Chang Jian Feng

L-Name modulates responses to adrenomedullin in the hindquarters vascular bed of the rat

Responses to synthetic human adrenomedullin (ADM), a novel hypotensive peptide recently discovered in human pheochromocytoma cells, and calcitonin gene-related peptide (CGRP), a structurally related peptide, were investigated in the hindquarters vascular bed of the rat. Under conditions of controlled hindquarters blood flow, intraarterial injections of ADM (0.01-0.3 nmol) and of CGRP (0.03-0.3 nmol) caused dose-related decreases in hindquarters perfusion pressure and decreases in systemic arterial pressure. Following administration of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME), hindquarters vasodilator and systemic depressor responses to ADM were significantly decreased, whereas L-NAME did not significantly decrease the vasodilator response to CGRP in either the hindquarters or systemic vascular beds. Following administration of the cyclooxygenase inhibitor, meclofenamate, vasodilator responses to ADM and to CGRP were not significantly decreased. When the relative vasodilator activity of the two peptides was compared on a nmol basis, responses to ADM were similar to responses with CGRP in the hindquarters vascular bed, whereas ADM was 30-100 fold less potent than CGRP in decreasing systemic arterial pressure. The present data demonstrate that ADM has significant vasodilator activity in the hindquarters vascular bed of the rat, that hindquarters vasodilator and systemic vasodepressor responses to ADM, but not to CGRP, are dependent upon the release of nitric oxide from the endothelium.

Responses to propofol in the pulmonary vascular bed of the rat

Background: Although a great deal is known about responses to propofol, controversy remains about its mechanism of action. The present study was undertaken to investigate the direct effects of 2,6‐diisopropyl phenol, disodium edetate, and its intralipid emulsion in the rat pulmonary vascular bed and to better understand the mechanisms involved in propofol‐mediated responses.

Nociceptin Has Vasodilator Activity in the Pulmonary Vascular Bed of the Rat

Background: Recent studies have shown that the newly discovered endogenous opioid-like peptide, nociceptin, has vasodilator activity in the peripheral vascular bed. However, little if anything is known about the effects of the peptide in the pulmonary vascular bed. There fore, responses to nociceptin in the pulmonary vascular bed were investigated and com pared with responses in the hindlimb and systemic vascular beds of the rat. Methods and Results: Responses to nociceptin were investigated in the pulmonary and hindquarters vascular beds in the rat under constant flow conditions and were compared with decreases in systemic vascular resistance. Under conditions of constant flow, injections of nociceptin in doses of 3-30 nM induced dose-related decreases in pulmonary arterial per fusion pressure when baseline tone was increased to a high steady level with U46619. Pul monary vasodilator responses to nociceptin were not modified by the opioid receptor antagonist naloxone, and the newly discovered ligand was 10-fold less potent than adreno medullin in decreasing pulmonary vascular resistance when decreases in pulmonary hind quarters and systemic vascular resistances were compared, nociceptin was significantly more potent in decreasing hindquarters and systemic vascular resistance than in reducing pulmonary vascular rcsistance. Conclusions: The results of the present study indicate that nociceptin decreases pulmonary vascular resistance by a natoxone-insensitive mechanism, and that the peptide is less potent in decreasing pulmonary vascular resistance than in decreasing systemic vascular resistance in the rat.

Hemodynamic Responses to Papaverine: Do Nitric Oxide, Cyclic GMP, or Calcium Mediate the Vasodilation?

Papaverine is a commonly used vasodilator of the internal mammary artery in cardiac surgery. The effects of papaverine with and without Nω-L-arginine methyl ester (L -NAME) (a nitric oxide production inhibitor) and/or zaprinast (a cyclic GMP inhibitor) or verapamil (calcium channel antagonist) on systemic vascular resistance in vivo have not been well documented. This study examines the hemodynamic responses to papaverine and attempts to identify the role of nitric oxide, cyclic guanosine monophosphate (GMP), and calcium in the vasodilation. The effects of varying doses of papaverine were evaluated with and without L-NAME and/or zaprinast or verapamil on the hindlimb vascular resistance in the male rat. With institutional approval, 40 male Sprague-Dawley rats (400–450 g) were anesthetized with intraperitoneal pentobarbital (50 mg kg−1). The carotid artery, jugular vein, and abdominal aorta were cannulated by cutdown; mean arterial pressure (MAP) and hindlimb perfusion pressure (HPP) were recorded. Rats were heparinized (1000 U kg−1). Papaverine (1,3,10,30, and 100 μg) was injected into the hindlimb, whereas MAP was maintained constant, and the HPP was recorded. Both L-NAME (25 mg kg−1) and/or verapamil and then papaverine (1, 3, and 10 μg) were injected into the hindlimb, and changes in HPP were recorded. A Students t-test was used for statistical analysis, with a p < 0.05 considered significant. Papaverine, in increasing doses, decreased HPP incrementally. L-NAME partially blocked the effects of papaverine (p < 0.05), as did verapamil (p < 0.05). The combination of L-NAME and verapamil further decreased papaverines vasodilation to almost eliminate it (p < 0.05). We demonstrated the effect of papaverine on the hindlimb vasculature is similar to its effects noted in the internal mammary artery. Nitric oxide is known to be an agent causing vasodilation. It was demonstrated that papaverine vasodilation in the hindlimb vascular bed is modified by L-NAME, which suggests that nitric oxide production inhibition is partially responsible for this effect. It was demonstrated that there is an effect of calcium channel blockade on the vasodilation caused by papaverine. Both L-NAME and verapamil together appear to modify further the vasodilation caused by papaverine, suggesting both calcium channel and nitric oxide mechanisms for vasodilation. Zaprinast, a specific cyclic GMP phosphodiesterase inhibitor, did not affect the vasodilation caused by papaverine, acetylcholine, nitroglycerin, or verapamil.

Nomega-Nitro-L-Arginine Benzyl Ester Enhances Pulmonary Vasopressor Responses to Hypoxia and to Angiotensin II.

The effects of Nomega-nitro-L-arginine benzyl ester (L-NABE), an inhibitor of nitric oxide (NO) synthase, were investigated on pulmonary arterial responses during baseline or low tone conditions and during elevated tone conditions induced by ventilatory hypoxia or by AII in the isolated blood-perfused rat lung. We also tested the influence L-NABE on the vasodilator responses to acetylcholine (ACh) and nitroglycerin (GTN) during elevated pulmonary arterial tone conditions. Under baseline conditions, L-NABE in doses of 10--1000 &mgr;g, induced small increases in pulmonary arterial perfusion pressure that were significant for the higher doses studied. Ventilation with an hypoxic gas mixture or administration of AII significantly increased pulmonary arterial perfusion pressure and the responses were reproducible with respect to time. Following administration of L-NABE, the pulmonary arterial responses to hypoxic ventilation (HPV) were significantly enhanced, and L-NABE significantly enhanced the pulmonary arterial pressor responses to angiotensin II. During elevated pulmonary arterial tone conditions induced with hypoxic ventilation, L-NABE inhibited the vasodilator responses to acetylcholine (ACh); however, the vasodilator responses to nitroglycerin (GTN) were not altered. The small effect of L-NABE on baseline pulmonary arterial pressure in the isolated blood-perfused rat lung suggests that NO plays only a small role in maintaining pulmonary vascular tone at low resting levels. However, the augmentation of the pressor responses by L-NABE during HPV and to AII suggests that NO plays an important role in modulating these pulmonary pressor responses during elevated tone conditions. Additionally, the inhibition of pulmonary vasodilator response to ACh supports the hypothesis that NO release plays a major role in mediating vasodilator responses to endothelial-dependent agents such as ACh, but not to endothelial-independent agents such as GTN. In conclusion, these data suggest that NO release is more important under stimulated conditions than under basal conditions.