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AT1 receptor antagonist treatment caused persistent arterial functional changes in young spontaneously hypertensive
1Smooth Muscle Research Programme and Department of Anaesthesia, McMaster University, Hamilton, Ontario, Canada.
Insights
An AT1 receptor antagonist, L-158,809, effectively prevented hypertension in spontaneously hypertensive rats (SHR) and reduced blood pressure in Wistar-Kyoto rats (WKY). This cardiovascular treatment also persistently decreased arterial reactivity post-withdrawal.
Area of Science:
- Cardiovascular Pharmacology
- Hypertension Research
- Renal Physiology
Background:
- Hypertension is a major risk factor for cardiovascular disease.
- Angiotensin II plays a key role in regulating blood pressure and cardiovascular function.
- AT1 receptor antagonists offer a therapeutic strategy for managing hypertension.
Purpose of the Study:
- To investigate the long-term effects of chronic AT1 receptor antagonist (L-158,809) treatment on hypertension development and cardiovascular parameters in SHR and WKY rats.
- To assess the persistence of these effects after treatment withdrawal.
- To evaluate the impact of L-158,809 on arterial reactivity and structure.
Main Methods:
- Chronic oral administration of L-158,809 (0.6 mg/kg) to SHR and WKY rats from 3 to 15 weeks of age.
- Measurement of systolic blood pressure, heart weight, body weight, and kidney weight.
- Assessment of mesenteric artery responsiveness to periarterial nerve stimulation and angiotensin II.
- Evaluation of arterial structure at different transmural pressures.
Main Results:
- L-158,809 prevented hypertension in SHR and lowered blood pressure in WKY rats during treatment.
- Treatment significantly reduced heart weight in both rat models.
- After withdrawal, blood pressure increased but remained lower than controls; arterial reactivity to nerve stimulation and angiotensin II was persistently reduced in treated SHR.
- No significant effects on body or kidney weight were observed.
Conclusions:
- L-158,809 is effective in preventing and reducing hypertension severity in a rat model.
- The antihypertensive effects and reduced arterial reactivity persist even after treatment cessation.
- This AT1 receptor antagonist demonstrates potential for long-term cardiovascular benefits beyond the treatment period.
Abstract:
The effects of chronic treatment with an AT1 receptor antagonist (L-158,809) on hypertension development and cardiovascular changes were studied in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). L-158,809 treatment (0.6 mg/kg PO) was initiated at 3 weeks of age and lasted 12 weeks, to 15 weeks of age. The treatment prevented hypertension development in the SHR (systolic blood pressure, BP, of 136+/-1 mm Hg compared with 198+/-3 mm Hg in control SHR), and lowered the BP of WKY (99+/-2 vs 128+/-1 mm Hg in control WKY). Treatment significantly reduced the heart weight in SHR and WKY. Ten weeks after treatment withdrawal (25 weeks of age), BP had increased in SHR and WKY to 172+/-8 and 117+/-3 mm Hg, respectively. Body weight and kidney weight were not affected by the treatment. Mesenteric arteries from treated SHR were less responsive than control SHR arteries to periarterial nerve stimulations at transmural pressures higher than 80 mm Hg (15 and 25 weeks). Control WKY arteries were less responsive than control SHR arteries at almost all transmural pressures tested (15 weeks) and to pressures greater than 80 mm Hg (25 weeks). Pretreatment of arteries with 10(-8) mol/L angiotensin II enhanced their response to nerve stimulation in vessels from control SHR and WKY (25 weeks) but not from treatment-withdrawn SHR and WKY. Treatment did not alter arterial reactivity in response to norepinephrine. Alteration in arterial structure due to L-158,809 treatment was found only when measured at a transmural pressure of 100 mm Hg. In conclusion, L-158,809 was effective in preventing hypertension during the treatment period, in reducing hypertension severity during the withdrawal period, and in persistently decreasing the reactivity of the arteries.