Pharmacodynamic Effects of a New Antihypertensive Drug, Catapres (ST-155)

Onesti, Gaddo; Schwartz, Allan B.; Kim, Kwan E.; Swartz, Charles; Brest, Albert N.

doi:10.1161/01.cir.39.2.219

Cited by 103 publications

(36 citation statements)

References 7 publications

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“…This has been exploited clinically by the development of pharmacological agents with ␣ 2 -agonistic properties (eg, clonidine) that suppress the central SNS and produce a sustained antihypertensive action. 12 However, existing ␣ 2 -agonists are nonselective for ␣ 2 -AR subtypes. Genetic targeting of each one of the ␣ 2 -AR gene subtypes has now produced evidence that suggests that the longrecognized sympathoinhibitory effect of central presynaptic ␣ 2 -AR may be a function of the ␣ 2A -AR subtype.…”

Section: Discussionmentioning

confidence: 99%

Sympathoinhibitory Function of the α _2A -Adrenergic Receptor Subtype

et al. 1999

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Abstract-Presynaptic ␣ 2 -adrenergic receptors (␣ 2 -AR) are distributed throughout the central nervous system and are highly concentrated in the brain stem, where they contribute to neural baroreflex control of blood pressure (BP). To explore the role of the ␣ 2A -AR subtype in this function, we compared BP and plasma norepinephrine and epinephrine levels in genetically engineered mice with deleted ␣ 2A -AR gene to their wild-type controls. At baseline, the ␣ 2A -AR gene knockouts (nϭ11) versus controls (nϭ10) had higher systolic BP (123Ϯ2.5 versus 115Ϯ2.5 mm Hg, PϽ0.05), heart rate (730Ϯ15 versus 600Ϯ18 b/min, PϽ0.001), and norepinephrine (1.005Ϯ0.078 versus 0.587Ϯ0.095 ng/mL, PϽ0.01), respectively. When submitted to subtotal nephrectomy and given 1% saline as drinking water, both ␣ 2A -AR gene knockouts (nϭ14) and controls (nϭ14) became hypertensive, but the former required 15.6Ϯ2.5 days versus 29.3Ϯ1.4 days for the controls (PϽ0.001). End-point systolic BP was similar for both at 155Ϯ2.1 versus 152Ϯ5.2 mm Hg, but norepinephrine and epinephrine levels were twice as high in the knockouts at 1.386Ϯ0.283 and 0.577Ϯ0.143 versus 0.712Ϯ0.110 and 0.255Ϯ0.032 ng/mL, respectively, PϽ0.05 for both. We conclude that the ␣ 2A -AR subtype exerts a sympathoinhibitory effect, and its loss leads to a hypertensive, hyperadrenergic state.(Hypertension. 1999;34:403-407.)Key Words: adrenergic receptors Ⅲ mice, knockout Ⅲ hypertension, sodium-dependent Ⅲ hyperadrenergic state T he sympathetic nervous system (SNS) is one of the major pressor systems involved in the regulation of blood pressure (BP). Aberrant function of various neuroendocrine components of the SNS contributes to abnormal BP in response to environmental stimuli, such as excessive sodium intake. Indeed, a large body of literature indicates that 1 of the mechanisms by which salt-loading raises BP is via activation of the central SNS, which leads to increased sympathetic outflow. 1,2 Experimental studies in animals with pharmacological probes in vivo 3-5 and radioligand techniques in vitro 6,7 have suggested that salt-induced hypertension is associated with alterations in the functional characteristics of the ␣ 2 -adrenergic receptors (␣ 2 -AR) in the central nervous system (CNS). None of these methods, however, can differentiate among the ␣ 2 -AR subtypes (␣ 2A , ␣ 2B , or ␣ 2 c) involved in this process.Recently, genetically engineered mice that are deficient in each one of the ␣ 2 -AR subtypes became available. 8,9 In our first series of experiments with these mice, we used animals deficient for the ␣ 2B -AR gene (ϩ/Ϫ) and ␣ 2C -AR gene knockouts (Ϫ/Ϫ) compared with their wild-type counterparts (␣ 2B ϩ/ϩ and ␣ 2C ϩ/ϩ, respectively) to study the role of each subtype in determining salt-sensitivity. We found that the ability to develop hypertension in response to salt-loading requires a full complement of the ␣ 2B -AR subtype gene. Indeed, the ␣ 2B ϩ/Ϫ mice failed to raise their BP after subtotal nephrectomy and dietary salt-loading for 5 weeks, whereas their wild-ty...

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Section: Discussionmentioning

confidence: 99%

Sympathoinhibitory Function of the α _2A -Adrenergic Receptor Subtype

et al. 1999

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“…Others have also found (Barnett and Cantor, 1968;Muir et al, 1969) that the circulatory response to exercise is not affected by clonidine. Another desirable feature is that clonidine does not reduce renal blood flow or glomerular filtration rate (Onesti et al, 1969), so that, like methyldopa, it is suitable for treating renal hypertension. The five patients with renal hypertension in this study did not differ from the other patients in blood pressure response or dosage requirement.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical trials of clonidine have been reported from Europe (Bock et al, 1966;Frank and von Loewenich-Lagois, 1966;Grabncr et al, 1966;Kochsiek and Fritsche, 1966;Lieb and Ridders, 1966;Michel et al, 1966;Iisalo and Laurila, 1967), America (Davidov et al, 1967;Onesti et al, 1969;Smet et al, 1969), and Australasia (Ng et al, 1967;Raftos, 1969), and several workers have carried out acute haemodynamic studies (Barnett and Cantor, 1968;Muir et al, 1969). These show that clonidine lowers the blood pressure in all grades of hypertension, irrespective of posture.…”

Section: Introductionmentioning

confidence: 99%

Treatment of Hypertension with Clonidine

Macdougall¹,

Addis²,

Mackay³

et al. 1970

BMJ

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Summary: Clonidine, in a daily dosage of 0-15-4-8 mg., effectively lowered systolic and diastolic pressures in 26 out of 28 inpatients with moderate to severe hypertension, including five with primary renal disease. The action of the drug did not depend on posture and was not associated with reduction in renal function. Sideeffects were not severe, but mental changes occurred in four patients.Clonidine is a useful alternative to currently available antihypertensive drugs, but further evaluation of its longterm efficacy is required.

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“…Onesti and co-workers' (3) observation of a decrease in Ux,V in the absence of any change in RPF gave rise to their suggestion of a direct tubular action of catapres. In their study, RPF was estimated by CLIAII, a method that cioes not give total RBF.…”

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confidence: 93%

Relationship of Sodium Retention Produced by Catapres to Changes in Renal Hemodynamics

Marchand

Willis

Williamson

1971

Experimental Biology and Medicine

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Clinically, catapres Clonidine,(2,6dichlorophenyl-1amino -2imidazoline Hell has been shown to be a potent oral antihypertensive agent (1, 2 ) . One of the few side effects that has been experienced with this compound is a decrease in sodium excretion (UNaV) (2, 3 ) . Onesti et al. ( 3 ) found that although Usi,V was depressed, renal plasma flow (KPF) and glomerular filtration rate (GFR), which were estimated by the clearance of para-aminohippurate ( CLIALI) and inulin, respectively, were not altered. Thus, in the absence of changes in renal hemodynamics, they suggested that catapres could be acting via a direct tubular mechanism to enhance the reabsorption of sodium. Laubie and Schmitt (4) noted a decrease in RPF and renal blood flow (RBF), estimated from PAH extraction, and UNaV but no change in GFR or renal vascular resistance (RVR) during the hypotension caused by systemic catapresThe present study was undertaken to further investigate the possibility that alterations in renal hemodynamics might be involved in the sodium retention. Total renal blood flow as well as the CpaH were determined. Catapres was infused into a renal artery in order to minimize systemic actions of the drug. I n addition, an attempt was made to antagonize the responses with an alpha adrenergic blocking agent.Methods. Mongrel dogs of either sex, weighing between 17 and 22 kg, were anesthetized with pentobarbital sodium (30 mg/kg, iv). The trachea was intubated and blood pressure ( 10-20 pg/kg) --(MAP) was monitered with a pressure transducer (Statham P23AA) via a carotid artery catheter. The femoral artery and vein were catheterized for the collection of blood and the administration of solutions, respectively. A sustaining infusion of 0.476 inulin, 0.08% PAH in 0.9% NaC1, was administered at a rate of 0.25 ml/kg per min. A kidney was approached via a retroperi toneal flank incision. If mo,re than one renal artery was encountered the contralateral kidney was used. If both kidneys had more than one renal artery the animal was not used. A catheter was passed into the exposed ureter for the unilateral collection of urine. A flow probe was placed around the renal artery and connected to a square wave electromagnetic flowmeter (Carolina Medical Electronics). This provided a direct measilrement of total RBF. The MAP and RBF were recorded continuously on a Beckman Type R Dynograph. A 23 gauge scalp needle was passed retrograde into the renal artery for the direct administration of drug into the kidney. A 0.9% solution of NaCl was continuously infused at a rate of 1.0 ml/min.When urine flow ( V ) had stabilized, three 10 min control urine collections were taken. Catapres was then infused, during the next three 10 min collection periods, directly into the renal artery. The catapres concentration was varied to provide different doses at the same infusion rate. Five animals were used at each dose. Blood was collected at the midpoint of each 30 min collection period.RVR is expressed as resistance units (RU) and was calculated by dividing MAP (mm Hg)...

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Pharmacodynamic Effects of a New Antihypertensive Drug, Catapres (ST-155)

Cited by 103 publications

References 7 publications

Sympathoinhibitory Function of the α _2A -Adrenergic Receptor Subtype

Sympathoinhibitory Function of the α _2A -Adrenergic Receptor Subtype

Treatment of Hypertension with Clonidine

Relationship of Sodium Retention Produced by Catapres to Changes in Renal Hemodynamics

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Pharmacodynamic Effects of a New Antihypertensive Drug, Catapres (ST-155)

Cited by 103 publications

References 7 publications

Sympathoinhibitory Function of the α 2A -Adrenergic Receptor Subtype

Sympathoinhibitory Function of the α 2A -Adrenergic Receptor Subtype

Treatment of Hypertension with Clonidine

Relationship of Sodium Retention Produced by Catapres to Changes in Renal Hemodynamics

Contact Info

Product

Resources

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Sympathoinhibitory Function of the α _2A -Adrenergic Receptor Subtype

Sympathoinhibitory Function of the α _2A -Adrenergic Receptor Subtype