KT3-671, an Angiotensin AT1 Receptor Antagonist, Attenuates Vascular but Not Cardiac Responses to Sympathetic Nerve Stimulation in Pithed Rats

Abstract

Effects of KT3-671 on vascular and cardiac sympathetic neurotransmission were investigated in pithed rats. The pressor response to spinal stimulation (5 Hz) of the pithed rat without the adrenals was approximately 75% of that with the adrenals. Guanethidine (8 mg/kg, i.v.) decreased by about 76% the pressor response to sympathetic stimulation in the pithed rat with intact adrenals and the guanethidine-resistant response was almost completely abolished by bilateral adrenalectomy. Therefore, the following experiments were done using the pithed rat without the adrenals. KT3-671 (1-10 mg/kg, i.v.) as well as losartan (1-10 mg/kg, i.v.) inhibited dose-dependently the pressor response to sympathetic stimulation. KT3-671 was approximately four times more potent than losartan in inhibiting the pressor response. The two angiotensin II subtype 1 receptor antagonists (10 mg/kg, i.v.) did not affect the pressor response to exogenously administered norepinephrine. Neither KT3-671 nor losartan influenced the tachycardia induced by spinal stimulation and isoprenaline. Intravenous infusion of angiotensin II (100 ng/kg/min) did not affect both pressor and tachycardic responses to sympathetic stimulation. In conclusion, KT3-671 as well as losartan inhibits vascular but not cardiac sympathetic neurotransmission of the pithed rats, which may contribute to its overall antihypertensive efficacy.

Captopril Enhances Cardiac Vagal but Not Sympathetic Neurotransmission in Pithed Rats

“…Reflex tachycardia as a consequence of hypotension results from both increased sympathetic activity and decreased vagal one. We previously showed that angiotensin II receptor antagonists inhibited the facilitatory action of angiotensin II on the electrically stimulated norepinephrine release in perfused rat hearts (3), while they did not affect the tachycardia induced by sympathetic nerve stimulation in pithed rats (4). Although vagal efferent activity plays an important role in regulating heart rate change in a number of autonomic reflexes (5), there are few reports on effects of ACE inhibitors on the cardiac vagal neurotransmission.…”

Angiotensin AT1–Receptor Blockers Enhance Cardiac Responses to Parasympathetic Nerve Stimulation via Presynaptic AT1 Receptors in Pithed Rats

“…In various hypertension models, KT3-671-induced blood pressure reduction also is not accompanied by a reflex tachycardia (15 -17). It has been reported that KT3-671 as well as losartan inhibited vascular but not cardiac sympathetic neurotransmission in pithed rats (11). In that paper, it showed that KT3-671 was approximately four times more potent than losartan in inhibiting vascular sympathetic neurotransmission.…”

“…KT3-671, a non-peptide ARB with no active metabolites (15), induced hypotension without causing reflex tachycardia in various animal models of hypertension (15 -17). Takata et al showed that neither KT3-671 nor losartan affected cardiac sympathetic neurotransmission in pithed rats (11). On the other hand, they showed that both ARB inhibited vascular sympathetic neurotransmission, and this vascular sympathoinhibitory effect by KT3-671 was more potent than that by losartan.…”

“…ACEI and ARB decrease blood pressure without producing reflex tachycardia in humans (1 -6). Reflex tachycardia as a consequence of hypotension results from both increased sympathetic activity and decreased vagal one, but there are some reports suggesting that ACEI (7 -9) and ARB (10,11) appear to have no effect on the tachycardia due to cardiac sympathetic nerve stimulation in pithed rats.…”

An update on non-peptide angiotensin receptor antagonists and related RAAS modulators

“…KT3-671 does not affect normal renal function and reduces hypertension-induced pathological changes in the kidney (Amano et al, 1995). KT3-671 has recently been demonstrated to produce vascular sympathoinhibitory activity (Takata et al, 2001). KD3-671 (10(− 8), 10(− 7), 10(− 6) M) dose-dependently attenuated fibronectin production in isolated nephritic glomeruli from experimental rat model of mesangioproliferative glomerulonephritis.…”