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3. Possible mechanism of the negative inotropic effect of α1-adrenoceptor agonists in rat isolated left atria after exposure to free radicals

Author

Peters, Stephan L M, Batink, Harry D, Michel, Martin C, Pfaffendorf, Martin, and van Zwieten, Pieter A

Subjects
Male, Free Radicals, Inositol Phosphates, In Vitro Techniques, Naphthalenes, Atrial Function, Myocardial Contraction, Methoxamine, Rats, Oxidative Stress, Receptors, Adrenergic, alpha-1, Type C Phospholipases, Papers, Animals, Adrenergic alpha-1 Receptor Agonists, Heart Atria, Enzyme Inhibitors, Rats, Wistar, Sodium-Potassium-Exchanging ATPase, Ouabain, Adrenergic alpha-Agonists, Protein Kinase C, Signal Transduction
Abstract

1. This study was designed to investigate the mechanism(s) of the negative inotropic effects of alpha1-adrenoceptor agonists observed in rat isolated left atria after exposure to free radicals. 2. Ouabain and calphostin C were used in contraction experiments to block the sodium pump and protein kinase C. Methoxamine-induced phospholipase C and Na+/K+ ATPase activities were measured. 3. Methoxamine (300 microM) increased contractile force by 1.6 +/- 0.2 mN in control atria but decreased contractile force in electrolysis-treated atria by 2.0 +/- 0.1 mN (P0.05), as determined 10 min after methoxamine addition. In contrast, the positive inotropic effects of endothelin-1 (30 nM) and isoprenaline (10 microM) were reduced from 2.6 +/- 0.3 to 1.3 +/- 0.1 mN and from 2.6 +/- 0.3 to 1.7 +/- 0.2 mN, respectively, by electrolysis treatment (P0.05), but not converted into a negative inotropic action. 4. In an inositol phosphate assay we observed that the stimulation of phospholipase C by methoxamine was attenuated by electrolysis when the (electrolyzed) medium from the organ bath was used, but the phospholipase C responses were restored by the use of fresh medium. However, fresh medium did not counteract the negative inotropic effect of methoxamine. Accordingly, the negative inotropic effect of methoxamine is not directly related to the impaired phospholipase C responses seen in atria subjected to electrolysis. 5. Ouabain (10 microM) and the protein kinase C inhibitor calphostin C (50 nM), completely prevented the negative inotropic effect of 300 microM methoxamine in electrolysis-treated atria. 6. Measurement of the Na+/K+ ATPase activity, revealed that in control atria, alpha1-adrenoceptor stimulation with 300 microM methoxamine, decreased the Na+/K+ ATPase activity by 14.4 +/- 7.7%. In contrast, methoxamine increased the Na+/K+ ATPase activity by 48.8 +/- 8.9% (P0.05) in electrolysis-treated atria. Interestingly, this increase in Na+/K+ ATPase activity was completely counteracted by calphostin C (1.4 +/- 0.1% over basal). 7. These results indicate that the negative inotropic effects of alpha1-adrenoceptor agonists, observed in rat isolated left atria exposed to free radicals, are likely to be caused by protein kinase C-mediated phosphorylation and subsequent activation of the Na+/K+ ATPase.

Published
1998

24. Effects of losartan on vasoconstrictor responses to angiotensin II in the forearm vascular bed of healthy volunteers.

Author

Baan, Jan, Chang, Peter C., Vermeij, Pieter, Pfaffendorf, Martin, and van Zwieten, Pieter A.

Abstract

Objectives: The angiotensin type 1 (AT1) receptor antagonist, losartan (orally administered), decreases vasoconstrictor effects of angiotensin II (Ang II). Oral losartan is converted into the active metabolite, Exp3174, which causes most of the antagonistic effects. Effects of losartan as such have not been studied after its intra-arterial administration in humans. Therefore, we investigated the effects of both intra-arterially and orally administered losartan on AT1-receptor-mediated vasoconstriction. Methods: Forearm vascular resistance (FVR) was determined by venous occlusion plethysmography in 24 healthy subjects. Ang II (0.01, 0.1, 1.0, and 10.0 ng/kg/min) was infused into the brachial artery, before and after losartan, administered intra-arterially (dose range 100–3000 ng/kg/min) or orally (50 mg once daily for 5 days). Results: Ang II concentration-dependently increased FVR (P < 0.05); tachyphylaxis did not occur. Losartan alone did not change FVR. Intra-arterially infused losartan dose-dependently inhibited Ang-II-induced vasoconstriction. At a concentration of 10−8 M Ang II, losartan reduced FVR, as a percentage of baseline values, from 287 ± 30 to 33 ± 8% (mean ± s.e.m.; P < 0.05). Orally given losartan reduced FVR from 297 ± 40 to 73 ± 19% (P < 0.05). Conclusions: Losartan, intra-arterially administered, causes no effect on baseline vascular resistance, but markedly inhibits Ang-II-induced vasoconstriction in the human forearm vascular bed. Relatively high doses of intra-arterial losartan were required when compared to the antagonism by the orally administered drug. These data indicate that Ang-II-induced vasoconstriction is mediated by AT1-receptors, which are blocked by losartan. The more effective antagonism exerted by oral losartan is presumably explained by the formation of Exp3174. Endogenous Ang II does not contribute to baseline vascular tone in healthy, sodium-replete, subjects. [ABSTRACT FROM PUBLISHER]

Published
1996
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27. Different AT1Receptor Subtypes at Pre- and Postjunctional Sites AT1Aversus AT1BReceptors

Author

Nap, Alexander, Balt, Jippe C., Mathy, Marie-Jeanne, Pfaffendorf, Martin, and Zwieten, Pieter A. van

Abstract

Angiotensin (AT) II is known to enhance responses to electrical field stimulation (EFS) via AT1receptors located on sympathetic nerve terminals. Differences in potency exist between AT1receptor antagonists regarding the inhibition of the prejunctional and postjunctional AT1receptors. It is hypothesized that prejunctional AT1receptors might belong to the AT1Breceptor subtype. Accordingly, the authors investigated whether AT1Breceptor inhibition by high concentrations of PD123319 could suppress ATII-augmented noradrenergic transmission (prejunctional) in the rabbit thoracic aorta by means of a noradrenaline spillover model. Additionally, the influence of PD123319 on ATII-enhanced constrictor responses to electrical field stimulation was investigated in the isolated rabbit mesenteric artery. Furthermore, the authors investigated whether PD123319 could influence the constrictor responses (postjunctional) to ATII in both preparations. In the thoracic aorta, ATII (10 n M) caused a significant enhancement of EFS-evoked 3H-noradrenaline release by a factor of 2.0 ± 0.1. This reinforcement could be inhibited by PD123319 (0.1, 1, and 10 M). The constrictor response to ATII was unaffected by PD123319. In the mesenteric artery, ATII (0.5 n M) caused a significant enhancement of constrictor responses to EFS by factors of 2.9 ± 0.3, 2.3 ± 0.3, and 1.6 ± 0.1 at 1, 2, and 4 Hz, respectively. This enhancement could be attenuated by PD123319 (1 and 10 M). The constrictor response to ATII was unaffected by PD123319. It is concluded that the prejunctional AT1receptors belong to the AT1Bsubtype whereas postjunctional AT1receptors do not.

Published
2004

28. Effect of the AT1Receptor Antagonists Losartan, Irbesartan, and Telmisartan on Angiotensin IIInduced Facilitation of Sympathetic Neurotransmission in the Rat Mesenteric Artery

Author

Balt, Jippe C., Mathy, MarieJeanne, Nap, Alexander, Pfaffendorf, Martin, and Zwieten, Pieter A. van

Abstract

The effect of the AT1receptor antagonists losartan, irbesartan, and telmisartan on angiotensin II Ang IIinduced facilitation of noradrenergic neurotransmission was investigated in the isolated rat mesenteric artery under isometric conditions. Electrical field stimulation 2, 4, and 8 Hz caused a frequencydependent increase of contractile force. At stimulation frequencies of 2, 4, and 8 Hz, Ang II 10 nMincreased the stimulationinduced vasoconstrictor responses by a factor 4.8 ± 0.9, 2.9 ± 0.7, and 1.3 ± 0.1, respectively p < 0.05 compared with control for all frequencies. The enhancement could be concentrationdependently antagonized by losartan 1 nM1 M, irbesartan 0.1 nM0.1 M, and telmisartan 0.01 nM0.01 M. At a stimulation frequency of 2 Hz, the relation between stimulationinduced vasoconstrictor responses in presence of Ang II 10 nMand the concentration of the AT1antagonists used could be described by linear regression. The order of potency concerning sympathoinhibition was telmisartan > irbesartan > losartan p < 0.05 between linear regression lines. Contractile responses to exogenous noradrenaline were unaltered in the presence of Ang II 10 nM. We conclude that the facilitating effect of Ang II on noradrenergic neurotransmission is mediated by presynaptically located AT1receptors. Conversely, this facilitating effect can be dosedependently counteracted by blockade of these receptors. Sympathoinhibitory properties are likely to contribute to the therapeutic effect of AT1blockers, in particular in conditions in which the sympathetic nervous system is activated, such as congestive heart failure and hypertension.

Published
2001

29. Discrepancies Between Inotropic Responses and βAdrenoceptor Characteristics After Global Ischemia in Isolated Hearts

Author

van den Ende, Romana, Batink, Harry D., Pfaffendorf, Martin, and Zwieten, Pieter A. van

Abstract

The influence of global ischemia on cardiac β-adrenoceptors was studied in rat and guinea pig Langendorff hearts (LH), both by functional and binding experiments using the specific β-adrenoceptor ligand ( – )-[125I]-iodocyanopindolol. Neither ischemia (30 or 60 min) nor postischemic reperfusion caused any change in β-adrenoceptor density, affinity or in the β1/β2ratio in LH of normal rats or in LH of rats pretreated with reserpine or 6-hydroxydopamine (6-OHDA), or in guinea pig LH, whereas perfusion of rat LH with 10−5Misoprena-line (15 min) caused the expected decrease in β-adrenoceptor density. After ischemia, isoprenaline was no longer able to influence β-adrenoceptor density, suggesting that the internalization mechanism is impaired. In functional studies, perfusion of the rat LH with 10−5Misoprenaline (15 min) shifted the concentration-response curve for isoprenaline to the right. Thirty-minute global ischemia virtually abolished the inotropic but not the chronotropic response to isoprenaline. Ischemia did not impair the inotropic response to ouabain or to calcium, indicating that the contractile apparatus itself was still largely intact. Our results suggest that the contractile failure after ischemia is not caused by a decrease in β-adrenoceptor density or by a defect in the contractile apparatus but by an impaired second-messenger system.

Published
1991

31. Role of T-type calcium channels in myogenic tone of skeletal muscle resistance arteries.

Author

VanBavel E, Sorop O, Andreasen D, Pfaffendorf M, and Jensen BL

Subjects
Animals, Arterioles drug effects, Arterioles metabolism, Calcium Channel Blockers pharmacology, Calcium Channels, L-Type drug effects, Calcium Channels, L-Type genetics, Calcium Channels, L-Type metabolism, Calcium Channels, T-Type drug effects, Calcium Channels, T-Type genetics, In Vitro Techniques, Male, Muscle Tonus drug effects, Potassium pharmacology, RNA, Messenger metabolism, Rats, Rats, Wistar, Reverse Transcriptase Polymerase Chain Reaction, Vascular Patency drug effects, Arterioles physiology, Calcium Channels, T-Type metabolism, Muscle Tonus physiology, Muscle, Skeletal blood supply, Vascular Resistance physiology
Abstract

T-type calcium channels may be involved in the maintenance of myogenic tone. We tested their role in isolated rat cremaster arterioles obtained after CO(2) anesthesia and decapitation. Total RNA was analyzed by RT-PCR and Southern blotting for calcium channel expression. We observed expression of voltage-operated calcium (Ca(V)) channels Ca(V)3.1 (T-type), Ca(V)3.2 (T-type), and Ca(V)1.2 (L-type) in cremaster arterioles (n = 3 rats). Amplification products were observed only in the presence of reverse transcriptase and cDNA. Concentration-response curves of the relatively specific L-type blocker verapamil and the relatively specific T-type blockers mibefradil and nickel were made on cannulated vessels with either myogenic tone (75 mmHg) or a similar level of constriction induced by 30 mM K(+) at 35 mmHg. Mibefradil and nickel were, respectively, 162-fold and 300-fold more potent in inhibiting myogenic tone compared with K(+)-induced constriction [log(IC(50), M): mibefradil, basal -7.3 +/- 0.2 (n = 9) and K(+) -5.1 +/- 0.1 (n = 5); nickel, basal -4.1 +/- 0.2 (n = 5) and K(+) -1.6 +/- 0.5 (n = 5); means +/- SE]. Verapamil had a 17-fold more potent effect [log(IC(50), M): basal -6.6 +/- 0.1 (n = 5); K(+) -5.4 +/- 0.3 (n = 4); all log(IC(50)) P < 0.05, basal vs. K(+)]. These data suggest that T-type calcium channels are expressed and involved in maintenance of myogenic tone in rat cremaster muscle arterioles.

Published
2002
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