Adverse interactions of rofecoxib with lisinopril in spontaneously hypertensive rats.
BACKGROUND
Hypertension and arthritis are frequent comorbidities. Nonsteroidal anti-inflammatory drugs (NSAIDs) are well known to produce hypertension or attenuate the effects of antihypertensive agents in a few patients. The influence of selective NSAIDs on blood pressure and the cardiovascular and renal effects of coxibs have still to be investigated. The purpose of this study was to test the hypothesis that rofecoxib interferes with antihypertensive activity and cardiorenal protective effects of lisinopril in spontaneously hypertensive rats (SHRs).


METHODS
Twenty-one unanaesthetised, male spontaneously hypertensive rats (SHRs), 16 weeks old, were randomized to receive lisinopril (LS) 15 mg/kg/d or rofecoxib (RF) 20 mg/kg/d or combination of lisinopril (LS) and rofecoxib (RF) for 2 weeks. The arterial blood pressure changes were recorded each week. The Sodium Hydrogen Exchange (NHE) activity of erythrocytes was determined 2 weeks after the study. The surviving animals were sacrificed 24 h after the last dose, and the sections of their hearts and kidneys were assessed histologically for injury by a pathologist masked to the treatment.


RESULTS
RF completely prevented the hypotensive effects of LS during the first week of treatment but the antihypertensive efficacy of LS was restored during the second week of treatment. The NHE in erythrocytes of 18-week-old SHRs was found to be significantly lower than the age-matched Wistar rats (P < 0.05), and LS treatment reversed these values to Wistar control in SHRs. RF was devoid of any effect on NHE of erythrocytes. The histological examination revealed that the myocardial and renal protection induced by LS was attenuated by concomitant RF therapy.


CONCLUSIONS
These results indicate that COX-2 inhibitors should be used judiciously in patients with history of hypertension, ischemic heart disease, or chronic renal failure.
Dubey
Kiran
K
Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, Hamdard University, New Delhi, India. kdb104@rediffmail.com
Balani
Dayal K
DK
Tripathi
C B
CB
Singh
Rajvir
R
Bajaj
Rajiv
R
Pillai
K K
KK
D000367:Age Factors; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D004195:Disease Models, Animal; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D007783:Lactones / Q000009:adverse effects*; D017706:Lisinopril / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D008571:Men; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D011918:Rats, Inbred SHR / Q000097:blood*; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000187:drug effects; D013450:Sulfones / Q000009:adverse effects*; D018675:Toxicity Tests / Q000379:methods
D000806:Angiotensin-Converting Enzyme Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C116926:rofecoxib; D012964:Sodium; D017706:Lisinopril