Ramipril therapy improves arterial dilation in experimental hypertension.
OBJECTIVE
Angiotensin-converting enzyme (ACE) inhibition has been shown to restore impaired endothelial function in hypertension, but the roles of different mediators in enhanced endothelium-dependent dilation have not been fully characterized.


METHODS
The effects of ACE inhibition with ramipril (1 mg.kg-1.day-1) on relaxation responses of mesenteric arterial rings in vitro were studied in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY).


RESULTS
The 12-week-long therapy effectively reduced blood pressure in SHR. In noradrenaline (NA)-precontracted arterial rings, endothelium-dependent relaxations to acetylcholine (ACh) as well as endothelium-independent dilations to isoprenaline and nitroprusside were more pronounced in WKY and ramipril-treated SHR than in untreated SHR. The cyclo-oxygenase inhibitor, diclofenac, which reduces the synthesis of dilating and constricting prostanoids, clearly enhanced the relaxation to ACh in untreated SHR, but was without effect in the other groups. The nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), attenuated the relaxations to ACh more effectively in untreated SHR than in the ramipril-SHR and WKY groups. However, when endothelium-dependent hyperpolarization was prevented by precontracting the preparations with potassium chloride (KCl), no significant differences were found in relaxations to ACh between the study groups. In addition, in NA-precontracted rings the diclofenac- and L-NAME-resistant relaxations to ACh were partially prevented by glibenclamide and apamin, inhibitors of ATP-dependent and Ca(2+)-activated K+ channels, respectively.


CONCLUSIONS
Long-term ACE inhibition normalized blood pressure and enhanced arterial dilation in SHR. The improved endothelium-mediated relaxation following ramipril therapy could be attributed to reduced release of cyclo-oxygenase-derived constricting factors and augmented endothelium-dependent hyperpolarization in this type of experimental hypertension.
Hutri-Kähönen
N
N
Medical School, University of Tampere, Finland.
Kähönen
M
M
Tolvanen
J P
JP
Wu
X
X
Sallinen
K
K
Pörsti
I
I
D000109:Acetylcholine / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D026902:Potassium Channel Blockers; D017257:Ramipril / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014664:Vasodilation / Q000187:drug effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D016861:Cyclooxygenase Inhibitors; D026902:Potassium Channel Blockers; D004008:Diclofenac; D009599:Nitroprusside; D019001:Nitric Oxide Synthase; D017257:Ramipril; D007545:Isoproterenol; D000109:Acetylcholine; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester