Cardiac and vascular effects of long-term losartan treatment in stroke-prone spontaneously hypertensive rats.
In previous studies in stroke-prone spontaneously hypertensive rats (SHRSP), we demonstrated that early-onset, long-term angiotensin-converting enzyme inhibitor treatment improved cardiac function and metabolism and increased aortic cGMP content even at sub-antihypertensive doses. These effects could be prevented by bradykinin type 2 (B2) receptor blockade with icatibant. In the present study, we studied the effects of long-term oral treatment with the angiotensin type 1 (AT1) receptor antagonist losartan (30 mg/kg per day) on functional and biochemical parameters of the heart and on cGMP content in the aorta in SHRSP treated prenatally and subsequently up to the age of 20 weeks. Losartan prevented the development of hypertension and left ventricular hypertrophy. Cardiac function measured ex vivo in isolated perfused hearts was improved, as demonstrated by significant increases in left ventricular pressure (22.4%), differentiated left ventricular pressure (dP/dtmax) (35.1%), and coronary flow (38%). The release of the intracellular enzymes lactate dehydrogenase and creatine kinase and of lactate into the coronary effluent was reduced by 46.4%, 47.2%, and 63.6%, respectively. In myocardial tissue, the concentrations of glycogen and the energy-rich phosphates ATP and creatine phosphate were increased by 43.2%, 33.1%, and 42.4%, respectively, whereas lactate was decreased by 57.0%. The aortic tissue content of cGMP was increased fivefold. Our results demonstrate that chronic blockade of AT1 receptors with losartan improved cardiac function and metabolism and increased aortic cGMP content in SHRSP to an extent similar to that observed previously after long-term angiotensin-converting enzyme inhibitor treatment at a comparably antihypertensive dose. Prevention of hypertension and cardiac hypertrophy as well as stimulation of non-AT1 receptors are discussed to explain the cardiac and vascular actions of losartan.
Gohlke
P
P
Department of Pharmacology, Christian-Albrechts University Kiel, Germany.
Linz
W
W
Schölkens
B A
BA
Wiemer
G
G
Unger
T
T
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects*; D001834:Body Water / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002561:Cerebrovascular Disorders / Q000235:genetics; D004326:Drinking / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR / Q000235:genetics / Q000502:physiology*; D017208:Rats, Wistar; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D019808:Losartan