Characteristics of adaptive supersensitivity in the left atrium of the guinea pig

Chronic pretreatment of guinea pigs with reserpine (0.1 mg/kg/day for 7 days) induces inotropic supersensitivity in left atria. The sensitivity is increased to isoproterenol, norepinephrine, 5'-guanylylimidodiphosphate and forskolin, and the maximum response is increased to the partial agonist albuterol. These results, coupled with data in the literature, suggest that adaptive supersensitivity in the guinea pig heart is due to a change in one or more of the components of the adenylate cyclase system that is specifically coupled to beta adrenoceptors. The results indicate that the supersensitivity is demonstrable when the concentration-response curves for agonists are determined in isolated whole left atria but not when they are determined in strips cut from left atria. This explains a discrepancy in the literature. It is suggested that cellular changes, possibly in electrolyte distribution, resulting from the additional manipulation of cutting the atria into slices obscure the sensitivity difference between the control and experimental tissues.     

Effect of reserpine pretreatment on mechanical responsiveness and [125I]Iodohydroxybenzylpindolol binding sites in the guinea-pig right atrium

The inotropic and chronotropic responses of the guinea-pig right atrium to several pharmacologic agents were measured after acute (0.1 mg/kg/day x 1) and chronic (0.1 mg/kg/day x 7) reserpine administration. A small increase in the sensitivity of the pacemaker to isoproterenol occurred after acute reserpine treatment which was followed by a much greater change in sensitivity to the beta agonist when pretreatment was extended for 7 days. Chronotropic responsiveness to calcium, histamine and pilocarpine was not altered by reserpine pretreatment. The acute administration of reserpine resulted in a slight inotropic supersensitivity of paced right atria to isoproterenol, calcium and histamine. Pretreatment for 7 days produced an additional increase in inotropic sensitivity to isoproterenol but did not affect contractile responses to the other agents. The catecholamine-specific nature of the supersensitivity induced by chronic reserpine treatment suggested that a change in the number and/or affinity of beta adrenergic receptors was involved. The radiolabeled beta adrenoceptor antagonist [125]iodohydroxybenzylpindolol (I-HYP) was used to test this hypothesis. Preliminary experiments revealed the presence of a single class of noninteracting (nH = 0.99), high affinity (Kd = 100 pM) binding sites which exhibited stereospecificity and saturability (47.2 fmol/mg of protein). The agonist potency series for the inhibition of I-HYP binding was identical to the series for mediating mechanical responses. Taken collectively this information suggests that the high affinity I-HYP binding site in the guinea-pig right atrium represents the beta adrenergic receptor. As determined by Scatchard analyses, neither acute (1-day) nor chronic (7-day) low-dose (0.1 mg/kg/day) reserpine administration altered the number or affinity of I-HYP binding sites. It is concluded that changes in beta receptor characteristics are not responsible for reserpine-induced supersensitivity in this tissue.     

Reserpine up-regulation of rat renal cortical beta adrenergic receptors is independent of its effect on the sympathetic nervous system

Experiments were performed to evaluate the mechanism underlying our recent observation that reserpine but not surgical denervation up-regulates rat renal cortical beta adrenergic receptors. The specific binding of [125I]iodocyanopindolol was used to quantitate the beta adrenoceptors. Chronic high-dose guanethidine, which decreased renal tissue and circulating catecholamines to the same extent as reserpine, failed to up-regulate renal beta adrenoceptors, which indicates that the effect of reserpine was not due to changes in the ambient catecholamine concentration. Isoproterenol-stimulated renin secretion, a measure of postsynaptic receptor function, was increased by reserpine but not denervation, which indicates that the failure to observe beta adrenoceptor up-regulation by radioligand binding studies after denervation was not an anomaly caused by loss of presynaptic receptors masking postsynaptic supersensitivity. Reserpine was effective even in denervated kidneys. Up-regulation of renal beta adrenoceptors with reserpine occurred even after destruction of peripheral sympathetic nervous system by a combination of adrenal demedullation and high-dose guanethidine administration. A lower daily dose of reserpine (0.3 mg/kg instead of 0.5 mg/kg), which caused no weight loss, was effective in producing beta adrenoceptor up-regulation. Antagonism of reserpine depletion of nerve terminal norepinephrine by tranylcypromine, a monoamine oxidase inhibitor, did not nullify renal beta adrenoceptor up-regulation. Overall, our results indicate that reserpine up-regulation of renal beta adrenergic receptors is independent of the sympathetic nervous system and possibly is a direct effect.     

In vivo cardiovascular responses to isoproterenol, dopamine and tyramine after prolonged infusion of isoproterenol

Effects of prolonged in vivo infusion of isoproterenol on acute cardiovascular responses to isoproterenol, dopamine and tyramine were studied in pithed rats. Isoproterenol infusion resulted in a significant decrease in control values for maximum left ventricular dP/dt; heart rate and left ventricular systolic blood pressure were not altered. This treatment also depleted both atrial and ventricular stores of norepinephrine and caused cardiac hypertrophy. Isoproterenol infusion resulted in a desensitization of drug-induced cardiovascular responses. The acute in vivo effects of isoproterenol on maximum left ventricular dP/dt, heart rate and left ventricular systolic blood pressure responses to isoproterenol were severely attenuated. The ED50 for maximum left ventricular dP/dt was increased 36-fold and maximal responses were reduced by half; changes in heart rate occurred in a parallel fashion. By contrast, ED50 values for inotropic responses to tyramine and dopamine were increased 14- and 4-fold, respectively, whereas increases in heart rate were blunted. Tyramine and dopamine-mediated increases in heart rate were completely attenuated by desensitization; chronotropic effects were again evident after pretreatment with the selective alpha-1 blocker prazosin. In addition, prazosin blocked the inotropic responses to tyramine and dopamine after desensitization and this antagonism was only slightly enhanced by addition of propranolol (prazosin + propranolol); propranolol alone was ineffective. These results are consistent with the down-regulation of beta adrenoceptors after prolonged exposure to catecholamines and indicate that under such conditions the alpha-mediated cardiovascular responses may be unmasked. Compared to pure beta agonists, agents with a degree of alpha-1 activity might be superior inotropes in heart failure patients who characteristically present with depleted stores of myocardial norepinephrine and minimal beta adrenoceptor reserve.     

Effect of reserpine pretreatment on calcium transport and Ca++-Mg++ adenosine triphosphatase activity of guinea-pig cardiac microsomes

A previous report from this laboratory showed that reserpine pretreatment, in appropriate doses and under restricted conditions, increased the inotropic responsiveness of guinea-pig hearts to calcium. The enhanced responsiveness was characterized by a selective increase in the rate of ventricular relaxation (-dP/dt). We therefore hypothesized that reserpine might alter calcium uptake or (Ca++-Mg++) adenosine triphosphatase (ATPase) activity of guinea-pig ventricular sarcoplasmic reticulum (SR). Pretreatment of guinea pigs with reserpine (2.5 mg/kg/day, 2 days) significantly elevated ATP-dependent, Tris oxalate-facilitated SR Ca++ uptake and increased the calcium-sensitive component of the SR (Ca++) ATPase activity. These changes appeared to be functionally related to a reserpine-induced potentiation of ventricular relaxation rate, as estimated by the relationship between negative and positive left ventricular dP/dt of isolated working guinea-pig hearts. An alternative dose of reserpine (5 mg/kg, -24 hr), which had been demonstrated to produce an equivalent degree of catecholamine depletion, had no effect on either the inotropic responsiveness to calcium or on the SR calcium uptake or ATPase activities. The exact mechanism for these reserpine-induced alterations in calcium homeostasis remains to be elucidated.     

Effects of prolonged isoproterenol infusion on cardiac and vascular responses to adrenoceptor agonists

In vitro responses of cardiac and vascular smooth muscle to both adrenoceptor agonists and phosphodiesterase inhibitors were studied in tissues from either saline- or isoproterenol-infused rats. After chronic isoproterenol infusion the sigmoidal relationship between concentration of acutely administered isoproterenol and inotropic response of cardiac muscle was shifted to the right; the maximum response was decreased by approximately 40%. Inotropic responses were attenuated further by the beta adrenoceptor antagonist, propranolol. By contrast, quantitatively comparable inotropic responses to phenylephrine were not altered after isoproterenol infusion. However, they were blocked by the selective alpha adrenoceptor antagonist, prazosin, but were not affected by propranolol. Inotropic effects of the phosphodiesterase inhibitor, isobutylmethylxanthine, were comparable in tissues from either saline- or isoproterenol-infused rats. Similar results were obtained in vascular tissues. Portal veins and aortas from isoproterenol-infused rats were less responsive to the acute relaxant properties of the beta adrenoceptor agonists, isoproterenol and salbutamol. However, as in cardiac muscle, relaxant effects to phosphodiesterase inhibitors (isobutylmethylxanthine and papaverine) were not attenuated. In addition, contraction to norepinephrine was comparable in tissues from either saline- or isoproterenol-infused rats. These data indicate that isoproterenol infusion attenuates beta adrenoceptor-mediated responses of vascular and cardiac muscle to similar degrees but does not alter responses to either alpha adrenoceptor agonists or phosphodiesterase inhibitors.     

Negative and positive inotropic responses to muscarinic agonists in guinea pig and rat atria in vitro

In the guinea pig atria, carbachol, acetylcholine and bethanechol elicited negative inotropic and positive inotropic effects. In the rat atria, a negative inotropic response occurred, but the positive inotropic response was small. The positive and negative inotropic responses to carbachol and bethanechol (but not acetylcholine) were unaffected by pretreating the animals with reserpine and were antagonised by pirenzepine with pKB values of 6.7. Pretreatment with pertussis toxin abolished the negative inotropic responses, but was without effect on the positive inotropic responses in the guinea pig. Pretreatment of rats with pertussis toxin abolished the negative inotropic response and enhanced the positive inotropic response. The positive inotropic response was attenuated by pretreatment with dietary lithium for 2 weeks, whereas no effect was observed on the negative inotropic response. Negative and positive inotropic responses to muscarinic agonists in these species are mediated directly through an M2 muscarinic receptor. The ability of dietary lithium to selectively inhibit the positive inotropic response may provide evidence for the involvement of inositol phospholipid hydrolysis in this effect.     

Characterization of the beta adrenoceptor subtype(s) mediating the positive inotropic effects of epinine, dopamine, dobutamine, denopamine and xamoterol in isolated human right atrium.

In patients with chronic heart failure cardiac beta-1 adrenoceptors are reduced, whereas beta-2 adrenoceptor changes vary depending on the etiology of the disease. Beta Adrenoceptor agonists can be used for short-term inotropic support in chronic heart failure; their clinical efficacy might depend on which beta adrenoceptor subtype(s) mediates their positive inotropic effect. Thus, the beta adrenoceptor subtype(s) involved in the positive inotropic effects of clinically used beta adrenoceptor agonists was characterized on isolated electrically driven human right atria by the use of the selective beta-1 adrenoceptor antagonist CGP 20712 A (300 nmol/l) and/or the selective beta-2 adrenoceptor antagonist ICI 118,551 (30 nmol/l). Epinine evoked positive inotropic effects through stimulation of beta-1 and beta-2 adrenoceptors to about the same degree, whereas dobutamine acted mainly at beta-1 adrenoceptors but had a significant beta-2 adrenoceptor component. Both agonists were full agonists causing the same maximum increase in contractile force (Emax) as did isoprenaline or Ca++ (Emax = 1.0). In contrast, denopamine was a partial selective beta-1 adrenoceptor agonist (Emax = 0.75-0.85). Dopamine was in the presence of uptake1-blockade (by 5 mumol/l phenoxybenzamine) a partial agonist (Emax = 0.60-0.70) acting selectively at beta-1 adrenoceptors; in the absence of uptake1-blockade, however, dopamine was a full agonist, indicating that part of its positive inotropic effect is indirect via the release of endogenous noradrenaline. Xamoterol did not exert positive inotropic effects, but concentration-dependently slightly decreased basal force of contraction.     

Both alpha and beta adrenoceptor-mediated components contribute to final inotropic response to norepinephrine in rat heart

The classical approach of displacing the dose-response curve by an alpha adrenoceptor blocker has most often failed to demonstrate a contribution of an alpha adrenoceptor-mediated component in the final inotropic response to norepinephrine unless the beta adrenoceptors are extensively blocked. To unmask and quantify the inotropic components in the response to norepinephrine, we took a different approach by studying reversal responses to appropriate adrenoceptor blockers in isolated paced rat papillary muscles maximally stimulated by norepinephrine. The inotropic response to norepinephrine was rapidly reversed by simultaneous addition of the beta adrenoceptor blocker timolol and the alpha adrenoceptor blocker prazosin. When the adrenoceptor blockers were added sequentially, both alpha and beta adrenoceptor-mediated components in the inotropic response to norepinephrine could be demonstrated: one beta adrenoceptor-mediated component (timolol sensitive only) that represented about 75% of the inotropic response and one alpha adrenoceptor-mediated component (prazosin sensitive only) that represented about 25% of the inotropic response. When one adrenoceptor population was eliminated by giving one of the adrenoceptor blockers before norepinephrine, the inotropic response in this situation could be completely reversed by the other adrenoceptor blocker. The expression of both alpha and beta adrenoceptor-mediated components was significantly less during concomitant receptor stimulation than when the respective receptor populations were stimulated separately. Thus, there was apparently a mutual inhibition of one component upon the other. Although the beta adrenoceptor-mediated inotropic component clearly was the dominating one, the present observations will explain the difficulties in demonstrating an alpha adrenoceptor-mediated component during unopposed beta adrenoceptor stimulation in the inotropic response to norepinephrine in earlier studies.     

Prazosin-sensitive component of the inotropic response to norepinephrine in rabbit heart

Earlier experiments have usually failed to demonstrate a competitively displaceable alpha adrenoceptor blocker-sensitive component in the dose-dependent inotropic response to norepinephrine in mammalian hearts. We reinvestigated if it was possible to reveal this phenomenon by carefully choosing a concentration of the alpha adrenoceptor blocker prazosin that would give a significant displacement while it still was possible to completely surmount the blockade by reasonable concentrations of norepinephrine. Both inotropic and lusitropic dose-dependent responses to norepinephrine in rabbit heart papillary muscles were recorded. In the presence of 3 X 10(-9) M prazosin there was a significant rightward shift of a component corresponding to about 20% of the total inotropic response to norepinephrine. The prazosin-sensitive component was shifted significantly more to the left by 3 X 10(-5) M cocaine than the nonsensitive component. The maximal inotropic response to norepinephrine was increased at lower prazosin-concentrations (3 X 10(-9) M), whereas at 10(-7) M prazosin the maximal response was unchanged compared to the absence of prazosin. The maximal lusitropic response to norepinephrine was increased monophasically and dose-dependently by prazosin. Thus, by carefully considering the relative potencies of the agonist and the antagonist it was possible to demonstrate an alpha adrenoceptor blocker sensitive component in the inotropic response to norepinephrine in rabbit heart. The effect of cocaine upon the prazosin-sensitive component would indicate that the alpha adrenoceptor population in rabbit myocardium is located more closely to the sympathetic nerve endings than the beta adrenoceptor population.(ABSTRACT TRUNCATED AT 250 WORDS)     

The relative efficiency of beta adrenoceptor coupling to myocardial inotropy and diastolic relaxation: organ-selective treatment for diastolic dysfunction.

The relative effects of drugs which elevate cytosolic cyclic AMP on inotropy and diastolic relaxation (lusitropy) of guinea pig atria were quantified in vitro. There was a temporal difference between these responses in that inotropy reached peak response considerably faster than lusitropy. Also, although the relaxation response was sustained to an elevated steady state, the inotropic responses to beta adrenoceptor agonists were transient and returned to base line over 90 min. However, the inotropic responses to forskolin and dibutyryl cyclic AMP (cAMP) were sustained. For all of the drugs tested, the lusitropic response was at least 4 times more sensitive than the inotropic response (i.e., the concentration response curve for relaxation was shifted to the left of the curve for inotropy). In the case of beta adrenoceptor agonists, these differences were greater, presumably because of the fading inotropic response over 90 min. It was found that although high efficacy beta adrenoceptor agonists such as isoproterenol (and the direct activator of adenylate cyclase forskolin) produced both inotropy and lusitropy, lower efficacy agonists produced predominant lusitropy. The low efficacy agonist prenalterol produced insignificant inotropy but 60% maximal lusitropy. These data were modeled mathematically by a "differential coupling model" which assumed that a uniform cytosolic level of elevated cAMP activated two biochemical processes of differing sensitivity. Thus, the lusitropic response (phosphorylation of phospholamban) was coupled more efficiently to the cAMP response than the inotropic response (phosphorylation of calcium channels). A second model ("differential messenger concentration model") which calculated the effects of a compartmentalization of cAMP concentration within the cardiac cell by restricted diffusion and/or selective degradation by phosphodiesterases also was used.(ABSTRACT TRUNCATED AT 250 WORDS)     

A positive inotropic effect of propranolol on the canine myocardium: a presynaptic effect.

Administration of propranolol directly into the anterior descending branch of the left coronary artery (LAD) resulted in a localized increase in myocardial contractile force in the area of the left ventricle perfused by the LAD. The onset of the positive inotropic response occurred within 30 seconds after drug administration with a duration of action of approximately 8 minutes and was associated with a significant increase in the coronary sinus/arterial ratio of norepinephrine. Contractile force in an area of the left ventricle perfused by the circumflex artery decreased concomitantly with the characteristic negative chronotropic action of propranolol. Pretreatment with reserpine abolished the positive inotropic effect of propranolol while ganglionic blockade with hexamethonium failed to alter the character of the response. Imipramine pretreatment not only blocked the positive inotropic effect of propranolol but resulted in an exaggerated negative inotropic effect in both areas of the left ventricle along with a significant fall in systemic arterial blood pressure. The data demonstrate that propranolol can evoke the release of norepinephrine from cardiac adrenergic nerve endings and raise the possibility that propranolol may be taken up by the amine uptake system.     

Cardiac responsiveness to alpha and beta adrenergic amines: effects of carbachol and hypothyroidism

Previous reports of cardiac beta to alpha adrenoceptor interconversion secondary to hypothyroidism left open the alternative possibility of a functional influence by hypothyroidism on the inotropic and chronotropic effects of adrenergic amines through a different mechanism. To test this possibility, the effects of hypothyroidism (thyroidectomy) were compared with those of acute carbachol pretreatment on the responses of isolated rat atria to the selective beta and alpha adrenoceptor agonists isoproterenol and methoxamine. Both hypothyroidism and acute carbachol pretreatment (3 X 10(-7) -10(-6) M): 1) reduced basal right atrial rates and left atrial tensions; 2) caused an apparent decrease in the inotropic and chronotropic potencies of isoproterenol; 3) reduced the degree of antagonism by propranolol of the responses to isoproterenol; 4) increased the maximum inotropic response of left atria to methoxamine; and 5) converted a lack of response to a positive chronotropic response of right atria to methoxamine. Equivalent reductions of basal rates by hypothermia, or of basal tensions by lowered calcium ion concentrations, did not affect the responses to isoproterenol or methoxamine. The results suggest that both carbachol pretreatment and hypothyroidism functionally antagonize the responses to isoproterenol and enhance the responses to methoxamine by means other than adrenoceptor interconversion.     

Adrenergic and possible nonadrenergic sources of adenosine 5'-triphosphate release from nerve varicosities isolated from ileal myenteric plexus

Pretreatment of guinea pigs with 6-hydroxydopamine in vivo for 24 h (250 mg/kg i.p.) reduced the norepinephrine and tyrosine hydroxylase contents of varicosities isolated from ileal myenteric plexus by 91 and 89%, respectively, indicating extensive destruction of noradrenergic varicosities. Destruction appeared to be restricted to noradrenergic varicosities because 5-hydroxytryptamine contents were unaffected. In vivo 6-hydroxydopamine treatment reduced the K+- and veratridine-evoked release of ATP from myenteric varicosities by 56 and 63%, respectively, indicating that much, but not all, of the evoked release of ATP probably originated from noradrenergic varicosities. Pretreatment of guinea pigs with 5 mg/kg of reserpine i.p. depleted norepinephrine contents of isolated varicosities by 90% but did not significantly reduce K+- or veratridine-evoked release of ATP, suggesting that the exocytotic release process was unaffected by reserpine. Selective destruction of serotonergic varicosities by treatment of guinea pigs with 50 mg/kg of desmethylimipramine i.p. followed by 40 mg/kg of 5,7-dihydroxytryptamine s.c. failed to diminish K+- or veratridine-evoked release of ATP from myenteric varicosities, indicating that the nonadrenergic release of ATP did not arise from serotonergic varicosities.     

Indirect stimulatory action of the calcium channel blocker AQA-39

AQA-39 is a new bradycardia-inducing drug chemically related to verapamil that reduces potassium conductance and blocks calcium channels. In canine ventricular trabeculae studied at 25 degrees C and at a pacing rate of 12 stimuli per minute. AQA-39, in concentrations of 1 and 2 X 10(-5) M, had a significant positive (and only positive) inotropic effect. Propranolol significantly diminished this positive inotropic action of AQA-39. After catecholamine depletion with reserpine, AQA-39 still elicited a significant increase in contractility but the magnitude of the increment in contractile performance was considerably less than the one observed when normal muscles were exposed to AQA-39. AQA-39 had no significant inotropic action on reserpinized and atropinized muscles. From these results we can conclude that AQA-39 is not a beta adrenoceptor agonist although adrenergic influences via neuronal norepinephrine release are mediating part of the inotropic effect of the drug. Furthermore, at this low rate of stimulation and at the concentrations used, AQA-39 has no direct inotropic action of its own but part of its indirect stimulatory action is mediated through an antimuscarinic effect.     

Cellular potentials, electrogenic sodium pumping and sensitivity in guinea-pig atria

Intracellular recording techniques in guinea-pig atrial pacemaker and nonpacemaker cells were used to investigate 1) the role of membrane potential changes in postjunctional supersensitivity, 2) the electrogenicity of the Na+,K+ pump and 3) the role of electrogenic pumping in sensitivity of the atria to agonists. In nonpacemaker cells, ouabain (10(-6) M) had no effect on resting membrane potential (left atria) or maximum diastolic potential (right atria). However, ouabain effectively suppressed the transient hyperpolarization that followed cessation of electrical stimulation. In pacemaker cells, ouabain and chronic treatment with reserpine (0.1 mg/kg/day) produced quite different patterns of changes in intracellular potentials. Chronic treatment with reserpine induced chronotropic supersensitivity to isoproterenol but not to histamine. Ouabain did not alter the chronotropic sensitivity to either agonist. The effects of isoproterenol and histamine on intracellular potentials in pacemaker cells were investigated in the presence and absence of ouabain and in control atria vs. atria from guinea pigs chronically pretreated with reserpine. Analysis of the data indicated that 1) electrophysiological measurements do not provide a discernible explanation for chronotropic supersensitivity, 2) the Na+ pump has the capacity for electrogenic pumping under conditions of Na+ loading, but demonstrates little indication of electrogenicity under basal conditions and 3) chronic treatment with reserpine does suppress the Na+,K+ pump in some areas of the right atrium, but this activity probably does not contribute to chronotropic supersensitivity. Other possible mechanisms of postjunctional supersensitivity in atria are discussed.     

Membrane potential in myenteric neurons associated with tolerance and dependence to morphine.

Chronic treatment of guinea pigs with morphine produces subsensitivity (tolerance) of the longitudinal smooth muscle-myenteric plexus preparation to a variety of inhibitory agonists (e.g., mu opioid, alpha adrenoceptor and adenosine receptor agonists) and supersensitivity (dependence) to a variety of excitatory agonists (e.g., nicotine, 5-hydroxytryptamine and potassium ions). The present investigation was to determine if these changes in sensitivity could be related to changes in electrical properties of the S and AH neurons in the myenteric plexus. S neurons from morphine-implanted animals were significantly depolarized (7 mV) relative to those from placebo-implanted animals, whereas the membrane potential of AH neurons was unchanged. Approximately 60% of S neurons were hyperpolarized by morphine. In this subset of neurons, membranes were significantly depolarized but the threshold was unchanged in morphine-implanted animals. This means that resting potentials of S neurons from tolerant preparations are closer to threshold. The hyperpolarization produced by morphine (0.1 microM) was similar in preparations from morphine- and placebo-implanted animals. Thus, the partially depolarized state of S neurons in the myenteric plexus is the cause of the subsensitivity and supersensitivity to agonists and can explain both tolerance and dependence. Changes in opioid receptors or their coupling to potassium channels do not appear to contribute to tolerance in the longitudinal smooth muscle-myenteric plexus.     

Inhibitory effect of alpha-1 adrenoceptor stimulation on cardiac sympathetic neurotransmission in pithed normotensive rats

In the present study we investigated the inhibitory effect of the selective alpha-1 adrenoceptor agonists cirazoline, amidephrine and St 587 on the cardiac sympathetic neurotransmission in pithed normotensive rats. Increases in heart rate were elicited by electrical stimulation of the cardiac sympathetic nerves or by i.v. administration of norepinephrine, isoproterenol or tyramine. Intravenous pretreatment of the animals with cirazoline, amidephrine or St 587 diminished the heart rate response to sympathetic stimulation significantly. However, the tachycardia produced by norepinephrine, isoproterenol or tyramine was also inhibited significantly by the selective alpha-1 adrenoceptor agonists. The selective alpha-1 antagonist prazosin blocked the sympathoinhibitory effect to alpha-1 adrenoceptor stimulation significantly. However, the inhibitory effect of cirazoline and St 587 was not suppressed completely by a maximally effective dose of prazosin. In contrast, the sympathoinhibitory action of amidephrine was antagonized completely by prazosin. However, the selective alpha-2 antagonist rauwolscine also produced a significant, albeit modest, attenuation of the sympathoinhibitory effect to amidephrine. The results of the present study indicate that alpha-1 adrenoceptor agonists, at relatively high doses, inhibit the sympathetic neurotransmission in rat heart. This sympathoinhibitory effect is mediated largely by alpha-1 adrenoceptors which are localized postjunctionally rather than prejunctionally.     

Pharmacological analysis of the cardiac actions of xamoterol, a beta adrenoceptor antagonist with partial agonistic activity, in guinea pig heart: evidence for involvement of adenylate cyclase system in its cardiac stimulant actions

The pharmacological effects of xamoterol, a beta adrenoceptor antagonist with partial agonistic activity, were examined in guinea pig cardiac preparations and compared with those of isoproterenol to assess possible mechanisms of its cardiac stimulant actions. Xamoterol produced a positive inotropic effect in the papillary muscles and a positive chronotropic effect in the spontaneously beating right atria in a concentration-dependent manner. The maximum inotropic and chronotropic effects of xamoterol were about 33 and 35% of those of isoproterenol, respectively. Although xamoterol failed to produce a consistent increase in contractile force in the left atria, the positive inotropic effect of the agent was observed clearly in preparations obtained from reserpine-pretreated animals. The positive inotropic and chronotropic effects of xamoterol were antagonized by atenolol, but not by ICI 118,551. On the other hand, xamoterol antagonized competitively the positive inotropic and chronotropic responses to isoproterenol. In papillary muscles the increases in contractile force induced by xamoterol and isoproterenol were depressed markedly in the presence of carbachol or adenosine. In all of left atria, right atria and papillary muscles obtained from reserpine-pretreated animals, xamoterol caused a significant elevation in cyclic AMP levels, while inhibiting the isoproterenol-induced increase in cyclic AMP levels. Computer-assisted analysis of concentration-response curves for the inhibition by xamoterol of the binding of [125I]iodocyanopindolol in the membranes from guinea pig ventricles showed the existence of the 5'-guanylylimidodiphosphate sensitive, highly affinity site of beta adrenoceptors for xamoterol, suggesting that xamoterol may induce the formation of a ternary complex with the beta adrenoceptor and a stimulatory guanine nucleotide regulatory protein.(ABSTRACT TRUNCATED AT 250 WORDS)     

Noradrenergic subsensitivity and supersensitivity of the cerebral cortex after reserpine treatment.

Changes in the sensitivity of the cyclic adenosine 3', 5'-monophosphate response of rat brain cerebral cortical slices to norepinephrine were measured in vitro after the rats received i.p. injections of reserpine (1 mg/kg). Subsensitivity was evident 1 hour after a single reserpine treatment compared with saline controls. However, if reserpine was injected daily for 4 days followed by 1 day without reserpine treatment, a supersensitive response to NE was shown compared to the controls. Mean pD2 values are presented to illustrate the shifts of the dose-response curves after reserpine treatment. The present work demonstrated the induction of noradrenergic sub- and supersensitivity to norepinephrine in rat cerebral cortical slices after acute and 4-day reserpine treatment, respectively.