The influence of vasoactive substances on blood flow and contractile responses of cat gastrocnemius.

1 The effects of several vasoactive substances have been studied on blood flow and acetylochline-induced contraction of the vascularly isolated gastrocnemius of the cat. All substances, including acetylcholine, were administered intra-arterially to the muscle. Blood flow and contractile tension were monitored simultaneously.2 All substances which increased blood flow, enhanced the contractile responses to acetylcholine; angiotensin, which decreased blood flow, attenuated them.3 Histamine was typical of the vasodilators in doses up to 1 mug (9 nmol), but in a dose tenfold higher it produced only a small and transient increase in blood flow and little or no enhancement of the acetylcholine-induced contractions. These paradoxical effects were brought about by that portion of the high dose of histamine which re-entered the cat's systemic circulation.4 The order of potency of the vasodilators was the same for their potentiating effect on the acetylcholine-induced contractile responses as for their enhancing effect on muscle blood flow: bradykinin >histamine>>papaverine>>NaH(2)PO(4) >KCl. Median effective doses (ED(50)S) determined only for bradykinin, histamine and papaverine were, respectively, 20.5, 49.8, and 3,352 pmol as potentiators, and 13.4, 199.8 and 85,000 pmol as vasodilators.5 In general, the effect of a given vasoactive substance on the contractile response to acetylcholine was dose-dependent and correlated well with its effect on muscle blood flow at the moment the acetylcholine was injected. Two important exceptions were, firstly, that the highest dose of papaverine was only moderately effective as a potentiator even though highly effective as an increaser of muscle blood flow; and, secondly, that histamine produced its greatest potentiating effect 10 s after it was injected, at which time its effect on muscle blood flow was quite small.6 It is suggested that these exceptions and, indeed, the much greater potentiating effectiveness of histamine and bradykinin versus papaverine may be due to the ability of histamine and bradykinin to increase the permeability of the muscle's capillaries as well as increasing blood flow through them, thus facilitating much better than mere vasodilators the access of bloodborne acetylcholine to its receptors on the muscle fibres.

Interaction of angiotensin with exogenous and neurally released norepinephrine on the cat nictitating membrane in vitro.

We have studied the effect of high (1-2.9 X 10(-5) M) and low 1.9 X 10(-9) M) concentrations of angiotensin on the retention and release of 3H-norepinephrine by the cat isolated nicititating membrane preparation in vitro in conjunction with their effect on the contractile responsiveness of the preparation to exogenous norepinephrine and transmural electrical stimulation. Both concentrations of angiotensin made the preparation contract, but only the high concentration affected the retention and spontaneous efflux of 3-H-norepinephrine. Retention was inhibited about 25% only when the preparation was preincubated with the angiotensin for 30 minutes (i.e., before adding 3H-norepinephrine). Under similar conditions cocaine, 2.9 X 10(-5) M, inhibited retention more than 90%. Spontaneous efflux was increased for as long as the high concentration of angiotensin was in contact with the preparation. Under similar conditions, tyramine, 5.7 X 10(-6) M, caused a much greater sustained increase in spontaneous efflux. Transmural stimulation of the preparation caused release of 3H-norepinephrine and frequency-dependent contractions. The contractions were selectively inhibited by phentolamine, 2.7 X 10(-6) M, or bretylium, 2.4 X 10(-5) M. Angiotensin had no effect on this neurally mediated 3H-norepinephrine release and contractile response or on contractions produced by exogenous norepinephrine. Since, as reported previously, angiotensin in vivo strongly inhibits contractile responses of the cat nicitating membrane to both neurally released and exogenous norepinephrine, the present results make it unlikely that such inhibition derives from angiotensin's relatively modest capacity for affecting the disposition of norepinephrine by this effector organ.

The influence of histamine and other vasoactive substances on contractile responses of cat skeletal muscle to acetylcholine.

1. The effect of vasoactive substances, chiefly histamine, on contractions of cat skeletal muscle evoked by acetylcholine has been studied. For this purpose all of these agents were administered intra-arterially to anterior tibialis, chiefly, and also to soleus and external rectus muscles in vivo.2. Under these conditions, histamine itself never altered the resting tension of the muscle, but always enhanced the increase in tension produced by acetylcholine injected shortly afterward.3. On the anterior tibialis muscle, it was determined that the threshold potentiating dose of histamine was 0.001 mug/kg, and that maximal enhancement occurred when 0.1 mug/kg was injected 15 s before fixed, submaximal doses of acetylcholine. Injected 15 s before graded doses of acetylcholine, histamine 0.1 mug/kg shifted the acetylcholine dose-response curves approximately 1.5 log units to the left.4. Under similar experimental conditions the vasodilator, bradykinin, 0.001-1 mug/kg, and procedures which produce a local increase in nutritive capillary blood flow also enhanced acetylcholine-evoked contractile responses of the anterior tibialis, whereas the vasoconstrictor, angiotensin, 0.001-1 mug/kg, inhibited them.5. The potentiating effect of histamine was antagonized by mepyramine, but was undiminished by denervation of the muscle either acutely or for 4 days.6. Histamine failed to enhance responses of the muscle to electrical stimulation of either the muscle, directly, or its motor nerve.7. Histamine also had no effect upon acetylcholine-evoked responses of the isolated external rectus muscle in vitro.8. It is suggested that the potentiating effect of histamine in vivo is due to its vasodilator action within the muscles which, by relaxing arterioles and precapillary sphincters, could allow more of the blood-borne acetylcholine to reach more of its receptors on the muscle fibres in a given time.

Inhibition by lidoflazine of the contractile response of the rat isolated colon to angiotensin.

1. In the rat isolated ascending colon, lidoflazine in a concentration of 5 x 10(-7)M slightly enhanced the response to angiotensin, but in a concentration of 10(-6)M it was a strong and unsurmountable antagonist.2. Exposure to lidoflazine (10(-6)M) also inhibited the contractile responses to acetylcholine, 5-hydroxytryptamine and barium ions. The antagonism of acetylcholine and 5-hydroxytryptamine was unsurmountable and quantitatively similar to that of angiotensin. The antagonism of barium ions was much weaker and probably competitive.3. The inhibitory effect of papaverine (10(-5)M) showed a pattern similar to that found for lidoflazine.4. It is concluded that the antagonism of angiotensin by lidoflazine in the rat colon is non-specific.

Analysis of some central actions of nicotine injected into the cerebral ventricles of cats.

1. In unanaesthetized cats intraventricular injections of 2.5-10 mug nicotine produced blinking, narrowing of the palpebral fissures, retching, vomiting and asynchronous twitching of the ears. With larger doses (30-100 mug) the ear twitching was interrupted for a short time by laying back of the ears. Respiration first became laboured and deep, then rapid and shallow following which panting occurred. There was salivation, loud calling, micturition and defaecation. With still larger doses (300-1000 mug) there was torticollis, ataxia and blind charging sometimes followed by a clonic-tonic convulsion.2. In cats anaesthetized with chloralose only some of these effects followed the intraventricular injection of nicotine, i.e. the ear response, respiratory changes and salivation. In addition, the pinna reflex was facilitated.3. The ear response and the facilitation of the pinna reflex did not occur on perfusion of nicotine from a lateral ventricle to aqueduct. They result from an action on superficial structures in the cervical cord between C1 and C2. Applied to this region of the cord, nicotine produced the ear response within 10-60 sec, sometimes in concentrations as low as 1/100,000. Applied below C2, nicotine was ineffective.4. Transecting the cord below C2 or cutting the dorsal and ventral roots of C1, C2 and C3 bilaterally did not affect the ear response produced by topical application or by intraventricular injection of nicotine. Transection of the cord above C1 abolished it.5. Hexamethonium applied to the cervical cord between C1 and C2 inhibited the ear response and the facilitation of the pinna reflex whether produced by nicotine applied topically or injected intraventricularly.6. The salivation and the respiratory changes produced by intraventricular injections of nicotine did not occur when nicotine was perfused from a lateral ventricle to the aqueduct. They result from an action of the nicotine on structures situated superficially in the brain stem. Nicotine had no sialogogue or respiratory effect when applied to the region of the cord at which it produced an ear response, but perfused through the subarachnoid space from interpeduncular fossa to cisterna magna or injected into the subarachnoid space alongside the brain stem, it produced these effects.7. Hexamethonium perfused from interpeduncular fossa to cisterna magna inhibited the salivary secretion as well as the respiratory changes produced by nicotine similarly applied.8. The efferent pathway for the salivation is parasympathetic since it no longer occurred after cutting the chorda-lingual nerve or after intravenous atropine.9. Intravenous injections of nicotine also produced the ear response with facilitation of the pinna reflex, salivation and hyperventilation in the anaesthetized cat, but only the ear response and facilitation of the pinna reflex are central effects. The salivation and hyperventilation following intravenous injection are due to peripheral actions of nicotine.