Influence of dietary salts on the cardiovascular effects of low-dose combination of ramipril and felodipine in spontaneously hypertensive rats.
1 In spontaneously hypertensive rat (SHR) we examined over a 4-week period the influence of control low sodium diet, common salt-enriched diet (sodium chloride 6% of the dry weight of the chow) and a novel mineral salt-enriched diet (potassium-, magnesium-, and l-lysine-enriched mineral salt added at a 75% higher level of 10.5% to produce the same sodium chloride concentration of 6%) on the cardiovascular effects produced by a low-dose combination of an angiotensin converting enzyme inhibitor ramipril (0.25 mg kg(-1) day(-1) in the food) and a calcium channel blocker felodipine (0.4 mg kg(-1) day(-1) subcutaneously via an osmotic minipump). 2 Common salt, but not the mineral salt, accelerated the development of hypertension and induced left ventricular and renal hypertrophy in SHR. Neither common salt nor mineral salt significantly affected heart rate. 3 The combination of ramipril and felodipine decreased systolic blood pressure and prevented the development of left ventricular hypertrophy effectively during the common salt diet without any significant effect on the heart rate. The cardiovascular effects of the drug combination were improved by the low sodium diet or by replacement of high common salt in the diet by mineral salt. 4 Responses of endothelium-intact mesenteric arterial rings in vitro were examined at the end of the four-week study. The combination of ramipril and felodipine markedly improved the endothelium-dependent vascular relaxation responses to acetylcholine and enhanced the endothelium-independent vascular relaxation responses to sodium nitroprusside in SHR on control and common salt diets. Replacement of common salt in the diet by mineral salt improved the endothelium-dependent vascular relaxation responses to acetylcholine. The drug combination attenuated the alpha-adrenoceptor-mediated vascular contractile responses to noradrenaline during the common salt diet. 5 Ramipril and felodipine in combination increased plasma renin activity by 1.9-3.2 fold without affecting serum aldosterone levels. 6 Our findings suggest that the cardiovascular effect of the low-dose combination of ramipril and felodipine was maintained during high salt intake. However, salt restriction or replacement of common salt in the diet by the potassium- and magnesium-enriched mineral salt improved the cardiovascular effects of the drug combination. In the face of a high intake of sodium, a part of the beneficial cardiovascular effects of the drug combination is apparently mediated by improved endothelium-dependent and endothelium-independent vascular relaxation responses and attenuated alpha-adrenoceptor-mediated vascular contractile responses.
Mervaala
E M
EM
Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Helsinki, Finland.
Malmberg
L
L
Teräväinen
T L
TL
Laakso
J
J
Vapaatalo
H
H
Karppanen
H
H
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects*; D004347:Drug Interactions; D015736:Felodipine / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D006984:Hypertrophy / Q000139:chemically induced; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000188:drug therapy; D007328:Insulin / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008239:Lysine / Q000494:pharmacology; D015636:Magnesium Chloride / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D012982:Sodium, Dietary / Q000494:pharmacology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001786:Blood Glucose; D002121:Calcium Channel Blockers; D007328:Insulin; D012982:Sodium, Dietary; D015636:Magnesium Chloride; D011189:Potassium Chloride; D008239:Lysine; D017257:Ramipril; D015736:Felodipine