dynorphins and Hypertension--Pulmonary

Previously study showed κ-opioid receptor stimulation with exogenous κ-opioid receptor agonist elicited a protective effect against hypoxic pulmonary hypertension (HPH). However, the effect of endogenous κ-opioid receptor agonist dynorphin A on HPH remains unclear. This study was to determine the role of dynorphin in HPH. Hypoxia for 2 weeks induced HPH. Compared with the HPH group, the HPH + nor-BNI (a selective κ-opioid receptor antagonist) group showed a significant increase in mean pulmonary arterial pressure (mPAP). Exogenous treatment with dynorphin A 1-13 significantly decreased mPAP in HPH rat. In addition, we evaluated the effect of exogenous κ-opioid receptor agonist U50,488H on mPAP. The anti-HPH effect of dynorphin A was less than that of U50,488H. Meanwhile, level of dynorphin A in serum and lung was increased during hypoxia for 2 weeks, while it decreased after hypoxia for 4 weeks. In addition, both the level of ET-1 and AngII were increased during hypoxia. Dynorphin A 1-13 and U50,488H time-dependently relaxed pulmonary artery from both normal and HPH rats. The relaxation of dynorphin A was less than that of U50,488H. Dynorphin A 1-13 inhibited the proliferation of pulmonary artery smooth muscle cells (PASMCs) during hypoxia, which was blocked by nor-BNI. κ-opioid receptor expression increased in PASMCs in both normoxia exposed to dynorphin A 1-13 and during hypoxia. Hypoxia-induced increase was enhanced by dynorphin A 1-13 and abolished by nor-BNI. In conclusion, endogenous dynorphin A released in the early stage of hypoxia plays a protective effect against HPH via stimulation of κ-opioid receptor.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Angiotensin II; Animals; Blood Pressure; Cell Hypoxia; Cell Proliferation; Dynorphins; Endothelin-1; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Lung; Male; Myocytes, Smooth Muscle; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa

The role of hippocampal dynorphin A (1-8) (Dyn A (1-8)) and kappa opioid receptors was investigated in the isolation-induced hypertensive rat (IHR). Male Sprague Dawley rats were either isolated (1 per cage) or grouped (3 per cage) for 7 days. Isolated rats exhibited increased blood pressure (systolic blood pressure 159.7 +/- 6.6 mmHg) whereas the grouped rats remained normotensive (systolic blood pressure 137 +/- 6.3 mmHg). Using radioligand binding techniques we observed a significant increase in kappa opioid receptor binding in the hippocampus of isolated rats (56% increase) and this further increased when the length of isolation was increased to 2 weeks (72% increase). Radioimmunoassay showed that isolation decreased the hippocampal content of Dyn A (1-8) from 12.7 +/- 0.4 to 11.6 +/- 0.2 pg Dyn A (1-8) per 10 mg tissue (rats weighing approximately 100 g) and from 13.3 +/- 0.8 to 9.7 +/- 1 pg Dyn A (1-8) per 10 mg tissue (approximately 200 g rats). These data suggest that functional alterations in the hippocampal dynorphin system may be involved in the maintenance of isolation induced hypertension.

Topics: Animals; Dynorphins; Hippocampus; Hypertension, Pulmonary; Ligands; Male; Protein Binding; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Social Isolation; Time Factors