Inhibitory Effect of Kt3-671, a Non-Peptide Angiotensin Subtype 1 Receptor Antagonist, on Sympathetic Neurotransmission in Isolated Rabbit Aorta

Takata, Yoshinobu; Tajima, S.; Kato, Harubumi

doi:10.1006/phrs.1999.0592

Cited by 2 publications

(1 citation statement)

References 21 publications

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“…KT3-671 is a novel chemical entity, which has been shown to be a potent, orally active, specific AT 1 receptor antagonist. KT3-671 has undergone in vitro and in vivo pharmacological studies in which it demonstrated a selective affinity for AT 1 receptors in a variety of animal models where a dose dependent reduction in blood pressure (BP) was observed [1][2][3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

The effects of KT3‐671, a new angiotensin II (AT 1) receptor blocker in mild to moderate hypertension

Patterson

Webster

McInnes

et al. 2003

Brit J Clinical Pharma

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AimsTo compare the antihypertensive effect, and tolerability and safety of once daily doses of KT3-671 with that of placebo in patients with mild to moderate uncomplicated essential hypertension. Methods A randomised, multicentre, double blind, parallel-group comparison of KT3-671 with placebo. Hypertensive patients [Ambulatory Blood Pressure Monitoring (ABPM), mean daytime DBP > 90 mmHg, Office sitting mean DBP 95-114 after a 7-28 day washout period] entered a 2-week, single blind, run-in phase. Patients eligible for the double-blind phase were randomised to receive KT3-671 40 mg, 80 mg, 160 mg or placebo once daily over 4 weeks. The primary end-point was trough mean sitting office DBP. The study had 90% power to detect a 5 mmHg change between treatments and placebo at the 5% level of significance. The secondary end-points were 24 hour, daytime and night time mean ABPM. Results Office DBP was significantly lower with KT3-671 40 mg but not the other 2 dosage groups ( -3.2; 95% CL -6.1 : -0.3 P < 0.03). Office SBP was significantly reduced with all dosage groups (40 mg -5.9, 95% CL -11 : -0.9; 80 mg -4.9, 95% CL -9.9 : 0.1 and 160 mg -5.7, 95% CL -10.8 : -0.7 P < 0.05). All doses of KT3-671 reduced systolic and diastolic ABPM. The number of patients with treatment related adverse events were comparable to placebo (38.8% KT3-671 vs 32.8% placebo). There was some evidence of a dose-response relationship with fall in nocturnal ABPM. Conclusions Oral KT3-671 was well tolerated. KT3-671 reduced office systolic BP at all doses and diastolic BP at some of the doses. Due to greater precision and power, the falls in mean ambulatory systolic and diastolic pressure were all significantly lower than placebo.

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Section: Introductionmentioning

confidence: 99%

The effects of KT3‐671, a new angiotensin II (AT 1) receptor blocker in mild to moderate hypertension

Patterson

Webster

McInnes

et al. 2003

Brit J Clinical Pharma

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

Takata

Kurihara²,

Yoda³

et al. 2001

Journal of Cardiovascular Pharmacology

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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.

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Inhibitory Effect of Kt3-671, a Non-Peptide Angiotensin Subtype 1 Receptor Antagonist, on Sympathetic Neurotransmission in Isolated Rabbit Aorta

Cited by 2 publications

References 21 publications

The effects of KT3‐671, a new angiotensin II (AT 1) receptor blocker in mild to moderate hypertension

The effects of KT3‐671, a new angiotensin II (AT 1) receptor blocker in mild to moderate hypertension

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

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