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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clonidine (Catapres, Catapresan), guanfacine (Estulic), and methyldopa (Aldomet) are the prototypes of centrally acting antihypertensive drugs. Clonidine and guanfacine are lipophilic drugs that readily penetrate into the brain, where they stimulate alpha-adrenergic receptors in the pontomedullary region. The stimulation of these central alpha-adrenergic receptors has been shown to activate an inhibiting neuron, which causes a reduction of peripheral sympathetic tone and a subsequent fall in arterial blood pressure and heart rate. Both a centrally initiated reduction of vagus reflex activity and the activation of presynaptic alpha 2-adrenergic blocking agents in the heart may contribute to the bradycardia. Studies indicate that methyldopa also penetrates into the brain, where it is converted into alpha-methylnorepinephrine. This amine may stimulate the same central alpha-adrenergic receptors as those activated by clonidine, which will result in a hypotensive effect. Possibly, alpha-methyldopamine might also play a role. Accordingly, the modes of action of clonidine and alpha-methyldopa probably are very similar at a basic level. The central adrenergic receptors probably are located postsynaptically. Their receptor demand corresponds more closely to that of the alpha 2-subtype. Central alpha 1-adrenergic receptors might possibly play a part in the modulation of vagally induced baroreflex bradycardia. A discussion on the pharmacological basis of the side effects of the centrally acting antihypertensives has been limited to those adverse reactions that are somehow related to alpha-adrenergic receptors. Sedation, a common side effect, appears to be mediated by central alpha 2-adrenergic receptors, at least in animal models.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension
PMID:The hypotensive activity and side effects of methyldopa, clonidine, and guanfacine. 609 46

In the rat model of hypertension induced by a clip on the right renal artery, sparing the left kidney, we compared the efficacity and the endocrine, renal and cardiac effects of classical therapy (CT) of hypertension (Clonidine 0.2 mg/kg and Dihydralazine 15 mg/kg in 2 daily subcutaneous injections and Furosemide 30 mg/kg/day in the drinking water), with inhibition of the angiotensin converting enzyme with a new drug, the S-9490-3 (0.5 mg/kg in one daily administration). The untreated animals (HT: n = 12) had an average systolic blood pressure (SBP) of 215 +/- 32 mmHg. After 1 month' treatment, S-9490-3 (n = 13) lowers SBP to 144 +/- 32 mmHg compared to CT (n = 12) which lowered SBP to only 172 +/- 18 mmHg. The average plasma renin concentrations of the HT animals was four times the normal value (39 +/- 33 ng/ml/h) and both treatment regimes increased it further (S-9490-3: 129 +/- 65 ng/ml/h; CT: 97 +/- 73 ng/ml/h). Angiotensin levels fell in proportion to the increase in renin concentration. Plasma aldosterone was normalised by S-9490-3 (460 +/- 320 pg/ml) but remained as high after CT (850 +/- 650 pg/ml) as in the untreated HT animals (830 +/- 260 pg/ml). Despite the Furosemide, plasma volume increased significantly in the CT group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Comparison of the cardiac, renal and endocrine effects of converting enzyme inhibition with those of a classical triple therapy in experimental renal hypertension]. 609 34

Clonidine represents the prototype of a new class of centrally acting antihypertensive agents, classed as partial alpha-adrenergic antagonists. Blood pressure reduction is characterized, hemodynamically, by reduced cardiac output with unchanged peripheral vascular resistance at rest. Reflex control of blood pressure during orthostasis and exercise appears to be unimpaired, and orthostatic hypotension is uncommon. As with most other antihypertensive agents, satisfactory reduction of blood pressure with clonidine given as a sole agent is limited to patients with relatively mild hypertension; an additive or synergistic effect of diuretic administration has been well documented. Abrupt withdrawal of clinidine has been reported to be followed, within 24 to 36 h, by rebound hypertension, tachycardia, cardiac arrhythmias, and other changes suggestive of sympathetic overactivity. The incidence and clinical significance of rebound hypertension after abrupt cessation of clonidine therapy, and indeed the profile of blood pressure responses to varying physical activity during therapy, remain to be evaluated.
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PMID:Drugs five years later: clonidine. 610 2

This report reviews a number of significant developments in the fields of noradrenergic transmission and adrenergic receptors which suggest that, in addition to the classical postsynaptic adrenoceptors, there are also presynaptic adrenoceptors that help modulate the release of norepinephrine (NE) from peripheral as well as central noradrenergic nerve endings during nerve stimulation. In particular, stimulation of presynaptic alpha-adrenoceptors reduces this release of transmitter and the reverse is observed after blockade of these receptors. Clearcut pharmacological differences exist between the postsynaptic alpha 1-adrenoceptors that mediate the responses of certain organs and the presynaptic alpha 2-adrenoceptors that modulate the NE release during nerve stimulation. Therefore, subclassification of alpha-adrenoceptors into alpha 1 and alpha 2 subtypes is warranted but must be considered to be independent of the anatomical location of these receptors. Some noradrenergic nerve endings have also been shown to possess beta-adrenergic receptors, the stimulation of which increases the quantity of transmitter released by nerve impulses. Physiologically, these receptors could be activated by circulating epinephrine (E) and be involved in essential hypertension. A third type of catecholamine receptor found at the noradrenergic nerve ending is the inhibitory dopamine (DA) receptor, which might be of significance in the development of new antihypertensive agents. Application of these new concepts of noradrenergic neurotransmission and the subclassification of alpha-adrenoceptors to the treatment of hypertension is presented. Clonidine, for example, appears to be a potent alpha 2-adrenoceptor agonist; the central receptor involved in its antihypertensive action is pharmacologically an alpha 2-type but located postsynaptically. Clonidine also induces activation of peripheral presynaptic alpha 2-adrenoceptors, which might contribute to its cardiovascular action. The antihypertensive effects of alpha-methyldopa are related to the formation of alpha-methylnorepinephrine, a preferential alpha 2-adrenoceptor agonist, which can stimulate peripheral presynaptic alpha 2-adrenoceptors leading to a decrease of NE release and a reduction in sympathetic tone. Prazosin is a new antihypertensive agent the mechanism of action of which involves a selective blockade of postsynaptic alpha 1-adrenoceptors. This drug does not antagonize several effects of clonidine that are mediated via alpha 2-adrenoceptors. The mechanisms presently considered to account for the antihypertensive activity of beta-adrenoceptor blocking agents are numerous. It is proposed that blockade of peripheral presynaptic facilitatory beta-adrenoceptors could be of significance in the antihypertensive action of these drugs.
Hypertension
PMID:Recent developments in noradrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents. 610 28

Blood pressure and heart rate were recorded in the sea gull, Larus argentatus, under light pentibarbitone anaesthesia. Clonidine 10(-7) and 10(-8) mol . kg-1 (27 and 2.7 microgram . kg-1) i.v. produced a biphasic effect on blood pressure, a brief initial increase being followed by a prolonged hypotensive response. There was an immediate reduction in heart rate rate which persisted throughout the hypotensive phase. After spinal transection at the level of C4, clonidine administration elicited hypertension and bradycardia. Bilateral vagotomy abolished the effect of clonidine on heart rate but did not alter the blood pressure response. Vagotomy in combination with spinal transection abolished the effect of clonidine on heart rate but the hypertensive response was accentuated. Yohimbine 10(-7) or 10(-6) mol . kg-1 (0.039 or 0.39 mg . kg-1) given 5 min after clonidine 10(-7) mol.kg-1 (27 microgram . kg-1) effectively antagonized the cardiovascular effects of clonidine, while prazosin 10(-7) or 10(-6) mol . kg (0.042 or 0.42 mg . kg-1) had no such effect. We conclude that clonidine acts in the central nervous system of the sea gull to produce a lowering of blood pressure and heart rate. These effects are mediated by central inhibition of sympathetic activity and, in the case of the heart rate, mostly by central activation of vagal activity to the heart. This central action of clonidine involves activation of alpha-adrenoceptors which are blocked by yohimbine but not by prazosin and therefore may belong to the alpha 2 subtype.
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PMID:Cardiovascular effects of clonidine in an avian species, Larus argentatus. 612 Apr 70

In urethane-anesthetized rabbits blood pressure was lowered by intraventricular clonidine (30 microgram) and increased by intraventricular methoxamine (1 mg). Clonidine is well known to cause hypotension by acting on central alpha-adrenoceptors. The hypertensive effect of intraventricular methoxamine was not observed in cord-sectioned rabbits, in guanethidine-treated adrenalectomized rabbits and in phentolamine-treated rabbits, indicating the effect was central in origin. These responses to intraventricularly administered clonidine and methoxamine were examined in rabbits pretreated intraventricularly with various alpha-adrenoceptor antagonists believed to exhibit preference for alpha 1- or alpha 2-adrenoceptors in the peripheral tissues. Pretreatment with 250 microgram of yohimbine and with 500 microgram of piperoxan inhibited the clonidine hypotension, but pretreatment even with 2 mg of either of these drugs did not affect the methoxamine hypertension. In contrast, pretreatment with 8 microgram of prazosin inhibited the methoxamine effect, whereas pretreatment even with 1 mg of prazosin did not affect the clonidine effect. Pretreatment with 8 microgram of thymoxamine inhibited the methoxamine effect, while it was necessary to increase the doses for each drug up to 4 to 8 times to oppose the clonidine effect. Pretreatment with 2 mg of labetalol inhibited the methoxamine effect but was ineffective against clonidine. Pretreatment with 500 microgram of phentolamine was effective in antagonizing the clonidine effect but twice the dose was needed to inhibit the methoxamine effect. From the findings that the hypertensive effect of methoxamine and the hypotensive effect of clonidine were inhibited differently by various alpha-adrenoceptor antagonists and that the selectivity of these antagonists for the methoxamine and clonidine effect is similar, respectively, to that for alpha 1- and alpha 2-adrenoceptors in the peripheral tissues, we concluded that the methoxamine hypertension and the clonidine hypotension are due to the stimulation of alpha 1- and alpha 2- adrenoceptors in the brain, respectively.
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PMID:Effects of alpha-adrenoceptor antagonists administered intraventricularly on central hypotensive action of clonidine and on central hypertensive action of methoxamine in rabbits. 612 61

Pharmacological treatment of hypertension can cause clinically significant alterations in endocrine function through effects on glucose homeostasis, thyroid and parathyroid hormones, adrenal steroid metabolism and reproductive/pituitary physiology. Long term use of thiazide diuretics causes deterioration in glucose tolerance, probably secondary to potassium depletion. Hypoglycaemic complications of beta-blockers (mainly the non-selective compounds) can be dramatic, especially in type I diabetics. Clonidine, diazoxide and calcium antagonists have all been associated with deterioration in glucose tolerance and their long term use should be avoided in type II diabetics if possible. Propranolol lowers T3 levels by decreasing the conversion of T4 to T3. Prazosin causes elevations in T4 and thyroid-stimulating hormone, while sodium nitroprusside use may result in hypothyroidism. Numerous agents are associated with sexual dysfunction, including methyldopa, reserpine, clonidine and spironolactone. Thiazide diuretics may cause hypercalcaemia, particularly in patients with hyperparathyroidism, by decreasing urinary calcium as well as directly influencing bone and gut calcium handling. Conversely, propranolol may decrease circulating parathyroid hormone levels and correct the hypercalcaemia seen in hyperparathyroidism. Awareness of drug-induced changes in endocrine function will facilitate the rational management of the hypertensive patient.
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PMID:Effects of antihypertensive drugs on endocrine function. 614 2

Intravenous administration of naloxone (0.5 mg/kg) to morphine dependent rats elicited classical autonomic and behavioral symptoms of narcotic abstinence including hypertension, tachycardia, withdrawal body shakes, escape attempts, diarrhea, etc. Pretreatment of dependent rats with either clonidine (3-90 micrograms/kg) or guanfacine (3-900 micrograms/kg) produced a dose-dependent reduction in the hypertensive response to subsequent injection of naloxone. Clonidine was about 12 times more potent than guanfacine in inhibiting this autonomic symptom of withdrawal. Both drugs were less effective at blocking body shakes and escapes, however, when all symptoms were combined in a ranked score, guanfacine was less effective than clonidine at reducing the ranked abstinence intensity score. Since clonidine blocked the autonomic component of withdrawal at doses more consistent with its clinical anti-withdrawal actions, it is possible that 1) measurement of behavioral signs of withdrawal in rats is a less sensitive index than is measurement of autonomic changes associated with withdrawal, or, 2) a reduction in autonomic outflow in general is most relevant to suppressing the apparent intensity of the abstinence syndrome.
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PMID:A comparison of the inhibitory effects of clonidine and guanfacine on the behavioral and autonomic components of morphine withdrawal in rats. 614 77

Clonidine has clearly been shown to be effective in the treatment of all grades of hypertension. Clonidine by itself, when compared with placebo, has proved its worth in the treatment of essential hypertension; it has also been found to be more effective than diuretic treatment alone. When clonidine and a diuretic have been combined, the combination has proved superior to either clonidine or the diuretic given alone. The combination of clonidine with a diuretic is equal in efficacy to combinations of a diuretic with a beta-blocker, alpha-methyldopa, or prazosin. Combinations of a diuretic, a vasodilator, and clonidine were useful in patients with refractory hypertension that failed to respond to a two-drug regimen. Clonidine has also been shown to be effective in patients with renal failure or in hypertensive crisis.
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PMID:Clonidine in the treatment of hypertension. 615 38

Reports on spontaneously hypertensive rats suggested that naloxone blocked the antihypertensive effects of clonidine. We compared the effects of an 8-hr intravenous naloxone infusion (6 micrograms/kg/hr) or 5% dextrose in water (D5/W) begun 2 hr before single oral doses of clonidine (0.3 mg) in six men with mild to moderate essential hypertension (EHT). Supine and standing (after 5 min) blood pressure (BP) and heart rate (HR) were measured every 20 min. Initial treatment with naloxone or placebo (D5/W) infusion was randomly allocated, with the alternate treatment given 1 wk later. Naloxone did not modify either supine or standing BP or HR. Clonidine induced a gradual, sustained reduction in both supine and standing systolic and diastolic BP and in supine HR, and there was an increase in standing HR. Naloxone did not modify the onset, maximal effect, or recovery of the hypotensive and HR effects of clonidine in both the supine and standing positions. Our data indicate that hypotensive and bradycardiac effects of clonidine in EHT are not mediated by naloxone-sensitive opioid receptors. They also suggest that opioid receptors play no role in the maintenance of hypertension nor in the BP and HR adjustments induced by postural changes in EHT.
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PMID:Naloxone does not antagonize the antihypertensive effect of clonidine in essential hypertension. 630 46


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