Adrenergic-cholinergic interactions in left atria: interaction of carbachol with alpha- and beta-adrenoceptor agonists

The purpose of the present investigation was to determine the nature of the functional interaction of muscarinic agonists with cAMP-generating and cAMP-independent agonists in left atria. Negative inotropic responses of rabbit isolated left atrial strips to the muscarinic agonist carbachol were measured in the absence and presence of equi-active inotropic doses of the beta-adrenoceptor stimulant isoproterenol (Iso), the mixed alpha- and beta-adrenoceptor stimulant phenylephrine (PE) plus 1 microM timolol to block the beta-receptor mediated component of its response, and elevated extracellular Ca2+. Carbachol produced dose-dependent negative inotropic responses in left atrial strips, which were much greater than control in the presence of either Iso, or PE plus timolol. However, carbachol responses were of a similar magnitude to the control in the presence of elevated extracellular Ca2+. In the presence of timolol, PE had no significant effect on cAMP levels in left atrial strips, and inotropic responses to carbachol alone and in combination with PE plus timolol were accompanied by significant increases in cGMP levels but no change in cAMP levels. Carbachol attenuated Iso-induced increases in cAMP levels, but decreases in left atrial tension were proportionally greater than the decreases in cAMP levels produced by carbachol in the presence of Iso. These results suggest that the antiadrenergic effects of muscarinic receptor stimulation may occur by a different mechanism in left atria than has been previously reported in ventricular muscle. While the nature of this mechanism is unknown, it may involve antagonism by muscarinic agents of both alpha- and beta-adrenoceptor mediated increases in Ca2+ influx.     

Calcium channel activation in vascular smooth muscle by BAY K 8644

BAY K 8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) pyridine-5-carboxylate) and CGP 28 392 (ethyl-4(2-difluoromethoxyphenyl)-1,4,5,7-tetrahydro-2-methyl-5-++ +oxofuro- [3,4-b]pyridine-3-carboxylate) are closely related in structure to nifedipine and other 1,4-dihydropyridine Ca2+ channel antagonists. However, both BAY K 8644 and CGP 28 392 serve as activators of Ca2+ channels. In the rat tail artery, responses to BAY K 8644 are dependent upon Ca2+ext and prior stimulation by K+ or by the alpha-adrenoceptor agonists, phenylephrine and BHT 920 (6-allyl-2-amino-5,6,7,8,-tetrahydro-4H-thiazolo[4,5-d]azepin dihydrochloride). Responses are blocked noncompetitively by the Ca2+ channel antagonists D-600 [-)-D-600 greater than (+)-D-600) and diltiazem, but competitively by nifedipine (pA2 = 8.27). This suggests that activator and inhibitor 1,4-dihydropyridines interact at the same site. BAY K 8644 potentiates K+ responses and Ca2+ responses in K+-depolarizing media. The leftward shift of the K+ dose--response curve produced by BAY K 8644 suggests that this ligand facilitates the voltage-dependent activation of the Ca2+ channel. The pA2 value for nifedipine antagonism of BAY K 8644 responses is significantly lower than that for nifedipine antagonism of Ca2+ responses in K+ (25-80 mM) depolarizing media (9.4-9.6), suggesting that the state of the channel may differ according to the activating stimulus.     

Effects of BAY K 8644, nifedipine, and low Ca2+ on halothane and caffeine potentiation.

The purpose of this investigation was to examine the effects of the Ca2+ agonist BAY K 8644 and the Ca2+ antagonist nifedipine on halothane- and caffeine-induced twitch potentiation of mammalian skeletal muscle. Muscle fiber bundles were taken from normal Landrace pigs and exposed to BAY K 8644 (10 microM), nifedipine (1 microM), and low Ca2+ media administered alone and in combination with halothane (3%) or with increasing concentrations of caffeine (0.5-8.0 mM). Both BAY K 8644 and halothane potentiated twitches by approximately 80%; when they were administered in combination, twitch potentiation was nearly double that caused by either drug alone. In the presence of nifedipine, halothane increased twitches by less than 30%. Low Ca2+ significantly depressed twitches by approximately 25% but also inhibited halothane's inotropic effect. BAY K 8644 augmented caffeine potentiation but only at low caffeine concentrations (0.5-2.0 mM). Nifedipine and low Ca2+ failed to inhibit caffeine's inotropic effects. These results suggest that halothane potentiates twitches via a mechanism that involves or is influenced by extracellular Ca2+.     

Ca2+ dependence of positive inotropic responses of guinea pig isolated cardiac preparations to cAMP-generating and cAMP-independent agonists

The effects of procedures which diminish Ca2+ influx into myocardial cells on responses of isolated cardiac preparations to cAMP-independent histamine H1 receptor stimulation and cAMP-generating beta-receptor stimulation were measured. The histamine response of guinea pig left atria, which appears to be primarily mediated by H1 receptors, was depressed to a greater extent than was the response of this preparation to isoproterenol by decreasing the extracellular Ca2+ concentration, and by the Ca2+ influx blocker D-600. Similarly, while the H1 agonist 2-pyridylethylamine dihydrochloride (PEA) produced increases in tension of a similar magnitude as the partial beta-agonist salbutamol in both left atria and in papillary muscles, responses of both preparations to PEA were depressed to a significantly greater extent by decreasing the extracellular Ca2+ concentration than were responses to salbutamol. Overall, both the basal developed force of papillary muscles and the responses of these preparations to H1 and beta-receptor stimulation appeared to be less depressed by decreasing the extracellular Ca2+ concentration than were those of left atria. These results indicate that responses mediated via cAMP-independent H1 receptors, like those arising from alpha-receptor stimulation, are more sensitive to procedures which diminish Ca2+ influx than are responses arising from stimulation of cAMP-generating beta-receptors. This may reflect differences in the mechanisms by which stimulation of H1, alpha-, and beta-receptors give rise to positive inotropic responses. In addition, left atria may be more dependent than papillary muscles on extracellular Ca2+ for the support of contraction.     

Effects of inotropic agents on isolated guinea pig heart under conditions that modify calcium pools involved in contractile activation

Positive inotropic effects of strophanthidin were compared with those of isoproterenol, BAY K 8644, grayanotoxin, veratridine, and monensin in electrically stimulated left atrial muscle preparations of guinea pig heart under conditions in which the calcium pool, playing a primary role in contractile activation, was altered. In concentrations that caused similar degrees of increase in developed tension under 1 Hz stimulation, grayanotoxin and strophanthidin caused a relatively large increase in potentiated postrest contraction compared with that caused by isoproterenol, whereas the effect of BAY K 8644 on the postrest contraction was the smallest. The effect of high concentrations of grayanotoxin or strophanthidin, however, resembled that of isoproterenol. The sensitivity of the isolated heart muscle to these agents was compared under conditions in which utilization of various calcium pools contributing to contractile activation was suppressed. Mn2+, which reduces contribution of very superficial Ca2+, reduced sensitivity of heart muscle to the positive inotropic effect of isoproterenol and enhanced the inotropic effect of monensin or veratridine. Verapamil, nifedipine, diltiazem, or ryanodine did not have marked effects on the positive inotropic action of Ca2+, monensin, veratridine, or strophanthidin. These results suggest that the positive inotropic actions of veratridine, grayanotoxin, and strophanthidin share a common mechanism and that low concentrations of strophanthidin may increase loading of Ca2+ pool, which plays an important role in potentiated postrest contraction.     

The inotropic effect of endothelin-1 on rat atria involves hydrolysis of phosphatidylinositol

Endothelin-1 induces a positive inotropic response in isolated left atria of the rat with an IC50 value of 20 nM. The contractile effect of endothelin is larger than that of other inotropic hormones such as phenylephrine and epinephrine and smaller than that of Bay K8644. In the spontaneously active right atria, endothelin induces a positive inotropic effect with no chronotropic effect. Endothelin does not modify intracellular levels of cAMP under basal conditions or after stimulation with isoproterenol but stimulates the formation of inositol phosphates. Mobilization of inositol phospholipids is observed in the same range of concentrations as for the contractile action of endothelin. The contractile action of endothelin is not mediated by protein kinase C. It is antagonized by blockers of L-type Ca2+ channels, low external Ca2+ concentrations and drugs such as caffeine and ryanodine that interfere with Ca2+ release by the sarcoplasmic reticulum.     

Effects of Ca2+ agonist and antagonists on cytosolic free Ca2+ concentration: studies on Ca2+ channels in rat parotid cells

1. Effects of Ca2+ agonist and antagonists on cytosolic free Ca2+ concentration [( Ca2+]i)were studied using quin2. 2. Nicardipine (NIC), diltiazem (DIL) and verapamil (VER) had no effect on the rise in [Ca2+]i evoked by carbachol. Methoxamine-elevated [Ca2+]i was inhibited by VER but not by NIC and DIL. 3. All Ca2+ antagonists tested produced a decline of [Ca2+]i elevated by isoproterenol to the resting level. 4. The addition of 30 mM K+ gradually elevated [Ca2+]i in normal and Ca2+-free media, but it did not increase 45Ca2+ uptake into cells. BAY K 8644 did not increase [Ca2+]i. 5. We suggest that voltage-sensitive Ca2+ channels are lacking and that at least 2 distinct receptor-operated Ca2+ channels exist in rat parotid cells.     

Characterization of the effects of AHN 086, an irreversible ligand of "peripheral" benzodiazepine receptors, on contraction in guinea-pig atrial and ileal longitudinal smooth muscle

The effects of AHN 086 and its reversibly acting structural analogue Ro 5-4864 were studied in the spontaneously beating guinea-pig atria and field-stimulated guinea-pig ileal longitudinal smooth muscle in the presence and absence of dihydropyridine calcium channel modulators. The treatment of guinea-pig atria with AHN 086 followed by extensive washing did not alter contraction. However, AHN 086 (0.5 microM) potentiated (88%) the positive inotropic responses by BAY K 8644, an effect that was not reversed by extensive washing of the tissue. Higher concentrations of AHN 086 (greater than 2 microM) irreversibly inhibited the intropic, but not the chronotropic responses to BAY K 8644, nifedipine, and isoproterenol. Ro 5-4864 (10 microM) produced a reversible enhancement of the inotropic responses and block of the chronotropic responses to BAY K 8644. In guinea-pig ileal longitudinal smooth muscle, both AHN 086 and Ro 5-4864 reversibly inhibited field-stimulated contractions. Neither Ro 5-4864 nor AHN 086 affected the ability of nifedipine to inhibit field-stimulated contractions of ileal longitudinal smooth muscle. Treatment of intact atrial with 5 microM AHN 086 followed by extensive washing resulted in a significant inhibition (30-50%) of [3H]Ro 5-4864 binding to peripheral benzodiazepine receptors and of [3H]nitrendipine binding to voltage-operated calcium channels, but did not affect [3H]dihydroalprenolol binding to beta-adrenergic receptors on atrial membranes. The same treatment applied to intact ileal longitudinal smooth muscle affected neither [3H] (-)-quinuclidinyl benzilate binding to muscarine receptors nor [3H]nitrendipine binding, but did result in a significant inhibition (30-50%) of [3H]Ro 5-4864 binding to ileal longitudinal smooth muscle membranes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of cAMP in the functional interaction of carbachol with different cAMP elevating agents in rabbit atrium.

The muscarinic agonist carbachol antagonized positive inotropic responses of rabbit left atria to the beta-adrenoceptor agonist isoproterenol, the adenylate cyclase activator forskolin and the phosphodiesterase inhibitor IBMX. Carbachol also reduced cAMP levels elevated by isoproterenol, but had no significant effect on cAMP levels in the presence of either forskolin or IBMX. Pre-treatment of rabbits with a dose of pertussis toxin which completely blocked the reduction by carbachol of isoproterenol-induced increases in cAMP, also blocked the reversal by carbachol of positive inotropic responses to isoproterenol, but only partially attenuated the antagonism by carbachol of inotropic responses to forskolin and IBMX. These data suggest that antagonism by carbachol of forskolin and IBMX-induced increases in cAMP levels does not play an important role in the functional interaction of carbachol with these cAMP-elevating agents.     

Calcium uptake studies of 1,4-dihydropyridine agonists into rabbit aortic smooth muscle cells in culture

The effects of the three dihydropyridine calcium channel agonists (+/-)BAY K 8644, (+)202-791 and (+/-)CGP 28392 on 45Ca++ uptake were studied in cultures of rabbit aortic smooth muscle cells. At 10(-7) M each agonist enhanced 45Ca++ uptake in 15-50 mM K+ but had no effect on the basal 45Ca++ uptake at 5 mM K+. At the uptake threshold of 15 mM K+ each agonist potentiated 45Ca++ uptake in a dose-dependent manner with half maximal effects at 2.4 nM for (+/-)BAY K 8644, 22 nM for (+)202-791 and 18 nM for (+/-)CGP 28392. The agonists showed no significant antagonistic activity. Responses were antagonized competitively by nifedipine and non-competitively by (+/-)D-600. The 45Ca++ uptake dose-response curves and the half maximal effects of the three agonists were over the same range of concentrations as their inhibition of [3H]nitrendipine binding to rat ventricular receptor membrane preparations. The data suggest that these cells mimic the calcium uptake by the intact aorta better than commercial vascular smooth muscle lines or cardiac cells.     

Effects of the calcium channel agonist, BAY K 8644, on electrical activity in mouse pancreatic B-cells.

We studied the effects of the dihydropyridine derivative BAY K 8644 on the membrane potential of B-cells in mouse pancreatic islets. BAY K 8644, in a dose-dependent manner, decreased the spike frequency but increased the duration of the spikes elicited by glucose with or without quinine or tetraethylammonium (TEA). These effects were antagonized by cobalt and nifedipine but not by tetrodotoxin. The interval between spikes was proportionate to the duration of the spikes and the ratio of the interval to the spike duration was constant at all concentrations of BAY K 8644 tested. Peak inward current, estimated from the derivative of the action potential recorded in the presence of TEA, was increased by BAY K 8644 and decreased by nifedipine. BAY K 8644 elicited spike activity when the membrane was moderately depolarized by either 5.6 mM glucose or 15 mM K+, but did not change the membrane potential of the resting hyperpolarized B-cell. These results suggest that BAY K 8644 acts on the open Ca2+-channels. The threshold occurs at a membrane potential of -50 mV. Also, the modifications of the shape of the spikes appear to reflect specific changes in Ca2+ entry. We propose the existence of a Ca2+-induced Ca2+-channel inactivation process in the pancreatic B-cell.     

Endothelin and Ca++ agonist Bay K 8644: different vasoconstrictive properties

The mechanism of vasoconstriction induced by endothelin was investigated in rat isolated aorta in comparison with the Ca++ agonist, Bay K 8644. Endothelin (EC50 = 4 nM) induced a slow and sustained contraction in control medium whereas the one elicited by Bay K 8644 (EC50 = 14 nM) necessitating a partly K+ depolarized medium was fast with superimposed rhythmic contraction. By opposition with Bay K 8644, endothelin contraction was not inhibited by the calcium antagonists (1 microM), nifedipine, diltiazem and D 600, and substantially persisted in Ca++ free medium or after depletion of intracellular Ca++ by phenylephrine (1 microM). These data show that endothelin does not act as an activator of potential dependent Ca++ channels but probably through specific receptor(s) as suggested by its mode of vasoconstriction.     

Postsynaptic alpha-adrenoceptor characterization and Ca2+ channel antagonist and activator actions in rat tail arteries from normotensive and hypertensive animals

Postsynaptic alpha-adrenoceptors in the rat tail artery have been examined by determining the pA2 values for antagonists against several alpha-adrenoceptor agonists. In this tissue the alpha-adrenoceptor agonists all produce concentration-dependent mechanical responses with the following rank order of potency: clonidine greater than norepinephrine greater than phenylephrine greater than UK 14304 greater than B-HT 920. Antagonism by prazosin and yohimbine of phenylephrine, norepinephrine, and clonidine responses does not reveal the anticipated discrimination between alpha 1- and alpha 2-adrenoceptors. Thus, pA2 values for prazosin (9.1-9.5), yohimbine (7.2-7.4), and corynanthine (7.0-7.1) and idazoxan (7.6) do not show large differences between these receptor agonists and suggests the predominance of alpha 1-adrenoceptor mediated contractile responses in this preparation. Significant differences between antagonist activities (pA2 values) in Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) artery preparations have not been observed. The sensitivity sequence of alpha-adrenoceptor agonist-induced responses to nifedipine and D 600 is B-HT 920 greater than clonidine greater than phenylephrine greater than norepinephrine. Dependence of agonist response upon extracellular Ca2+ parallels the sensitivity to Ca2+ channel antagonists. Sensitivity to D 600 of phenylephrine responses increased with decreasing concentration of phenylephrine or with receptor blockade by phenoxybenzamine: sensitivity of responses to B-HT 920 was not affected by these procedures. Tail artery strips from WKY and SHR do not exhibit major differences in sensitivity to D 600 or to Ca2+ depletion. Bay k 8644, a Ca2+ channel activator, produces concentration-dependent mechanical responses in the tail artery in the presence of modestly elevated K+ concentrations (10-15 mM): these actions of elevated K+ can be mimicked by both alpha 1- and alpha 2-adrenoceptor agonists including methoxamine, St 587, UK 14304, and clonidine. These studies do not provide clear evidence for the existence of discrete postsynaptic alpha 1- and alpha 2-adrenoceptor populations in rat tail artery as indicated by pA2 values or Ca2+ dependence of response.     

The regulation of L-type Ca2+ currents in cardiac myocytes of hibernating animals

The action of isoproterenol and BAY K 8644 on voltage-dependent Ca2+ currents in isolated ground squirrel cardiac myocytes was studied in two (active and hibernating) states of the animal. In cardiac myocytes of active animals the effect of both drugs was shown to depend on the holding potential. At Vh of about -50 mV both isoproterenol and BAY K 8644 increased the Ca2+ current and their action was additive. At Vh of about -20 mV, both drugs inhibited the Ca2+ current. In cardiac myocytes from hibernating animals, isoproterenol increased the Ca2+ current at any holding potentials, while the effect of BAY K 8644 did not differ significantly from its effect on active animals. The combined action of the two drugs caused the inhibition of the Ca2+ current at high holding potentials. In terms of the two-site Ca2+ channel model, this means that one of the two pathways of channel phosphorylation is blocked in hibernating animal cardiac cells, and BAY K 8644 restores this pathway.     

Functional interactions between organic calcium channel antagonists in smooth muscle

The Ca2+ channel antagonists D-600, diltiazem, and nifedipine are competitive antagonists of Ca2+ responses in K+-depolarized guinea pig taenia coli and rat mesenteric artery preparations. pA2 values for D-600, diltiazem, and nifedipine in taenia coli were 8.28, 7.44, and 9.27, respectively and in mesenteric artery, 9.6, 7.83, and 10.4, respectively. The combination of nifedipine plus diltiazem gave in both tissues antagonism greater than that calculated on the basis of additivity. This suggests, consistent with published 3H-labelled radioligand binding data, that diltiazem and nifedipine interact at distinct sites. However, the combination nifedipine plus D-600 yielded antagonism consistent with additivity of response.     

The indirect negative inotropic effects of the P1-receptor agonist, L-phenylisopropyladenosine, in guinea-pig isolated cardiac preparations: comparison with cromakalim.

The possible mechanisms of the indirect negative inotropic responses to the P1-receptor agonist, L-phenylisopropyladenosine (L-PIA) were evaluated in electrically paced (2 Hz, 5 ms pulse width, voltage 50% above threshold) left atria and papillary muscles of guinea pigs. The responses were compared in naive tissues (direct effects) or after prestimulation with submaximal concentrations of either cAMP-dependent positive inotropes (isoprenaline or forskolin) or the cAMP-independent inotrope Bay K 8644. Cumulative concentration-response curves were obtained in naive or prestimulated preparations for L-PIA or the potassium channel activator, cromakalim, for comparison. L-PIA and cromakalim exerted negative inotropy in naive atrial tissues, whereas only cromakalim was active in naive papillary muscles. In atria prestimulated with isoprenaline (31 nM) or forskolin (1.4 microM), the negative inotropy of L-PIA was enhanced compared with naive tissues. In contrast, prestimulation with Bay K 8644 (1 microM) exerted a significant functional antagonism of the response to L-PIA. In the case of cromakalim, prestimulation with isoprenaline exerted a functional antagonistic effect. In papillary muscles, an indirect negative inotropic effect of L-PIA was only seen in tissues prestimulated with the cAMP-dependent inotropes isoprenaline (31 nM) or forskolin (2.4 microM), and not in naive tissues or those prestimulated by Bay K 8644 (333 nM). As with atria, prestimulation with isoprenaline exerted a functional antagonistic effect on the response to cromakalim. These results suggest that the P1-receptor agonist, L-PIA, exerts its indirect negative inotropic effects in left atria by two mechanisms.2+ with cAMP-dependent positive inotropes.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vitro secretion of calcitonin from a rat C cell line: effect of repetitive stimulation with the calcium channel agonist BAY K 8644.

Calcium and BAY K 8644 acutely stimulate calcitonin secretion by influx of extracellular calcium (Ca) through voltage-dependent calcium channels, leading to an increase in cytosolic free Ca. Repetitive exposure to BAY K 8644 (10(-6) M) resulted in an increase in calcitonin (CT) secretion in the rat C-cell line (rMTC 6-23) lasting 9 hours, in comparison to that of 3 mM Ca2+ which lasted 6 hours. Equimolar concentration of nifedipine did not inhibit the stimulatory effect of BAY K 8644 as compared to the nifedipine only group. The decrease in stimulated CT secretion during long-term exposure to BAY K 8644 is due to desensitization of cells which may be attributed to down-regulation of dihydropyridine receptors. After 12 h exposures to 3 mM Ca2+ alone, BAY K 8644 (10(-6) M) alone or in combination with nifedipine (10(-6) M), CT content decreased below the control level, indicating a decrease in synthesis. Overall cellular protein content was not affected by the test agents. Repetitive exposure of C-cells to BAY K 8644 revealed a desensitization of the stimulatory effect on CT secretion and a decrease in CT cell content.     

Antagonism with dibenamine, D-600, and Ro 3-7894 to estimate dissociation constants and receptor reserves for cardiac adrenoceptors in isolated rabbit papillary muscles

In papillary muscles isolated from reserpinized rabbits, positive inotropic responses to the alpha (alpha)-adrenergic agonist, (-)-phenylephrine in the presence of 10(7) M timolol and the beta (beta)-adrenergic agonist. (-)-isoproterenol were antagonized with the irreversible alpha-adrenergic antagonist, dibenamine, the irreversible beta-adrenergic antagonist. Ro 3-7894, and the calcium blocker, D-600. D-600 was employed as a functional antagonist of both alpha- and beta-adrenoceptor responses. Dissociation constants (Ka values) for drug-receptor interactions were calculated by the method of Furchgott and used to estimate fractional receptor occupancy and agonist efficacies. Comparison of responses showed that the receptor reserve for cardiac beta-adrenoceptors was greater than for alpha-adrenoceptors. D-600 was an effective inhibitor of both cardiac alpha- and beta-adrenoceptor responses; however, estimates of KA and receptor reserves were similar to estimates using an irreversible antagonist for alpha-but not beta-adrenoceptors.     

Adrenergic reactivity of the myocardium in hypertension

Adrenoceptor-mediated inotropic and chronotropic responses have been studied in isolated atria from a younger and an older group of spontaneously hypertensive (SHR) and age-matched normotensive rats (NR). The isoproterenol/phenylephrine potency ratios were significantly lower in the older SHR than in age-matched NR. Exposure of left atria to cocaine, iproniazid and tropolone to inhibit major pathways of agonist inactivation significantly enhanced the potency of both agonists in NR but did not influence agonist potencies in SHR and the agonist potency ratios remained different in the two groups. Inotropic responses to phenylephrine were blocked by metoprolol less effectively and by phentolamine more effectively in older SHR than in NR. Atrial sensitivity to isoproterenol was significantly higher in the younger than in the older SHR. Chronic treatment of SHR with propranolol, 5–20 mg/kg/day i.p. from age 4 to 14 weeks and stopped 2 days before the experiment, limited the increase in blood pressure and increased the potency of isoproterenol and decreased the potency of phenylephrine to or beyond levels in NR. The effectiveness of adrenoceptor antagonists in SHR did not significantly change with age or after propranolol treatment. The results were interpreted to indicate that 1) mechanisms of agonist inactivation are impaired or non-functional in the SHR myocardium; 2) there is a shift in the balance of cardiac inotropic adrenoceptors from β toward α between normotensive and hypertensive rats, and 3) β-adrenoceptors are subsensitive in adult SHR, but become supersensitive to isoproterenol after chronic treatment with propranolol.     

Alterations in alpha 1-adrenoceptor stimulation of isolated atria from experimental diabetic rats

This purpose of this investigation was to determine the influence of experimental diabetes (3 months) on the responsiveness of rat isolated atria to alpha 1-adrenoceptor stimulation by phenylephrine. Diabetes was chemically induced with streptozotocin (65 mg/kg i.v.) in 42- to 43-day-old, nonfasted male Sprague-Dawley derived rats. Chronotropic (right atria) and inotropic (left atria) indices were recorded in response to alpha 1-adrenoceptor stimulation by phenylephrine. These experiments were performed in the presence of beta-adrenoceptor antagonism (timolol). Isolated right atria from diabetic rats demonstrated a greater increase in heart rate in response to phenylephrine than did corresponding control atria. Left atria were supersensitive (decrease in EC50 values) and hyperresponsive to alpha 1-adrenoceptor stimulation by phenylephrine when compared with stimulation of control left atria. Diabetic left atria in response to phenylephrine were observed to exchange more radioactive calcium (45Ca2+) than control left atria, whereas both diabetic and control left atria exchanged the same amount of 45Ca2+ during basal contractile conditions. Phenylephrine had no effect on 45Ca2+ efflux from either diabetic or control atria. These results indicate that 3 months of uncontrolled experimental diabetes in the rat produces an enhancement of alpha 1-adrenoceptor activation of isolated atria, and that there is an alteration in Ca2+ mobilization which may contribute to the enhanced receptor activation.