G. Desideri

Effects of Naloxone on Myocardial Ischemic Preconditioning in Humans

OBJECTIVES We attempted to establish whether naloxone, an opioid receptor antagonist, abolishes the adaptation to ischemia observed in humans during coronary angioplasty after repeated balloon inflations. BACKGROUND Experimental studies indicate that myocardial opioid receptors are involved in ischemic preconditioning. METHODS Twenty patients undergoing angioplasty for an isolated stenosis of a major epicardial coronary artery were randomized to receive intravenous infusion of naloxone or placebo during the procedure. Intracoronary electrocardiogram and cardiac pain (using a 100-mm visual analog scale) were determined at the end of the first two balloon inflations. Average peak velocity in the contralateral coronary artery during balloon occlusion, an index of collateral recruitment, was also assessed by using a Doppler guide wire in the six patients of each group with a stenosis on the left anterior descending coronary artery. RESULTS In naloxone-treated patients, ST-segment changes and cardiac pain severity during the second inflation were similar to those observed during the first inflation (12+/-6 vs. 11+/-7 mm, p = 0.3, and 58+/-13 vs. 56+/-12 mm, p = 0.3, respectively), whereas in placebo-treated patients, they were significantly less (6+/-3 vs. 13+/-6 mm, p = 0.002 and 31+/-21 vs. 55+/-22 mm, p = 0.008, respectively). In both naloxone- and placebo-treated patients, average peak velocity significantly increased from baseline to the end of the first inflation (p = 0.04 and p = 0.02, respectively), but it did not show any further increase during the second inflation. CONCLUSIONS The adaptation to ischemia observed in humans after two sequential coronary balloon inflations is abolished by naloxone and is independent of collateral recruitment. Thus, it is due to ischemic preconditioning and is, at least partially, mediated by opioid receptors, suggesting their presence in the human heart.

Endogenous Insulin Modulates Circulating Endothelin-1 Concentrations in Humans

OBJECTIVE To assess the effect of oral glucose loading on plasma endothelin-1 (ET-1) levels in humans. RESEARCH DESIGN AND METHODS A total of 75 g D-glucose was given orally to 14 nonobese nondiabetic essential hypertensive subjects (eight men and six women, mean age 43.1 ± 3.0 years) and eight normotensive subjects (four men and four women, mean age 45.2 ± 4.1 years). Blood samples for plasma ET-1 measurement were drawn every 30 min for 2 h and then at 180 and 240 min. RESULTS After glucose load, insulin increased more significantly in hypertensive subjects than in normotensive subjects at times 60 (P = 0.004) and 90 (P = 0.001) min. Glucose loading was followed by a mild but significant increase in circulating ET-1 levels in both groups (hypertensive subjects, from 0.87 ± 0.25 pg/ml at time 0 to 1.64 ± 0.33 pg/ml at 120 min and 1.74 ± 0.38 pg/ml at 180 min, P < 0.05; normotensive subjects, from 0.82 ± 0.38 pg/ml at time 0 to 1.42 ± 0.18 pg/ml at 180 min, P < 0.05). Whereas baseline ET-1 levels were similar between the two groups, postload ET-1 levels were higher in hypertensive subjects than in normotensive subjects (P = 0.003 at 120 min; P = 0.04 at 180 min). CONCLUSIONS This study indicates that significant changes in circulating ET-1 levels occur after oral glucose loading, probably due to a glucose-induced increment in endogenous insulin concentration.

Effects of ACE inhibition on spontaneous and insulin-stimulated endothelin-1 secretion: in vitro and in vivo studies.

To evaluate the effect of angiotensin-converting inhibition enzyme on spontaneous and insulin-stimulated endothelin-1 (ET-1) secretion in vitro and in vivo, human endothelial cells derived from umbilical cord veins were cultured onto acellular collagen-coated permeable membrane, thus mimicking in vivo conditions with a luminal and abluminal side. Insulin (10−6,−8,−9 mol/l) significantly stimulated ET-1 secretion by cultured cells (P < 0.05 starting from 2-h incubation). Captopril (10−7,−8,−9 mol/l) significantly reduced both spontaneous and insulin-stimulated ET-1 secretion, while increasing nitric oxide production. Considering each cell side, captopril significantly inhibited the apical secretion of ET-l, while its effect on the basolateral compartment was modest. In the presence of D-Arg,[Hyp3,Thi5,8,D-Phe7]-bradykinin (10−6 mol/l), a bradykinin B2 receptor antagonist, captopril had no effects on ET-1 and nitric oxide production and also when insulin was added to the culture media. With regard to in vivo experiments, oral captopril therapy (25 mg twice daily for 1 week) was given to normotensive (n = 5) and hypertensive (n = 6) subjects and significantly decreased plasma ET-1 concentration (normotensive subjects, before: 0.98 ± 0.09 pg/ml; after: 0.55 ± 0.08 pg/ml, P < 0.0001; hypertensive subjects, before: 1.05 ± 0.03 pg/ml; after: 0.56 ± 0.05 pg/ml, P < 0.0001). Transient hyperinsulinemia was accompanied by a significant rise in plasma ET-1 concentrations in both groups (P < 0.0001 at 180 and 210 min) before but not after captopril treatment. In conclusion, captopril inhibits both spontaneous and insulinstimulated ET-1 secretion by endothelial cells, acting on angiotensin-converting enzyme bound to the luminal cell side. In vivo, captopril significantly reduces plasma ET-1 levels in both basal and insulin-stimulated conditions.

Elevated plasma endothelin-1 levels as an additional risk factor in non-obese essential hypertensive patients with metabolic abnormalities.

Summary Circulating endothelin-1 concentration was evaluated in 93 lean patients with essential hypertension, of whom 16 had impaired glucose tolerance and hyperlipidaemia, 25 had impaired glucose tolerance, 28 had hyperlipidaemia and 24 had no metabolic abnormalities; we also studied 22 control subjects. All groups were age- and sex-matched. Plasma endothelin-1 levels were higher (p < 0.05) in hypertensive patients with impaired glucose tolerance and hyperlipidaemia than in the remaining groups, and were directly correlated with fasting insulin levels (r = 0.506, p = 0.045). Therefore, circulating endothelin-1 concentrations are elevated in hypertensive patients with a high-risk profile due to the presence of metabolic abnormalities, and might favour the development of vascular damage. [Diabetologia (1997) 40: 100–102]

Salt-sensitivity is associated with a hyperinsulinaemic and hyperglycaemic response to atrial natriuretic peptide infusion in human essential hypertension

SummaryTo evaluate the influence of salt-sensitivity on the plasma insulin and glucose response to infusion of ANP, we studied 22 men with essential hypertension, who were between 40 and 60 years old. After 1 month under normal Na+ intake (120 mmol Na+ per day), patients were randomly assigned to receive either ANP (0.04 μg · kg−1 · min−1) (n=15) or vehicle (50 ml saline) (n=7) over a 60-min period, while in the supine position. Plasma insulin and glucose were measured at time −60, 0, 20, 40, 60, 120, 180, 240 min. Ten days after ANP infusion, blood pressure sensitivity to changes in di etary salt intake was assessed according to a randomized double-blind crossover protocol. Patients were classified into two groups either salt-sensitive (n=8) or salt-resistant (n=7). Our results showed that plasma insulin and glucose did not change during ANP infusion in both groups. However, both plasma insulin (from 75.6 ± 45.1 pmol/l at 60 min to 121.2 ± 48.6 pmol/l at 240 min, p <0.05 vs time 0) and glucose levels (from 4.86 ± 0.73 mmol/l at 60 min to 6.56 ± 1.03 mmol/l at 240 min, p <0.01 vs time 0) rose after discontinuation of ANP in salt-sensitive patients, but did not change at all in salt-resistant patients. In conclusion, this randomized vehicle-controlled study demonstrates that plasma insulin and glucose levels increase in salt-sensitive hypertensive patients after the infusion of ANP. The increase of plasma insulin levels observed after ANP discontinuation, if occurring under physiologic conditions, could influence the blood pressure sensitivity to dietary Na+ intake.