Sepsis decreases phenylephrine- and KCl-induced aortic ring contraction and decreases the frequency of oscillations in active wall tension.

Impaired vascular contractility is a hallmark of sepsis and endotoxemia. The purpose of the present investigation was to determine mechanisms responsible for the abnormal contractility in sepsis using the rat cecal ligation and perforation (CLP) model. 24 h after CLP or sham surgery, rats were anesthetized with halothane and a segment of the thoracic aorta removed. Aortic rings measuring 1.6-2.0 mm in length were mounted in a water bath and stretched to optimal diameter. Aortic rings from control rats demonstrated a 57% increase in maximum contraction to phenylephrine and a 68% increase to KCl compared to aortic rings from rats with sepsis (p < .01). There was no difference in the concentrations of phenylephrine or KCl which elicited a half-maximal contraction (EC50) in control versus septic aortic rings. Removal of the endothelium increased the sensitivity of aortas to both phenylephrine and KCl in septic and control aortic rings but did not reverse the defects in contraction in sepsis. Treatment of the aortic rings with N gamma-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, increased contraction in aortic rings from both septic and control rats but also failed to correct the contractile defect in sepsis. The frequency and amplitude of the oscillations in wall tension which occurred with phenylephrine were slower, i.e., .07 +/- .10 vs. .17 +/- .02 Hz, for septic and control rings, respectively (p < .05), and had a greater amplitude .65 +/- .01 vs. .41 +/- .09 mN/mm, for septic and control rings, respectively (p < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of nitric oxide formation by guanidines.

Aminoguanidine, N,N'-diaminoguanidine, methylguanidine, and 1,1-dimethylguanidine were compared to NG-monomethyl-L-arginine (L-NMMA) for their ability to inhibit nitric oxide (NO) formation by cytokine-inducible and vascular constitutive isoforms of NO synthase. These comparisons were performed by assessing (1) cytokine-induced production of nitrite by RINm5F cells, (2) vasoconstrictor responses of isolated rat mesenteric arteries, and (3) in vivo blood pressure responses following intravenous bolus injection into anesthetized rats. Aminoguanidine and L-NMMA were the most potent inhibitors of cytokine-induced NO formation in RINm5F cells, while the other guanidine compounds were 10 (1,1-dimethylguanidine) to 100 (methylguanidine) times less potent. L-NMMA and 1,1-dimethylguanidine were the most potent inhibitors of the vascular constitutive isoform of NO synthase in both assay systems, while aminoguanidine and N,N'-diaminoguanidine were the least potent. These results (1) confirm the selective inhibition of the inducible isoform of NO synthase by aminoguanidine, (2) indicate that N,N'-diaminoguanidine, while approximately 30 times less potent than aminoguanidine in inhibiting inducible NO synthase, has very little effect on constitutive NO synthase activity, and (3) 1,1-dimethylguanidine, like L-NMMA, is a relatively potent inhibitor of both isoforms of NO synthase.

Lipoprotein(a) levels in relation to diabetic complications in patients with non-insulin-dependent diabetes.

The relationship between serum levels of lipoprotein(a) Lp(a)) and the presence of chronic diabetic complications was studied in 194 patients with non-insulin-dependent diabetes mellitus (NIDDM; 75 males, 119 females; age 66 +/- 11 years; duration of diabetes, 11 (range 1-35) years). They were taking various treatments (diet alone, oral hypoglycaemic agents and/or insulin). Metabolic status and prevalence of diabetic complications were assessed by detailed history, physical examination, laboratory analysis and ECG. Average metabolic control was moderate (HbA1c 8.2 +/- 1.7%). Median serum Lp(a) level was 183 U l-1 (range 8-2600 U l-1), which was significantly higher than in control subjects of comparable age (median 101; range 8-1747 U l-1; P < 0.05), while HDL-cholesterol levels were lower (1.14 +/- 0.38 vs. 1.35 +/- 0.35 mmol l-1; P = 0.001), and total cholesterol levels were comparable. No significant relationships between diabetes treatment or metabolic control and Lp(a) levels were observed. In the quartile of patients with the highest Lp(a) levels, total cholesterol and triglycerides were slightly higher (P < 0.05), whereas HDL-cholesterol was not different. With increasing Lp(a) levels, higher prevalences of preproliferative retinopathy and of coronary artery disease (CAD) were observed, but not of the other complications. No relationship was found between the degree of albuminuria and Lp(a) levels. We conclude that in NIDDM patients, Lp(a) levels are elevated compared with non-diabetic subjects, and that higher Lp(a) levels are associated with higher prevalences of CAD and of retinopathy.

[Effects of dietary fiber and insulin treatment on serum levels of lipids and lipoprotein (a) in patients with type II diabetes mellitus]. / De effecten van voedingsvezel en insuline-behandeling op het serumgehalte van lipiden en lipoproteïne (a) bij patiënten met diabetes mellitus type II.

OBJECTIVE: As lipoprotein(a) is an independent risk factor for the development of coronary heart disease we determined the effect on serum lipid and lipoprotein(a) levels of dietary fibre and of treatment with insulin in patients with diabetes mellitus type II. METHODS: Twelve type II diabetic patients (mean age 62 (SD 10) yrs, body mass index 25.8 (SD 3.5) kg/m2), all treated with oral antidiabetic agents, were studied in a randomised cross-over trial, in which they used breads meals prepared with guar gum (a mean of 11.2 g guar per day) for 3 months in comparison with normal high-fibre bread. Fifteen other patients (age 70 (8), BMI 27.4 (5.6) kg/m2) poorly controlled on oral hypoglycaemic agents, were treated with insulin. RESULTS: The guar treatment of the 12 patients resulted in lower total cholesterol (5.24 vs 5.7 mmol/l, p less than 0.1) and LDL cholesterol (3.77 vs 4.33 mmol/l, p less than 0.001) in comparison with normal high-fibre bread. Lipoprotein(a) levels were not different (76 vs 82 mg/l). Insulin therapy in the 15 other patients decreased HbA1c levels after 6 months from 11.0 to 7.7% (p less than 0.001), total cholesterol from 6.8 to 6.1 mmol/l (p less than 0.05), and LDL cholesterol from 4.4 to 4.1 mmol/l (p less than 0.05). Lp(a) decreased only slightly in 11/15 patients, from 491 to 441 mg/l (p = 0.07). CONCLUSION: Neither the use of the dietary fibre guar nor improved metabolic control with insulin therapy lowered elevated lipoprotein(a) levels in type II diabetic patients.

Effects of cyclic AMP-affecting agents on contractile reactivity of isolated mesenteric and renal resistance arteries of the rat.

1. Effects of adenosine 3':5'-cyclic monophosphate (cyclic AMP)-affecting agents were compared in mesenteric and renal resistance arteries that had been isolated from 20 week old Wistar-Kyoto rats, chemically sympathectomized, stretched to their optimal diameter for mechanical performance and made to contract in response to 30 mM potassium. 2. In mesenteric resistance arteries, isoprenaline, dopamine, NaF, forskolin, isobutyl-methylxanthine, milrinone and dibutyryl-cyclic AMP induced relaxation. Clonidine induced further increases in tension that could be reduced by pertussis toxin and prazosin but not by yohimbine. Clonidine also reduced relaxant responses to isoprenaline. 3. In renal resistance arteries, isoprenaline and dopamine failed to induce relaxation. Compared to mesenteric resistance arteries, renal vessels were less sensitive to the relaxant effect of NaF, forskolin and isobutyl-methylxanthine. Relaxant responses to dibutyryl-cyclic AMP did not differ between the two resistance arteries. 4. Indirect evidence thus suggests that in mesenteric resistance arteries, adenylate cyclase is susceptible to pharmacological activation and inhibition and is functionally coupled to relaxation. The refractory nature of renal resistance arteries to the relaxant effects of isoprenaline and dopamine could be due primarily to absence of appropriate receptors and to a relatively low activity of adenylate cyclase.