Positive inotropic action of angiotensin II in the pithed rat

Summary The cardiovascular effects of angiotensin II were examined in aortic blood pressure-controlled and-uncontrolled pithed rats. Angiotensin II induced a dose-dependent increase in diastolic blood pressure, left ventricular pressure (LVP), dP/dt (the first derivative of LVP) and heart rate in pithed rats. The maximal responses for these parameters were similar to those to noradrenaline, except for the rise in diastolic blood pressure, where noradrenaline caused a greater increase than angiotensin II. After treatment with propranolol, the positive chronotropic effect of angiotensin II was abolished. Angiotensin II produced a dose-dependent increase in diastolic blood pressure, which was similar to that of vasopressin, and an increase in dP/dt_max, which proved much greater than that of vasopressin. When aortic blood pressure was controlled and the -receptors were blocked by propranolol, angiotensin II caused a dose-dependent increase in dP/dt_max without affecting the left ventricular enddiastolic pressure. The same results were obtained after both - and -adrenoceptors were blocked by propranolol and phentolamine. Losartan but not PD 123177 caused parallel rightward shifts of the dose-response curve of angiotensin II for dP/dt_max in the aortic blood pressure controlled pithed rat without altering the maximal response. It is concluded that in the pithed rat angiotensin II produced an increase in myocardial contractile force which is not mediated by - or -adrenoceptors. The inotropic effect appears to be mediated by angiotensin receptors, of the AT₁-subtype.Correspondence to J. Zhang at the above address     

Positive chronotropic and inotropic responses to guanosine in the isolated dog atrium.

The effects of guanosine on chronotropism and inotropism in isolated dog atria were studied in spontaneously beating preparations which were suspended in a bath perfused with arterial blood from a carotid artery of a heparinized support dog. Guanosine administered into the cannulated sinus node artery in a dose range of 30 microgram to 3 mg produced a dose-related positive inotropic and chronotropic effect. The positive responses to guanosine were not inhibited by treatment with propranolol or a non-depressant beta-blocker, carteolol, in doses which blocked responses to norepinephrine. From these results, it is concluded that guanosine has a direct effect on atrial rate and contractility.     

Positive inotropic and chronotropic effects of trypsin and some other proteolytic enzymes in the guinea-pig heart.

1 In atrial preparations of the young guinea-pig (body weight 150-250 g), five proteolytic enzymes (trypsin, chymotrypsin, bacterial-Al-proteinase (nagarse), bromelain and kallikrein) produced concentration-dependent positive inotropic and chronotropic effects, while they exerted only minimal effects on the papillary muscle preparations. 2 To characterize the effects, further experiments were conducted in atrial preparations using trypsin. There was a strong tendency for tachyphylaxis: a second exposure to the same concentration of trypsin resulted in considerably smaller positive inotropic and chronotropic effects. The positive inotropic and chronotropic effects of this substance were not affected by propranolol (5 X 10(-7)M). However, an accumulation of cyclic AMP was observed and the positive inotropic and chronotropic effects were potentiated by aminophylline (10(-4)M) in association with an augmentation of the accumulation of cyclic AMP. In preparations partially depolarized with high K+ (22mM) medium (contractions ceased under this condition) trypsin 100 micrograms ml-1 reinstated the contraction. Treatment of the preparation with aprotinin (200 u ml-1) resulted in a strong inhibition of the positive inotropic and chronotropic effects. 3 Islet activating protein (IAP), a specific inhibitor of the 'inhibition specific' guanine nucleotide binding regulatory protein of the adenylate cyclase system, did not produce significant inhibition of the positive inotropic and chronotropic effects of trypsin, whereas it produced a complete inhibition of the negative inotropic and chronotropic effects of carbachol.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo effects of angiotensin antagonists on plasma aldosterone in the dog.

The effects of infusions of equimolar doses of Sar1-Ile8-angiotensin II and of Sar1-Ala8-angiotensin II on plasma aldosterone, plasma renin activity and arterial blood pressure were compared in normal dogs. Plasma aldosterone increased significantly after Sar1-Ile8-angiotensin II whereas it was unaffected by Sar1-Ala8-angiotensin II. Changes in blood pressure and renin activity were small without marked differences between both groups of animals. The experiments demonstrate a clear steroidogenic potency of Sar1-Ile8-angiotensin II. Therefore, Sar1-Ala8-angiotensin II should be preferred as antagonist of the action of angiotensin II in the adrenal gland.     

Positive inotropic response to 5-HT in human atrial but not in ventricular heart muscle

Summary The effects of 5-hydroxytryptamine (5-HT) on force of contraction (F_C), action potential (AP) and calcium current (I_Ca) were studied in human right atrial and left ventricular heart muscle. 5-HT exerted a concentration-dependent increase in F_C in multicellular atrial preparations; the EC₅₀ was approximately 3 × 10^–7 mol/l. Maximal increases in F_C (252±58% of control values; means ± SEM, n=6) were obtained at 5-HT 10^–5 mol/l. At this concentration, I_Ca was increased four- to sevenfold in enzymatically isolated atrial myocytes. In contrast, ventricular preparations did not respond to 5-HT; F_C, AP and I_Ca remained unaffected. In the same preparations, F_C was increased by isoprenaline three- to fourfold. These results confirm the observation that 5-HT induces a positive inotropic effect in the human atrium, possibly mediated by activation of the adenylyl cyclase — cyclic AMP system. Our study demonstrates, however, the complete lack of functional 5-HT receptors, with respect to changes in F_C, in the human ventricle. Since the positive inotropic effect of 5-HT in the human heart is obviously restricted to the atrium, our findings question the concept of developing 5-HT receptor agonists for the treatment of heart failure. Correspondence to: H. Nawrath at the above address     

Positive inotropic and negative chronotropic effects of proton pump inhibitors in isolated rat atrium

The effects of three specific H+/K+-ATPase inhibitors (omeprazole, lansoprazole and SCH 28080 (2-methyl-8-(phenylmethoxy)-imidazo[1,2-a] pyridine-3-acetonitrile)) were investigated on the mechanical and electrophysiological properties of rat atrium, in vitro. Omeprazole (100-300 microM), lansoprazole (100-300 microM) and SCH 28080 (10-100 microM) increased the amplitude of contractions and decreased the beating rate. These effects are reversible, reproducible and correlated with their order of potency as gastric H+/K+-ATPase inhibitors; SCH 28080 > omeprazole = lansoprazole. Cardiac effects of proton pump inhibitors were not inhibited with phentolamine (5 microM), propranolol (15 microM), atropine (1 microM), ouabain (2 microM), theophylline (300 microM) and milrinone (100 microM). Ouabain-induced increase in beating rate and contracture development were antagonized by H+/K+-ATPase inhibitors. Ouabain increased the positive inotropic effect of H+/K+-ATPase inhibitors. Lansoprazole (300 microM) significantly prolonged the duration of action potentials in rat atrial cells. H+/K+-ATPase may play a crucial role in the mechanical and electrophysiological properties of rat atrial myocardium.     

Relative activities of substances related to 5-hydroxytryptamine as depolarizing agents of superior cervical ganglion cells

Membrane potential changes evoked by 5-HT and related substances were recorded by the sucrose-gap method from rabbit ganglia superfused with Krebs solution at 20°C. A solution of the substance under test was injected into the superfusion stream. The activity of 23 substances was compared to that of 5-HT in respect of depolarizing capacity. 0.01 μmol 5-HT produced a near-threshold depolarization, while 0.6–0.8 μmol induced a maximal one. Some 5-HT analogues evoked prolonged responses distinctly different from the rapid depolarization and repolarization characteristic of 5-HT, while others were inactive. Compounds di- or trimethylated at the side-chain nitrogen atom were capable in addition of activating nicotinic receptors. The results suggest that: (1) the optimal requirements for activating ganglionic 5-HT receptors are a hydroxyl group at position 5 on the indole nucleus and a side-chain bearing an ethylamine amino group; (2) methyl substituents around the terminal nitrogen atom are well tolerated and a quaternary nitrogen may increase activity at the 5-HT receptor; and (3) substitution of a methyl group at carbon atom 2 of the indole nucleus reduces activity. a limitation of the technique is the difficulty of obtaining more than one dose-response curve from a particular preparation; a reduction in potency due to lower affinity cannot be readily distinguished from one due to lower intrinsic activity.     

Analysis of the heart rate effects of 5-hydroxytryptamine in the cat; mediation of tachycardia by 5-HT1-like receptors

Summary The effects of 5-hydroxytryptamine (5-HT) on heart rate in anaesthetized cats were analysed both in intact animals and after spinal section plus vagotomy.The intact cat responded to 5-HT (3, 10 and 30 g·kg^–1, i.v.) with a brief, but intense, bradycardia and a longerlasting hypotension. Administration of MDL 72222, a selective antagonist of M-type 5-HT receptors, blocked bradycardia elicited by 5-HT without affecting that caused by stimulation of the vagus nerve.In spinal cats the same doses of 5-HT increased heart rate and blood pressure. These effects remained essentially unchanged after bilateral adrenalectomy, guanethidine, propranolol and burimamide, suggesting that 5-HT acted directly on the myocardium and blood vessels. The tachycardic responses to 5-HT in spinal cats were little affected by 0.5 mg·kg^–1 doses of MDL 72222 or of the 5-HT₂ receptor antagonists, ketanserin, ritanserin or cyproheptadine. In contrast, the non-selective 5-HT receptor antagonist, methysergide, which binds to both 5-HT₁ and 5-HT₂ recognition sites in rat brain membranes, potently antagonized the 5-HT-induced tachycardia in doses of 0.05 to 0.5 mg·kg^–1. However pizotifen and mianserin, two other 5-HT₂ antagonists which show poor affinity for 5-HT₁ recognition sites, were also effective against the tachycardic response to 5-HT in doses of 0.5–4.5 mg·kg^–1. The pressor responses to 5-HT in the spinal cat were markedly inhibited by all six 5-HT₂ antagonists at a dose of 0.5 mg·kg^–1.5-Carboxamido-tryptamine, which has a high and selective affinity for 5-HT₁ recognition sites, elicited marked tachycardia in doses of 0.1–10 g/kg^–1 in spinal cats treated with saline. These responses were not affected in animals treated with 4.5 mg·kg^–1 of ketanserin, which was able to shift the dose-response curve for 5-HT to the right. On the other hand, methysergide (0.5 mg·kg^–1) displaced the dose-response curves for both 5-carboxamidotryptamine and 5-HT to a similar extent.Unlike on the dog saphenous vein, methysergide showed no agonist effects on heart rate in the spinal cat.On the basis of the above results, we conclude that: (i) the reflexogenic bradycardic response elicited by 5-HT overshadows its direct tachycardic response on heart rate in the intact cat; (ii) M-type 5-HT receptors mediate the bradycardic response; (iii) the pressor response to 5-HT in the spinal cat involves 5-HT₂ receptors; (iv) tachycardia by 5-HT in the spinal cat is mediated mainly by 5-HT₁-like receptors, but an additional, though less important, non-5-HT₁ mechanism may also be involved; (v) the cardiac 5-HT₁ receptors are similar, but perhaps not identical, to those delineated in the dog saphenous vein or rat brain membrane preparations; and (vi) the tachycardic responses to 5-HT and, in particular the more selective, 5-carboxamidotryptamine may be conveniently utilized to characterize new chemical compounds designed for potential 5-HT₁ receptor antagonist activity.     

Facilitating interaction between rauwolscine and angiotensin in the mesenteric artery of the rabbit

Summary The interaction between rauwolscine and angiotensin II was investigated in the isolated mesenteric artery of the rabbit. Rauwolscine, known as an antagonist at ₂-adrenoceptors, did not induce contraction itself but interacted with angiotensin to produce a facilitated response of the vascular tissue. In the presence of rauwolscine, the contractile response of the tissue to angiotensin was markedly enhanced. The degree of facilitation appeared to be dependent on the rauwolscine concentration used rather than that of angiotensin. Moreover, rauwolscine induced a concentration-dependent increase in tension (pD₂=6.8) in the presence of even subcontractile concentrations of angiotensin (10^–10 mol/l). This effect was not attributable to an indirect action involving presynaptic catecholamines, as revealed by the use of tissue strips from animals pretreated with reserpine or after chemical sympathectomy. Furthermore, an interaction via the prostaglandin system was excluded by negative results obtained with indomethacin. The agonistic effect of rauwolscine was significantly attenuated by phentolamine (₁/₂) but not by prazosin (₁) or phenoxybenzamine when applied for only a short time. The ₂-antagonist BDF 6143 behaved like rauwolscine whereas the ₁-antagonist corynanthine, a stereoisomer of rauwolscine, did not. The results indicate that the rauwolscine effect is mediated by a receptor with ₂-characteristics. In general, angiotensin appears to interfere with some process which determines the expression of a drug's intrinsic effect.This study was supported by a grant of the Deutsche Forschungsgemeinschaft     

Positive inotropic and negative chronotropic effects of (-)-cis-diltiazem in rat isolated atria.

1. The cardiovascular effects of (-)-cis-diltiazem, an optical isomer of diltiazem, were studied in the isolated atrium and aortic strip. (-)-cis-Diltiazem (30 microM or more) increased the developed tension of the rat left atrium, while (+)-cis-diltiazem (1 microM or more) decreased it. 2. (-)-cis-Diltiazem (1 to 100 microM) decreased the rate of spontaneous beating in the right atrium as did (+)-cis-diltiazem. 3. The potency of the positive inotropic action of (-)-cis-diltiazem was almost the same as that of ouabain in the rat left atrium, but in the guinea-pig left atrium it was considerably weaker than that of ouabain. 4. In both endothelium-intact and endothelium-denuded aortic strips, (-)-cis-diltiazem relaxed the Ca(2+)-induced contraction. In the endothelium-intact rat aortic strip depolarized by 15 mM KCl, Bay K 8644, a calcium channel agonist, increased the contractile force, whereas (-)-cis-diltiazem did not. 5. These results indicate that (-)-cis-diltiazem has a positive inotropic action in isolated atria in rats and guinea-pigs, but the mode of positive inotropic action of (-)-cis-diltiazem is different from that of ouabain or Bay K 8644.     

Comparison of the positive inotropic effects of serotonin,histamine, angiotensin II,endothelin and isoprenaline in the isolated human right atrium

Summary The receptor systems through which serotonin (5-HT), histamine, angiotensin II and endothelin increase the force of contraction were studied in isolated right atria from patients without apparent heart failure.All agonists increased the atrial force of contraction in a concentration-dependent manner; maximal effects, however, were significantly less than those evoked by isoprenaline or Ca²⁺. 5-HT and histamine, but not angiotensin II and endothelin, activated adenylate cyclase, whereas endothelin and angiotensin II stimulated inositol phosphate generation. Experiments with subtype-selective antagonists revealed that histamine effects were mediated by H₂-receptors (sensitive to ranitidine), 5-HT-effects by 5-HT₄-receptors (sensitive to SDZ 205-557) and angiotensin II effects by AT₁-receptors (sensitive to losartan).We conclude that in human right atria the force of contraction can be increased by cyclic AMP-dependent (histamine, 5-HT) and -independent (angiotensin II, endothelin) pathways. Compared to -adrenoceptors, however, all other receptor systems increase the force of contraction only submaximally indicating that the -adrenoceptor pathway is the most important physiological mechanism to regulate force of contraction and/or heart rate in the human heart.Correspondence to O. E. Brodde at the above address     

Dual action of angiotensin II on coronary resistance in the isolated perfused rabbit heart

Summary We studied the functional role of angiotensin II (AII) receptor subtypes and vasodilatory endothelial autacoid release in response to AII in isolated perfused rabbit hearts. AII infusion induced biphasic changes in coronary perfusion pressure (CPP): an initial increase was followed by a decrease until a plateau was reached. At higher concentrations of AII (10 nmol/l) this plateau phase was lower than the initial CPP level. AII infusion elicited inverse changes in peak left ventricular pressure (LVP): coronary constriction was associated with a transient decline, and during the plateau phase LVP was clearly increased. AII also moderately augmented prostacyclin (PGI₂) release from the coronary vascular bed. The AII-induced changes in CPP, LVP, and PGI₂ release were effectively inhibited by the AT₁ receptor subtype antagonist ICI D8731 (30 nmol/l), but not by the AT₂ receptor antagonist CGP 42112 (30 nmol/l). The adenosine A₁ receptor antagonist 8-phenyltheophylline (0.1 mol/l) attenuated the decline in CPP following the constriction phase without affecting the changes in LVP during AII infusion. The cyclooxygenase inhibitor diclofenac (1 mmol/l) had no effect on the AII-induced changes in CPP, whereas the nitric oxide-synthase inhibitor N^G-nitro-L-arginine (30 mol/l) markedly potentiated the vasoconstriction but was without effect on the plateau phase of the response. In contrast to AII, the thromboxane analogue U46619 elicited sustained increases in CPP which were associated with slight decreases in LVP.In conclusion, AII induced a biphasic pressor response in the rabbit coronary vascular bed consisting of a transient vasoconstriction followed by a dilatation especially at higher concentrations of AII, an effect which was independent of the endothelial autacoids nitric oxide and PGI₂. The AII-induced dilatation probably reflected rapid desensitization of the coronary arterial smooth muscle to the constrictor effect, and the concomitant accumulation of vasodilatory metabolites such as adenosine, generated during the positive inotropic action of AII. All the effects of AII in the rabbit heart appeared to be mediated via the AT, receptor subtype localized on coronary endothelial and smooth muscle cells, as well as on cardiomyocytes.On leave from the Department of Biomedical Sciences, University of Tampere, P.O. Box 607, FIN-33101 Tampere, FinlandCorrespondence to: I. Pörsti     

Differential chronotropic and inotropic effects of 2-nicotinamidoethyl nitrate (SG-75) in the dog isolated atrium

1. The chronotropic and inotropic effects of the anti-anginal agent SG-75 (2-nicotinamidoethyl nitrate) and 1-verapamil were investigated in isolated blood-perfused canine atrial preparations. The compounds were administered via the cannulated sinus node artery. 2. SG-75 induced a selective negative inotropic as opposed to a chronotropic effect. Verapamil showed no selective negative chronotropic or inotropic activity. 3. Effects of SG-75 and 1-verapamil on the frequency-force relationship were studied. SG-75 produced a uniform depression of the developed tension at all frequencies tested which the depression with 1-verapamil was greater at higher than at lower frequencies.     

The mode of action of 4-aminopyridine on the chronotropic and inotropic responses in the isolated, blood-perfused dog heart

The effects of 4-aminopyridine (4-AP, 0.3 to 300 micrograms) on atrial rate and atrial muscle contractile force were investigated in the isolated, blood-perfused dog atrial preparation. Low doses (less than 30 micrograms) of 4-AP injected into the sinus node artery caused a dose-dependent positive inotropic response and a negligible positive chronotropic response. A higher dose (300 micrograms) of 4-AP induced a transient positive chronotropic response followed by a negative response and positive and negative inotropic responses. The negative cardiac responses to 4-AP were completely inhibited by an adequate dose of atropine and were potentiated by physostigmine. TTX or C6 suppressed partly, but significantly the negative responses induced by 4-AP. On the other hand, the negative responses to electrical stimulation (ES) were inhibited by atropine, C6 and TTX and those to ACh were blocked by atropine but not by C6 or TTX. The positive responses to 4-AP were not affected by propranolol but were potentiated by atropine. The positive inotropic response to 4-AP was significantly suppressed by a calcium channel blocker, diltiazem. From these results, it is concluded that the cardiac responses to 4-AP are composed of direct positive responses and negative responses which are related to activation of parasympathetic ganglionic neurotransmission.     

Action of two hypothalamic factors (TRH, MIF) and of angiotensin II on the behavioral effects of L-DOPA and 5-hydroxytryptophan in mice

Melanocyte stimulating hormone release-inhibiting factor (MIF), thyrotropin releasing hormone (TRH) and angiotensin II, injected i.p. to mice, potentiate the behavioral effect of L-DOPA and 5-hydroxytryptophan.     

Possible mechanism of inotropic and chronotropic effects of Rosa damascena on isolated guinea pig heart

Background

The possible mechanism(s) of inotropic and chronotropic effects of the extract from Rosa damascena (R. damascena) on heart was examined.

Methods

Inotropic and chronotropic effects of four concentrations of the extract from R. damascena and isoprenaline were examined in isolated guinea-pig hearts perfused through aorta in a Langendorff model. All measurements were performed in three different groups: 1) In the presence and absence of propranolol, 2) In the presence and absence of methacholine and 3) In the presence of diltiazem (n = 12 for each group).

Results

In all groups both isoprenaline and the extract caused an increase in heart rate and contractility (p < 0.05 to p < 0.001). Only in group 1, the final concentration of isoprenaline in the absence of propranolol caused significant greater increase in heart rate compared to the extract (207.6 ± 11.0 compared to 162.6 ± 11.8, p < 0.01). The percent increase in heart contractility due to the final concentration of the extract in the absence (362.4 ± 36.9 compared to 227.7 ± 31.6, p < 0.01) and presence of propranolol (577.1 ± 62.9 compared to 357.5 ± 45.6, p < 0.001) in group 1 and absence (403.7 ± 42.1 compared to 244.8 ± 18.9, p < 0.005) and presence of methcholine (499.88 ± 64.64 compared to 323.90 ± 44.49, p < 0.05) in groups 2 was significantly greater than the increase caused by isoprenaline.

Conclusions

The results of this study suggest that inotropic and chornotropic effect of R. damascena is possibly due to the stimulatory effect of this plant on beta-adrenoceptors.     

Pharmacodynamic differentiation of chronotropic and inotropic beta-adrenergic receptors in rabbit heart

Isolated, perfused rabbit hearts were used to identify substituted phenylethylamines selective for either chronotropic or inotropic stimulation relative to norepinephrine. Heart rate and dF/dtmax were measured; the difference in their normalized values was used as an index of selectivity. p-Octopamine (OA) showed chronotropic preference, while phenylephrine (PE) showed a significant inotropic preference. Their effects were not prevented by reserpine pretreatment, cocaine, butoxamine, or phenoxybenzamine, but were antagonized by propranolol, which suggests that OA and PE exert their selective actions directly at beta 1-receptors. These findings provide further evidence for the existence of separate chronotropic and inotropic beta-adrenergic receptors in the heart.     

Chronotropic effects of angiotensin I,angiotensin II,bradykinin and vasopressin in guinea pig atria

Chronotropic responses to angiotensin I and angiotensin II, vasopressin and bradykinin were measured in guinea pig isolated right atria. Angiotensin II (100–30 000 pg/ml) was slightly more potent than angiotensin I and caused a maximum tachycardia of 30–40 b/min; only 20% of the maximum response to (?)-noradrenaline. Propranolol (1 μM) or reserpine pretreatment (1 mg/kg i.p., 24 h) did not alter the response to angiotensin II or bradykinin. Converting enzyme inhibition by captopril (10 μg/ml) did not affect resting rate nor the response to angiotensin II but shifted the location of the angiotensin I curve by 40 fold to the right. Bradykinin (5–500 ng/ml) caused small increases in rate while vasopressin 1–100 ng/ml was completely without effect. These results suggest that angiotensin II has a small positive chronotropic effect that is not dependent on tissue noradrenaline release or β-adrenoceptors and that tissue converting enzyme is active in right atria. Relatively high concentrations of angiotensin and bradykinin were required to directly stimulate the sino-atrial node compared with plasma levels measured during physiological stimuli. Therefore these effects on atria are probably of little physiological significance for peptide concentrations in plasma but may be important in relation to local tissue generation of angiotensin II.