Cardiovascular and renal effects of the combination of felodipine and metoprolol during a high-salt and a moderate-salt diet in spontaneously hypertensive rats.
In the present study the influence of dietary salt on the cardiovascular and renal effects of the calcium channel blocker felodipine (1.2 mg/kg sc) and the beta 1-adrenoceptor blocking drug metoprolol (250 mg/kg po), alone and in combination, was examined in the spontaneously hypertensive rats (SHRs) in a 4-week study. In addition, the influence of different diet and drug regimens on vascular functions was assessed by measuring the vascular relaxation and contractile responses of mesenteric arterial rings in vitro at the end of the experimental period. In SHRs, a high-salt diet caused a marked rise in blood pressure, impaired the endothelium-dependent vascular relaxation responses to acetylcholine and induced left ventricular hypertrophy (LVH) and renal hypertrophy. Metoprolol had little if any effect on salt-induced changes in blood pressure, endothelium-dependent vascular relaxation or renal hypertrophy, but it partially prevented the development of salt-induced LVH. Felodipine during the high-salt diet lowered blood pressure to normotensive level and completely prevented salt-induced left ventricular and renal hypertrophy as well as endothelial dysfunction. Felodipine produced tachycardia, especially at the beginning of drug treatment. The combination of felodipine and metoprolol abolished the effects of the individual drugs on heart rate. The drug combination also completely prevented the detrimental cardiovascular and renal effects induced by a high salt intake. Although salt restriction did not further enhance the profound antihypertensive effect of the combination of metoprolol and felodipine, it enhanced the effects of the drug combination on LVH and renal hypertrophy. Our findings indicate that felodipine treatment, alone and in combination with metoprolol, normalizes blood pressure and prevents the development of salt-induced LVH and renal hypertrophy. During the high-salt diet the beneficial vascular effects of felodipine as well as those of the combination of felodipine and metoprolol are mediated, at least in part, by prevention of salt-induced endothelial dysfunction. The only apparent benefit from the use of metoprolol in combination with a relatively high dose of felodipine was the prevention of tachycardia.
Mervaala
E M
EM
Department of Pharmacology and Toxicology, University of Helsinki, Finland.
Teräväinen
T L
TL
Malmberg
L
L
Laakso
J
J
Pörsti
I
I
Vapaatalo
H
H
Karppanen
H
H
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D015736:Felodipine / Q000008:administration & dosage / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000652:urine; D006984:Hypertrophy; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000517:prevention & control; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D008790:Metoprolol / Q000008:administration & dosage / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D017673:Sodium Chloride, Dietary; D014665:Vasodilator Agents; D008790:Metoprolol; D015736:Felodipine