The influence of atherosclerosis on the mechanical responses of human isolated coronary arteries to substance P, isoprenaline and noradrenaline.

1 The responses to substance P, isoprenaline and noradrenaline were observed on human isolated coronary arteries removed from 30 human hearts, and were classified according to the age of the hearts, the presence or absence of cardiac failure and the degree of atherosclerosis. 2 The endothelium-dependent vasodilator, substance P (0.1 microM), relaxed rings precontracted with prostaglandin F2 alpha, (PGF2 alpha, 1 microM) when they were devoid of atherosclerosis. The presence of moderate or severe lesions of atherosclerosis abolished this response. There was no difference in the response, related to either the age of the hearts or to the presence or absence of cardiac failure. 3 The dose-response curves to isoprenaline (an endothelium-independent vasodilator) were also markedly altered by the presence of atherosclerotic lesions, while aging and the presence of cardiac failure did not alter the maximal relaxation. These last 2 factors induced only a rightward shift of the dose-response curves. 4 On severely atherosclerotic rings, beta-adrenoceptor-mediated responses were so altered that the effect of noradrenaline was wholly vasoconstrictor (via alpha-adrenoceptors). This response was not modified after pretreatment with atenolol (10 microM). 5 It is concluded that atherosclerosis in human coronary arteries, induces alterations in the responses to substance P and to beta-adrenoceptor agonists. The beta-adrenoceptor-mediated relaxations seem more influenced by the presence of atherosclerosis than they are by aging or by the down-regulation induced by cardiac failure. Conversely, the alpha-adrenoceptor responses appear to be well preserved

Interaction of the islet nitric oxide system with L-arginine-induced secretion of insulin and glucagon in mice.

1. Several recent in vitro studies have suggested that production of nitric oxide (NO) from the islet NO system may have an important regulatory influence on the secretion of insulin and glucagon. In the present paper we have investigated, mainly with an in vivo approach, the influence and specificity of the NO synthase (NOS) blocker NG-nitro-L-arginine methyl ester (L-NAME) on L-arginine-induced secretion of insulin and glucagon. 2. In freely fed mice, L-NAME pretreatment (1.2 mmol kg-1) influenced the dynamics of insulin and glucagon release following an equimolar dose of L-arginine, the specific substrate for NOS activity, in that the NOS inhibitor enhanced the insulin response but suppressed the glucagon responses. This was reflected in a large decrease in the plasma glucose levels of the L-NAME pretreated animals. 3. L-NAME pretreatment did not influence the insulin and glucagon secretory responses to the L-arginine-enantiomer D-arginine, which cannot serve as a substrate for NOS activity. 4. Replacing L-NAME pretreatment by pretreatment with D-arginine or L-arginine itself, which both carry the same cationic change and are devoid of NOS inhibitory properties, did not mimic the effects of L-NAME on L-arginine-induced hormone release. 5. Fasting the animals for 24 h totally abolished the L-NAME-induced potentiation of L-arginine stimulated insulin release suggesting that the sensitivity of the beta-cell secretory machinery to NO-production is greatly changed in the fasting state. However, the L-NAME-induced suppression of L-arginine stimulated glucagon release was unaffected by starvation. 6. In isolated islets from freely fed mice, L-arginine (5 mM) stimulated insulin release was greatly enhanced and glucagon release markedly suppressed by the presence of the NOS inhibitor L-NAME in the incubation medium. These effects were abolished in isolated islets taken from 24 h fasted mice. 7. Our present results, which showed that the NOS inhibitor L-NAME markedly enhances insulin release but suppresses glucagon release induced by L-arginine in the intact animal, give strong support to our previous hypothesis that the islet NO system is a negative modulator of insulin secretion and a positive modulator of glucagon secretion. Additionally, we observed that the importance of the beta-cell NO-production for secretory mechanisms, as evaluated by the effect of L-NAME on L-arginine-induced insulin release, was greatly changed after starvation, an effect less prominent with regard to glucagon release