The ET(A) antagonist BQ-123 inhibits anoxic contractions of canine coronary arteries without endothelium

Experiments were designed to determine whether or not endogenous endothelin (ET) contributes to endothelium-independent anoxic contractions of canine coronary arteries. Rings without endothelium were suspended for isometric tension recording in conventional organ chambers filled with modified Krebs-Ringer bicarbonate solution. Anoxia (PO2 ≤1 mm Hg) caused reproducible contractions. The anoxic contractions were augmented by exogenous endothelin-1 (ET-1). At 10-6 M and 10-5 M, BQ-123 (a specific endothelin antagonist) inhibited both the facilitatory effect of ET-1 and the anoxic contractions. At these concentrations BQ-123 caused a parallel shift to the right of the concentration-response curve to ET-1 and a small but significant depression of the response to norepinephrine, without affecting the maximal response to the catecholamine. BQ-123 did not significantly affect the concentration-response curve to Ca2+ in depolarizing solution (60 mM KCl). Monoclonal antibodies against ET-1 (70 μg/ml) inhibited the response to exogenous ET-1 and abolished the facilitating effect of the peptide, but did not affect the anoxic contractions. These results suggest that ET-1 contributes to anoxic contractions in canine coronary arteries without endothelium. The receptor involved belongs to the ET(A)-subtype and is not accessible to monoclonal antibodies.link_to_subscribed_fulltex

Postmortem changes in endothelium-dependent and independent responses of porcine coronary arteries

Studies were performed in porcine left circumflex coronary arteries to determine the time course of changes in their responses to smooth muscle and endothelial cell agonists following death. The pigs were kept at room temperature for 3, 6, 12 and 24 hr after death before removing the arteries, and the responses compared with fresh arteries. Rings of the arteries were mounted in organ chambers filled with modified Krebs-Ringer solution for isometric tension recording. Fresh rings with endothelium relaxed with stretching, whereas 3- and 6-hr rings developed an increase in tension and often rhythmic activity. In 3-hr rings, there were diminished contractile responses to KCl and serotonin. The contractile responses to prostaglandin F(2α) were depressed at 3 and 6 hr. At 6 hr, rings from six of 14 pigs failed to contract and the responses of the other eight to histamine and serotonin but not to KCl or acetylcholine, were depressed compared to fresh rings. 6hr after death endothelium-mediated relaxation to bradykinin and calcium ionophore A-23187 were depressed while endothelium-mediated as well as direct smooth muscle relaxation by adenosine diphosphate did not change. These studies indicate that caution must be observed in interpreting the findings in autopsy specimens examined as early as 3 hr after death.link_to_subscribed_fulltex

Effect of nitric oxide and carbon monoxide on uterine contractility during human and rat pregnancy

OBJECTIVE: We sought to study the effects of authentic nitric oxide and carbon monoxide on the contractile activity of pregnant human and rat myometrium. STUDY DESIGN: Strips were prepared from uterine biopsy specimens of 10 pregnant, nonlaboring women at term gestation undergoing cesarean delivery. In addition, rings were prepared from the uteri of pregnant rats at midterm (day 14) and at term (day 22) gestation (n = 10-12). The tissues were mounted in organ chambers filled with Krebs-Henseleit solution continuously aerated with 5% carbon dioxide in air (37 degrees C, pH similar to 7.4) for isometric tension recording. The effects of nitric oxide and carbon monoxide gases on spontaneous contractile activity were studied. Responses to hemin (hemoxygenase substrate), which produces endogenous carbon monoxide, were also examined. Responses to nitric oxide and carbon monoxide were also studied in aortic and tail artery rings from pregnant rats after contraction with phenylephrine. RESULTS: Nitric oxide significantly inhibited contractility of human myometrium at term (area under the concentration-response curve, 145.36 +/- 30.02 vs 40.56 +/- 22.81 in controls; P < .05) and rat myometrium at midterm gestation (264.23 +/- 47.86 vs 121.82 +/- 23.50; P < .05) but not at term. No statistically significant inhibition was induced in human or rat myometrium by carbon monoxide, whereas hemin significantly attenuated contractility in human myometrium at term and in rat myometrium at midterm gestation (P < .05). Nitric oxide, carbon monoxide, and hemin relaxed aortic and tail artery rings. CONCLUSIONS: Authentic nitric oxide inhibits rat uterine contractile activity at midterm gestation but not at term. However, nitric oxide inhibits human myometrium activity at term. Authentic carbon monoxide does not appear to modulate uterine contractility, whereas hemin may have some inhibitory properties

Enhanced growth and improved vascular function in offspring from successive pregnancies in endothelial nitric oxide synthase knockout mice

Objective: Transgenic mice that lack endothelial nitric oxide synthase have offspring with growth deficiency and abnormal vascular reactivity in later life. Our objective was to evaluate the role of parity in the modulation of the fetal programming of growth and vascular responses in these transgenic mice. Study design: Oligoparous (0-2 previous pregnancies) and multiparous (5-9 previous pregnancies) nitric oxide synthase knockout (-/-KO) female mice were bred with nitric oxide synthase(-/-KO) and wild type (+/+WT) male mice to produce nitric oxide synthase-/-KO and maternally derived heterozygous (+/-Mat) litters. The pups were weighed weekly. Carotid arteries of the adult females from these litters were used for in vitro vascular reactivity studies. Results: Nitric oxide synthase knockout and nitric oxide synthase maternal litters that were born to oligoparous mothers had significant growth lag compared with corresponding multiparous litters. Length-tension characteristics were not different between the groups. However, optimal diameter, which is a measure of vascular tensile properties and resistance, was decreased in oligoparous compared with multiparous female offspring. Acetylcholine-mediated vasorelaxation was abolished, and contraction by phenylephrine and Ca++ was increased in oligoparous, but not multiparous, female offspring (P <.05). Conclusion: These data support the role of abnormal uterine environment in the fetal programming of postnatal growth and vascular function in later life. Successive pregnancies may lead to maternal uterine adaptations that bypass the lack of a functional nitric oxide synthase, which leads to improvement in postnatal growth and vascular function in the offspring. Given the reported effect of parity on the risk of preeclampsia, similar mechanisms may be operative in human pregnancy. (C) 2004 Elsevier Inc. All rights reserved