Antihypertensive Effect of Clonidine

Onesti, Gaddo; Schwartz, Allan B.; Kim, Kwan E.; Paz-Martínez, V.; Swartz, Charles

doi:10.1161/01.res.28.5_suppl_2.ii-53

Cited by 98 publications

(32 citation statements)

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“…Clonidine doses used for antihypertensive therapy in humans are typically in the range of 150 to 900 g/d, but doses up to 3600 g/d have also been used in patients with essential hypertension. 37 Interestingly, in tetraplegic patients with complete cervical spinal cord transsection and preganglionic sympathetic denervation, clonidine significantly lowered heart rate without affecting blood pressure. 38 Inhibition of cardiac HCN channels by clonidine in humans may be of particular relevance during high-dose application of the drug, including rapid intravenous injection during hypertensive crisis or opioid detoxification.…”

Section: Discussionmentioning

confidence: 95%

Direct Inhibition of Cardiac Hyperpolarization-Activated Cyclic Nucleotide–Gated Pacemaker Channels by Clonidine

et al. 2007

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Background-Inhibition of cardiac sympathetic tone represents an important strategy for treatment of cardiovascular disease, including arrhythmia, coronary heart disease, and chronic heart failure. Activation of presynaptic ␣ 2 -adrenoceptors is the most widely accepted mechanism of action of the antisympathetic drug clonidine; however, other target proteins have been postulated to contribute to the in vivo actions of clonidine. Methods and Results-To test whether clonidine elicits pharmacological effects independent of ␣ 2 -adrenoceptors, we have generated mice with a targeted deletion of all 3 ␣ 2 -adrenoceptor subtypes (␣ 2ABC Ϫ/Ϫ ). ␣ 2ABC Ϫ/Ϫ mice were completely unresponsive to the analgesic and hypnotic effects of clonidine; however, clonidine significantly lowered heart rate in ␣ 2ABC Ϫ/Ϫ mice by up to 150 bpm. Clonidine-induced bradycardia in conscious ␣ 2ABC Ϫ/Ϫ mice was 32.3% (10 g/kg) and 26.6% (100 g/kg) of the effect in wild-type mice. A similar bradycardic effect of clonidine was observed in isolated spontaneously beating right atria from ␣ 2ABC -knockout and wild-type mice. Clonidine inhibited the native pacemaker current (I f ) in isolated sinoatrial node pacemaker cells and the I f -generating hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 and HCN4 channels in transfected HEK293 cells. As a consequence of blocking I f , clonidine reduced the slope of the diastolic depolarization and the frequency of pacemaker potentials in sinoatrial node cells from wild-type and ␣ 2ABC -knockout mice. Conclusions-Direct inhibition of cardiac HCN pacemaker channels contributes to the bradycardic effects of clonidine gene-targeted mice in vivo, and thus, clonidine-like drugs represent novel structures for future HCN channel inhibitors.

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Section: Discussionmentioning

confidence: 95%

Direct Inhibition of Cardiac Hyperpolarization-Activated Cyclic Nucleotide–Gated Pacemaker Channels by Clonidine

et al. 2007

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“…4 The sympatho-inhibitory effect of clonidine is largely due to a central action of the drug, and there is evidence that the suppression of renin activity is also centrally mediated. For example, injection of clonidine into the cisterna magna 2 or the 3rd ventricle 4 of dogs, in doses which are ineffective when administered intravenously, decreases plasma renin activity.…”

Section: Suppression Of Renin By Clonidine/nolan and Reidmentioning

confidence: 99%

Mechanism of suppression of renin secretion by clonidine in the dog.

Nolan¹,

Reid²

1978

Circulation Research

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SUMMARY The mechanism by which clonidine suppresses renin secretion was investigated in pentobarbitalanesthetized dogs in which renal perfusion pressure was controlled by means of an aortic clamp. Clonidine (30 /ig/ kg, iv) lowered mean arterial pressure (MAP) from 124 ± 8 to 104 ± 4 mm Hg (P < 0.01) and reduced plasma renin activity (PRA) to 32 ± 4% of the control value (P < 0.01) after 60 minutes. Ganglion blockade with pentolinium (3 mg/kg, im) decreased MAP from 148 ± 7 to 117 ± 3 mm Hg (P < 0.01) and reduced PRA to 55 ± 13% of the control value (P < 0.05) after 45 minutes. Pentolinium converted the hypotension produced by clonidine to hypertension (108 ± 9 to 146 ± 10 mm Hg at 60 minutes, P < 0.05) and abolished the suppression of PRA (105 ± 14% of control at 60 minutes, P > 0.05). In a further series of experiments, the effects of oxymetazoline, an a-adrenergic receptor agonist which is closely related to clonidine but which does not cross the blood brain barrier, were studied. Oxymetazoline (10 /ig/kg, iv) increased MAP from 127 ± 3 to 154 ± 2 mm Hg (P < 0.01) and elevated PRA to 176 ± 22% of the control value (P < 0.02) after 30 minutes. A higher dose of oxymetazoline (30 pg/kg) increased MAP from 129 ± 10 to 161 ± 9 mm Hg (P < 0.05) and increased PRA to 256 ± 37% of control (P < 0.05) after 30 minutes. Taken together, these data support the hypothesis that the inhibition of renin secretion by clonidine results from a centrally mediated decrease in sympathetic neural activity.

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“…6 ' 9 In patients, no direct information is available on the effect of clonidine on sympathetic activity, but renal excretion of catecholamines is reduced during "chronic" treatment with clonidine and this has been taken as an indication of reduced sympathetic activity. 11 However, cardiac output 13 and renal blood flow 3 are reported to be reduced after bolus injections of clonidine in doses of 0.2-1 Mg/kg. The reduction in catecholamine excretion could therefore partly be explained by these circumstances.…”

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confidence: 99%

The antihypertensive mechanism of clonidine in man. Evidence against a generalized reduction of sympathetic activity.

Wallin¹,

Frisk-Holmberg²

1981

Hypertension

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SUMMARY Recordings of multi-unit sympathetic activity were made from muscle branches of the peroneal nerve during i.v. bolus injection of 100 to 275 pg clonidine in seven hypertensive patients. Blood pressure was reduced in all patients, but sympathetic activity and heart rate could either increase or decrease. When plasma levels of clonidine were low, sympathetic activity tended to Increase, and when plasma levels were high, activity tended to decrease. A CUTE and chronic administration of clonidine lowers blood pressure (BP) in humans and is used in the treatment of hypertension. The effect is concentration-dependent, and after intravenous bolus injections, the BP reduction is linearly related to the logarithm of the plasma concentration of clonidine.1 The mechanism for the BP reduction is only incompletely understood. Clonidine is a partial pre-and postsynaptic a-adrenoreceptor agonist.2 From animal experiments, it has been postulated that the hypotensive effect is elicited centrally, 3 since the drug is active after intracisternal administration 4 and induces a BP reduction in baroreceptor-denervated animals.' The mechanism has been suggested to be a stimulation of central aadrenoreceptors, causing a reduction in peripheral sympathetic outflow.3 ' *"" The arterial baroreflex may be potentiated by clonidine, 9 " 11 but since the BP reduction remains after baroreceptor denervation, this cannot be the main hypotensive mechanism of the drug. 6 ' 9 In patients, no direct information is available on the effect of clonidine on sympathetic activity, but renal

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Antihypertensive Effect of Clonidine

Cited by 98 publications

References 0 publications

Direct Inhibition of Cardiac Hyperpolarization-Activated Cyclic Nucleotide–Gated Pacemaker Channels by Clonidine

Direct Inhibition of Cardiac Hyperpolarization-Activated Cyclic Nucleotide–Gated Pacemaker Channels by Clonidine

Mechanism of suppression of renin secretion by clonidine in the dog.

The antihypertensive mechanism of clonidine in man. Evidence against a generalized reduction of sympathetic activity.

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