Nerve-induced tachykinin-mediated vasodilation in skeletal muscle is dependent on nitric oxide formation.

Nerve-induced vasodilatation was studied by intravital microscopy of the rabbit tenuissimus muscle, pretreated with pancuronium, phentolamine, and guanethidine. Nerve stimulation of the tenuissimus nerve induced a vasodilatation which was frequency and pulse duration-dependent and insensitive to atropine and propanolol but abolished by tetrodotoxin. The nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 100 microM), but not its enantiomer, D-NAME, markedly inhibited the vasodilation induced by nerve stimulation or by exogenous substance P or neurokinin A. Vasodilatation due to calcitonin gene-related peptide, prostaglandin E2 or nitroprusside was unaffected. The substance P antagonist, spantide (30 microM), significantly attenuated nerve-induced vasodilatation, in parallel with L-NAME. Our results indicate that nerve-induced vasodilatation in skeletal muscle can be attributed to the release of substance P and/or other tachykinins and that nitric oxide subsequently mediates the response to endogenous tachykinins released from nerves.

Role of adenosine in functional hyperemia in skeletal muscle as indicated by pharmacological tools.

The hypothesis that adenosine mediates blood flow increments in contracting skeletal muscle was evaluated by intravital microscopy of the microcirculation in the tenuissimus muscle of anesthetized rabbits. Motor nerve stimulation elicited muscle contractions and frequency-dependent arteriolar dilatation, particularly in terminal arterioles. The pulse duration (0.05 ms) and voltage (1.5-5 V) precluded activation of vasoconstrictor fibers, as also indicated by the lack of effect of phentolamine on resting vascular tone and on the hyperemic response to nerve stimulation. The specific adenosine receptor antagonist, 1,3-dipropyl-8-p-sulfo-phenylxanthine (DPSPX; 10(-5) M), attenuated the hyperemic response to muscle contractions. The adenosine uptake inhibitor dipyridamole (10(-8)-10(-6) M) dose-dependently dilated microvessels, an effect prevented by DPSPX (10(-5) M). Moreover, dipyridamole (10(-7) M) augmented contraction-induced hyperemia. The enhancement by dipyridamole was reversed by DPSPX (10(-5) M). The effects of adenosine uptake inhibitor and antagonist were invariably more marked in terminal than in transverse arterioles, and also more pronounced at higher stimulation frequencies. Motor nerve stimulation failed to induce alterations in vascular diameters when the neuromuscular junction was blocked by pancuronium. Thus, our observations indicate that functional hyperemia after motor nerve-induced contractions of the skeletal muscle was of postjunctional origin. Apparently, activation of adenosine receptors was responsible for a part of the evoked vasodilation.

Pharmacological actions of "kyushin," a drug containing toad venom(2): effects on urinary volume and electrolyte excretion.

A study was conducted on the pharmacological actions of the toad venom-containing drug "Kyushin" (KY-2 and KY-R) on urinary volume and electrolytes excretion, regional blood flow, renal artery blood flow and carrageenin-induced hind-paw edema. In rabbits, KY-2 and KY-R significantly increased urinary volume after intravenous administration of 8 mg/kg. In guinea pigs, KY-2 and KY-R produced a significant increase in urinary volume after intraduodenal administration (i.d.) of 80 mg/kg. In guinea pigs treated with propranolol, KY-2 at 20 and 40 mg/kg p.o. and KY-R at 40 mg/kg p.o. increased urinary volume. At 40 mg/kg i.d. both KY-2 and KY-R produced an increase in regional blood flow, as determined by the hydrogen gas clearance method, of the brain areas including the amygdaloid nucleus, but did not affect regional blood flow in liver, kidney and skeletal muscle, or renal artery blood flow. In rats, carrageenin-induced hind-paw edema was inhibited by KY-2 or KY-R at 600 mg/kg p.o.

Muscle blood flow and rate of recovery from pancuronium neuromuscular blockade in dogs.

The effect of changes in muscle blood flow on the rate of recovery from neuromuscular block produced by pancuronium was investigated in dogs, and were shown to be independent variables. The significance of this finding in relation to recent work on blood concentrations of the drug and on the pharmacodynamics of the drug is discussed.

Onset time and duration of action for atracurium, Org NC45 and pancuronium.

Speed of onset, maximum block, duration of action and 10-25% recovery time for atracurium, Org NC 45 and pancuronium were determined using equipotent doses: 330 micrograms kg-1, 66 micrograms kg-1 and 75 micrograms kg-1 respectively. Vein-to-muscle and artery-to-muscle onset times were measured by use of simultaneous recordings. Mean speeds of onset to 95% twitch depression were: atracurium 2.7 min, Org NC 45 2.8 min and pancuronium 3.6 min. The median value of maximum neuromuscular block exceeded 98.5% for all drugs and the mean durations of action to 25% recovery of control twitch height were: atracurium 27.6 min, Org NC 45 21.9 min and pancuronium 45.1 min. The differences were statistically significant. The recovery period from 10% to 25% twitch response was considerably longer for pancuronium than for the other drugs, which did not differ significantly from each other. We were unable to validate the artery-to-muscle technique in the determination of onset time.

A comparison of systemic and regional hemodynamic effects of d-tubocurarine, pancuronium, and vecuronium.

This study was designed to compare the effects of three neuromuscular blocking agents, in a clinically relevant dose range, on the regional distribution of blood flow measured with 15-microns radioactive microspheres in anesthetized, optimally ventilated cats. d-Tubocurarine (400, 800, and 1,600 micrograms X kg-1) caused hypotension and a decrease in ascending aortic blood flow. Pancuronium (20, 40, and 80 micrograms X kg-1) only caused a moderate tachycardia, while vecuronium (40, 80, and 160 micrograms X kg-1) was devoid of any systemic hemodynamic effect. Neither pancuronium nor vecuronium caused major changes in regional blood flows. On the other hand, d-tubocurarine increased blood flow to the stomach but decreased that to the kidneys, liver, skin, spleen, intestine, and adrenal glands. These effects of d-tubocurarine show a striking resemblance to those elicited by the infusion of histamine. Blood flow to the nerve-stimulated tibialis anterior muscle, which was about six times that of the unstimulated muscle, was decreased significantly by all three neuromuscular blockers. In conclusion, the results clearly show that, while d-tubocurarine produces major cardiovascular disturbances, pancuronium and, in particular, vecuronium do not cause serious changes in systemic and regional hemodynamics in doses that are two to four times the ED90 for neuromuscular blocking action.

Measurement of blood flow and oxygen consumption in the pelvic limb of fetal sheep.

In order to determine blood flow and oxygen consumption in the pelvic limb of fetal sheep, we applied the Fick principle of measurement of oxygen consumption in seven paired experiments in seven fetal sheep under normal conditions and after treatment with pancuronium bromide. Catheterization procedures, which minimized interference with the study limb circulation, avoided changes of catheter tip position during fetal movements,n and prevented collateral circulation to and from tissues not located in the pelvic limb, were utilized. Blood flow through the external iliac artery was measured by means of a transit time ultrasonic method. Six sample sets for oxygen content were drawn from the external iliac artery and vein during 45-min control period and repeated after neuromuscular blockade. Normal oxygen consumption under these experimental conditions was determined to be 20.7 +/- 1.9 (mean +/- SEM) mumole.min-1.100 g-1. Neuromuscular blockade caused oxygen consumption to decrease significantly (P less than 0.01) by 12% to 18.1 +/- 2.1 mumole.min-1.100 g-1 and decreased the average coefficient of variation from 15 to 8%. The data demonstrate that spontaneous skeletal muscle activity accounts for a significant amount of oxygen consumption, the level of which can vary widely over brief periods of time. These results suggest that such tissues with significant spontaneous changes in metabolic activity require repeated blood flow measurements with simultaneous determination of substrate arteriovenous differences to best describe metabolism under normal conditions.