The role of adrenal medullary catecholamine release in the response to a cold pressor test.

We studied the effects of a cold pressor test on the plasma catecholamine levels of ten patients undergoing coronary angiography, to determine whether the pressor changes were related to adrenergic activity. To investigate the relative contribution of adrenal medullary catecholamine release, we subjected two adrenalectomised volunteers to the same test. Arterial blood was assayed for dopamine (DA), adrenaline (A) and noradrenaline (NA). We found significant rises in the levels of all three catecholamines in the angiography patients, accompanied by a significant elevation in arterial blood pressure. In both the adrenalectomised patients a rise in blood pressure was seen but no significant rise in plasma catecholamines could be demonstrated. We postulate that although adrenal medullary catecholamine release occurs in response to the cold pressor test, the blood pressure elevation is independent of such adrenal activity. Sampling radial arterial blood may not reflect changes in plasma levels of peripherally released NA.

Antihypertensive efficacy and safety of perindopril in mild-to-moderate essential hypertension: results of a double-blind multicenter study versus atenolol.

A 3-month double-blind multicenter trial compared the efficacy and safety of perindopril, a new angiotensin-converting enzyme (ACE) inhibitor, with atenolol in mild-to-moderate essential hypertension. A total of 190 patients, 49 of whom were diabetic, entered the perindopril-atenolol comparison. Of these, 163 had been previously treated and had a 4-week run-in period on placebo; 27 had previously been untreated and received placebo for 2 weeks. At entry, all patients who had a supine diastolic blood pressure (DBP) of 95-115 mm Hg were randomized to receive perindopril 2 mg or atenolol 25 mg, once daily. Patients were assessed at 2 weekly intervals for the first month and then monthly for 2 more months. If supine DBP was greater than 90 mm Hg, treatment was increased by stepwise doubling of dose up to 8 mg perindopril or 100 mg atenolol once daily, and later by the addition of hydrochlorothiazide 25 mg, (indapamide 2.5 mg in diabetic patients) once daily. The two groups were homogeneous prior to treatment except for supine and erect heart rate, which were higher in the perindopril group than in the atenolol group (p less than 0.05). Mean supine DBP was 101.1 +/- 0.6 mm Hg in the perindopril group (n = 94) and 99.9 +/- 0.6 mm Hg in the atenolol group (n = 96). After 3 months' active treatment, 74% of patients in the perindopril group achieved a supine DBP of less than or equal to 90 mm Hg and 73% of patients in the atenolol group achieved the same goal. Monotherapy controlled supine DBP in 67% of the perindopril group and 63% of the atenolol group. The decrease in supine DBP was not significantly different between the two groups (-12.9 +/- 0.9 versus -14.7 +/- 0.9 mm Hg) but the decrease in erect DBP was lower in the perindopril group (-10.3 +/- 0.9 versus - 13.4 +/- 1.0 mm Hg, p less than 0.02). Heart rate was reduced in the atenolol group (p less than 0.001). Sixteen patients withdrew from the study; nine were attributed to adverse events, two in the perindopril group and seven, including one death, in the atenolol group. Cough was spontaneously reported by 13% patients of the perindopril group and 1% patients of the atenolol group. In 5% of the perindopril cases this was mild and associated with upper respiratory tract infection. The nature and incidence of other symptoms were similar with both drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of ethyl alcohol and chlorpromazine on the response of the hand blood vessels to cold.

1. The response of hand blood flow to a measured cold stimulus was determined using venous occlusion plethysmography in normal subjects, before and after orally administered alcohol, and in patients on chlorpromazine therapy.2. The average resting hand blood flow of the patients taking chlorpromazine, as well as the constriction of these blood vessels to cold, was the same as in the normal subjects.3. Oral alcohol caused a rise in resting hand blood flow in the normal subjects and also modified the response of the hand blood vessels to cooling.4. A patient with a completely denervated hand was also studied. Oral alcohol did not increase the blood flow through the part, but it modified the hand vascular response to cold.5. These results suggest a diminished reactivity of the hand blood vessels to cold in the presence of alcohol.

Modification of the vasoconstrictor action of sympathomimetic agents by bretylium tosylate and tranylcypromine in man.

1. The vasoconstrictor actions of tyramine, methylamphetamine and ephedrine on the blood vessels of the human hand have been found to be potentiated by administration intra-arterially of the adrenergic neurone blocking agent, bretylium tosylate.2. One mechanism suggested for the enhancement of vasoconstriction is that bretylium possesses monoamine oxidase inhibiting activity, which, in the case of tyramine, is protective both to the sympathomimetic agent and the intra-neuronal transmitter which it releases. In the case of methylamphetamine and ephedrine, which are not substrates for the enzyme, protection of the intra-neuronal transmitter alone might occur, accounting for the lesser degree of potentiation of the effect of these amines by bretylium.3. Comparison of the influences of bretylium and the monoamine oxidase inhibitor, tranylcypromine, on the vasoconstrictor action of the sympathomimetic agents shows a similar pattern of enhancement in the presence of both these drugs.4. Tranylcypromine caused enhancement of the response of the hand vessels to noradrenaline, and this action could contribute to its potentiation of the effect of the sympathomimetic amines.5. For a monoamine oxidase inhibiting action of bretylium to be effective in potentiating the constrictor actions of the sympathomimetic agents on the hand blood vessels at a time when reflex sympathetic activity is blocked it is necessary to postulate that these drugs and reflex nerve activity act either on different compartments of the transmitter store or by different release mechanisms.

Clinical and haemodynamic effects of minoxidil in refractory hypertension.

Thirteen patients whose hypertension had been resistant to conventional drug therapy, had minoxidil added to their regimen in doses from 5 to 60 mg/day. All responded with satisfactory reductions of blood pressure to mean values of 149/90mm Hg (supine) and 143/89mm Hg (standing). A significant portion of their previous antihypertensive therapy was either greatly decreased or withdrawn completely. Although fluid retention occurred in most patients as the dose of minoxidil was increased, this could be successfully checked by the use of diuretics. It was considered that in addition to beta-adrenoreceptor blocking drugs to control the reflexly induced cardiac stimulation, sufficiently aggressive diuretic therapy is mandatory to ensure the successful use of this drug. Haemodynamic evaluations in seven patients clearly showed that lowering of blood pressure was the result of decreases in peripheral vascular resistance as significant increases in the cardiac index occurred in all patients.

Comparative enzyme-inducing effects of chlorpromazine and fluphenazine therapies in psychotic patients.

Antipyrine elimination kinetics were measured in psychotic patients receiving either long-term chlorpromazine or fluphenazine decanoate therapy and in non-medicated control subjects. Patients receiving chlorpromazine metabolised antipyrine faster than the controls while, in patients receiving fluphenazine decanoate, there was not change. The results suggest that long-term chlorpromazine therapy induced the activity of drug-metabolising enzymes, whereas fluphenazine decanoate therapy had no effect.

A comparison of the efficacy of captopril and enalapril given once daily for the treatment of hypertension: a study using 24-hour ambulatory blood pressure monitoring.

Sixteen patients who had essential hypertension were stabilized on either captopril or enalapril monotherapy and had 24-hour blood pressure profiles monitored by using one of two automatic, non-invasive ambulatory systems: Spacelabs 5300 (Squibb, Princeton, NJ) or PAR Physioport II (Kardiotec, Mannheim). In four subjects (group 1), ambulatory pressures were repeated 4 to 6 weeks later using the same equipment and the same drug. In four subjects (group 2), the drug was changed (dose ratio: captopril:enalapril, 5:1) after the first measurement, but the monitoring equipment was not changed. In four subjects (group 3), the drug was constant, but the equipment was changed for the second measurement of ambulatory pressure. In four subjects (group 4), both drug and equipment were reversed after the first measurement. The results showed that both drugs (given once daily) controlled blood pressure during the 24-hour period, with no clinically significant difference between them.

The effect of sympathomimetic agents on noradrenaline efflux from a blood vessel.

The effect of several sympathomimetic agents on the efflux of noradrenaline and its metabolites has been evaluated using the ventral artery of the rat tail as the experimental model. This vessel is richly endowed with sympathetic nerves and is therefore well suited to examine the efflux patterns of that transmitter. Etilefrine, tyramine, ephedrine and REN-293 were all found to increase the efflux of 3H-noradrenaline and/or 3H-DOPEG to different degrees from the artery. Possible reasons for this variation in metabolite efflux are discussed.

Effect of alpha 1-adrenoceptor blockade on the development of hypertension in the spontaneously hypertensive rat.

There is a large body of evidence to suggest that the sympathetic nervous system plays a critical role in the development of hypertension and vascular medial hypertrophy in the spontaneously hypertensive rat (SHR). The synthesis of a water soluble, specific alpha 1-adrenoceptor antagonist (terazosin) has permitted an examination of the influence of alpha 1-adrenoceptors on those two phenomena. Thus, in the present study, terazosin (43 mg/kg per day) was administered to SHR and Wistar-Kyoto (WKY) rats from 4.5 to 12 weeks of age, and a number of assessments made in vitro and in vivo. In the SHR, the development of hypertension was not prevented by terazosin. The drug did not influence blood pressure in the WKY. This was despite the fact that animals which had been chronically treated with terazosin displayed marked alpha-adrenoceptor blockade in vivo. The response of systolic blood pressure to tyramine and noradrenaline was significantly reduced in animals which had been chronically treated with terazosin. In both the SHR and WKY, chronic administration of terazosin did not influence vascular concentrations of 3-methylhistidine, a biochemical marker for contractile proteins and vascular medial hypertrophy. The results therefore argue against a role of alpha 1-adrenoceptors in the development of hypertension and vascular medial hypertrophy in the SHR.

The effect of local anaesthetics on the vasoconstrictor response of the isolated perfused artery to adrenaline and noradrenaline.

The vascular response to intraluminally and extraluminally administered catecholamines mixed in combination with local anaesthetics has been studied using the isolated perfused rabbit ear artery as the model system. Potentiation of the vascular response to extraluminal adrenaline was observed when prilocaine, lignocaine or cocaine were combined in low concentrations with the vasoconstrictor. No potentiation of the vascular response to extraluminally administered noradrenaline could be demonstrated in the presence of prilocaine or lignocaine. Further, no potentiation to either catecholamine was found if the artery had been denervated or the drugs were applied intraluminally. Possible mechanisms for the potentiation of extraluminally applied adrenaline are discussed.

Phenytoin and postoperative epilepsy. A double-blind study.

A double-blind trial of phenytoin therapy following craniotomy was performed to test the hypothesis that phenytoin is effective in reducing postoperative epilepsy. A significant reduction in the frequency of epilepsy was observed in the group receiving the active drug up to the 10th postoperative week. Half of the seizures occurred in the first 2 weeks and two-thirds within 1 month of cranial surgery. High rates of epilepsy were observed after surgery in patients with meningioma, metastasis, aneurysm, and head injury. Routine prophylaxis with phenytoin (in a dosage of 5 to 6 mg/kg/day) would seem to be indicated, particularly in high-risk patients and, where possible, this treatment should be started 1 week preoperatively. Seizure control is best when therapeutic levels of phenytoin are maintained.

Adverse reactions during intravenous urography: are these due to histamine release?

The effects of four different radiographic contrast media (Urovison 58%, Hexabrix 320, Iopamiro 370 and Omnipaque 300) have been examined with respect to histamine release, cardiovascular changes and adverse drug reaction (ADR) in a group of 200 patients undergoing intravenous urography. Each patient received only one of the four agents, which were allocated on a random basis. Urovison produced the greatest number of ADRs. Iopamiro caused the least. No significant correlation between the magnitude of the change in plasma histamine following injection of radiographic contrast medium and the production of a particular ADR could be demonstrated. Heart rate increased significantly following the administration of Urovison, Hexabrix and Iopamiro in the absence of any appreciable change in blood pressure. These results and our earlier findings would favour the use of the low-osmolality contrast media in intravenous urography to minimize ADRs, histamine release and patient discomfort.

Plasma histamine levels following administration of radiographic contrast media.

The effect of two conventional high-osmolality and two new low-osmolality contrast media on plasma histamine levels has been examined. The study population included 25 patients undergoing intravenous urography with Urovison 58% (sodium and meglumine diatrizoate), 24 patients receiving intravenous Hexabrix 320 (sodium and meglumine ioxaglate) for urography, 16 patients receiving intravenous Iopamiro 370 (iopamidol) for urography and 12 patients receiving Urografin 76% (sodium and meglumine diatrizoate) for coronary angiography. Seventy-four percent of the 77 patients studied suffered adverse reactions ranging from a feeling of warmth and nausea to laryngeal oedema and bronchospasm. Hexabrix 320 and Iopamiro 370 were associated with the least patient discomfort. All contrast agents usually produced a rise in plasma histamine following injection (Iopamiro 370 causing the least change) and the histamine levels then fell towards preinjection values over a space of about 10 minutes. No relationship was observed between the magnitude of the increase in histamine and the severity of the reaction that occurred. However, a relationship was suggested between the mean peak plasma histamine level achieved and the occurrence of a Grade II reaction (i.e., dry retching/vomiting, mild urticaria or rash). These findings raise the probability that histamine contributes to the more severe grades of reaction to radiographic contrast media.

The effects of etilefrine on blood vessels in the rat tail.

Etilefrine was found to constrict blood vessels in the rat tail through a mechanism which was partly dependent on the sympathetic nerves present in these vessels. The response to the drug was enhanced by pretreagment with noradrenaline and cocaine, and totally abolished by the alpha-receptor antagonist phentolamine. When compared with several other sympathomimetic agents which were tested on the vessel, etilefrine appeared to have a low order of vasoconstrictor activity. These findings would seem to have considerable relevance to the clinical situation where an attempt has been made to use etilefrine in the treatment of patients with orthostatic hypotension.

The indirect sympathomimetic activity of etilefrine--a comparison with tyramine and ephedrine using [3H] noradrenaline.

The indirect sympathomimetic activity of etilefrine has been examined using the ventral caudal artery of the rat. This vessel has a rich sympathetic innervation and lends itself to studies on [3H]noradrenaline efflux from these sites. Etilefrine possessed significant indirect activity on the artery and this action, although less than that of tyramine, was equivalent to that caused by ephedrine. Pretreatment of the vessels with a mixture of iproniazid, doca, cocaine and UO521 (3',4'-dihydroxy-2-methyl propiophenone) significantly enhanced[3H]-noradrenaline efflux from the artery.

Therapeutic drug monitoring: a survey of sub- and supra-therapeutic serum drug levels in a large teaching hospital.

One thousand five hundred serum drug levels lying outside the defined therapeutic range have been followed up by the clinical pharmacology service at the Royal Adelaide Hospital over a thirteen month period. It was found that digoxin, phenytoin and theophylline were the most frequently monitored drugs. Blood levels outside the therapeutic range tended to be on the high side with digoxin, but were usually sub-therapeutic for the other two. Drug related toxicity was observed in 11.2 percent of those with a high serum level. Several potential drug interacting situations were also noted during the study. The value of therapeutic drug monitoring, to maximise efficacy of therapy and minimise side effects, is stressed. However, correct blood sampling, based on a knowledge of the clinical pharmacology and pharmacokinetics of the drug, must be performed in order to obtain optimal benefit from this exercise.

Compliance with aerosol therapy in chronic obstructive lung disease.

The compliance of 114 patients with chronic airways disease to therapy with aerosol salbutamol and beclomethasone dipropionate was examined over two consecutive periods of approximately four weeks. Values ranging from 90-110 percent compliance were recorded for the two agents and a further increase in compliance was noted with both aerosols during the second month of surveillance. Over-use of salbutamol occurred in those patients who had been recently discharged from hospital. It was concluded that the high level of compliance was due to the symptomatic nature of the illness and the over-use of the bronchodilator was attributed to the usually prompt relief it provided.

Atenolol in hypertension: follow-up of patients crossed over to this agent from propranolol, pindolol or metoprolol.

Thirty hypertensive patients treated with a drug regimen which contained a beta-receptor antagonist (either propranolol, pindolol or metoprolol) exhibited an improvement in blood pressure control when atenolol was substituted for the corresponding beta-blocker in the drug regimen. Additional benefits noted were a reduction in concomitant drug therapy and an improvement in reported side effects. Atenolol caused a significant decrease in heart rate in the group for which the mean follow-up period was 23.6 months.

The comparative effects of prilocaine, lignocaine and cocaine on the response of the rabbit ear artery to adrenaline and noradrenaline.

The effects of prilocaine, lignocaine or cocaine together with either adrenaline or noradrenaline was tested by applying combinations of these preparations to an isolated rabbit ear artery and measuring changes in intra-arterial pressure. Potentiation of the response was greatest with combinations of local anaesthetic and adrenaline; with noradrenaline the response was significantly potentiated only when the lowest concentrations of cocaine were used. It is suggested that some of this effect could be attributed to the differential inhibition by the local anaesthetic agents of the neuronal uptake of the catecholamines. This inhibition was prominent with all combination which contained adrenaline, but only occurred with noradrenaline when that vasoconstrictor agent was combined with cocaine.

The effect of irradiation and heat on the content of adrenaline in commercially manufactured local anaesthetic solutions--a pilot study.

Carpules of commercially available local anaesthetic solutions containing adrenaline have been exposed to varying conditions of heat, ultra-violet and infra-red light over a period of two months. The adrenaline content in the solutions was assessed by fluorometric assay both at the commencement of study and at regular intervals over the period of exposure. Infra-red light appeared to have little or no effect on the concentration of adrenaline, while ultra-violet light, either alone or in combination with infra-red light, caused the adrenaline levels to diminish rapidly. The results suggest that the ultra-violet component of light is probably responsible for the breakdown of catecholamines in local anaesthetic solutions when these solution are stored in areas exposed to sunlight.