Hypertension induced by nitric oxide synthase inhibitor increases responsiveness of ventricular myocardium and aorta of rat tissue to adrenomedullin stimulation in vitro.
In this work, we aimed to observe the changes in adrenomedullin (ADM) and its receptor-calcitonin receptor-like receptor (CL), receptor activity-modifying protein (RAMP) 1, RAMP2 and RAMP3-in cardiac ventricles and aortas of hypertensive rats, and the responsiveness of injured cardiovascular tissue to ADM, then to illustrate the protective mechanism of ADM on the cardiovascular system. Male SD rats were subjected to treatment with chronic N(G)-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide synthase. The ADM contents and cAMP production in myocardia and aortas were measured by RIA. The mRNA levels of ADM, CL, and RAMP1-3 were determined by RT-PCR. L-NNA induced severe hypertension and cardiomegaly. The ir-ADM content in plasma, ventricles and aortas in L-NNA-treated animals increased by 80%, 72% and 57% (all p<0.01), respectively. Furthermore, mRNA levels of ADM, CL, RAMP2 and RAMP3 were elevated by 91%, 33%, 50% and 72.5% (all p<0.01), respectively, in ventricles and by 95%, 177%, 74.7% and 85% (all p<0.01), respectively, in aortas. mRNA level of RAMP1 was elevated by 129% (p<0.01) in aortas but no significant difference in ventricles. The elevated mRNA levels of RAMP2 and RAMP3 were positively correlated with that of ADM in hypertrophic ventricles (r=0.633 and 0.828, p<0.01, respectively) and the elevated mRNA levels of CL, RAMP2 and RAMP3 were positively correlated with that of ADM in aortas (r=0.941, 0.943 and 0.736, all p<0.01, respectively). The response of ventricular myocardia and aortas to ADM administration potentiated, and the production of cAMP was increased by 41% and 68% (both p<0.01), respectively. ADM-stimulated cAMP generation in ventricular myocardia and aortas was blocked by administration of both ADM22-52, the specific antagonist of ADM receptor, and CGRP8-37, the antagonist of the CGRP1 receptor. The results showed an increased in cardiovascular ADM generation and an up-regulation of the gene expression of ADM and its receptor-CL, RAMP1-3 during hypertension, augmented responsiveness of ventricular myocardia and aortas of hypertensive rats to ADM, suggesting that these receptors may play a role in the cardiovascular adaptation in response to sub-chronic NO-inhibition.
Pan
Chun Shui
CS
Institute of Cardiovascular Diseases, Peking University First Hospital, Beijing 100034, China.
Jiang
Wei
W
Zhong
Guang Zhen
GZ
Zhao
Jing
J
Pang
Yong Zheng
YZ
Tang
Chao Shu
CS
Qi
Yong Fen
YF
D053607:Adrenomedullin; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism* / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology*; D010455:Peptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018003:Receptors, Calcitonin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; D012333:RNA, Messenger; D018003:Receptors, Calcitonin; D053607:Adrenomedullin; D019335:Nitroarginine; D000242:Cyclic AMP