Bulent Gumusel

NOCICEPTIN : AN ENDOGENOUS AGONIST FOR CENTRAL OPIOID LIKE1 (ORL1) RECEPTORS POSSESSES SYSTEMIC VASORELAXANT PROPERTIES

The purpose of the present study was to investigate the effects of nociceptin on peripheral arterial rings from the cat. When feline renal, mesenteric, carotid and femoral rings with intact endothelium were precontracted with phenylephrine (100 nanomolar), nociceptin (3 x 10(-11)-3 x 10(-6) M) decreased tension in a concentration-dependent manner. The present data suggest nociceptin possesses biologic activity outside the CNS and may contribute to the regulation of systemic blood pressure and regional blood flow.

Adrenomedullin dilates rat pulmonary artery rings during hypoxia: role of nitric oxide and vasodilator prostaglandins.

Hypoxia decreases vasorelaxation and leads to pulmonary arterial hypertension. A newly identified 52 amino-acid peptide adrenomedullin (ADM) exerts vasodilator effect in intact animals under normoxic condition. We studied the effect of human ADM on rat pulmonary arterial and aortic rings under normoxic and hypoxic conditions. During normoxia, ADM caused a concentration-dependent relaxation of precontracted aortic and pulmonary arterial rings; the relaxation was much more pronounced in pulmonary arterial rings and was abolished by the nitric oxide (NO) synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) and by deendothelialization. A fragment of ADM, ADM13-52, caused a degree of relaxation similar to that induced by ADM in pulmonary arterial rings, but not in the aortic rings, and the relaxation of pulmonary artery caused by ADM13-52 was not affected by the cyclooxygenase inhibitor indomethacin but was abolished by L-NAME and by deendothelialization. During hypoxia, ADM13-52 failed to relax pulmonary arterial rings, whereas ADM caused modest relaxation of pulmonary arterial rings (one third of the relaxation during normoxia), which was abolished by pretreatment with indomethacin. Our results indicate that the vasorelaxant effect of ADM is more pronounced in pulmonary artery than in the aorta; ADM has more potent vasodilator effect than ADM13-52 during hypoxia; ADM relaxes hypoxic pulmonary artery through an indomethacin-sensitive pathway; amino acids 1-12 in ADM must be present for relaxation of chronic hypoxic pulmonary arterial rings; and last, the presence of endothelium is necessary for the expression of ADM-mediated relaxation.

Novel catheterization technique for the in vivo measurement of pulmonary vascular responses in rats

A novel cardiac catheterization technique was devised to investigate the pulmonary arterial pressure-blood flow relationship in intact spontaneously breathing rats (ISBR) under physiological conditions with constant left atrial pressure and controlled blood flow within the normal range. Observations using this new technique in vivo were contrasted with data derived with isolated perfused rat lungs in vitro. Unlike results in in vitro isolated perfused rat lungs, the pressure-flow curves in vivo were curvilinear, with pulmonary artery pressure increasing more rapidly at low pulmonary blood flows of 4-8 ml/min and less rapidly at higher flow rates. Pressure-flow curves were reproducible and were not altered by 1-1.5 h of arrested perfusion, cyclooxygenase blockade, or perfusion with aortic or mixed venous blood. In contrast to results in in vitro isolated perfused rat lungs, NG-nitro-L-arginine methyl ester (L-NAME) increased pulmonary arterial pressure at all but the lowest flow rates with a slight effect on the curvilinear pressure-flow relationship. L-NAME reversed pulmonary vasodilator responses to acetylcholine and bradykinin and enhanced the pulmonary vasodilator response to nitroglycerin. The present data suggest that actively induced pulmonary hypertension is under greater control by endothelium-derived relaxing factor (EDRF). Unlike previous results in in vitro perfused rat lungs, results in ISBR demonstrate that the pulmonary vasodilator response to adrenomedullin-(13-52) is not mediated by calcitonin gene-related peptide receptors, which are not coupled to the release of EDRF. These results indicate that this novel technique may provide a useful model for the study of the pulmonary circulation in the intact chest rat.A novel cardiac catheterization technique was devised to investigate the pulmonary arterial pressure-blood flow relationship in intact spontaneously breathing rats (ISBR) under physiological conditions with constant left atrial pressure and controlled blood flow within the normal range. Observations using this new technique in vivo were contrasted with data derived with isolated perfused rat lungs in vitro. Unlike results in in vitro isolated perfused rat lungs, the pressure-flow curves in vivo were curvilinear, with pulmonary artery pressure increasing more rapidly at low pulmonary blood flows of 4-8 ml/min and less rapidly at higher flow rates. Pressure-flow curves were reproducible and were not altered by 1-1.5 h of arrested perfusion, cyclooxygenase blockade, or perfusion with aortic or mixed venous blood. In contrast to results in in vitro isolated perfused rat lungs, N G-nitro-l-arginine methyl ester (l-NAME) increased pulmonary arterial pressure at all but the lowest flow rates with a slight effect on the curvilinear pressure-flow relationship. l-NAME reversed pulmonary vasodilator responses to acetylcholine and bradykinin and enhanced the pulmonary vasodilator response to nitroglycerin. The present data suggest that actively induced pulmonary hypertension is under greater control by endothelium-derived relaxing factor (EDRF). Unlike previous results in in vitro perfused rat lungs, results in ISBR demonstrate that the pulmonary vasodilator response to adrenomedullin-(13-52) is not mediated by calcitonin gene-related peptide receptors, which are not coupled to the release of EDRF. These results indicate that this novel technique may provide a useful model for the study of the pulmonary circulation in the intact chest rat.

Agmatine: A novel endogenous vasodilator substance

The purpose of the study was to investigate the effects of agmatine, an endogenous clonidine-displacing substance (CDS), on systemic hemodynamics in the anesthetized rat. Bolus intravenous (i.v.) injections of agmatine decreased systemic arterial pressure (SAP) and systemic vascular resistance in a dose-dependent manner. The development of acute tachyphylaxis to the systemic vasodepressor response to agmatine did not induce cross-tachyphylaxis to the systemic vasodepressor responses to bradykinin, isoproterenol and nitroglycerin. The present data demonstrate agmatine, as a CDS and agonist for imidazoline (I) receptors, possesses marked systemic vasodilator activity in the rat. The present data suggest that activation of I receptors may represent a novel mechanism of vasodilation in vivo.

Adrenotensin: An adrenomedullin gene product contracts pulmonary blood vessels

The purpose of the present study was to determine the effects of adrenotensin, a newly described product of the ADM gene, on cat pulmonary arterial (PA) rings. Under resting conditions, adrenotensin increased tension of PA rings in a concentration-dependent manner. Although addition of diphenhydramine, ONO-3708, phentolamine, methysergide, atropine, and meclofenamate did not alter the contractile response to adrenotensin, removal of the endothelial cell layer significantly reduced this response. Moreover, precontraction of PA rings with adrenotensin selectively attenuated the pulmonary vasorelaxant response to ADM but not to other vasodilator substances, including isoproterenol, pinacidil, nifedipine, and adenosine. The present data suggest that adrenotensin acts in an endothelium-dependent manner to contract PA rings. Moreover, the present data suggest that adrenotensin may act in a modulatory manner to influence vasorelaxation in response to ADM, a sister proADM product.