ZENECA ZD6169: a novel KATP channel opener with in vivo selectivity for urinary bladder.

(S)-N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionamide (ZD6169) is a novel ATP-sensitive potassium channel opener. Bladder activity and selectivity after oral dosing were studied in conscious, normotensive rats and dogs by monitoring cystometric and cardiovascular (CV) parameters. The reference ATP-sensitive K+ channel opener cromakalim was also evaluated in this study. ZD6169 significantly reduced micturition frequency in rats (ED50 = 0.16 mg/kg), but its effect on CV parameters was minimal (ED20 = 30 mg/kg), yielding a selectivity dose ratio of 187. The duration of action was between 7 and 24 hr at doses of 0.3 and 3 mg/kg, but it was more than 24 hr at 10 mg/kg. The ED50 value for bladder activity in dogs was less than 1.0 mg/kg, and the ED20 value for CV activity was slightly greater than 15 mg/kg but less than 20 mg/kg; the selectivity ratio was greater than 15. A significant improvement in bladder compliance was noted in dogs with ZD6169, and the bladder activity in rats was blocked by i.v. glibenclamide (3 mg/kg). Cromakalim had a bladder profile similar to that of ZD6169 but appeared to be more selective for CV parameters. In conclusion, ZENECA ZD6169 is a unique ATP-sensitive K+ channel opener with in vivo selectivity of relaxing bladder smooth muscle. This agent has the potential for treating patients with urge incontinence.

A prototype instrument combining laser Doppler flowmetry and reflection pulse oximetry.

A prototype instrument has been developed to combine the monitoring techniques of laser Doppler flowmetry and reflection pulse oximetry, both of which depend on laser light backscattered from the skin tissue. Simultaneous and continuous measurements of both microvascular blood flow and blood oxygen saturation were obtained from the same measurement site. Oximetry readings from the combined instrument were calibrated using a model system, and compared with those determined using a Nellcor N-100 transmission pulse oximeter in a limited clinical study: they showed a variability of +4% and read low by 5-10%.

Comparative study of two laser Doppler blood flowmeters.

A new infrared laser Doppler blood flow instrument (Moor MBF3D) was evaluated using an in vitro model allowing measurements over a range of flow velocities and concentrations. The responses correlated well (r = 0.96, p less than 0.01) with those obtained simultaneously using a Perimed PF3 laser Doppler instrument. The different processing bandwidths of the instruments were investigated and the wideband mode of operation is recommended for flow measurements where there may be fast moving red blood cells (rbcs). The infrared instrument is capable of dual-channel operation, and the two channels are shown to respond almost identically for similar changes in blood flow through the in vitro model (r = 0.999, p less than 0.01). The main advantage of the dual-channel instrument is that continuous measurements may be made simultaneously at two different skin sites allowing dynamic flow responses to be compared.

Can ATP stimulate P1-receptors in guinea-pig atrium without conversion to adenosine?

The aim of this study was to determine whether ATP must be hydrolysed to adenosine in order to activate the P1-purinoceptor. Isometric contractions of electrically paced guinea-pig isolated left atria were recorded. Purines evoked negative inotropic responses that were competitively antagonised by theophylline. The order of agonist potency was 2-chloroadenosine greater than adenosine greater than beta, gamma-methylene ATP greater than ATP. Adenosine deaminase alone, or combined with 5'-nucleotidase, attenuated responses to adenosine and 5' AMP, respectively, but did not decrease those to ATP or beta, gamma-methylene ATP. Inhibition of 5'-nucleotidase did not alter responses to ATP. Dipyridamole potentiated responses to ATP both in the absence and in the presence of adenosine deaminase. Alpha, beta-methylene ATP had little agonist activity, however this was not due to its resistance to hydrolysis as the stable beta, gamma-methylene isostere of ATP was a potent agonist. These results indicate that hydrolysis of ATP to adenosine or 5' AMP is not a pre-requisite for activation of the P1-receptor in the guinea-pig atrium.

A new centrally acting antihypertensive (ICI 106270) which separates antihypertensive effects from sedation.

1. 6-(2-Chloro-6-fluorophenyl)-2,3,6,7-tetrahydro-5H-pyrrolo-[1,2-a]-imidazole hydrobromide (ICI 106270) has been developed with the objective of achieving satisfactory blood pressure (BP) reduction while minimising the side-effects seen with clonidine. 2. In the pentobarbitone sodium anaesthetised rat the dose of ICI 106270 to lower BP by 20 mmHg (ED20) was 5.45 micrograms/kg i.v. (ED20 clonidine 1.18 micrograms/kg i.v.). In conscious spontaneously hypertensive rats 10 mg/kg orally of ICI 106270 lowered BP by 70 +/- 12.2 mmHg. A similar fall in BP of 67 +/- 6.5 mmHg was seen with 1 mg/kg of clonidine orally. 3. In conscious renal-hypertensive dogs ICI 106270 is 2--3 times less potent than clonidine when dosed either p.o. or i.v. but was equipotent with clonidine at lowering BP when administered into a lateral cerebral ventricle. 4. Clonidine (250--750 micrograms/kg) administered i.p. in rats caused a marked potentiation of anaesthesia induced by pentobarbitone. ICI 106270 similarly administered in the same doses was without effect. 5. In a test for locomotor activity the ED50 (dose to reduce locomotor activity by 50%) was 15.3 micrograms/kg i.v. for clonidine and 237.5 micrograms/kg i.v. for ICI 106270. On oral administration the ED50 for clonidine was 26 micrograms/kg and for ICI 106270 it was 2.14 mg/kg. 6. In the chloralose anaesthetised cat pre- and post-ganglionic sympathetic efferent nerve activity was reduced by ICI 106270 in doses which also reduced BP. 7. The hypotensive effect of i.v. ICI 106270 in anaesthetised rats was antagonised by the alpha-adrenoceptor antagonists yohimbine and piperoxan. 8. These results indicate that ICI 106270 is a potent antihypertensive with a similar mechanism of action to clonidine although it is relatively less sedative. It is an alpha-stimulant and its site of action is probably within the CNS.

The withdrawal of centrally acting antihypertensives in dogs.

1. The effects of the withdrawal of clonidine and 6-(2-chloro-6-fluoro-phenyl)-2,3,6,7-tetrahydro-5H-pyrrolo-(1,2-a)-imidazole hydrobromide (ICI 106270) on the blood pressure and heart rate of chronically dosed beagle dogs has been investigated. 2. The control heart rate was 75.4 beats/min and it varied considerably during therapy with clonidine (100-200 microgram/kg orally 2 X or 3 X daily for 10 days). 3 h after dosing it was always depressed, this reduction varying from 48.5% on day 1 to 32.2% on day 9. The heart rate was depressed 8 h after the initial dose but by day 9 heart rate was 37.6% above control at this time. 3. On withdrawal of clonidine heart rate displayed a marked rebound which reached a maximum of 59.9% above control 16 h after the last dose. 4. During clonidine treatment diastolic blood pressure fell by 23.3% from a control of 87.4 mmHg and on withdrawal it returned to control with no overshoot. 5. During treatment with ICI 106270 (600 microgram/kg orally 3 X daily for 10 days) heart rate did not rise above the control level of 88.9 beats/min and diastolic blood pressure was decreased 21.6% from a control value of 113.7 mmHg. 6. On withdrawal of ICI 106270 both blood pressure and heart rate returned to control levels without any overshoot. 7. The tachycardia on withdrawal of clonidine in dogs occurred with every animal treated and may represent a useful model for assessing the likelihood of other centrally acting antihypertensives to produce rebound in man. In this test situation ICI 106270 did not produce rebound tachycardia.