Biomedical subjects

J Zanzinger

Publications and source records attributed to J Zanzinger.

At least 19 recordsLinked to original sources

PubMed2000

Chronic oxidative stress in the RVLM modulates sympathetic control of circulation in pigs.

Oxidative stress is a key event in the pathogenesis of several cardiovascular diseases and may be similarly induced by long-term treatment with organic nitrates. We examined the effects of inhibiting extracellular oxidative stress in the rostral ventrolateral medulla (RVLM), the brain stem area which primarily controls sympathetic tone. Superoxide dismutase (SOD, 10 U/microl) was microinjected into the RVLM of anesthetized pigs that were either untreated (control, n=10), treated for 4 weeks with the organic nitrate isosorbidedinitrate (ISDN, 4 mg kg(-1) day(-1), n=6) or ISDN-treated followed by a 2-week recovery period (recovery, n=4). In control animals SOD produced moderate inhibitory effects on baseline sympathetic activity, indicated by decreases in renal sympathetic nerve activity (RSNA), mean arterial blood pressure (MAP), and heart rate (HR) without causing changes in femoral vascular conductance (FC). These effects of SOD were greatly enhanced in ISDN-treated pigs. Following the recovery period, SOD again produced smaller effects in the RVLM but they were, however, still significantly greater than in untreated animals. In contrast, the transmission of sympathoexcitatory reflexes by the RVLM, as evoked by sciatic nerve stimulation, was not affected by SOD injections in either experimental group. Furthermore, the number of NO-synthase-positive neurons in the RVLM region was significantly reduced both in ISDN-treated and the recovery pigs, suggesting that oxidative stress caused sustained changes in NOS activity within the brain stem. These data suggest that excitatory actions of oxidative stress contribute significantly to the generation of baseline sympathetic tone in the RVLM during long-term treatment with organic nitrates. Similar mechanisms could promote sympathetic tone in cardiovascular diseases that are associated with endogenous oxidative stress for longer periods.

Animals↗

PubMed1999

Role of nitric oxide in the neural control of cardiovascular function.

The discovery in 1990 that nitric oxide (NO) acts as a neuromodulator within the central and peripheral nervous system triggered intensive research which considerably extended our understanding how this factor regulates cardiovascular functions. In addition to its direct effects on blood vessels NO has additional targets at all levels of the neural control of circulation. When not scavenged by hemoglobin, NO is relatively stable and diffuses over large distances (> 500 microns) so that one NO-producing cell can influence several thousands of adjacent cells in vivo. In different brain regions, NO and its metabolites have excitatory as well as inhibitory effects. The modulation of autonomic functions by these factors is therefore highly complex and often variable between the different levels from the brain to postganglionic nerve endings. This review is focused on the available evidence derived from animal studies and will summarize the current discussion about (i) the modulation of the generation of sympathetic and parasympathetic activities within the brain stem by NO; (ii) the actions of NO on cardiovascular reflexes and (iii) the role of NO as a modulator of autonomic functions within the target organs. Finally, the available evidence from human studies and some pathophysiological implications of altered NO-mediated modulation of the neural control of circulation will be discussed.

Animals↗

PubMed1999

Sympathoinhibitory effects of clonidine are transmitted by the caudal ventrolateral medulla in cats.

We examined mechanisms of the central sympathoinhibitory actions of systemically administered clonidine in anesthetized cats. To avoid influences of sympathetic chemo- and baroreflexes, the animals were deafferentated by cutting the carotid sinus and vagal nerves bilaterally. Intravenous (i.v.) injections of clonidine (25-250 nmol/kg) caused significant (50-90%) decreases in preganglionic sympathetic nerve activity (SNA) recorded from the white ramus of the third thoracic segment. Microinjections (500 nl) into the rostral ventrolateral medulla (RVLM) of clonidine at doses (50-500 pmol in 500 nl), which probably produced higher local concentrations than produced by systemic administration, caused only slight reductions of SNA and small decreases in arterial blood pressure (BP). Furthermore, sympathoinhibition and hypotension caused by intravenous clonidine was almost unaffected by prior microinjection of alpha2-receptor antagonist rauwolscine (500 pmol) into the RVLM. Microinjections of clonidine into the caudal ventrolateral medulla (CVLM), which provides important inhibitory input to the RVLM, had no significant effects. However, chemical lesions of the CVLM with kainate (5.0 nmol), effectively blocked the sympathoinhibitory effects of subsequently administered intravenous clonidine. The results suggest that the central sympathoinhibitory effects of therapeutically relevant doses of systemically administered clonidine may be primarily mediated by pathways that activate the CVLM rather than by direct actions within the RVLM.

Adrenergic alpha-2 Receptor Antagonists↗

PubMed1998

Impaired modulation of sympathetic excitability by nitric oxide after long-term administration of organic nitrates in pigs.

BACKGROUND: Endogenous nitric oxide (NO) reduces sympathetic vasoconstriction by attenuating neuronal excitability in the brain stem and inhibition of postganglionic neurotransmission. We studied whether this modulation of sympathetic circulatory control by NO may be altered during chronic administration of NO donor drugs in pigs. METHODS AND RESULTS: Nitrate tolerance was induced by oral administration of isosorbide dinitrate (ISDN, 4 mg/kg per day for 4 weeks) in eight pigs. Four of them were chronically instrumented for the measurement of mean arterial blood pressure and cardiac output in the conscious state. ISDN treatment caused hemodynamic tolerance to NO donors and significantly increased the hypotensive responses to pharmacologic ganglionic blockade in conscious pigs. In general anesthesia, ISDN-treated animals and age-matched controls (n=5) had similar baseline renal sympathetic nerve activity and in both groups neither inhibition of NO synthases (NOS) nor administration of NO donors to the brain stem by intracerebroventricular (i.c.v.) infusions caused significant changes in baseline renal sympathetic nerve activity. However, whereas sympathoexcitatory responses to glutamate (0.5 mL, 0.1 mol/L, i.c.v.) or electrical stimulation of somatic nerve afferents were significantly potentiated by central NOS inhibition and attenuated by NO donors in controls, these treatments no longer had significant effects in ISDN-treated pigs. Furthermore, reflex sympathetic activation in response to intravenous NO donor treatment was more pronounced in nitrate tolerant animals, which suggests loss of central sympathoinhibitory effects of NO. Subsequent histology on brain stem slices with NADPH-diaphorase as NOS marker revealed significant reduction of NOS density in ISDN-treated pigs. CONCLUSIONS: Long-term administration of organic nitrates reduces the number of NO-producing neurons in the brain stem and causes loss of inhibitory effects of NO on sympathetic excitability. This component of tolerance to organic nitrates may be important in patients confronted frequently with sympathetic activation caused by mental and/or physical stressors.

Animals↗

PubMed1998

Nitric oxide in the ventrolateral medulla regulates sympathetic responses to systemic hypoxia in pigs.

The role of nitric oxide (NO) in the regulation of sympathetic activity during hypoxia was studied in anesthetized pigs (n = 21). Hypoxia (fractional concentration of O2 in inspired air = 0.1) increased pulmonary arterial pressure and decreased arterial blood pressure and peripheral vascular resistance. Renal sympathetic nerve activity (RSNA) was moderately increased during hypoxia but decreased instantaneously on reoxygenation. Blockade of NO synthesis by NG-nitro-L-arginine (L-NNA, 0.3 mmol/l) administered to the ventral surface of the medulla oblongata (VLM) significantly enhanced RSNA increases induced by hypoxia and abolished the RSNA response to reoxygenation. Furthermore, L-NNA significantly reduced peripheral hypoxic vasodilation but did not affect pulmonary vasoconstriction. The inactive enantiomer D-NNA had no measurable effects at the same concentration. Actions of L-NNA were effectively counteracted by the NO donor S-nitroso-N-acetyl-penicillamine (0.1 mmol/l). Deafferentiation (carotid sinus and vagal nerves cut) abolished sympathetic responses to hypoxia and their modulation by NO. The results suggest that activation of peripheral chemoreceptors induces NO release in the VLM that buffers sympathoexcitation during hypoxia and contributes to sympathoinhibition during reoxygenation.

Animals↗

PubMed1997

Species differences in the distribution of nitric oxide synthase in brain stem regions that regulate sympathetic activity.

The distribution of nitric oxide synthases (NOS) in the lower brain stem was studied by NADPH-diaphorase staining with emphasis on the nucleus of the solitary tract and the ventrolateral medulla. The order of NOS density was hamster > rabbit = rat > mouse > guinea-pig > cat with little variation within species or between regions. This heterogeneity may partly explain qualitatively and quantitatively variable effects of NO on sympathetic activity in different species.

Animals↗

PubMed1997

Activation of chemosensitive neurons in the ventrolateral medulla by capsaicin in cats.

We examined effects of centrally administered capsaicin on sympathetic nerve activity (SNA), blood pressure (BP) and heart rate (HR) in chloralose anesthetized cats (n = 18). Upon perfusion of the lower brain stem via the left vertebral artery, capsaicin (0.1-1.0 microM) caused dose-dependent increases in preganglionic SNA (recorded from the white ramus T3) that were associated with rises in BP and HR. These responses resembled closely those obtained during perfusions with CO2-enriched (40-80%) saline. Coadministration of capsaicin and CO2 resulted in additively increased responses. The effects of capsaicin, but not those of CO2, were significantly counteracted by the capsaicin antagonist capsazepine and ruthenium red. These results suggest that a specific central chemosensitivity activated by vanilloid receptor agonists may modulate hypercapnic and/or acidic sympathoexcitatory stimuli in vivo.

Analysis of Variance↗

PubMed1997

Neuronal nitric oxide reduces sympathetic excitability by modulation of central glutamate effects in pigs.

Mechanisms of the modulation of sympathetic activity by neuronal NO were studied in vagotomized anesthetized pigs. Inhibition of neuronal NO synthase (nNOS) within the brain stem by intracerebroventricular (ICV) administration of 7-nitroindazole (7-NI, 1 mmol/L) or S-methyl-L-thiocitrulline (MeTC, 0.1 mmol/L) caused slight increases in renal sympathetic nerve activity (RSNA) but did not affect arterial blood pressure (BP) or cardiac output (CO). However, the sympathoexcitatory effects of glutamate (0.5 mL, 0.1 mol/L ICV) that were associated with marked increases in BP, CO, and heart rate were potentiated by both nNOS inhibitors. Furthermore, 7-NI and MeTC significantly enhanced the responses of RSNA, BP, and CO to activation of somatosympathetic reflexes via stimulation of the left greater sciatic nerve (nervus ischiadicus, 10 to 20 V, 30 Hz, 1-millisecond pulses). Subsequent systemic inhibition of either the neuronal (by 7-NI) or all isoforms of NOS by NG-nitro-L-arginine-methyl ester (20 mg/kg) had no significant additional effects on these responses. The effects of NOS inhibition were effectively counteracted by the endogenous NOS substrate L-arginine and by S-nitroso-N-acetyl-penicillamine (SNAP), a stable analogue of endogenous S-nitroso factors. Disruption of sympathoinhibitory baroreflex mechanisms by bilateral cutting of the carotid sinus nerves caused increases in RSNA and slightly increased responses to all excitatory stimuli but had no effects on the actions of the NOS inhibitors or SNAP. These results suggest that modulation of glutamate effects by nNOS-derived NO may be an important mechanism by which NO affects sympathetic activity in pigs.

Animals↗

PubMed1996

Lack of nitric oxide sensitivity of carotid sinus baroreceptors activated by normal blood pressure stimuli in cats.

We examined the effects of inhibition of nitric oxide (NO) synthesis and local administration of NO-donors on baroreceptor activity in anaesthetized cats. Baroreceptor activity was assessed by measuring changes in the pulse synchronous carotid sinus nerve discharge in a modified blind sack preparation. Within physiological mean arterial blood pressure (BP) ranges (BP = 70-150 mmHg), neither abluminal (in a pool around the carotid sinus, n = 15) nor intravascular (via the A. lingualis, n = 10) administration of the NO-synthase inhibitor N(G) nitro-L-arginine (L-NNA, 30 mu M) significantly modulated baroreceptor activity. The NO donors S-nitroso-N-acetylpenicillamine, sodium nitroprusside and glyceryltrinitrate caused significant decreases in baroreceptor activity only when applied intravascularly at concentrations > or = 100 mu M. In contrast, prostacyclin (1 mu M, n = 5) attenuated and indomethacin (10 mu M, n = 5) enhanced baroreceptor activity significantly upon intravascular administration. Baroreceptor activity was also effectively inhibited by gadolinium (Gd(3+), 1 mM). These results suggest that carotid sinus baroreceptor function in cats is rather insensitive to changes in the supply of endogenous or exogenous NO.

Animals↗

PubMed1996

Role of calcium-dependent K+ channels in the regulation of arterial and venous tone by nitric oxide in pigs.

Effects of inhibition of calcium-dependent potassium channels (K+Ca channels) on the regulation of arterial and venous tone by nitric oxide (NO) were studied in anaesthetized pigs following vagotomy and blockade of autonomic ganglia. Selective inhibition of K+Ca channels by charybdotoxin (CTX, 2 microg/kg iv) or iberiotoxin (IbTX, 1 microgram/kg) significantly augmented mean total peripheral resistance (TPR) to levels 30-60% above control. Venous and pulmonary vascular tone were assessed by changes in effective compliances of the venous (EVC) and pulmonary (EPC) vascular beds as calculated from changes in central venous and diastolic pulmonary arterial blood pressure during haemorrhagia (-5 ml/kg) and hypervolaemia (+5 ml/kg). Blockade of K+Ca channels significantly decreased both EVC (-20 to -30%) and EPC (-30 to -50%). Both CTX and IbTX significantly diminished the vasodilation caused by the NO-donor S-nitroso-N-acetylpenicillamine (SNAP) both during control conditions and following experimental vasoconstriction induced by systemic inhibition of NO-synthesis by NG-nitro-L-arginine methyl ester (L-NAME) or infusion of vasoconstrictor agonists. Dilator effects of the adenosine 3',5'-cyclic monophosphate (cAMP)-dependent agonist adenosine were only slightly reduced. However, blockade of K+Ca channels did not increase vasoconstriction induced by L-NAME significantly. These results suggest that activation of vascular K+Ca channels is an important mechanism by which NO attenuates the constrictor tone of resistance and capacitance vessels in vivo.

Angiotensin II↗

PubMed1995

Effects of nitric oxide on sympathetic baroreflex transmission in the nucleus tractus solitarii and caudal ventrolateral medulla in cats.

We have previously shown that nitric oxide (NO) attenuates baseline sympathetic tone in the rostral ventrolateral medulla (RVLM), while having no effects on baroreflex transmission in this region in cats. In the present study, we tested the effects of microinjections (500 nl) of NG-nitro-L-arginine (L-NNA, 0.3 mM) or the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 10 microM) in the nucleus tractus solitarii (NTS) and in the caudal ventrolateral medulla (CVLM) which are the two other relays of the sympathetic baroreflex within the brainstem. Neither L-NNA nor SNAP significantly changed the length of inhibition of renal sympathetic nerve activity (SNA) evoked by electrical stimulation of the ipsilateral carotid sinus nerve. In contrast, glutamate (1 mM) in the NTS markedly increased baroreflex inhibition of SNA and the glutamate receptor antagonist kynurenate (5 mM) in the CVLM significantly decreased baroreflex transmission in the same experiments. These results suggest that sympathetic baroreflex function is preserved during both impaired endogenous synthesis and excess exogenous supply of NO in the brainstem.

Animals↗

PubMed1995

Inhibition of basal and reflex-mediated sympathetic activity in the RVLM by nitric oxide.

We examined possible functional roles for nitric oxide (NO) in the rostral ventrolateral medulla (RVLM), which is the final area for integration of sympathetic nerve activity (SNA) within the brain stem. Chloralose-anesthetized cats were completely baro- and chemoreceptor denervated, the RVLM was exposed for microinjections, and preganglionic SNA was recorded from the white ramus of the 3rd thoracic segment. Injections of NG-nitro-L-arginine (L-NNA), an inhibitor of NO synthase, but not of NG-nitro-D-arginine, caused distinct increases in SNA and arterial blood pressure (BP). Excitatory somatosympathetic reflex amplitudes evoked by electrical stimulation of the 4th intercostal nerve were significantly increased by L-NNA whereas inhibitory responses to baroreflex activation by stimulation of the carotid sinus nerve were not affected. The effects of L-NNA were counteracted by the NO-donor compounds glyceryltrinitrate and S-nitroso-N-acetylpenicillamine, which decreased BP and SNA below control values at higher doses. These results suggest that endogenous NO, in addition to its peripheral actions, modulates the central nervous control of cardiovascular functions by reduction of basal sympathetic tone and by attenuation of excitatory reflex responses.

Animals↗

PubMed1994

Excitatory somato-sympathetic reflexes are relayed in the caudal ventrolateral medulla in the cat.

The caudal ventrolateral medulla (CVLM) modulates sympathetic outflow from the rostral ventrolateral medulla (RVLM). We studied the possible role of the CVLM in the transmission of excitatory somato-sympathetic reflexes in baro- and chemoreceptor denervated chloralose-anesthetized cats. Neurotoxic doses of kainate, injected in the CVLM, caused marked increases in baseline sympathetic nerve activity (SNA) and arterial blood pressure (BP). Concomitantly, excitatory somato-sympathetic reflex responses evoked by electrical stimulation of the 4th intercostal nerve disappeared almost completely. Similar effects on SNA and BP but not on somato-sympathetic reflexes were observed when the GABA-antagonist bicuculline was injected in the RVLM. Bicuculline injected in the RVLM after kainate had no additional effects. These results suggest that in addition to a tonic GABA-ergic inhibition on the RVLM, the CVLM controls somato-sympathetic reflex transmission through interneurons located in this region.

Animals↗

PubMed1994

Somato-sympathetic reflex transmission in the ventrolateral medulla oblongata: spatial organization and receptor types.

Tonic sympathetic activity in vivo is continuously modulated by inhibitory and excitatory reflex mechanisms. We studied the properties of somato-sympathetic excitatory reflex transmission in the rostral ventrolateral medulla (RVLM) of baroreceptor-denervated and vagotomized chloralose-anesthetized cats. Electrical stimulation of the left intercostal nerve of the 4th thoracic segment (IC-T4) elicited an early spinal and a late supraspinal reflex in the ipsilateral white ramus T3 from which recordings were made. Bilateral cooling of the ventral surface of the RVLM reversibly reduced the supraspinal reflex amplitude to 18.0 +/- 3.1% of control (100%). The spinally evoked reflex was enhanced to maximally 154.7 +/- 5.3%. Cooling of only the ipsilateral side of the RVLM was nearly equieffective in both, suppressing the supraspinal and enhancing the spinal reflex component. In contrast, cooling of the contralateral side had no significant effects on supraspinal reflex transmission but caused slight increases of the spinal reflex amplitudes. Similar effects were obtained by microinjection (RVLM) of the glutamate antagonist kynurenic acid (5 x 10(-3) M, n = 7) and the specific non-NMDA receptor antagonist CNQX (4 x 10(-3) M, n = 4) which, however, blocked the supraspinal reflex less effectively. These results demonstrate that the RVLM represents an essential relay in the transmission of both somatosympathetic reflex components. The experiments further suggest an almost completely ipsilateral neuronal pathway for the supraspinal reflex component which projects from the RVLM to the intermediolateral cell column (IML). The descending inhibition of the spinal reflex, however, receives neuronal inputs from the contralateral side.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1994

Reduced nitric oxide formation causes coronary vasoconstriction and impaired dilator responses to endogenous agonists and hypoxia in dogs.

We investigated the relative contribution of basal and agonist stimulated EDRF/NO release to the adjustment of coronary tone and myocardial perfusion in conscious dogs by inhibiting coronary endothelial NO formation with NG-nitro-L-arginine methyl ester (L-NAME). Chronically instrumented conscious dogs (n = 9) were prepared for measurement of mean arterial blood pressure (MAP), heart rate (HR), coronary blood flow (CF) and diameter of the left circumflex (CDLC) and left anterior descending (CDLAD) coronary artery, respectively. Intracoronary infusions of L-NAME (30.3 mM; 0.25 ml x min-1) caused significant increases in MAP and decreases in HR. CDLC decreased by 3.8% from 3.01 +/- 0.04 to 2.90 +/- 0.04 mm and CF decreases by 30% from 12.9 +/- 0.2 to 9.1 +/- 0.2 (aU). Peak reactive hyperemia (CFmax) evoked by 20-s-lasting occlusions of the left circumflex coronary artery decreased from 29.9 +/- 0.8 to 25.8 +/- 1.0 aU and maximal flow-dependent coronary dilation were reduced from 2.04 +/- 0.08 to 0.91 +/- 0.12% after inhibition of NO-synthesis. Intracoronary infusions of acetylcholine (ACh), adenosine (Ado), bradykinin (Bk), and papaverine (Pap) caused dose-dependent increases in CDLC and CF. Infusion of L-NAME nearly abolished the dilator effect of Ado on CDLC and reduced those to ACh, Bk and Pap. Increases in CF to ACh, Ado and Bk but not to Pap were reduced by L-NAME. Subsequent intracoronary infusions of L-arginine (303 mM; 0.25 ml x min-1) reduced L-NAME-induced CF-changes partly, but did not reverse coronary constriction. These results suggest that inhibition of the continuous release of nitric oxide markedly reduces myocardial perfusion in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Low dose calcium-antagonism compensates for impaired myocardial blood supply resulting from deficient nitric oxide synthesis.

Coronary artery disease (CAD) has been documented to be usually associated with endothelial dysfunction. Thus, the present experiments were performed to investigate whether non-hypotensive doses of calcium antagonists can compensate for the effects of deficient endogenous formation of nitric oxide (NO) in the coronary vascular bed in vivo. In chronically instrumented conscious dogs (n = 6) which were prepared for the measurement of coronary blood flow (CBF), coronary diameter of the left circumflex artery (LCX), mean arterial blood pressure (MAP) and heart rate (HR), continuous intravenous infusions of 0.2 micrograms/kg/min nisoldipine (NI) or 2.0 micrograms/kg/min diltiazem (DT) were performed after intracoronary pretreatment with either vehicle or the inhibitor of NO synthesis NG-nitro-L-arginine methyl ester (L-NAME, 6 mg/kg). NI dose-dependently increased CBF up to a maximum of +74 +/- 7.5% from control, while LCX diameter and HR were not significantly affected. MAP fell slightly (-5 +/- 3 mmHg). The maximum CBF increase in response to diltiazem at 10-fold higher doses was +39 +/- 13% while MAP fell -12 +/- 2 mmHg at the highest cumulative dose (100 micrograms/kg). HR and LCX diameter remained unaltered. Pretreatment with L-NAME caused marked hypertension and bradycardia, associated with reduction in CBF (-34 +/- 16%) and LCX diameter (-9.5 +/- 0.8%). Subsequent infusion of NI or DT increased CBF up to the control values obtained before L-NAME. In contrast, both calcium antagonists failed to reverse the effects on MAP or HR.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Endothelium dependent vasomotor responses to endogenous agonists are potentiated following ACE inhibition by a bradykinin dependent mechanism.

OBJECTIVE: The aim was to investigate the effects of angiotensin converting enzyme inhibition on agonist induced endothelium dependent vasodilatation in vivo. METHODS: Chronically instrumented conscious dogs (n = 8) were prepared for the measurement of coronary blood flow, diameter of the left circumflex coronary artery, mean arterial blood pressure, and heart rate. Intracoronary infusions of acetylcholine, adenosine, and bradykinin that induced dose dependent increases in coronary blood flow and diameter were performed with and without intracoronary administration of captopril (1 mg.kg-1) and enalapril (0.4 mg.kg-1). The effects were studied of concomitant inhibition of bradykinin actions by the specific B2 kinin antagonist HOE-140 (10(-7) M), NO-synthesis by NG-nitro-L-arginine-methyl ester (L-NAME, 2 x 10(-5) M), or cyclo-oxygenase by indomethacin (10(-7) M) (all intracoronary). RESULTS: Neither captopril nor enalapril had significant vasodilating effect on the coronary vasculature when given alone. In contrast, both ACE inhibitors potentiated the agonist induced increases in coronary blood flow by bradykinin and acetylcholine (p < or = 0.01). HOE-140 strongly antagonised the effects of infused bradykinin and prevented the potentiation of acetylcholine responses by ACE inhibition. L-NAME caused hypertension and bradycardia and abolished the responses to acetylcholine and adenosine, but only partially attenuated the bradykinin induced increases in coronary blood flow. Simultaneous ACE inhibition reduced the hypertensive effect of L-NAME and partially restored the responses to bradykinin. Indomethacin reduced the responses to bradykinin but did not affect acetylcholine and adenosine induced coronary vasodilatation. The potentiation of the response to acetylcholine induced by ACE inhibition was, however, diminished by indomethacin. CONCLUSIONS: In the coronary vasculature of the dog, ACE inhibitors enhance vasomotor responses to endothelium dependent agonists by facilitating the release of both NO and PGI2, a mechanism which is coupled to endogenously formed bradykinin. ACE inhibitors may thus mediate their effects in vivo partly by increasing the capacity of the endothelium to release autacoids.

Acetylcholine↗

PubMed1994

Novel organic nitrates are potent dilators of large coronary arteries with reduced development of tolerance during long-term infusion in dogs: role of the sulfhydryl moiety.

The vasodilator action of organic nitrates can be severely impaired by induction of drug tolerance. A critical depletion of sulfhydryl groups has been proposed to play a key role in impairment of the biotransformation of organic nitrates to nitric oxide (NO). We studied the effects of the new cysteine-containing nitrate SPM-5185 and the corresponding cysteine-free compound SPM-4744 on hemodynamics and large coronary artery dilation in chronically instrumented conscious dogs. Both nitrates caused dose-dependent increases of the diameter of the left circumflex artery (LCX); the cysteine-containing compound SPM-5185 however, caused such increases at < or = 30-fold lower doses as compared with SPM-4744. Coinfusion of the cysteine-containing analogue of SPM-5185 lacking the nitrate group (SPM-5267) did not alter the dose-response relationship to SPM-4744. Continuous infusion of SPM-5185 (4 micrograms/kg/min, n = 6) and SPM-4744 (2.7 micrograms/kg/min, n = 5) elicited LCX diameter increases of 0.24 +/- 0.06 and 0.17 +/- 0.07 mm, respectively, representing 60-70% of maximal dilator capacity. In contrast to classic organic nitrates, both SPM-5185 and SPM-4744 caused LCX diameter to decrease only slightly during 5-day infusions. Both compounds elicited sustained dilation even at day 5 (p < or = 0.05). SPM-5185 caused an initial decrease in mean arterial pressure (MAP) and evoked sustained increases in heart rate (HR), whereas SPM-4744 had no significant peripheral effects. On withdrawal of SPM-5185, LCX diameter was decreased below pretreatment values for several hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗