Differential constrictor responses of cephalic and caudal vasculature to α-adrenoceptor agonist after hind limb unloading.

We examined the effects of hind limb unloading (HLU, 14 days) on constriction of carotid and iliac arterial beds in vivo in thiobutabarbital-anaesthetized rats and isolated carotid and iliac arteries in vitro. Both control and HLU rats had similar arterial pressure and carotid and iliac arterial flows. The HLU rats had increased carotid arterial but reduced iliac arterial constriction in response to methoxamine (α1-adrenoceptor agonist) in vivo. In contrast, constriction in response to methoxamine was reduced in the isolated carotid and unchanged in the iliac artery of HLU rats relative to control rats. Thus, HLU is associated with increased constriction of carotid arterial bed but reduced constriction of the isolated carotid artery, and reduced constriction of iliac arterial bed but unchanged constriction of the isolated iliac artery. These results show differential influence of HLU on constriction of cephalic and caudal arterial beds, and differential effect on constrictions of arterial beds relative to conduit arteries.

Development and pilot testing of the Neuromuscular Blockade Advisory System.

The neuromuscular blocker advisory system (NMBAS) is a computer program developed to provide advisory guidance to anesthesiologists on the timing and dose of rocuronium to paralyze patients during surgery. It is believed that the use of such a system will administer the minimally effective amount of drug, maintaining the patient in a state of paralysis that is useful for surgery yet easily reversible. This will improve patient safety and result in more efficient care. In this paper we present the NMBAS, its basic methodology, and its development though a pilot study. Novel methods of handling neuromuscular response data are presented, including relaxation measurement and the enhanced-train-of-four sensing modality. New methods of handling nonlinearities at the neuromuscular junction to allow application of adaptive control techniques are presented. A novel form of modelling combining model swapping and RLSE adaptation to accommodate the patient variation seen with NMB drugs is introduced. A pilot study testing the NMBAS was undergone to prepare the NMBAS for application in a full clinical trial, in which patients undergoing prostate brachytherapy surgeries using rocuronium for intubation were admitted.

Inducible nitric oxide synthase depresses cardiac contractile function in Zucker diabetic fatty rats.

Cardiac contractile dysfunction is a common occurrence in type 2 diabetes. The aim was to examine if inducible nitric oxide synthase (iNOS) causes cardiac dysfunction in Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. ZDF and Zucker lean control rats (20 week old) were studied at 6 h after recovery from halothane anaesthesia and surgery that involved insertions of catheters into the iliac arteries, iliac veins and the left ventricle via the right carotid artery. Protein expression and activity of iNOS in the hearts were measured by immunostaining and arginine-citrulline conversion assay, respectively. Both groups had similar baseline left ventricular developed pressure and maximum rate of rise of left ventricular pressure (+dP/dt), but heart rate and rate pressure product were lower in the ZDF than control rats. Dobutamine dose-dependently increased left ventricular developed pressure, +dP/dt, heart rate and rate pressure product in both groups, but the responses were less in the diabetic than control rats. The activity and protein expression of iNOS and nitrotyrosine were higher in the hearts of the diabetic than control rats. Selective inhibition of iNOS by 1400 W (N-3-aminomethyl-benzyl-acetamidine) did not alter responses to dobutamine in the control rats, but augmented the effects of dobutamine on left ventricular developed pressure and rate pressure product in the diabetic rats. The results indicate that activation of iNOS contributed to left ventricular contractile dysfunction in the ZDF rats, and this was partially reversed by selective inhibition of the activity of iNOS.

Impaired in vivo venous constriction in conscious obese Zucker rats with metabolic syndrome.

The venous system plays a crucial role in regulating cardiac output and blood pressure. Although the relationship between obesity and hypertension is well recognized, little is known about the effect of obesity on venous function. We examined if 16-week-old obese Zucker rats, relative to age-matched lean Zucker rats, had altered in vivo venoconstriction to noradrenaline. The obese rats, compared to the controls, had higher mean arterial pressure (MAP), body weight, and plasma insulin and triglycerides, but reduced pressor and mean circulatory filling pressure (MCFP, index of venous tone) responses to noradrenaline (2.5-30x10(-9) mol/kg/min, i.v.). N(G)-nitro-L-arginine methyl ester (L-NAME, 8 mg/kg, i.v., non-selective inhibitor of nitric oxide synthase) did not alter MCFP in either group, but increased MAP of both groups, though the increase was markedly less in the obese than lean rats. Therefore, obese Zucker rats had increased baseline MAP, but impaired in vivo pressor and MCFP responses to noradrenaline, and reduced pressor response to L-NAME. The increased baseline MAP in the obese rats was not due to increased arterial and venous constriction to noradrenaline but rather to reduced influence of the nitric oxide/L-arginine system.

The ruthenium-based nitric oxide scavenger, AMD6221, augments cardiovascular responsiveness to noradrenaline in rats with streptozotocin-induced diabetes.

Excess production of nitric oxide by inducible nitric oxide synthase (iNOS) has been implicated in cardiovascular dysfunction associated with the acute phase of diabetes mellitus. We examined if the selective nitric oxide scavenger, AMD6221 (ruthenium[hydrogen(diethylenetrinitrilo)pentaacetato] chloride) improved cardiovascular function in rats with streptozotocin (60 mg/kg, i.v.)-induced diabetes. The cardiovascular effects of noradrenaline (16.5 nmol/kg/min, i.v.) were measured in thiobutabarbitone-anaesthetised diabetic and control rats before and after acute administration of AMD6221 (80 mg/kg). Rats in the acute phase of diabetes (3 weeks post injection of streptozotocin) had impaired mean arterial pressure, left ventricular systolic pressure and maximum rate of increase (+dP/dt) and decrease (-dP/dt) of left ventricular pressure responses to noradrenaline compared with control rats. AMD6221 significantly augmented noradrenaline-induced increases in left ventricular systolic pressure and +/-dP/dt in the diabetic but not control rats. The results show that selective scavenging of nitric oxide by AMD6221 improved cardiac response to noradrenaline in rats with streptozotocin-induced diabetes.

Pharmacological evidence for a key role of voltage-gated K+ channels in the function of rat aortic smooth muscle cells.

The role of voltage-dependent (I(K(v))) and large conductance Ca(2+)-activated (BK(Ca)) K(+) currents in the function of the rat aorta was investigated using specific BK(Ca) and K(V) channel inhibitors in single rat aortic myocytes (RAMs) with patch-clamp technique and in endothelium-denuded aortic rings with isometric tension measurements. The whole-cell K(+) currents were recorded in RAMs dialysed with 200 and 444 nm Ca(2+) and in perforated-patch configuration. Electrophysiological analysis demonstrated that I(K(v)) appeared at >/=-40 mV, while BK(Ca) (isolated using 1 microm paxilline) were seen positive to -20 mV in all conditions. Voltage-dependent characteristics, but not maximal conductance, of I(K(v)) was significantly altered in increased [Ca(2+)](i). Correolide (1 microm) (a K(V)1 channel blocker) did not inhibit the I(K(v)), whereas millimolar concentration of TEA (IC(50)=3.1+/-0.6 mm, n=5) and 4-aminopyridine (4-AP, IC(50)=5.9+/-1.9 mm, n=7) suppressed I(K(v)). These results and immunocytochemical analysis suggest the K(V)2.1 channel to be a molecular correlate for I(K(v)). In nonstimulated aortic rings 1-5 mm TEA and 4-AP (inhibitors of I(K(v))), but not paxilline (1 microm), caused contraction. The frequency of contractile responses to TEA and 4-AP was increased in the presence of 10 mm KCl, which itself did not significantly affect the aortic basal tone. Phenylephrine (15-40 nm) induced sustained tension with superimposed slow oscillatory contractions (termed OWs). OWs were blocked by diltiazem, ryanodine and cyclopiazonic acid, suggesting the involvement of L-type Ca(2+) channels and ryanodine-sensitive Ca(2+) stores in this process. TEA and 4-AP, but not IbTX, paxilline or correolide, increased the duration and amplitude of OWs, indicating that I(K(v)) is involved in the control of oscillatory activity. In conclusion, our findings suggest that the K(V)2.1-mediated I(K(v)), and not BK(Ca), plays an important role in the regulation of the excitability and contractility of rat aorta.