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Background Peripheral conduit artery endothelium-dependent dilatation decreases with aging in humans. Lactotripeptides (LTPs) and regular exercise can improve endothelium-dependent dilatation, but combining these lifestyle modifications may be more effective than either treatment alone. We conducted a randomized, place-controlled trial with four different intervention arms. Methods A total of 43 postmenopausal women (50-65 years old) were randomly divided into placebo, LTP, exercise and placebo (Ex+placebo), or exercise and LTP (Ex+LTP) groups. LTP or placebo was administered orally for 8 weeks. The exercise groups completed an 8-week moderate aerobic exercise (walking or cycling) intervention. Results There were no statistically significant differences in baseline flow-mediated dilatation (FMD) and most other key dependent variables among the groups. FMD significantly increased in the LTP, Ex+placebo, and Ex+LTP groups whereas no such changes were observed in the placebo control group. The magnitude of increases in FMD was significantly greater in the Ex+LTP group than other intervention groups. Conclusion We concluded that LTP ingestion combined with regular aerobic exercise improves endothelium-dependent dilatation to a greater extent than monotherapy with either intervention alone in postmenopausal women.

Evidence is presented that compounds which stimulate the soluble form of the enzyme guanylate cyclase or which inhibit the enzyme cGMP phosphodiesterase (PDE), responsible for the degradation of cGMP (including endothelium-derived relaxing factor) are inhibitors of sympathetic neurotransmission to vascular smooth muscle and inhibit the efflux of norepinephrine from sympathetic nerves. Moreover, prostacyclin, papaverine, iloprost, and forskolin, compounds which stimulate the enzyme adenylate cyclase, and rolipram (neural specific) and milrinone, enoximone, and piroximone (muscle specific) inhibitors of Type III cAMP PDE and degradation of cAMP, do not inhibit nerve stimulation to most blood vessels. The data support the concept that cGMP may act as a negative feedback modulator of physiologic frequencies of sympathetic nerve activity to blood vessels. cAMP does not appear to modulate adrenergic neurotransmission to vascular smooth muscle at physiologic frequencies of neural stimulation.

Calcium channel antagonists are commonly used to treat chronic hypertension. Several studies of intact vascular tissues suggest that these agents may impair the production of the endothelium-derived relaxing factor and alter endothelium-dependent vascular relaxation. These studies are difficult to interpret because the calcium channel antagonist may have direct effects on vascular smooth muscle. In our study, a chemiluminescence assay was used to measure the release of nitrogen oxides from bovine aortic endothelial cells (BAEC) grown in monolayer. Under basal conditions, the release of nitrogen oxides was 0.2 nmol/100 mg protein and was increased approximately two-fold by 0.1 micrograms, bradykinin. Incubations with diltiazem, verapamil, and nifedipine for 60 min did not influence the basal and bradykinin-stimulated release of nitrogen oxides by BAEC. These data illustrate that the production of the endothelium-derived relaxing factor is not altered by the calcium channel antagonist, and are compatible with an absence of L-type calcium channels in vascular endothelial cells. Chronic hypertension produces myriad adverse effects in the coronary circulation. After coronary occlusion, infarct size, expressed as a function of myocardial mass perfused, is increased by 33%, and the wavefront of infarction from subendocardium to subepicardium is hastened. Both chronic and acute hypertension produce numerous abnormalities of coronary flow regulation. These include impairments of autoregulation, changes in vascular responsiveness, and alterations of endothelial cell function. Many of these may worsen the clinical consequences of ischemic heart disease, either by producing structural alterations of the coronary vasculature, or equally importantly, by altering coronary vascular responsiveness to either mechanical or neurohumoral stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

The release of norepinephrine from adrenergic nerve endings is inhibited by substances which raise cyclic 3',5'-guanosine monophosphate (cGMP) in neural tissue. Endothelium-derived relaxing factor (EDRF) elevates cGMP in vascular smooth muscle. Thus, EDRF may also modulate the release of norepinephrine (NE) from adrenergic nerves. We tested this postulate in isolated canine pulmonary arteries and veins using the technique of superfusion and measurement of the efflux of radiolabeled NE during transmural nerve stimulation at 1, 2, 4, 8, 16 and 32 Hz for 10 min. In segments of artery and vein with intact endothelium the contractile responses to low frequency nerve stimulation were decreased when compared to endothelium rubbed blood vessels. Electrical stimulation of arteries and veins with intact endothelium for 10 min released less 2-[14C]-NE than rubbed blood vessels, especially at the lower frequencies of 1, 2 and 4 Hz, with lesser effects at frequencies of 16 and 32 Hz. Using the technique of bioassay, EDRF from porcine thoracic aorta inhibited the efflux of 2-[14C]-NE from the pulmonary artery and vein. The findings support the conclusion that the endothelium can inhibit release of NE from sympathetic nerve innervating canine pulmonary artery and vein. The endothelium, in part through EDRF, can act as an endogenous inhibitor or sympathetic neurotransmitter release.

Impairment of endothelium-dependent relaxations may be of primary importance in hypertension, if this impairment were to occur in resistance arteries. Therefore, endothelium-dependent relaxations to acetylcholine were studied in the mesenteric resistance vessels of spontaneously hypertensive and Wistar-Kyoto rats. Rings with and without endothelium were suspended in a myograph filled with physiological salt solution at 37 degrees C and aerated with 95% O2/5% CO2; the isometric tension was recorded. Acetylcholine caused relaxations only in rings with endothelium. In the spontaneously hypertensive rat, relaxations were impaired and markedly biphasic with an early rapid relaxation followed by a secondary contraction. Indomethacin inhibited the secondary response and augmented the duration of the relaxations induced by acetylcholine in the arteries from spontaneously hypertensive rats. These findings suggest that the decreased endothelium-dependent relaxation to acetylcholine in mesenteric resistance vessels of the spontaneously hypertensive rat is due to the release of a constrictor prostanoid which partly offsets the response of the vascular smooth muscle to endothelium-derived relaxing factor(s).

Calcium channel blockers such as amlodipine are effective antihypertensive agents. In this study we investigated the effects of amlodipine on vascular oxidative stress, expression of the lectin-like oxidized low-density lipoprotein receptor (LOX-1), and endothelial function in angiotensin (Ang) II-infused rats.Sprague-Dawley rats were treated with Ang II (0.7 mg/kg/day subcutaneously injected by mini-pump), with or without amlodipine (10 mg/kg/day by gavage), for 5 days and compared with control rats. Levels of aortic ring superoxide (O(2)(-)) and peroxynitrite (ONOO(-)) were determined, and systolic blood pressure (SBP) and endothelium-dependent relaxation were evaluated.Compared with control rats, Ang II-infused rats developed hypertension (175 +/- 3 v 135 +/- 2 mm Hg, P.05), aortic hypertrophy (16.9 +/- 1.3 v 13.2 +/- 0.3 mg/cm, P.05), left ventricular hypertrophy (0.236 +/- 0.003 v 0.204 +/- 0.004 g/100 g body weight, P.05), and impaired endothelium-dependent relaxation (ED(50): 6.6 +/- 0.2 v 8.0 +/- 0.2 -log mol/L acetylcholine concentration, P.05). Compared with control rats, Ang II-infused rats also had higher aortic levels of LOX-1 mRNA expression, O(2)(-)production (1005 +/- 140 v 608 +/- 159 counts/min/mg, P.05), ONOO(-) production (1875 +/- 295 v 782 +/- 115 counts/min/mg, P.05), and plasma free 8-F(2)alpha-isoprostanes (67.4 +/- 19.1 v 27.2 +/- 6.1 pg/mL, P.05). In Ang II-infused rats SBP, aortic hypertrophy, endothelial dysfunction, LOX-1 expression, aortic O(2)(-) and ONOO(-) production, and plasma free 8-F(2)alpha-isoprostane levels were significantly reduced by amlodipine treatment.Amlodipine has antihypertensive and antioxidant activity in vivo, which effectively inhibits many of the oxidative stress-dependent mechanisms involved in Ang II-mediated cardiovascular injury.

The basal levels of cGMP in renal medulla slices were enhanced when the slices were stimulated with both endothelium-dependent (acetylcholine) and endothelium-independent (molsidomine) vasodilators. When preincubated with NG-mono-methyl-L-arginine, a specific inhibitor of endothelium-derived relaxing factor, only the acetylcholine-stimulated increase was completely abolished. Furthermore, a preincubation with L-arginine, a selective precursor of endothelium-derived relaxing factor, enhanced the cGMP levels. The results indicate that the renal medulla, presumably the endothelial cells of the vasa recta, is able to produce endothelium-derived relaxing factor.