ABSTRACT
Excessive aldosterone secretion is detrimental to the heart, vessels and kidneys, contributing to hypertension and the signs and progression of heart failure. Aldosterone secretion, abnormally elevated in heart failure and hypertension, can be blunted with angiotensin-converting enzyme inhibitors. Amlodipine, used to treat hypertension and heart failure, was hypothesized to activate the renin-angiotensin-aldosterone system (RAAS). A study was conducted with six normal adult male beagle dogs. Each dog received amlodipine (0.57 mg/kg b.i.d.) for 6 days, followed by amlodipine (0.57 mg/kg b.i.d.) and enalapril (0.57 mg/kg b.i.d.) for 4 days. Blood pressure, heart rate, serum chemistries and urinary aldosterone excretion, as a measure of RAAS activation, were compared with baseline values. Blood pressure fell by approximately 7% with amlodipine (P = 0.05) and a further 7% with the combination of amlodipine and enalapril (P < 0.01). Blood urea nitrogen increased with the combination (P < 0.05) but only one dog became mildly azotemic. Renin-angiotensin-aldosterone system activation, based on 24 h urinary aldosterone excretion and by aldosterone:creatinine ratio was increased by approximately threefold (P < 0.05) with amlodipine administration. This effect was blunted by enalapril, such that aldosterone excretion was no longer different from that observed under control conditions, although values for 24-h aldosterone excretion did not return to pretreament levels.
Subject(s)
Amlodipine/pharmacology , Antihypertensive Agents/pharmacology , Dogs/metabolism , Enalapril/pharmacology , Renin-Angiotensin System/drug effects , Administration, Oral , Aldosterone/urine , Amlodipine/administration & dosage , Amlodipine/blood , Animals , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/blood , Blood Pressure/drug effects , Blood Urea Nitrogen , Drug Therapy, Combination , Enalapril/administration & dosage , Enalapril/blood , Heart Rate/drug effects , MaleABSTRACT
The 5500T allele variant of the C5500T single nucleotide polymorphism in the human G protein beta3 subunit (GNB3) has been reported to be associated with primary hypertension. In this study, the GNB3 gene of primary hypertensive and normotensive dogs was examined for an analogous nucleotide polymorphism associated with hypertension. The genomic GNB3 dna, with 10 exons and nine introns coding for 340 amino acids, is described. PCR product sequencing of the GNB3 exon 9 from 25 dogs (including five hypertensive animals) failed to detect any nucleotide polymorphism. In contrast to human beings, there was no polymorphism at either the analogous nucleotide or in the respective exon. Only the human hypertension-associated thymine was detected, regardless of whether the dogs were hypertensive or normotensive. Furthermore, examinations of 565 dogs of 85 distinct breeds for the presence of the human 5500C nucleotide at the analogous nucleotide side failed to detect a cytosine that is present with high allele frequency in normotensive man. Owing to the lack of allele variance, it is concluded that canine primary hypertension is not associated with a polymorphism at either the respective human hypertension-associated nucleotide site or in the entire exon.