alterations are the principal causes of mortality in patients with diabetes. Premature and accelerated atherosclerosis cannot be the sole cause of diabetic heart disease because functional disorders develop both in experimental and in clinical diabetes before the onset of the detectable morphological changes of the vessel wall. Namely, altered adrenergic responses and prostaglandin metabolism and diminished vasodilatory ability can be seen in diabetic vessels.

Characteristics of coronary endothelial dysfunction in experimental diabetes.

Objective: To study the influence of diabetes on the endothelium-dependent vasodilation in the coronary arterial bed.

Methods: The effects of acetylcholine (ACh 2-36 pmol.kg-1; 18 nmol.

Comparison of the vasodilatory effects of bradykinin in isolated dog renal arteries and in buffer-perfused dog kidneys.

This study was undertaken to investigate the role of nitric oxide (NO), cyclooxygenase products and bradykinin (Bk) receptors in the Bk evoked responses of canine renal arteries and perfused kidneys. Rings of isolated canine renal arteries were mounted in organ chambers for measurement of isometric force. The isolated canine kidneys were perfused with Krebs-solution (constant flow) and the perfusion pressure was continuously recorded.

Captopril produces endothelium-dependent relaxation of dog isolated renal arteries. Potential role of bradykinin.

The effects of the angiotensin-converting enzyme inhibitors, captopril, lisinopril and enalapril-maleate (the latter being a prodrug that has to be converted into enalaprilat), and bradykinin were investigated in the presence or absence of indomethacin and bradykinin receptor antagonists in dog renal arterial rings precontracted with either prostaglandin F2 alpha or phenylephrine. At a high precontraction level (10 microM of prostaglandin F2 alpha), captopril did not relax the arteries. However, when the tension was low (0.

Disturbed lipid metabolism in diabetic coronary vessels.

The aim of this study was to clarify whether or not arachidonic acid metabolic disorders are caused by a substrate inavailability and whether such disorders might contribute to circulatory disturbances in the diabetic myocardium. Norepinephrine induced a decrease in the conductivity of both coronary arterial bed and myocardial microcirculation in alloxan-diabetic dogs. It was markedly (p less than 0.

Increased vasoconstrictor response to noradrenaline in femoral vascular bed of diabetic dogs. Is thromboxane A2 involved?

Study Objective: The aim was to determine the role of cyclo-oxygenase products in the vasoconstrictor response of femoral arterial bed to noradrenaline and to analyse the role of vascular adrenoceptors in the synthesis of cyclo-oxygenase products.

Design: The influence of intra-arterially injected cyclo-oxygenase inhibitors indomethacin and acetylsalicylic acid on alterations in conductance of femoral arterial bed induced by noradrenaline was compared in metabolically healthy and alloxan diabetic dogs. PGI2 and TXA2 synthesising ability of isolated femoral arterial rings was measured with and without inhibition of alpha adrenoceptors by phentolamine.

Critical evaluation of the in vivo selectivity between hypotensive and platelet antiaggregating actions of iloprost and prostacyclin in beagle dogs.

We compared the hypotensive and antiaggregatory effects of PGI2 and iloprost using our computerized aggregometric system. The concentration producing 50% inhibition (IC50) of ADP-induced platelet aggregation in vitro was 0.35 +/- 0.

Altered responsiveness of diabetic dog renal arteries to acetylcholine and phenylephrine: role of endothelium.

The mechanical responses to acetylcholine (ACh), sodium nitroprusside and phenylephrine (PE) were determined in normal and diabetic dog renal arterial strips with and without endothelium. Experimental diabetes increased the sensitivity, IC50 = (2.9 +/- 0.

Insulin induced reversibility of altered responsiveness in femoral arterial bed of diabetic dogs.

The altered reactivities of femoral arterial bed to noradrenaline, phenylephrine, adenosine and prostacyclin were compared in 18, clinically manifest but aketotic, alloxan diabetic mongrel dogs. Alloxan treatment markedly increased the vasoconstrictor responses to noradrenaline and phenylephrine, as well as the adenosine-induced vasodilation in the femoral vasculature. These changes were prevented or normalized, respectively, in the early or late insulin-treated alloxan diabetic animals.

Relationship between vascular adrenergic receptors and prostaglandin biosyntheses in canine diabetic coronary arteries.

Before the onset of histologically detectable alterations of diabetic arteries, a considerable decrease of vasodilation ability develops. The role of an altered prostaglandin biosynthesis in this phenomenon was investigated in connection to the altered vascular adrenergic mechanisms. The effect of phenylephrine on prostacyclin production of isolated coronary arterial rings (100 mumol/l) as well as on conductivity of the coronary arterial bed (7.

Influence of experimental diabetes on the mechanical responses of canine coronary arteries: role of endothelium.

The influence of experimental diabetes on the endothelium mediated relaxation and contractile responses of canine isolated coronary arteries was studied in arteries removed from alloxan treated diabetic (280 mmol.kg-1) and control mongrel dogs. Strips with and without endothelium were suspended in Krebs bicarbonate solution for isometric recording.

Vasodilator responses in perfused rabbit kidney: the role of endothelium.

The responses to vasodilator agents of renal vasculature were studied in perfused rabbit kidney. Acetylcholine (ACh) and calcium-ionophore (A23187), as endothelium-dependent relaxing agents, and prostacyclin (PGI2), an endothelium-independent vasodilator, induced a rapid and reversible fall in perfusion pressure of the noradrenaline (NA) constricted renal vasculature. The vasodilator responses of the preparations were not lost after perfusing the kidney with hypotonic Krebs-solution or 10 mumol/l mepacrine.

Contractile and relaxant responses of diabetic dog femoral arteries.

Strips of femoral arteries of normal and alloxan-treated dogs were set up for isometric recording. The contractile response to phenylephrine and the relaxant response to acetylcholine were determined. Neither alloxan treatment nor mechanical removal of endothelium altered the EC50 value for phenylephrine.

Prostaglandins and altered diabetic vasoregulation.

In previous studies an enhanced tendency to vasconstriction could be demonstrated in special regions, first of all in the coronary arterial bed of the diabetic vasculature. Analysing the role of prostaglandins in this phenomenon, the present work demonstrates that in vivo the dose-dependent decrease in the conductivity of the coronary arterial bed induced by PGF2 alpha (3, 6, 12, 24, 48 nmol/kg) administration in alloxan- (560 mumol/kg) diabetic dogs (n = 6) proved to be more expressed after indomethacin (10 mumol/kg) treatment compared with metabolically healthy (n = 6) animals. In the presence of indomethacin (3 mumol/l) PGF2 alpha (1, 3, 10, 30 mumol/l) evoked also considerably higher vasoconstriction in the isolated coronary rings of the diabetic dogs in comparison to the metabolically healthy state.

Actions of PGE2 and indomethacin on adrenergic neuroeffector transmission in the rabbit coeliac artery.

In the present study we have investigated the pre- and post-synaptic actions of PGE2 and indomethacin on the adrenergic transmission in isolated coeliac arteries of rabbits. The artery segment was preloaded with (3H)NA and suspended in an organ bath (37 degrees C, 5% CO2 - 95% O2, isometric recording). The preparation was superfused with Krebs-solution containing the uptake blockers cocaine and corticosterone.

Relaxation by prostacyclin (PGI2) of human, dog and rabbit femoral artery strips. Interspecies difference.

Helically cut femoral artery strips from humans (bypass surgery), dogs and rabbit were set up for isometric recording. The endothelial layer was removed by rubbing, hence the vascular strips used in this study are considered to be arterial smooth muscle preparations without endothelium. The indomethacin-, prostaglandin F2 alpha- and PGI2-induced changes in tone were determined.

In vivo antiaggregatory effect of BM 13.177 on the spontaneous platelet aggregation in anaesthetized beagle dogs.

The arterial blood of anaesthetized heparin-treated beagle dogs was directed through a 30/um diameter pore size screen by a roller pump at a constant rate. As a result, the pressure proximal to the filter continuously increased. The filtration pressure stabilizing concentration of prostacyclin (infused proximal to the filter) was determined.

Effects of PGI2, CH-7284 and CH-7384 on spontaneous platelet aggregation and blood pressure of anaesthetized beagles.

Chinoin-7284 and Chinoin-7384 are chemically stable derivatives of prostacyclin. We compared the hypotensive and antiaggregatory effects of PGI2 and the two analogues using our computerized aggregometric system. The in vivo antiaggregatory activity was measured with a modified filtration pressure technique in anaesthetized beagle dogs: The change in arterial blood pressure was measured simultaneously.

Effects of hypoxia and adrenergic stimulation induced alterations in PGI2 synthesis by diabetic coronary arteries.

Before the onset of histologically detectable alterations in diabetic arteries, a considerable decrease in vasodilatory potential is seen. While analyzing this phenomenon, the role of altered PGI2 synthesis in rings of coronary arteries from metabolically healthy and alloxan-diabetic dogs was measured by radioimmunoassay during baseline, under the influence of phenylephrine (100 mumol/L), and during hypoxia with or without the presence of the alpha adrenergic blocker phentolamine (5 mumol/L). Basal levels of PGI2 synthetized by healthy and diabetic coronaries were no different (7.

Endothelium-dependent vasodilator actions of acetylcholine, calcium-ionophore (A23187) and substance P in perfused renal arteries from rabbits.

The role of endothelium on the responses of the perfused rabbit renal artery segments to vasoconstrictor and vasodilator agents was studied. The vasoconstrictor responses of rabbit renal arteries to phenylephrine were enhanced by endothelium destruction. Acetylcholine (ACh), calcium-ionophore (A23187) and substance P (SP), in the presence of indomethacin, induced endothelium-dependent vasodilation of the phenylephrine-constricted renal arteries.

Inhibition by quinine of endothelium-dependent relaxation of rabbit aortic strips.

1 The effects of quinine sulphate, tetramethylammonium chloride (TMA) and tetraethylammonium chloride (TEA) (all blockers of the Ca2+-activated K+ channels) on the relaxations induced by acetylcholine (ACh), calcium ionophore A23187 and sodium nitrite were studied in helical strips of rabbit aorta. 2 The strips were contracted to a moderate stable tone with phenylephrine (10(-7) M). ACh (4 X 10(-9) to 10(-6) M) as well as A23187 (10(-8) to 3 X 10(-7) M) reduced this tone in a concentration- and endothelium-dependent manner.

Differential contractile responsiveness of femoral arteries from healthy and diabetic dogs: role of endothelium.

Phenylephrine-induced contraction and acetylcholine-induced relaxation of isolated femoral arterial strips (with and without endothelium) of diabetic (alloxan-treated) and metabolically healthy dogs were determined. Alloxan treatment did not change the contractile responsiveness to phenylephrine (PE) of the arteries with intact endothelium. After mechanical removal of the endothelial layer, however, the maximum force generated by the diabetic vessels (22.