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H M Piper

Publications and source records attributed to H M Piper.

At least 73 records · Page 4Linked to original sources
PubMed1998

Atrial natriuretic peptide clearance receptor participates in modulating endothelial permeability.

The atrial natriuretic peptide (ANP)-C receptor is generally believed to clear ANP; however, the ANP-C receptor may serve to reduce cAMP by inhibiting adenylate cyclase. ANP decreases endothelial permeability in coronary endothelial cell monolayers. We tested the hypothesis that part of this effect might be mediated by the ANP-C receptor. We used an endothelial cell monolayer from rat coronary endothelium and measured albumin flux. We applied either ANP or a ring-deleted ANP (C-ANP), which only stimulates the ANP-C receptor. ANP and C-ANP both decreased permeability from 100 pM to 100 nM by 60 and 30%, respectively. ANP increased endothelial cGMP contents 5.5-fold, whereas C-ANP had no effect. ANP reduced endothelial cAMP contents by 75%, which was only partly blocked by pertussis toxin. C-ANP also reduced cAMP; however, this effect was completely blocked by pertussis toxin. Protein kinase G inhibition blocked the ANP-mediated decrease in permeability by 50%. In contrast, pretreatment with pertussis toxin, in the face of protein kinase G inhibition, blocked the effect completely. C-ANP decreased permeability by half the amount of ANP. This C-ANP effect was completely blocked by pertussis toxin but not by protein kinase G inhibition. Isoproterenol (10 microM) increased permeability by almost 50%, which was completely blocked by ANP but only partially blocked by C-ANP. The C-ANP effect was blocked completely by pertussis toxin. Isoproterenol increased cAMP threefold, which was abolished by ANP. C-ANP reduced the isoproterenol-induced increase in cAMP by 50%. Isoproterenol had no effect on cGMP. We conclude that agonist binding to the ANP-C receptor inhibits cAMP production via a Gi protein-coupled signaling system. This inhibition may contribute to the decreased endothelial permeability evoked by ANP in this system.

Animals↗
PubMed1997

Halothane protects cardiomyocytes against reoxygenation-induced hypercontracture.

BACKGROUND: Resupply of oxygen to the myocardium after extended periods of ischemia or hypoxia can rapidly aggravate the already existing injury by provoking hypercontracture of cardiomyocytes (acute reperfusion injury). Previous studies indicated that halothane can protect ischemic-reperfused myocardium. The aim of the present study was to analyze on the cellular level the mechanism by which halothane may protect against reoxygenation-induced hypercontracture. METHODS AND RESULTS: To simulate ischemia-reperfusion, isolated adult rat cardiomyocytes were incubated at pH 6.4 under anoxia and reoxygenated at pH 7.4 in the presence or absence of 0.4 mmol/L halothane. Reoxygenation was started when intracellular Ca2+ (measured with fura 2) had increased to > or = 10(-5) mol/L and pHi (BCECF) had decreased to 6.5. Development of hypercontracture was determined microscopically. In the control group, reoxygenation provoked oscillations of cytosolic Ca2+ (72+/-9 per minute at fourth minute of reoxygenation) accompanied by development of hypercontracture (to 65+/-3% of end-ischemic cell length). When halothane was added on reoxygenation, Ca2+ oscillations were markedly reduced (4+/-2 per minute, P<.001) and hypercontracture was virtually abolished (90+/-4% of end-ischemic cell length, P<.001). Halothane did not influence the recovery of pHi during reoxygenation. Similar effects on Ca2+ oscillations and hypercontracture were observed when ryanodine (3 micromol/L), an inhibitor of the sarcoplasmic reticulum Ca2+ release, or cyclopiazonic acid (10 micromol/L), an inhibitor of the sarcoplasmic reticulum Ca2+ pump, were applied instead of halothane. CONCLUSIONS: Halothane protects cardiomyocytes against reoxygenation-induced hypercontracture by preventing oscillations of intracellular Ca2+ during the early phase of reoxygenation.

Anesthetics, Inhalation↗
PubMed1997

Effects of PTH-rP(107-111) and PTH-rP(7-34) on adult cardiomyocytes.

We investigated whether parathyroid hormone-related peptide (PTH-rP), recently found expressed in the heart, exerts growth and contractile effects on adult cardiomyocytes from rat hearts. Synthetic PTH-rP peptides were used covering either a protein kinase C (PKC)-activating domain [PTH-rP(107-111)], or an adenylate cyclase activating domain [PTH-rP(1-34) and PTH-rP(7-34)]. PTH-rP(107-111) (1 micro M) increased creatine kinase BB activity (CK-BB), a CK isoform re-expressed during cardiac hypertrophy, within 24 h by 62+/-12%. This induction was abolished in the presence of the mitogen-activated-protein (MAP)-kinase-kinase inhibitor PD 98059. PTH-rP(107-111) activated p42-MAP-kinase within 15 min, increased protein synthesis (19+/- 4%), total protein mass (19+/-5%), cell volume (45+/-7%), and cross-sectional area (38+/-9%) of cardiomyocytes. Activation of p42-MAP-kinase and increase in protein synthesis were abolished in presence of bisindolylmaleimide, a PKC inhibitor. PTH- rP(107-111) did not directly influence contractile activity but reduced the contractile response to isoprenaline. In contrast, PTH-rP(1-34) and PTH-rP(7-34) induced spontaneous contractile activity in 3-day-old cultures. This induction was abolished in presence of Rp-cAMPS, a protein kinase A inhibitor, indicating an involvement of cAMP in this response. PTH-rP(1-34) also increased the cellular accumulation of cAMP. It is concluded that PTH-rP exert direct effects on adult cardiomyocytes by activating either PKC via a functional domain covered by amino acids 107-111 or by activation of cAMP-dependent protein kinase via a functional domain covered by amino acids 7-34. Since these parts of PTH-rP have either no homology [PTH-rP(107-111)] or only a limited structural similarity [PTH-rP(7-34)] to parathyroid hormone, these activities of PTH-rP have to be clearly distinguished from those described for parathyroid hormone.

Animals↗
PubMed1997

Prevention of ischemic rigor contracture during coronary occlusion by inhibition of Na(+)-H+ exchange.

OBJECTIVE: To determine the effect of Na(+)-H+ exchange blockade on ischemic rigor contracture and reperfusion-induced hypercontracture. METHODS: Thirty-six pigs were submitted to 55 min of coronary occlusion and 5 h reperfusion. Myocardial segment length analysis with ultrasonic microcrystals was used to detect ischemic rigor (reduction in passive segment length change) and hypercontracture (reduction in end-diastolic length). RESULTS: Pretreatment with the new, highly selective Na(+)-H+ exchange inhibitor HOE642 before occlusion reduced ischemic rigor (P < 0.05), attenuated segment shrinkage (P < 0.05) during subsequent reperfusion, dramatically reduced infarct size (P < 0.0001) and attenuated arrhythmias (P < 0.01). Inhibition of Na(+)-H+ exchange only during reperfusion by means of direct intracoronary infusion of HOE642 into the area at risk prevented reperfusion arrhythmias but had no effect on final infarct size, while treatment with intravenous HOE642 immediately before reperfusion had no detectable effects. CONCLUSION: These results indicate that inhibition of Na(+)-H+ exchange during ischemia is necessary to limit myocardial necrosis secondary to transient coronary occlusion, and that this action could by mediated by a protective effect against ischemic contracture. Inhibition of Na(+)-H+ exchange only during reperfusion has a partial and transient beneficial effect, but only when the inhibitor reaches the area at risk before reflow.

Animals↗
PubMed1997

Dual role of cGMP in modulation of macromolecule permeability of aortic endothelial cells.

The effect of guanosine 3',5'-cyclic monophosphate (cGMP) on cytosolic Ca2+ dynamics and associated alterations in macromolecule permeability was investigated in cultured monolayers of aortic endothelial cells. Addition of the membrane-permeable cGMP analogue 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP, 5 x 10(-4)M) or activators of the soluble (3-morpholinosydnonimine, 10(-5) M) or the particulate guanylyl cyclase (atrial natriuretic peptide, 10(-7) M) to unstimulated monolayers led to a decrease in permeability (8-BreGMP: 62 +/- 8% of control) without affecting low basal cytosolic Ca2+ concentration ([Ca2+]i, 87 +/- 8 nM). In contrast, under conditions of elevated [Ca2+]i (503 +/- 95 nM) and increased permeability (155 +/- 7% of control) induced by 10(-6) M ionomycin, 8-BrcGMP, 3-morpholinosydnonimine, or atrial natriuretic peptide provoked a further increase in permeability (8-BrcGMP: 255 +/- 27%). These agents failed to increase permeability when added before or after the ionomycin-triggered transitory rise in [Ca2+]i. The increase in permeability in response to 8-BrcGMP was due to a secondary further rise in [Ca2+]i (758 +/- 87 nM), which was abolished in the absence of extracellular Ca2+, indicating influx of exogenous Ca2+ as the cause. Changes in [Ca2+]i and permeability were inhibited, in the presence of the Rp diastereomer of 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphothioate (2 x 10(-5) M), an inhibitor of the cGMP-dependent protein kinase. These findings show that, depending on [Ca2+]i, cGMP can play opposite roles in endothelial permeability in one and the same cell preparation.

Animals↗
PubMed1997

ANP protects against reoxygenation-induced hypercontracture in adult cardiomyocytes.

It was investigated whether atrial natriuretic peptide (ANP) or the related peptide urodilatin can be used for protecting cardiomyocytes against reoxygenation-induced hypercontracture. Isolated ventricular cardiomyocytes (from adult rats) were used as the experimental model. When the cells were submitted to substrate-free anoxia (135 min) and subsequent reoxygenation (30 min), the onset of reoxygenation provoked their hypercontracture. It was studied whether the temporary presence of ANP or urodilatin (1 nM to 1 microM) or 8-bromo-guanosine 3',5'-cyclic monophosphate (8-BrcGMP; 1 microM to 1 mM) during the last 15 min of anoxia and the first 15 min of reoxygenation prevented hypercontracture. It was found that ANP (1 microM) prevented hypercontracture in 82 +/- 8% (SD), urodilatin (1 microM) in 80 +/- 9%, and 8-BrcGMP (1 mM) in 72 +/- 10% of the cells (n = 40 cells). When ANP (1 microM) was added during the last 15 min of anoxia and the first 15 min of reoxygenation, the cellular concentration of cGMP increased from 0.41 +/- 0.04 to 2.80 +/- 0.81 pmol/mg protein (n = 6 cultures). The results show that the reoxygenation-induced hypercontracture in cardiomyocytes can be attenuated by the temporary presence of the stimulators of particulate guanylate cyclase, ANP or urodilatin.

Aerobiosis↗
PubMed1997

Vinculin phosphorylation and barrier failure of coronary endothelial monolayers under energy depletion.

We studied the hypothesis that, in energy-depleted endothelial cells, Ca(2+)-dependent activation of protein kinase C (PKC) causes phosphorylation of vinculin and that this effect is involved in the early loss of endothelial barrier function. Vinculin localization and phosphorylation, PKC activity, and albumin permeability were studied in cultured coronary endothelial monolayers from rats. Ten minutes after the onset of metabolic inhibition by 5 mM potassium cyanide and 5 mM 2-deoxy-D-glucose, immunofluorescence of vinculin at cell-to-cell and cell-to-matrix contacts faded, whereas total cellular vinculin content remained unchanged. During the same time period, vinculin phosphorylation at tyrosine and serine sites increased by 3.9- and 3.5-fold, respectively. Vinculin phosphorylation was related to activation of PKC and an unidentified tyrosine kinase and was elicited by a rise in cytosolic Ca2+ within energy-depleted endothelial cells. Conditions inhibiting vinculin phosphorylation also reduced monolayer permeability induced by energy depletion. These data indicate that vinculin phosphorylation is involved in the progression of hyperpermeability during energy depletion in coronary endothelial monolayers.

Animals↗
PubMed1997

Simulated ischemia increases the susceptibility of rat cardiomyocytes to hypercontracture.

The hypothesis that rat cardiomyocytes become susceptible to hypercontracture after anoxia/reoxygenation was investigated. The cells were gradually overloaded with Ca2+ after different periods of simulated ischemia (substrate-free anoxia, medium at pH 6.4) followed by 20 minutes of reoxygenation. The cytosolic Ca2+ concentration (measured with fura 2) at which the cells developed maximal hypercontracture (Camax) was used as an index for their susceptibility to hypercontracture (SH). SH was increased in cardiomyocytes after prolonged periods of simulated ischemia; ie, these cells developed hypercontracture at significantly lower cytosolic Ca2+ levels than did normoxic cells (Camax, 0.80 +/- 0.05 mumol/L versus 1.27 +/- 0.05 mumol/L; P < .01). To find the possible cause of increased SH, the influence of Ca2+ overload, acidosis, and protein dephosphorylation were studied. Prevention of cytosolic Ca2+ overload in anoxic cardiomyocytes or imitation of ischemic acidosis in normoxic cells did not influence Camax. In contrast, use of 10 mumol/L cantharidin (inhibitor of protein phosphatases 1 and 2A) during anoxic superfusion prevented the reduction of Camax. Furthermore, treatment of normoxic cardiomyocytes with 20 mmol/L of the chemical phosphatase 2,3-butanedione monoxime reduced Camax. Therefore, prolonged simulated ischemia increases susceptibility of cardio-myocytes to hypercontracture. This seems to be due to protein dephosphorylation.

Acidosis↗
PubMed1996

Parathyroid hormone-related protein antagonizes the action of parathyroid hormone on adult cardiomyocytes.

Ventricular cardiomyocytes have been identified as target cells for parathyroid hormone (PTH). A structurally related peptide hormone, parathyroid hormone-related peptide (PTH-rP), is expressed in the heart. In the present study, it was investigated whether PTH-rP can mimic or modify effects of PTH on cardiomyocytes. The investigated effect was induction of creatine kinase (CK) activity, which is associated with cardiac hypertrophy. PTH and PTH-rP have a similar secondary structure within the active domain 28 34, with exception of amino acid 29. At this position the hydrophilic glutamine in the PTH molecule corresponds to hydrophobic alanine in the PTH-rP molecule. Synthetic PTH or PTH-rP peptides covering domain 28 34 and recombinant full-length PTH(1 84) were used. PTH(28 48) (100 nm) induced CK activity within 24 h (123 +/- 3%; means +/- S.D., n = 4). PTH-rP(7-34) (1 nm to 1 microm) failed to induce CK activity in cardiomyocytes. Given simultaneously, PTH-rP (1 mum) reduced the stimulation of CK activity by PTH(1-84), PTH(1-34), and PTH(28-48) by 94 +/- 9, 79 +/- 8, and 69 +/- 14%, respectively (means +/- S.D., n = 4). In contrast, PTH-rP(7-34) was sufficient to stimulate proliferation of chicken chondrocytes. Thus, PTH-rP exerts different effects on cardiomyocytes and classical target cells for PTH. A synthetic hybrid peptide was synthesized, [Ala29]PTH(28-48), in which alanine replaced glutamine at position 29, as in the PTH-rP molecule. In contrast to PTH(28-48), this mutated peptide [Ala29]PTH(28-48) had no intrinsic activity but antagonized the effect of PTH(1-84) and PTH(28-48) on cardiomyocytes. The results demonstrate that on cardiomyocytes the effect of PTH can be antagonized by PTH-rP. This antagonism seems due to a hydrophobic replacement at position 29.

Animals↗
PubMed1996

Myocardial segment shrinkage during coronary reperfusion in situ. Relation to hypercontracture and myocardial necrosis.

We have investigated the changes in myocardial segment length induced by reperfusion, and their relation to myocyte hypercontracture and contraction band necrosis. Regional wall function was monitored by ultrasonic gauges in 39 pigs submitted to 48-min occlusion of the left anterior descending coronary artery (LAD) and 6h of reperfusion. Infarct size (triphenyltetrazolium reaction), the extent of contraction band necrosis (quantitative histology) and myocardial water content (desiccation) were measured. Reperfusion induced a marked reduction in end-diastolic length of the LAD segment in all animals, maximal within 15 min after reflow. After 30 min of reperfusion, end-diastolic length of the LAD segment remained below the basal value in 15 animals. The 15 animals that showed shrinkage of the reperfused segment did not differ from the remaining animals in heart rate, aortic pressure, or control segment variables, but had larger infarcts (mean +/- SEM: 32.1 +/- 5.4 vs 12.1 +/- 3.2% of the area at risk, P = 0.003). There was an inverse correlation between end-diastolic length of the LAD segment after 30 min of reperfusion and infarct percentage (r = -0.72) or the extent of contraction band necrosis (r = -0.71). End-diastolic length reduction was more pronounced in larger infarcts despite a more severe myocardial oedema. Neither systolic shortening of the LAD segment nor end-diastolic length or systolic shortening of the control segment, or haemodynamic variables after 30 min of reperfusion correlated to infarct percentage or to the extent of contraction band necrosis. It is concluded that myocardial segment shrinkage during reperfusion reflects myocyte hypercontracture leading to contraction band necrosis.

Animals↗
PubMed1996

Myocardial protection during reperfusion.

After prolonged periods of energy depletion, myocardial cells may rapidly deteriorate during the early stage of reperfusion. It has now been clearly demonstrated that this kind of acute lethal reperfusion injury is due to specific processes elicited by cellular re-energization. The most prominent single cause of acute harm to the reoxygenated myocardial cells is myofibrillar hypercontraction. Hypercontraction is caused by a resupply of energy of the myofibrils at excessive cytosolic Ca2+ concentrations. Additionally, the ability of the cytoskeleton to withstand large mechanical forces seems to be weakened after a prolonged period of energy depletion. Intracellular acidosis during the early stage of reperfusion represents a natural mechanism of protection against acute reperfusion injury. The reperfused myocardial cell may also suffer from uncontrolled water uptake and increased sarcolemmal fragility, favoring osmotic damage of cell membranes. As yet therapeutical interventions trying to specifically interfere with these pathomechanisms of reperfusion injury have only been tested experimentally. It seems promising to evaluate their utility for myocardial protection in cardio-surgical operations.

Acidosis↗
PubMed1996

Functional antagonism between cAMP and cGMP on permeability of coronary endothelial monolayers.

The role of the intracellular second messengers guanosine 3', 5'-cyclic monophosphate (cGMP) and adenosine 3', 5'-cyclic monophosphate (cAMP) in the control of macromolecule permeability was studied in cultured monolayers of microvascular coronary endothelial cells from rat. Macromolecule permeability was determined as passage of fluorescein isothiocyanate (FITC)-labeled albumin across the monolayers. Activation of adenylyl cyclase by the beta-adrenoceptor agonist isoproterenol (Iso; 10(-5) M) and the A2-adenosine receptor agonist 5'-(N-ethylcarboxamido)-adenosine (NECA; 10(-7) M) induced an increase in cellular cAMP contents that was accompanied by an increase in albumin flux. Effects of Iso and NECA on cellular cAMP level and albumin flux could be antagonized by a stimulator of the particular guanylyl cyclase, atrial natriuretic peptide (ANP; 10(-7) M), and stimulators of the soluble guanylyl cyclase, 3-morpholinosydnonimine (SIN-1; 10(-7) M) and sodium nitroprusside (SNP; 10(-6) M). ANP, SIN-1, and SNP also reduced cAMP content and basal macromolecule flux in unstimulated monolayers. 8-Bromoguanosine 3', 5'-cyclic monophosphate (8-BrcGMP; 5 x 10(-6) M), a stimulator of protein kinase G, reduced the increase in albumin flux under Iso (10(-5) M), NECA (10(-7) M), or 8-bromoadenosine 3', 5'-cyclic monophosphate (8-BrcAMP; 5 x 10(-6) M). The present study shows that cGMP and cAMP are functional antagonists in the control of macro molecule permeability.

Adenylyl Cyclases↗
PubMed1996

Protection of reoxygenated cardiomyocytes against osmotic fragility by nitric oxide donors.

In ischemic-reperfused myocardium, myocardial cells are jeopardized not only by reoxygenation-induced hypercontracture but also by the development of a transsarcolemmal osmotic gradient. Here the question of whether osmotic fragility of cardiomyocytes can be reduced by interventions during reoxygenation was addressed. Isolated ventricular cardiomyocytes (from adult rats), exposed to 120 min of hypoxia and subsequent reoxygenation, were used as model. With reoxygenation, medium osmolarity was reduced from 270 to 80 mosM. Loss of sarcolemmal integrity was characterized by enzyme loss from cells (creatine kinase and lactate dehydrogenase). Cardiomyocytes reoxygenated after 120 min of hypoxia hypercontracted, but enhanced enzyme loss was observed only at 80 mosM. The nitric oxide (NO) donors 3-morpholinosydnonimine (10 mM), sodium nitroprusside (10 mM), S-nitroso-N-acetyl-DL-penicillamine (100 microM), and the antilipid peroxidant diphenylphenylenediamine (DPPD, 2.5 microM) reduced enzyme loss with hyposmolar reoxygenation. Agents activating guanosine 3',5'-cyclic monophosphate (cGMP)-dependent pathways [atrial natriuretic peptide (1 microM), urodilatin (1 microM), and 8-bromo-cGMP (10 mM)], the contractile inhibitor 2,3-butanedione monoxime (10 mM), and the SIN-1 metabolite SIN-1C (10 mM) did not protect cardiomyocytes against osmotic fragility. The results show that increased osmotic fragility of isolated adult rat cardiomyocytes can be prevented at the time of reoxygenation by NO donors and DPPD in a cGMP-independent way.

Animals↗
PubMed1996

Neuropeptide Y reduces macromolecule permeability of coronary endothelial monolayers.

The effect of neuropeptide Y (NPY) on cellular adenosine 3',5'-cyclic monophosphate (cAMP) contents and macromolecule permeability was studied in cultured monolayers of microvascular coronary endothelial cells from rat. Macromolecule permeability was continuously determined as passage of albumin across the monolayers. NPY (10(-10)-10(-7) M) decreased albumin flux and cellular cAMP content in a dose-dependent manner, with a half-maximal effect on albumin flux at 1.4 x 10(-9) M and on cAMP contents at 0.7 x 10(-9) M. A maximum effect of NPY was observed at 10(-7) M, decreasing albumin flux by 71 +/- 8% and cellular cAMP contents by 80 +/- 9% (mean +/- SD, n = 6, P < 0.05) compared with control. The effect of NPY on albumin flux was not altered in the presence of 10(-5) M indomethacin (an inhibitor of cyclooxygenase) and 10(-5) M NG-nitro-L-arginine (an inhibitor of nitric oxide synthase). NPY (10(-7) M) also antagonized the increase of albumin flux and cAMP content induced by 10(-6) M isoproterenol. Pretreatment of endothelial monolayers with pertussis toxin (1 microgram/ml for 2 h) abolished the effect of NPY on albumin flux and cAMP contents. This study shows that NPY can modulate macromolecule permeability of endothelial monolayers by reducing the cellular cAMP contents. Together with the effect of pertussis toxin, the data suggest that NPY exerts its antiadrenergic effect on cAMP metabolism and endothelial barrier function by receptors linked to adenylyl cyclase via an inhibitory guanosine-binding protein in coronary endothelial cells.

Adenylate Cyclase Toxin↗
PubMed1996

Low increase in cGMP induced by organic nitrates and nitrovasodilators improves contractile response of rat ventricular myocytes.

Whether organic nitrates are bioactivated to NO in cardiac muscle cells and may thus directly affect cardiac contractile function has remained an open question. Therefore, we determined the effects of the organic nitrates glyceryl trinitrate (100 mumol/L), pentaerythritol tetranitrate (10 mumol/L), and isosorbide-5-mononitrate on electrically stimulated contractile response (CR) and cAMP and cGMP content of isolated adult rat ventricular cardiomyocytes compared with different concentrations of the spontaneous NO donors S-nitroso-N-acetyl-d,1-penicillamine (SNAP) and 2,2-diethyl-1-hydroxy-1-nitroso-hydrazine (DEA/NO). A high concentration of spontaneous NO donors (100 mumol/L caused a large increase in cGMP content that was accompanied by a decrease in CR to 73.8 +/- 6.7% (SNAP) and 80.9 +/- 6.1% (DEA/NO) of the control values. Inhibition of cGMP-dependent protein kinase by 10 mumol/L KT 5822 converted this effect into a pronounced improvement of CR (163.5 +/- 14.0%) By contrast, the organic nitrates caused a small but significant increase in cGMP, which was accompanied by an increase in cAMP and CR identical to that induced by 10 nmol/L isoprenaline (141.6 +/- 6.4%) A similar effect was observed with a low concentration (1 mumol/L of SNAP and DEA/NO. All increases in CR induce by nitrates were abolished after inhibition of cAMP-dependent protein kinase by Rp-cAMPS (10 mumol/L). The positive contractile effect of isoprenaline was enhanced by 1 mumol/L SNAP. This effect was also demonstrated in isolated rat papillary muscles. These results indicate that in cardiac muscle (1) organic nitrate are bioactivated to NO; (2) this results in a moderate increase in cGMP, which causes an improved CR by increasing cAMP and activating cAMP-dependent protein kinase; and (3) a large increase in cGMP, produced by high doses of NO donors, reduces CR because of the activation of CGMP-dependent protein kinase.

Animals↗
PubMed1995

The new NO donor SPM3672 increases cGMP and improves contraction in rat cardiomyocytes and isolated heart.

Recent evidence indicates that organic nitrate esters may directly affect heart muscle. In the present study we investigated the effects of the new organic nitrate ester, N-(3-nitratopivaloyl)-1-cysteineethylester (SPM3672), on isolated adult rat ventricular myocytes and on Langendorff preparations of spontaneously beating rat hearts perfused in a volume-constant manner. In cardiomyocytes SPM3672 (100 microM) induced a significant increase in the basal level of cGMP to 232 +/- 44% (n=8) indicating its metabolism to nitric oxide. This was associated with an enhanced contractile response to electrical field stimulation (to 174 +/- 9%, n=108). In isolated hearts SPM3672 elicited a slight reduction of coronary perfusion pressure (-15 +/- 8%) and a significant increase in maximal left ventricular pressure (LVPmax), dp/dtmax and dp/dtmin amounting to 18 +/- 7%, 18 +/- 6% and 21 +/- 7% (n=7), respectively. Oxygen consumption and heart rate remained constant. Thus, SPM3672 improved the contractile response of cardiomyocytes and of isolated heart. This is probably due to the metabolism of SPM3672 to nitric oxide in ventricular cardiomyocytes.

Animals↗