Effects of sympathetic denervation or chronic reserpine on potassium (42K) and chloride (36Cl) efflux from guinea-pig vas deferens.

Potassium (42K) or chloride (36Cl) efflux curves were determined in guinea-pig vas deferens from control, reserpine-treated animals (1 mg/kg/day i.p. for 5 days), and from animals whose vas deferens had been sympathetically denervated 1 week before. Steady-state 42K turnover in control tissues was 0.0052 +/- 0.0002 min-1; neither reserpine treatment nor sympathetic denervation changed this parameter signicantly. Control 36Cl turnover was 0.058 +/- 0.002 min-1 and it was unaffected by either procedure. Methoxamine (3 x 10(-6) to 10(-4) M) induced dose-related increases in the fractional exchange of 42K and 36Cl. These were of greater magnitude after sympathetic denervation or reserpine treatment. Furtrethonium also produced dose-dependent increases in 42K efflux; its dose-response curve was shifted 2.6-fold to the left of the control curve by reserpine treatment. These results indicate that interruption of adrenergic transmission to the guinea-pig vas deferens is associated with increased changes in membrane permeability to Cl and possibly K in response to drug activation of alpha-adrenergic and cholinegic receptors. It is suggested that the supersensitivity phenomenon observed in the guinea-pig vas deferens after reserpine or sympathetic denervation is, in part, related to improved transduction of drug-receptor interaction into ionic permeability changes.

Preparation and biological actions of N-2,2,2-trifluoroethyl-2-(3,4-dihydroxyphenyl)ethylamine.

N-2,2,2,-Trifluoroethyl-2-(3,4-dihydroxyphenyl)ethylamine was synthesized and compared to N-ethyl-2-(3,4-dihydroxyphenyl)-ethylamine and dopamine for activity on adenylate cyclase in the rat striatum. Both dopamine and N-ethyl-2-(3,4-dihydroxyphenyl)ethylamine stimulated adenylate cyclase activity in a dose-dependent fashion. The N-trifluoroethyldopamine analog at 1 x 10(-4) M induced a weak effect. The compounds were evaluated further by studying their relaxant effects in isolated rabbit renal and ear arteries. Both the N-ethyl- and N-trifluoroethyldopamine analogs produced a relaxant effect but demonstrated no selectivity for dopamine receptors.

(3,4-Dihydroxybenzyl)-2-imidazoline (DHBI): an analogue of dopamine.

(3,4-Dihydroxybenzyl)-2-imidazoline (DHBI) was prepared and evaluated for dopamine receptor activity by studying its relaxant effects in the rabbit isolated renal and ear arteries and by measuring its ability to enhance dopamine sensitive adenylate cyclase in the rat striatum. DHBI relaxed both the rabbit isolated renal and ear arteries in the presence of phenoxybenzamine (2. 9 X 10(-5)M) and propranolol (3.4 X 10(-7) M) while dopamine and the specific renal dopamine agonist 6,7-dihydroxy-2-aminotetrahydronaphthalene (6,7-ADTN) demonstrated a ratio of specificity for the renal versus the less responsive ear artery. DHBI did not cause a typical increase in adenylate cyclase activity, however DHBI did attenuate the stimulatory a

Cardiovascular effects of benzquinamide.

The cardiovascular effects of benzquinamide were evaluated in anesthetized dogs. Intravenous benzquinamide, 0.5 to 5 mg/kg, caused tachycardia, elevated blood norepinephrine levels, frequent ventricular arrhythmias, and brief hypotension. Ganglionic blockade by hexamethonium prior to administration of benzquinamide prevented the tachycardia and alterations in norepinephrine levels but prolonged the period of hypotension. In isolated mesenteric arterial preparations benzquinamide interfered with contractile force generated by potassium chloride, norepinephrine, and prostaglandin F2 alpha. It is concluded that benzquinamide directly relaxes vascular smooth muscle thereby producing in vivo reduced peripheral vascular resistance and hypotension, which are compensated for by reflex sympathetic activation.

The effects of ouabain and alterations in potassium concentration on the sensitivity to drugs and the membrane potential of the smooth muscle of the guinea-pig and rat vas deferens.

Previous work has suggested partial depolarization of the smooth muscles cells to be an important factor in the post junctional supersensitivity induced in the guinea-pig vator in the post junctional supersensitivity induced in the guinea-pig vas deferens by chronic denervation or decentralization. The present experiments were undertaken to explore, under acute in vitro conditions, the relationship between membrane potential changes and sensitivity in the vasa deferentia of guinea pigs and rats. The results indicate that sensitivity was altered whenever resting potential was changed by 7 to 10 mV. The results also indicated that considerable electrophysiologic differences exist between the smooth muscles of the guinea-pig and rat vas deferens. Notably, ouabain or lowered external potassium caused a partial depolarization of the guinea-pig, but not the rat, vas deferens. The results, especially when combined with evidence that the rat vas deferens does possess a considerable amount of (Na+-K+)-adenosine triphosphatase, which is ouabain-sensitive, indicates that under the conditions of these experiments the Na pump is electrogenic in the guinea-pig, but not the rat, vas deferens.

Prolonged contraction of isolated human and canine cerebral arteries induced by uridine 5'-triphosphate.

Uridine 5'-triphosphate (UTP) induced long-lasting contractions of isolated human brain arteries; contractions without decrement were observed for periods of up to 20-24 hours at which time the tissues were relaxed in a dose-dependent manner by theophylline. In some vessels, rhythmic oscillations accompanied the prolonged elevation in tension. In canine middle cerebral arteries, UTP produced dose related contractions within the dose range of 1.7 X 10(-6) to 1.7 X 10(-4) M; these responses were unaffected by methysergide 2.8 X 10(-7) M, phenoxybenzamine 2.9 X 10(-5) M or indomethacin 9.8 X 10(-6) M, suggesting that the UTP mechanism of action is probably independent of tryptaminergic or alpha adrenergic receptor activation, or of prostaglandin biosynthesis. The ability of UTP to produce prolonged contraction of cerebral vessels, thus, provides an in vitro preparation in which it is possible to study some of the basic mechanisms that are associated with cerebral vasospasm.

Electrophysiological correlations with postjunctional supersensitivity.

Several lines of evidence have been found which suggest that a partial depolarization is an important event in the development of postjunctional (nondeviation) supersensitivity in the vas deferens and atrium. In the vas deferens of the guinea pig, experiments with microelectrodes indicate that a depolarization of approximately 10 mV occurs after denervation or decentralization. The time course of the depolarization is the same as the time course of the development of supersensitivity found 7 days after denervation in the rat vas deferens. An analysis of the magnitude of junction potentials in the vas deferens supports the conclusion that changes in adrenergic receptors are not a significant factor in postjunctional supersensitivity. An analysis of membrane potential in guinea pig atria demonstrates a high correlation between the appearance of supersensitivity and a partial depolarization in that tissue alsomit is suggested that chronic interruption of the innervation to smooth or cardiac muscle leads to an alteration in the binding of calcium to the cell membrane and a consequent depolarization. The result is a resting membrane potential closer to the threshold for excitation.

Adrenergic mechanisms in cerebral circulation of the goat.

The effects of electrical stimulation of the cervical sympathetic nerves and tyramine on cerebral blood flow (CBF) were investigated in 13 unanesthetized goats in which electromagnetic flow probes had been previously implanted on the internal maxillary artery. Nerve stimulation (1.5-12 cycles/s) produced frequency-dependent reductions in CBF, a decrease of 50 percent occurring with the highest frequency. Injections of tyramine (50-500 mug) into the internal maxillary artery produced dose-dependent reductions in CBF, a decrease of 36 percent occurring with the highest dose. Both reserpine and phentolamine diminished the vasoconstriction induced by nerve stimulation and tyramine. Cocaine partially abolished the effects of tyramine and did not alter those of nerve stimulation. In addition, phentolamine produced cerebral vasodilatation, which was greatly reduced by previous treatment with reserpine. These results show that sympathetic stimulation and tyramine produce cerebral vasoconstriction by the release of the transmitter from the perivascular nerve endings, and they suggest the presence of a tonic sympathetic activity in the cerebral vessels.

Pharmacological receptors of the cerebral arteries of the goat.

5-Hydroxytryptamine (5-HT), norepinephrine (NE), histamine (H) and potassium (K+) chloride induce dose-dependent changes in tension of the isolated middle crerbral artery of the goat. Vasopressin produces highly variable responses followed by tachyphylaxis; angiotensin II is ineffective over a wide dose range. The order of potencies of these vasoactive agents is 5-HT greater than NE greater than H greater than K+. With regard to their ability to induce maximal contractile responses, the order is: H greater than 5-HT, K+ greater than NE. Lysergic acid diethylamide (LSD) antagonizes the actions of 5-HT in a manner which progresses from surmountability to unsurmountability of the blockade depending on the concentration of LSD. The blockade exerted by LSD is reversed by washing. Phentolamine and diphenhydramine competitively antagonize the actions of NE and H, respectively. The potency of phentolamine and diphenhydramine in the cerebral arteries of the goat is similar to that determined in different tissues obtained from a variety of animal species. It is concluded that the cerebral arteries of the goat possess receptors for biogenic amines, the most effective of which is 5-HT; receptors for vasoactive peptides are ill defined.?25

Action of cocaine and chronic sympathetic denervation on vagal escape.

1. The effect of cocaine has been studied on vagal escape and on the tachycardia due to vagal stimulation in the atropinized dog. All the dogs were submitted to acute cervical section of the spinal cord and acute or chronic sympathetic denervation.2. Cocaine, 5 mg/kg or 40 mug/kg/min, I.V., induces a significant enhancement of the ventricular escape. The effects of a continuous infusion of cocaine are more reproducible than those of a single injection of the drug.3. Cocaine, 40 mug/kg/min, I.V., potentiates the tachycardia due to vagal stimulation in the atropinized dog.4. Chronic thoracic sympathectomy markedly retards the recovery of the ventricular rate from the inhibitory action of the vagus. Under this condition, the infusion of cocaine does not significantly enhance the ventricular escape.5. These findings suggest that an adrenergic mechanism located at the sympathetic nerves supplying the heart is substantially involved in the phenomenon of vagal escape.