Chronic ACE-inhibitor treatment and adrenergic mechanisms in spontaneously hypertensive rats.
We investigated the effects of chronic treatment with the angiotensin-converting enzyme (ACE) inhibitor fosinopril on cardiac and vascular noradrenergic neurotransmission as related to cardiovascular hypertrophy in spontaneously hypertensive rats (SHRs). SHRs were treated with fosinopril at "high dose" (SHR-HD, 25 mg/kg/day) or "low dose" (SHR-LD, 1 mg/kg/day) from the 6th to the 12th week of age, and compared to age-matched untreated SHRs (SHR-C) and Wistar-Kyoto controls (WKY). Blood pressure was significantly reduced in SHR-HD but not in SHR-LD when compared to SHR-C. The antihypertensive dose of fosinopril reduced both cardiac and vascular hypertrophy, whereas the low dose was effective only in reducing vascular hypertrophy. Several differences in presynaptic and postsynaptic cardiovascular noradrenergic neurotransmission were observed between SHR-C and WKY rats (increased cardiac norepinephrine concentration, down-regulation of cardiac beta-adrenoceptors, reduced alpha-adrenergic receptor-mediated vasoconstrictor response of small mesenteric arteries to exogenous norepinephrine). All these differences were abolished by ACE inhibitor treatment, both at antihypertensive or at subantihypertensive doses. The results of this study are consistent with the hypothesis that chronic ACE inhibition may exert an inhibitory modulation on the peripheral adrenergic transmission, which is not related to blood pressure reduction. This modulation does not appear to be a determinant in preventing the development of cardiac hypertrophy but may play a role in the regression of vascular structural alterations in spontaneously hypertensive rats.
Castellano
M
M
Department of Scienze Mediche, University of Brescia, Italy.
Rizzoni
D
D
Beschi
M
M
Böhm
M
M
Porteri
E
E
Bettoni
G
G
Cinelli
A
A
Rosei
E A
EA
D000704:Analysis of Variance; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D006332:Cardiomegaly / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D017328:Fosinopril / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy*; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D009638:Norepinephrine / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012260:Ribonucleases / Q000737:chemistry; D009435:Synaptic Transmission / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D012333:RNA, Messenger; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D012260:Ribonucleases; D017328:Fosinopril; D009638:Norepinephrine