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Objective: To examine the clinical profile and, in particular, the psychopathology of 33 survivors of self-inflicted firearm injury., Design: An eight-year retrospective case history analysis. Information was obtained from databases in the Psychiatry, Trauma and Medical Records departments of Westmead Hospital., Results: In the sample most survivors of self-shooting were young men who did not suffer from major depression or psychosis. Most shootings occurred in the context of interpersonal disputes with sexual partners or family members., Conclusions: Most patients who survive self-inflicted firearm injuries have shot themselves impulsively in a crisis, are not psychotic, and have ready access to firearms. Psychiatric care is usually given in the trauma ward. Close cooperation is required between psychiatric and surgical teams in management. Recommendations to assist in the more accurate assessment of patients with self-inflicted firearm injury include: careful scrutiny of alleged accidental shootings; the inclusion of police information in the assessment; routine drug screening and determination of blood alcohol level; repeated interviews and corroboration of patient claims by family and friends; and psychiatric review of all patients with self-inflicted injury.

There is mounting evidence to suggest that lean body mass (LBM) may be a better predictor of drug dosage than either total bodyweight (TBW) or body surface area (BSA), although the rationale for this is not clear. LBM, which is similar but not identical to fat-free mass, can be determined by many different methods. A simple equation based on TBW and height, or determination by bioelectrical impedance are probably the most suitable for use in drug disposition studies. Volume of distribution of relatively hydrophilic drugs correlates very well with LBM, with correlation coefficients of up to 0.9. LBM can be used to accurately predict the loading dose required for these drugs to attain a target peak plasma concentration. For lipophilic drugs, volume of distribution correlates better with TBW than with LBM. Investigation of the relationship between renal drug clearance and LBM has received little attention, probably because creatinine clearance is a useful and readily available marker of renal function. However, limited data suggest that creatinine clearance and LBM together may account function. However, limited data suggest that creatinine clearance and LBM together may account for more variability in renal clearance than creatinine clearance alone. For many drugs eliminated predominantly by the liver, there is a good correlation between systemic clearance and LBM. Such a correlation could be due to a correlation between systemic clearance and liver size or liver blood flow, which has been demonstrated for a few drugs, and a correlation between LBM and liver size and blood flow. The presence of a relationship between LBM and organ size and blood flow has, however, not been investigated to date. A good correlation between drug clearance and LBM indicates that LBM may be an accurate predictor of maintenance dosage, especially in obese patients, in whom there is a large discrepancy between LBM and TBW. BSA is an accurate predictor of drug dosage in infants and children, but whether LBM is superior to BSA in this population remains to be determined. In most studies in adults in which dosage based on LBM has been evaluated prospectively, LBM has been shown to be superior to other measures of body size as a predictor of drug dosage.

P1075 [N-cyano-N'-(1,1-dimethylpropyl)-N"-3-pyridylguanidine], an analogue of the K+ channel opener pinacidil, was shown to be a K+ channel opener in rat aorta, based on (i) its ability to stimulate 86Rb+ efflux, (ii) its ability to relax contractions in response to noradrenaline under normal conditions (5 mM KCl) but not under depolarized conditions (55 mM KCl), and (iii) the sensitivity of these effects to inhibition by the sulfonylurea glibenclamide. In these assays, P1075 was approximately 20 times more potent than cromakalim. Using a tritiated derivative, [3H] P1075, specific binding could not be detected in microsomal preparations from various tissues. However, in rat aortic strips specific binding of [3H]P1075 has been observed and was reduced by lowering the temperature or by decreasing intracellular ATP levels via metabolic inhibition. Specific [3H]P1075 binding was influenced neither by depolarization (55 mM KCl) nor by lowering the pH from 7.4 to 6.0. Binding was inhibited by representatives from all major families of K+ channel openers, with potencies that correlated well with the potencies obtained in 86Rb+ efflux and relaxation studies. However, stimulation of 86Rb+ efflux occurred at 40 times higher concentrations than did binding (and vasorelaxation). Of the various inhibitors of the K+ channel openers tested, only the sulfonylureas inhibited [3H] P1075 binding with the same rank order of potencies as that required for inhibition of P1075-induced 86Rb+ efflux, although at higher concentrations. The results show that binding of [3H] P1075 is independent of membrane potential but decreases concomitantly with the intracellular ATP level. The excellent correlation between the potencies of the openers and sulfonylurea blockers in binding assays and functional studies suggests that the 'drug receptor' labeled by [3H]P1075 in rat isolated aorta is of functional relevance. However, the fact that binding of the openers occurred at concentrations considerably lower than those required for K+ channel opening and that binding of the sulfonylureas was only reflected at concentrations higher than those needed to block the channel requires complex models to link binding and effect, possibly involving two agonist binding sites coupled by negative cooperativity.

The K+ channel openers, including cromakalim, pinacidil, minoxidil sulfate, diazoxide, and nicorandil, form a chemically heterogeneous group of compounds, which relax smooth muscle by opening plasmalemmal K+ channels. At present it is not known whether these drugs elicit their effects by binding to the same target, presumably the K+ channel. In order to address this question, a binding assay for K+ channel openers has been developed in vascular smooth muscle. The novel tritiated K+ channel opener, [3H]P1075, an analogue of pinacidil, binds with high affinity (KD = 6 +/- 1 nM) to endothelium-denuded rings of rat aorta. Inhibition studies indicate that the different families of K+ channel openers bind to a common target. Evidence is presented to suggest that the binding site for the sulfonylurea, glibenclamide, the major blocker of the K+ channel openers, is coupled in a negative allosteric manner to the binding site(s) for the openers. The binding assay described here may open the way to the biochemical characterization of the drug receptor for the K+ channel openers.

The K+ channel openers (KCOs) form a structurally heterogeneous group of compounds which relax smooth muscle by opening K+ channels in the plasmalemma. At present it is not known whether these drugs open the same K+ channel in smooth muscle and, if so, whether they bind to the same site of this channel. To address these questions we present the first binding study with KCOs in a smooth muscle preparation. In intact rat aortic strips, the novel tritiated KCO, 3H-P1075 (N-cyano-N'-(1,1-dimethyl[2,2,3,3(3)H]propyl)-N"-3-pyridylguanidine++ +), a potent pinacidil analogue, showed saturable specific binding of high affinity (KD = 6 +/- 1 nM, Bmax = 23 +/- 3 fmol/mg tissue wet weight). Specific binding of 3H-P1075 was inhibited stereospecifically by representatives from all major families of K+ channel openers, with a rank order of potency that correlated well with the potencies for vasorelaxation in rat aorta. The sulfonylurea glibenclamide, a relatively specific blocker of ATP-sensitive K+ channels and an inhibitor of the effects of KCOs, also inhibited 3H-P1075 binding and increased the rate of dissociation of 3H-P1075 from the tissue in a concentration-dependent manner. Lowering temperature (from 37 degrees C to 2 degrees C) and decreasing intracellular ATP levels by metabolic poisoning, diminished specific 3H-P1075 binding by reducing Bmax. However, depolarization (KCl = 55 mM) or lowering pH from 7.4 to 6.0 did not influence binding. The data demonstrate the existence of a specific binding site for the KCO 3H-P10756 in rat isolated aorta, which seems to be of functional relevance.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Cromakalim (1 and 10 microM), RP49356 (5 and 50 microM) and diazoxide (100 and 300 microM) produced full relaxation of smooth muscle strips pre-contracted with 25 mM KCl. These agents caused membrane hyperpolarization and increased 42K and 86Rb efflux. The time taken to achieve the maximum change in each of these parameters (tmax) was less for the higher concentration levels of cromakalim, RP49356 and diazoxide than for the lower concentration levels. 2. Calculation of permeability (P) changes showed that cormakalim (1 and 10 microM) produced a greater rise in PK than PRb, although the PRb:PK ratio was similar at both concentration levels. Similarly RP49356 produced a greater change in PK than PRb. However, in contrast to cromakalim, this difference was more marked at the higher concentration (50 microM) and was reflected by a differential effect of the two concentrations of RP49356 on the PRb:PK ratio. Diazoxide (100 and 300 microM) produced similar changes in PK and PRb. 3. For cromakalim (1 and 10 microM) the tmax for the electrical and mechanical effects and also the profile of change in these parameters corresponded to changes in both PK and PRb. For RP49356 (5 microM), changes in tension and membrane potential were related to both changes in PK and PRb, whereas at 50 microM these responses more closely corresponded to changes in PK. For diazoxide (100 and 300 microM) the electrical and mechanical effects corresponded to changes in both PK and PRb. 4. The results show that changes in 42K and 86Rb efflux induced by cromakalim, RP49356 and diazoxide are good indicators of changes in membrane PK and PRb evoked by these agents. Furthermore, it is concluded that the K channels involved in the mechanical and electrical effects of cromakalim are represented by the opening of a single population through which Rb can pass less easily than K, whilst the K channels associated with actions of diazoxide are equally permeable to both K and Rb. In contrast, the relaxant and membrane hyperpolarizing actions of RP49356 may involve the opening of more than one group of K channels which differ in their permeability to Rb.

1. The effects of cromakalim on endothelium-denuded rabbit aortic strips were compared with those of the calcium (Ca2+) entry blocking agent, nifedipine. 2. Pre-incubation with cromakalim or nifedipine had no significant effect on the initial phasic component of noradrenaline (NA)-induced responses. 3. Cromakalim (0.3-10 microM), but not nifedipine, inhibited the maintained tonic contractions produced by NA. The effects of cromakalim were antagonized by raising extracellular [K+] or by glibenclamide. 4. Nifedipine inhibited contractions produced by KCl (40 mM) whereas cromakalim had no effect. 5. In Ca2(+)-free physiological salt solution (PSS), cromakalim produced a significant inhibition of both the refilling of and the release of Ca2+ from NA-releasable Ca2+ stores, whereas nifedipine was ineffective. 6. In tissues preloaded with 42K+ cromakalim (0.3-10 microM) produced a concentration-dependent increase in the 42K+ efflux rate coefficient. NA (0.3 microM) also produced an increase in the rate of efflux of 42K+, an effect which was not antagonized by nifedipine (0.3 microM). 7. When microelectrodes were used, cromakalim (1-10 microM) produced a maintained concentration-dependent membrane hyperpolarization. However, low concentrations of cromakalim (less than 1 microM) which relaxed the aorta had no effect on membrane potential. NA had no significant effect on membrane potential. 9. It is concluded that the ability of cromakalim to relax NA-induced contractions in rabbit aorta is not exerted by the indirect closure of nifedipine-sensitive Ca2+ channels. Instead, cromakalim may exert a direct inhibitory action on Ca2+ uptake into and release from Ca2+ stores and additionally inhibit the pathway through which Ca2+ passes from the extracellular fluid to intracellular Ca2+ stores.

1. The actions of diazoxide and minoxidil sulphate have been compared with those of cromakalim in rat aorta and portal vein. 2. Diazoxide and minoxidil sulphate hyperpolarized the rat portal vein in a similar manner to cromakalim. 3. Cromakalim, diazoxide and minoxidil sulphate increased 42K and 86Rb efflux from rat portal vein, although minoxidil sulphate had only a small effect on 86Rb efflux. 4. Cromakalim, diazoxide and minoxidil sulphate increased 42K efflux from rat aorta but only cromakalim and diazoxide increased 86Rb efflux from this tissue. 5. Glibenclamide inhibited the relaxant actions of cromakalim, diazoxide and minoxidil sulphate on rat aorta and the increase in 42K efflux produced by these agents in this tissue. 6. Diazoxide relaxed an 80 mM KCl-induced contraction of rat aorta, whilst cromakalim and minoxidil sulphate were without effect. 7. Cromakalim, diazoxide and minoxidil sulphate had no effect on cyclic AMP or cyclic GMP concentrations in rat aorta. 8. It is concluded that diazoxide and minoxidil sulphate like cromakalim exhibit K+ channel opening properties in vascular smooth muscle. Diazoxide exerts an additional inhibitory action not related to the production of cyclic AMP or cyclic GMP. The action of minoxidil sulphate may be primarily located at a K+ channel which is relatively impermeable to 86Rb.

Cromakalim, pinacidil, nicorandil, diazoxide and RP-49356 belong to the class of drugs termed potassium channel openers. In rat portal vein diazoxide, like cromakalim, abolished spontaneous mechanical and electrical activity and in rat aorta caused an increase in 86Rb efflux and inhibited KCl(20 mM)-induced contractions. However, in contrast to cromakalim, diazoxide (greater than 100 microM) also inhibited mechanical responses evoked by 80 mM KCl in rat aorta suggesting that it possesses pharmacological properties in addition to K channel opening. Since glibenclamide can attenuate the effects of cromakalim and diazoxide in vascular tissues, it is possible that a channel resembling the ATP-sensitive K channel found in pancreatic beta-cells may be involved in the vasorelaxant effects of these agents. However, differences exist in the order of potency of cromakalim and diazoxide for producing smooth muscle relaxation and for decreasing insulin secretion in pancreatic beta-cells. Furthermore galanin (which opens ATP-sensitive K channels in beta-cells) increases mechanical activity in rat portal vein. It is anticipated that new chemical developments will produce K channel opening molecules with greater potency and tissue selectivity.

The effects of pinacidil have been compared with those of glyceryl trinitrate (GTN) using the aorta and portal vein of the rat and the trachealis and taenia caeci of the guinea-pig. In aorta, both pinacidil and GTN inhibited responses to noradrenaline and showed some selective inhibition of contractions to 20 mM K+. Responses to 80 mM K+ were little affected. In trachealis, both pinacidil and GTN inhibited spontaneous tone and selectively relaxed spasms to 20 mM K+. Responses to 80 mM K+ were unaffected. In portal vein, pinacidil completely inhibited spontaneous electrical and mechanical activity. GTN reduced the amplitude of tension waves and extracellularly-recorded discharges, but increased the frequency of spontaneous electrical and mechanical activity. In portal vein, pinacidil inhibited contractions to noradrenaline and selectively inhibited responses to 20 mM K+. GTN had little inhibitory effect on responses to either noradrenaline or K+. In portal veins loaded with 86Rb as a K+-marker, pinacidil significantly increased the 86Rb efflux rate coefficient whilst GTN had no effect on 86Rb exchange. In taenia caeci, both pinacidil and GTN inhibited the spontaneous tone of the preparation. These inhibitory effects were not antagonized by apamin. It is concluded that pinacidil and GTN do not share a common relaxant mechanism. Evidence has been obtained that pinacidil exerts its inhibitory effects by the opening of apamin-insensitive, 86Rb-permeable K+ channels.

In rat portal vein and aorta, pinacidil (0.3-100 microM) inhibited spontaneous mechanical activity (portal vein) and responses to norepinephrine (0.001-100 microM) and to KCl (5-80 mM). Pinacidil and its analogs P1060 and P1368 inhibited established contractions to 20 mM KCl but had little effect on responses to 80 mM KCl. The order of spasmolytic potency was P1060 greater than pinacdil greater than P1368. Intracellular electrical recording showed that in a portal vein, pinacidil (0.3-10 microM) abolished spontaneous electrical activity and hyperpolarised the cells to the region of the calculated EK. Pinacidil (3-10 microM) produced a similar hyperpolarisation in rat aorta, and in both tissues the hyperpolarisation was maintained in the continuing presence of pinacidil. Using 86Rb as a K+ marker, pinacidil increased 86Rb exchange in both the rat portal vein and aorta. The analog P1060 also increased 86Rb efflux in the rat portal vein; P1368 had no significant effect. It is concluded that the inhibitory effects of pinacidil in rat blood vessels are associated with the opening of 86Rb-permeable K+ channels. This mechanism produces a low-resistance pathway in the membrane and this inhibits the ability of pressor agents to produce smooth muscle contraction.

In rat aorta and rat portal vein, (-)- and (+)-pinacidil each produced a concentration-dependent inhibition of tension development. Although the (-) isomer was the more potent, concentration effect curves for each isomer were steep with similar slopes. In rat portal vein, tetraethylammonium and procaine antagonised the relaxant effect of (+/-)-pinacidil, whereas 3,4-diamino-pyridine was without effect. Intracellular microelectrode recording in rat portal vein showed that low concentrations of (+/-)-pinacidil reduced the duration of multispike electrical complexes. In both rat aorta and rat portal vein, higher concentrations of (+/-)-pinacidil hyperpolarised the membrane towards the potassium equilibrium potential. (+/-)-Pinacidil increased 86Rb efflux from rat aorta and rat portal vein in a concentration dependent manner. In a separate study, (+/-)-pinacidil increased 42K efflux from rat portal vein. (+/-)-Pinacidil had no effect on cyclic GMP or cyclic AMP levels in rat aorta. It is concluded that pinacidil opens 86Rb-permeable potassium channels in rat aorta and rat portal vein. This mechanism is independent of cyclic nucleotide changes and may be responsible for the antihypertensive effect of pinacidil.

(+/-) Pinacidil inhibited noradrenaline-induced contractions in rat aorta and portal vein. The spontaneous tone of guinea-pig bronchial and taenia caeci muscles was relaxed and the spontaneous mechanical activity of rat portal vein was abolished. (+/-) Pinacidil abolished contractions produced by low concentrations of KCl in rat aorta and portal vein, but had relatively little effect on responses to high KCl concentrations. The mechano-inhibitory effects of (+/-) pinacidil were antagonised by tetraethylammonium or procaine. In studies with the purified enantiomers of pinacidil, (-) pinacidil was approximately 20 times more potent that (+) pinacidil. Measurements of electrical activity showed that low concentrations of (+/-) pinacidil selectively inhibited spontaneous electrical discharges in rat portal vein. The duration of multispike electrical complexes was shortened, but spike frequency within a complex and the rate of spike rise and fall were unaffected. At higher concentrations, a dose-dependent hyperpolarisation was observed in both rat aorta and portal vein and the membrane potential approached EK. Using both 86Rb and 42K, (+/-) pinacidil produced a concentration-dependent increase in isotope exchange which correlated with those concentrations at which electrical and mechanical inhibitory effects were observed. Using radioimmunoassay, no pinacidil-induced changes in cyclic AMP or cyclic GMP concentrations were detected in rat aorta. These electrical, ion flux and biochemical measurements suggest that the in vitro mechano-inhibitory effects of pinacidil are associated with the opening of 86Rb-permeable K+ channels in smooth muscle. These effects were observed at concentrations of pinacidil similar to those found in vivo in the plasma of experimental animals and man. It is thus concluded that the hypotensive and antihypertensive effects of pinacidil are the consequence of the cessation of ongoing electrical activity and hyperpolarisation which follows the opening of K+ channels in vascular smooth muscle.