CARDIAC AND VASCULAR EFFECTS OF LONG-TERM LOSARTAN TREATMENT IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

In previous studies in stroke-prone spontaneously hypertensive rats (S HRSP), we demonstrated that early-onset, long-term angiotensin-convert ing enzyme inhibitor treatment improved cardiac function and metabolis m and increased aortic cGMP content even at sub-antihypertensive doses . These effects could be prevented by bradykinin type 2 (B-2) receptor blockade with icatibant. In the present study, we studied the effects of long term oral treatment with the angiotensin type 1 (AT(1)) recep tor antagonist losartan (30 mg/kg per day) on functional and biochemic al parameters of the heart and on cGMP content in the aorta in SHRSP t reated prenatally and subsequently up to the age of 20 weeks. Losartan prevented the development of hypertension and left ventricular hypert rophy. Cardiac function measured ex vivo in isolated perfused hearts w as improved, as demonstrated by significant increases in left ventricu lar pressure (22.4%), differentiated left ventricular pressure (dP/dt( max)) (35.1%), and coronary flow (38%). The release of the intracellul ar enzymes lactate dehydrogenase and creatine kinase and of lactate in to the coronary effluent was reduced by 46.4%, 47.2%, and 63.6%, respe ctively. 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 r esults demonstrate that chronic blockade of AT(1) receptors with losar tan improved cardiac function and metabolism and increased aortic cGMP content in SHRSP to an extent similar to that observed previously aft er long-term angiotensin-converting enzyme inhibitor treatment at a co mparably antihypertensive dose. Prevention of hypertension and cardiac hypertrophy as well as stimulation of non-AT(1) receptors are discuss ed to explain the cardiac and vascular actions of losartan.