Medicinal products that, as an unwanted effect, prolong the QT interval of the electrocardiogram (ECG) can trigger episodes of polymorphic ventricular dysrhythmias, called torsades de pointes, which occasionally culminate in sudden death. The accurate measurement of QT interval requires the adoption of appropriate criteria of recording, measurement and data processing. Traditionally, QT interval is standardised to a reference heart rate of 60 beats/min by using the Bazett algorithm. However, this correction method can bias observed QT intervals in either direction. The ECG reflects cardiac electrical currents generated by ions (Na+, K+ and Ca2+) entering and leaving the cytosol mainly via transmembrane channels. Na+ and Ca2+ carry inward depolarising currents (INa, ICa) whereas K+ carries outward repolarising currents (Ito, IKr, IKS and IK1). Sometimes, a prolonged QT interval is a desired drug effect but, more commonly it is not, and reflects abnormalities in cardiac repolarisation heralding torsades de pointes. Furthermore, the potential torsadogenic activity of drugs is favoured by concurrent cardiac risk factors (old age, female gender, bradycardia, electrolyte imbalances, cardiac diseases etc.) which reduce cardiac repolarisation reserve. The evaluation of the cardiac safety of drug candidates can be started by determining their potency as IKr blockers in cloned Human Ether-a-go-go Related Gene (HERG) channels expressed in mammalian cells. Compounds passing successfully this test (desirable cardiac safety index > 30, calculated as ratio of IC50 against IKr over ED50 determined in an efficacy test) should be further investigated in other relevant human cardiac ion currents, in in vitro animal heart preparations and finally in in vivo pharmacodynamic models. The decision as to whether the potential benefit of a new drug outweighs the cardiac risk inherent in its therapeutic use should be made in the light of the condition that it is expected to treat and with reference to alternative drug therapies. If a drug represents a unique therapeutic advance, non-clinical and clinical signals of unsatisfactory cardiac safety may not constitute sufficient grounds to abandon its development. However, if the drug offers only marginal benefits over existing therapies, decisions concerning its possible development should be taken by corporate policy makers.
( -)-A9-t~ans-Tetrahydrocannabinol (A9-THC), when given intravenously (2 mg kg-I) to cats, produced marked decreases in blood pressure and heart rate which developed gradually and were of prolonged duration. Cervical spinal transection (Cl-C,) abolished these effects whereas surgical removal of neurogenic tone to the myocardium selectively eliminated the bradycardia. Bilateral vagotomy alone did not modify the action of AS-THC upon heart rate or blood pressure. Recordings of spontaneous sympathetic outflow in the inferior cardiac nerve indicated a rapid reduction in neural discharge rate after AS-THC administration. These observations support the hypothesis that AS-THC produces a cardiodecellerator and hypotensive effect by acting at some level within the sympathetic nervous system. Experiments conducted to investigate transmission in the superior cervical and stellate ganglia demonstrated that AS-THC did not alter ganglionic function. Also, responses to intravenous isoprenaline and noradrenaline were unchanged which suggested that AS-THC did not interact with a-or p-adrenoceptors. The possible action of Ag-THC on central sympathetic structures was investigated by perfusion of As-THC into the lateral cerebral ventricle. AS-THC so administered produced a significant reduction in heart rate without a substantial lowering of blood pressure. Tritiated or 14C-A9-THC perfused into the lateral ventricle demonstrated that the amount of radioactive compound passing into the peripheral circulation was insignificant and could not account for the decrease in heart rate. The current data are in agreement with the proposal that A9-THC produces cardiovascular alterations by an action on the central nervous system which results in a decrease in sympathetic tone.(-)-As-trans-Tetrahydrocannabinol (A9-THC), a psychoactive constituent of marihuana, and several other tetrahydrocannabinols produce cardiovascular alterations in man (Hollister,
Bacwkground. Several recent studies suggest that activation of ATP-dependent potassium (KATp) channels in the myocardium plays an important cardioprotective role during ischemia. The present study was undertaken to examine further the role of this ion channel in vivo in a model of "stunned" myocardium.Methds and Resuls. Barbital-anesthetized dogs were subjected to 15 minutes of left anterior descending (IAD) coronary artery occlusion followed by 3 hours of reperfusion.
Potassium channel opening is a physiological mechanism which excitable cells exploit to maintain or restore their resting state. Thus drugs that open vascular potassium channels have the potential to restrain or prevent contractile responses to excitatory stimuli or clamp the vessel in a relaxed condition. Hence, potassium channel openers, such as aprikalim and levcromakalim, relax agonist precontracted vascular preparations in vitro and lower systemic and regional vascular resistances in intact animals. Glibenclamide, a blocker of ATP sensitive potassium (KATP) channels, antagonises these effects. The main vasorelaxant mechanism of the potassium channel openers is to increase the potassium efflux through opening plasmalemmal potassium channels, which repolarises and/or hyperpolarises the membrane. This effect lowers the opening probability of voltage dependent calcium channels, restrains agonist induced calcium release from intracellular sources through inhibition of inositol trisphosphate formation, decreases the sensitivity of intracellular contractile elements to calcium, and accelerates the clearance of intracellular calcium via the Na+/Ca+ exchanger. Experimental evidence indicates that mechanisms not linked to potassium channel opening may also contribute to the potassium channel opener induced vasorelaxation; these remain to be clearly defined (for example, inhibition of the refilling of intracellular calcium stores). Potassium channel openers displace the binding of 3H-P1075, a potent potassium channel opener, in myocytes and intact rings from the rat aorta. In patches from vascular myocytes, potassium channel openers primarily open a small conductance (10-20 pS) KATP channel which is gated by [ATP]i and particularly by nucleotide diphosphates and magnesium.(ABSTRACT TRUNCATED AT 250 WORDS)
SUMMARY This report reviews a number of significant developments in the fields of noradrenergic transmission and adrenergic receptors which suggest that, hi addition to the classical postsynaptic adrenoceptors, there are also presynaptic adrenoceptors that help modulate tbe release of norepinephrine (NE) from peripheral as well as central noradrenergic nerve endings during nerve stimulation. In particular, stimulation of presynaptic a-adrenoceptors reduces this release of transmitter and tbe reverse is observed after blockade of these receptors. Clearcut pharmacological differences exist between the postsynaptic aradrenoceptors that mediate the responses of certain organs and the presynaptic aradrenoceptors that modulate the NE release during nerve stimulation. Therefore, subdassification of a-adrenoceptors into a, and a, 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 /3-adrenergic receptors, tbe stimulation of which increases the quantity of transmitter released by nerve impulses. Physiologically, these receptors could be activated by circulating epinepbrine (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 neurotransraission and the subdassification of a-adrenoceptors to tbe treatment of hypertension is presented. Gonidtne, for example, appears to be a potent aradrenoceptor agonist; the central receptor involved in its antihypertensive action is pharmacologically an a,-type but located postsynaptically. Clonidine also induces activation of peripheral presynaptic aradrenoceptors, which might contribute to its cardiovascular action.The antihypertensive effects of a-methyldopa are related to tbe formation of a-methylnorepinephrine, a preferential a r adrenoceptor agonist, which can stimulate peripheral presynaptic aradrenoceptors leading to a decrease of NE release and a reduction in sympathetic tone.
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