Potentiation of natriuretic peptide action by the beta-adrenergic blocker carvedilol in hypertensive rats: a new antihypertensive mechanism.
Treatment with a beta-adrenergic blocker (beta-blocker) in hypertension is associated with increased plasma atrial natriuretic peptide (ANP) levels despite a decrease in cardiac overload. The mechanism and pathophysiological significance of the phenomenon remain unclear. To clarify the role of the ANP system in the antihypertensive effects of the beta-blocker, we investigated the effects of carvedilol (30 mg/kg x day, orally, for 4 weeks) on the ANP system in stroke-prone spontaneously hypertensive rats (SHR-SP/Izm). Plasma ANP levels showed a significant increase despite a significant decrease in blood pressure and heart rate in the carvedilol group. Although ANP messenger RNA levels in the heart did not change, messenger RNA levels of the natriuretic peptide-C (NP-C) receptor as a clearance receptor showed a significant decrease in both the aorta and lung in the carvedilol group. NP-C receptor densities were also significantly decreased in the lung in this group. The biological half-life of exogenous ANP in circulating blood was prolonged in the carvedilol group compared with that in the control group. Administration of the ANP receptor antagonist, HS-142-1, resulted in a greater increase in systolic blood pressure in the carvedilol group than in the control group. In addition, both basal and ANP-stimulated cGMP contents in the aorta were significantly higher in the carvedilol group. These results suggest that carvedilol potentiates the hypotensive action of ANP by increasing plasma ANP levels and enhancing the vascular response to ANP. These effects were closely related to the down-regulation of the NP-C receptor. The newly found mechanism seems to account for a sizable portion of the antihypertensive effects of carvedilol and could be of potential importance in the treatment of cardiovascular disease with beta-blockers.
Yoshimoto
T
T
Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical College, Japan.
Naruse
M
M
Tanabe
A
A
Naruse
K
K
Seki
T
T
Imaki
T
T
Muraki
T
T
Matsuda
Y
Y
Demura
H
H
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D009320:Atrial Natriuretic Factor / Q000097:blood*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D006152:Cyclic GMP / Q000096:biosynthesis; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D011412:Propanolamines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D002227:Carbazoles; D011412:Propanolamines; D012333:RNA, Messenger; D000077261:Carvedilol; D009320:Atrial Natriuretic Factor; D017461:Receptors, Atrial Natriuretic Factor; D006152:Cyclic GMP