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Biomedical subjects

P Gohlke

Publications and source records attributed to P Gohlke.

At least 37 records · Page 2Linked to original sources
PubMed1997

Antihypertensive and cardioprotective effects after angiotensin-converting enzyme inhibition: role of kinins.

Kinins are potent bioactive peptides formed by the enzymatic action of kallikrein on kininogens. The discovery that angiotensin-converting enzyme, which generates angiotensin II, is also a major degrading enzyme of kinins, gave rise to the hypothesis that kinin potentiation, in addition to angiotensin II reduction, may be involved in the therapeutic actions of angiotensin-converting enzyme inhibitors. Angiotensin-converting enzyme inhibitors have become important drugs in the treatment of hypertension, congestive heart failure, postmyocardial infarction, and diabetic nephropathy. Although angiotensin II reduction appears to be the predominant mechanism of the antihypertensive effect of chronic angiotensin-converting enzyme inhibitor treatment, the role of kinins in the antihypertensive effects of angiotensin-converting enzyme inhibitors seems to be renin dependent and cannot be generalized for all models of hypertension. On the other hand, at least under experimental conditions, various cardioprotective effects of angiotensin-converting enzyme inhibitors appear to be due to the potentiation of endogenous kinins, including improved cardiac function, structural changes following myocardial ischemia, and induction of capillary growth in hypertension-induced left ventricular hypertrophy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Blockade of bradykinin B2 receptors prevents the increase in capillary density induced by chronic angiotensin-converting enzyme inhibitor treatment in stroke-prone spontaneously hypertensive rats.

We investigated the mechanism of action of the ACE inhibitor-induced increase in cardiac capillary length density. Stroke-prone spontaneously hypertensive rats were treated prenatally and up to the age of 20 weeks with the ACE inhibitor ramipril (0.01 and 1 mg/kg per day PO) and the AT1 receptor antagonist losartan (30 mg/kg per day PO). The contribution of endogenous bradykinin potentiation to the ACE inhibitor actions was assessed by cotreatment with the bradykinin B2-receptor antagonist Icatibant (0.5 mg/kg per day, SC via osmotic minipumps) from 6 to 20 weeks of age. At the end of the treatment period, cardiac capillary length density was measured stereologically using the orientator method. The development of hypertension and left ventricular hypertrophy was prevented by high- but not low-dose ramipril and was not affected by chronic bradykinin B2-receptor blockade. Low- and high-dose ramipril significantly increased cardiac capillary length density (3577 +/- 279, n = 11 and 3988 +/- 300 mm/mm3; n = 10; P < .05) compared with vehicle-treated animals (2935 +/- 137 mm/mm3; n = 13). These effects were abolished by chronic bradykinin B2-receptor blockade. The bradykinin antagonist alone was without effect on cardiac capillary length density. Losartan prevented hypertension and left ventricular hypertrophy but did not significantly alter cardiac capillary length density (3429 +/- 309 mm/mm3; n = 7). Our results demonstrate that chronic ACE inhibitor treatment can increase cardiac capillary length density in stroke-prone spontaneously hypertensive rats independently of a reduction in blood pressure or left ventricular hypertrophy. This effect is related to the ACE inhibitor-induced potentiation of endogenous bradykinin since it was prevented by chronic bradykinin B2-receptor blockade and was not observed following antihypertensive treatment with the AT1-receptor antagonist losartan.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Contribution of bradykinin to the cardioprotective action of angiotensin converting enzyme inhibition in hypertension and after myocardial infarction.

Angiotensin converting enzyme (ACE) is identical with kininase II. Besides reducing the production of angiotensin II, inhibition of ACE potentiates the biological actions of endogenous kinins. In hypertension-induced left ventricular hypertrophy, potentiation of endogenous kinins contributes to the improvement of cardiac function and energy metabolism and to capillary proliferation effected by ACE inhibitors. In myocardial infarction (MI), the potentiation of kinins has been shown to be involved in the reduction of infarct size and improvement of cardiac function by ACE inhibition. The cardioprotective actions of ACE inhibition in MI seem to be, in part, mediated by the augmentation of myocardial blood flow, especially in the ischemic region of the heart.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Cardiac and vascular effects of long-term losartan treatment in stroke-prone spontaneously hypertensive rats.

In previous studies in stroke-prone spontaneously hypertensive rats (SHRSP), we demonstrated that early-onset, long-term angiotensin-converting enzyme inhibitor treatment improved cardiac function and metabolism and increased aortic cGMP content even at sub-antihypertensive doses. These effects could be prevented by bradykinin type 2 (B2) receptor blockade with icatibant. In the present study, we studied the effects of long-term oral treatment with the angiotensin type 1 (AT1) receptor antagonist losartan (30 mg/kg per day) on functional and biochemical parameters of the heart and on cGMP content in the aorta in SHRSP treated prenatally and subsequently up to the age of 20 weeks. Losartan prevented the development of hypertension and left ventricular hypertrophy. Cardiac function measured ex vivo in isolated perfused hearts was improved, as demonstrated by significant increases in left ventricular pressure (22.4%), differentiated left ventricular pressure (dP/dtmax) (35.1%), and coronary flow (38%). The release of the intracellular enzymes lactate dehydrogenase and creatine kinase and of lactate into the coronary effluent was reduced by 46.4%, 47.2%, and 63.6%, respectively. In myocardial tissue, the concentrations of glycogen and the energy-rich phosphates ATP and creatine phosphate were increased by 43.2%, 33.1%, and 42.4%, respectively, whereas lactate was decreased by 57.0%. The aortic tissue content of cGMP was increased fivefold. Our results demonstrate that chronic blockade of AT1 receptors with losartan improved cardiac function and metabolism and increased aortic cGMP content in SHRSP to an extent similar to that observed previously after long-term angiotensin-converting enzyme inhibitor treatment at a comparably antihypertensive dose. Prevention of hypertension and cardiac hypertrophy as well as stimulation of non-AT1 receptors are discussed to explain the cardiac and vascular actions of losartan.

Angiotensin Receptor Antagonists↗
PubMed1996

Substrate metabolism, hormone interaction, and angiotensin-converting enzyme inhibitors in left ventricular hypertrophy.

Left ventricular hypertrophy is considered to be an independent risk factor giving rise to ischemia, arrhythmias, and left ventricular dysfunction. Slow movement of intracellular calcium contributes to the impaired contraction and relaxation function of hypertrophied myocardium. Myofibril content may also be shifted to fetal-type isoforms with decreased contraction and relaxation properties in left ventricular hypertrophy. Myocyte hypertrophy and interstitial fibrosis are regulated independently by mechanical and neurohumoral mechanisms. In severely hypertrophied myocardium, capillary density is reduced, the diffusion distance for oxygen, nutrients, and metabolites is increased, and the ratio of energy-production sites to energy-consumption sites is decreased. The metabolic state of severely hypertrophied myocardium is anaerobic, as indicated by the shift of lactate dehydrogenase marker enzymes. Therefore, the hypertrophied myocardium is more vulnerable to ischemic events. As a compensatory response to severe cardiac hypertrophy and congestive heart failure, the ADP/ATP carrier is activated and atrial natriuretic peptide is released to increase high-energy phosphate production and reduce cardiac energy consumption by vasodilation and sodium and fluid elimination. However, in severely hypertrophied and failing myocardium, vasoconstrictor and sodium- and fluid-retaining factors, such as the renin-angiotensin system, aldosterone, and sympathetic nerve activity, play an overwhelming role. Angiotensin-converting enzyme inhibitors (ACEIs) are able to prevent cardiac hypertrophy and improve cardiac function and metabolism. Under experimental conditions, these beneficial effects can be ascribed mainly to bradykinin potentiation, although a contribution of the ACEI-induced angiotensin II reduction cannot be excluded.

Adenosine Diphosphate↗
PubMed1996

Vascular and cardiac protection by ramipril in spontaneously hypertensive rats: prevention versus regression study.

The effect of chronic oral treatment with the angiotensin converting enzyme (ACE) inhibitor ramipril at antihypertensive and sub-antihypertensive doses, on vascular morphology and function as well as left ventricular hypertrophy (LVH) and cardiac capillary length density was investigated in spontaneously hypertensive rats (SHR). Treatment was commenced before hypertension developed (prevention study) or in adult animals with established hypertension (regression study). In both studies, high-dose ramipril reduced ACE activity in plasma, heart and aorta, normalised blood pressure, and prevented LVH or caused regression of LVH. Low-dose ramipril did not prevent the development of hypertension or LVH, but caused an increase in cardiac capillary length density. In adult hypertensive animals, low-dose ramipril did not reduce blood pressure but caused regression of LVH. In both studies, vascular function as tested in the aortic vessels was improved not only after high- but also after low-dose ACE inhibitor treatment: an inhibition of vascular ACE was associated with attenuated vasoconstrictor responses to norepinephrine and enhanced dilator responses to acetylcholine and bradykinin. A reduction of vascular hypertrophy/hyperplasia in the mesenteric vessels was achieved by the antihypertensive dose of ramipril in the prevention but not the regression study. Our data demonstrate that an improvement of vascular function in SHR can be achieved by chronic ACE inhibition with ramipril independently of structural changes and of the antihypertensive action exerted by the drug. LVH was reduced even at a sub-antihypertensive dose of ramipril in the regression but not the prevention study. In the prevention study, however, low-dose ramipril, like high-dose ramipril, was able to protect the heart by preventing cardiac microvascular rarefaction.

Acetylcholine↗
PubMed1996

Angiotensin receptors.

INTRODUCTION: The octapeptide angiotensin II, the potent effector molecule of the renin-angiotensin system, has been implicated in the pathology of hypertension, in cardiovascular diseases like cardiac left ventricular hypertrophy and in structural alterations of the heart such as post-infarct remodelling. ANGIOTENSIN RECEPTORS: The development of highly selective angiotensin II receptor ligands allowed the identification of angiotensin II receptor subtypes, designated AT1, AT2, AT3 and AT4. Most of the known effects of angiotensin II can be attributed to the AT1 receptor (e.g. vasoconstriction, aldosterone and vasopressin release and proliferative effects on vascular smooth muscle and other cells). The AT1 receptor is coupled to G-proteins and engages classical intracellular second messenger systems, for example activation of phospholipase C or inhibition of adenylate cyclase. In contrast, the function and the signal transduction pathways of the AT2 receptor, which exhibits only a 32-34% homology to the AT1 receptor, are so far not fully understood. Coupling of the AT2 receptor to phosphatases and inhibitory actions on AT1 receptor- and growth factor-mediated proliferation in endothelial and other cells as well as induction of neuronal outgrowth in PC12w cells have been demonstrated. Due to its wide distribution in fetal tissues including the central nervous system and its transient reappearance in the adult organism under pathological conditions (for instance after myocardial infarction) the AT2 receptor has been associated with cell differentiation and regeneration. RECEPTOR ANTAGONISTS: The application of orally active AT1 receptor antagonists as antihypertensive drugs has, compared to angiotensin converting enzyme inhibitors, the potential advantage of a more specific renin-angiotensin system inhibition. It is conceivable that the AT2 receptor, left unopposed by AT1 receptor antagonists, contributes to some of the actions of these drugs.

Animals↗
PubMed1995

Chronic low-dose treatment with perindopril improves cardiac function in stroke-prone spontaneously hypertensive rats by potentiation of endogenous bradykinin.

We investigated the effect of chronic angiotensin-covering enzyme (ACE) inhibitor treatment on functional and biochemical cardiac parameters in stroke-prone spontaneously hypertensive rats (SHRsp). Animals were treated prenatally and, subsequently, up to the age of 20 weeks with the ACE inhibitor perindopril (0.01 and 1 mg/kg per day). The contribution of endogenous bradykinin potentiation to the actions of the ACE inhibitor was assessed by co-treatment with the bradykinin B2-receptor antagonist, icatibant (500 micrograms/kg/day s.c.), from 6 to 20 weeks of age and by measurement of myocardial prostacyclin and cyclic guanosine monophosphate (GMP) concentrations. Chronic high-dose treatment with perindopril attenuated the development of hypertension and left ventricular hypertrophy while low-dose perindopril treatment had no effect on these parameters. However, low-dose perindopril improved cardiac function of isolated perfused hearts as demonstrated by an increasing left ventricular pressure and dp/dtmax without change in heart rate. Low-dose perindopril further reduced lactate concentrations and the enzymatic activities of lactate dehydrogenase and creatine kinase in the coronary venous effluent and increased tissue concentrations of glycogen, adenosine triphosphate, and creatine kinase in the myocardium. Concomitant chronic bradykinin receptor blockade abolished all ACE inhibitor-induced effects on cardiac function and metabolism. Cardiac prostacylin concentrations were 3-fold elevated in perindopril-treated animals when compared to vehicle-treated controls, while cardiac cyclic GMP concentrations remained unchanged. Our data demonstrate that chronic ACE inhibitor treatment can improve cardiac function and metabolism independently of the antihypertensive and antihypertrophic drug actions by potentiation of endogenous bradykinin.

Analysis of Variance↗
PubMed1995

Role of bradykinin in the antihypertensive and cardioprotective actions of converting enzyme inhibitors.

Angiotensin converting enzyme inhibitors (ACEIs) not only reduce angiotensin II synthesis but also potentiate endogenous kinins. In addition to their antihypertensive actions, accumulated evidence has demonstrated an improvement by ACEIs of cardiac function, cardiac structural and metabolic status, and myocardial blood flow in conditions such as cardiac ischemia, left ventricular hypertrophy, and myocardial infarction. The mechanisms underlying the antihypertensive and cardioprotective actions of ACEIs are under intensive investigation. A reduction of angiotensin II synthesis is undoubtedly responsible for a major part of the antihypertensive effects of ACEIs. However, in experimental renal hypertension but not in genetic hypertension, bradykinin potentiation has been shown to partially mediate the acute and chronic antihypertensive actions of these drugs. In addition, experimental observations suggest that bradykinin potentiation plays a pivotal role in the cardioprotective effects of ACEIs.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Moexipril, a new angiotensin-converting enzyme (ACE) inhibitor: pharmacological characterization and comparison with enalapril.

The pharmacodynamic profile of the new angiotensin-converting enzyme (ACE) inhibitor moexipril and its active diacid, moexiprilat, was studied in vitro and in vivo. In vitro, moexiprilat exhibited a higher inhibitory potency than enalaprilat against both plasma ACE and purified ACE from rabbit lung. Upon oral administration of moexipril (10 mg/kg/day) to spontaneously hypertensive rats, plasma angiotensin II concentration decreased to undetectable levels, plasma ACE activity was inhibited by 98% and plasma angiotensin I concentration increased 8.6-fold 1 h after dosing. At 24 h, plasma angiotensin I and angiotensin II concentrations had returned to pretreatment levels, whereas plasma ACE activity was still inhibited by 56%. Four-week oral administration of moexipril (0.1-30 mg/kg/day) to spontaneously hypertensive rats lowered blood pressure and differentially inhibited ACE activity in plasma, lung, aorta, heart and kidney in a dose-dependent fashion. Equidose treatment (10 mg/kg/day) with moexipril and enalapril over 4 weeks led to comparable decreases in blood pressure, inhibition of plasma ACE and reduction of plasma angiotensinogen and to a similar attenuation of the pressor responses to angiotensin I and potentiation of the depressor responses to bradykinin. In contrast, ACE inhibition in aorta, heart and lung was significantly greater with moexipril than with enalapril, whereas in the kidney both drugs inhibited ACE activity to a similar extent. In summary, moexipril is an orally active ACE inhibitor that is comparable to enalapril in potency and duration of antihypertensive activity. The results of the present study demonstrate that 1) the antihypertensive potency of a given ACE inhibitor cannot be predicted from its in vitro characteristics and 2) the degree of blood pressure reduction does not correlate with tissue ACE inhibition.

Angiotensin I↗
PubMed1995

Experimental evidence for effects of ramipril on cardiac and vascular hypertrophy beyond blood pressure reduction.

In renal hypertensive rats with pressure overload left ventricular hypertrophy the angiotensin converting enzyme inhibitor ramipril, given in a high blood pressure lowering dose as well as in a low, non-antihypertensive dose, prevented and regressed left ventricular hypertrophy. These beneficial effects were abolished by coadministration of the specific bradykinin receptor antagonist (HOE 140) in the prevention--but not in the regression studies. Vascular function of rats with pressure overload left ventricular hypertrophy was impaired, whereas treated animals showed a reversal to normal. The angiotensin II subtype AT1 receptor antagonist, losartan, was barely active in the prevention, however markedly active in the regression of left ventricular hypertrophy. From these experimental studies in rats with pressure overload left ventricular hypertrophy and vascular dysfunction we conclude that inhibition of bradykinin degradation induced by ramipril may contribute to the antihypertrophic action during the prevention phase, whereas attenuation of angiotensin II formation may be more important during the regression period. In another model, the spontaneously hypertensive rat (SHR and stroke prone SHR)--a non-renal hypertensive model--cardiac left ventricular hypertrophy could be reduced by chronic high-dose ramipril treatment in prevention and regression studies, whereas the low dose regimen only reduced left ventricular hypertrophy in the regression experiments. In addition, both doses improved the myocardial capillary supply to the heart leading to improved function and metabolism. In comparison, vascular hypertrophy of the mesenteric artery could only be prevented by early-onset high dose treatment with the angiotensin converting enzyme inhibitor but not once hypertrophy has been established.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors.

From pharmacological investigations and clinical studies, it is known that ACE inhibitors exhibit additional local actions that are not related to hemodynamic changes and that cannot be explained only by interference with the renin-angiotensin system by means of an inhibition of ANG II formation. Because ACE is identical to kininase II, which inactivates the nonapeptide BK and related kinins, potentiation of kinins might be responsible for these additional effects of ACE inhibitors. ACE inhibition, concentration, and time dependently increased the formation of NO and PGI2 in cultured endothelial cells of different origin and from different species, including humans. The specific B2 kinin receptor antagonist, icatibant, suppressed the ACE inhibitor-induced increase in endothelial cyclic GMP accumulation index for NO-formation and, in parallel, attenuated the increase in PGI2 release. In renovascular models of hypertension associated with a stimulated renin-angiotensin system (two-kidney, one-clip), blood pressure reduction by ACE inhibitors was attenuated by icatibant, whereas in rats with genetic hypertension with normal to low plasma renin, blood pressure reduction through ACE inhibitors was not affected. In experimental atherosclerosis in rabbits, ACE inhibitors were able to preserve endothelial function and vascular reactivity and to reduce surface involvement. In the balloon denudation model of carotid arteries in rats, it was found that ACE inhibition markedly reduced neointima formation. However, when the ACE inhibitor was given together with icatibant, its effect was significantly blunted. Perfusion with ACE inhibitors induced a reduction of the incidence, as well as of the duration, of ventricular fibrillation and improved cardiodynamics and myocardial metabolism. BK perfusion induced comparable cardioprotective effects. In addition, perfusion with ACE inhibitors markedly increased the outflow of BK and related kinins from isolated rat hearts. The antiischemic effect of ACE inhibitors and BK were abolished by the addition of L-NNA (1 x 10(-6) mol/l) or icatibant (1 x 10(-9) mol/l). Similar results were found in dogs and rabbits with myocardial infarction. BK and related kinins also seem to be involved in preconditioning and remodeling. The effect of ACE inhibition in LVH was investigated in rats made hypertensive by aortic banding. ACE inhibition with ramipril, in the antihypertensive dose of 1 mg/kg/day for 6 weeks, prevented the increase in blood pressure and the development of LVH. A lower, nonantihypertensive dose of the ACE inhibitor (10 micrograms/kg/day for 6 weeks) had no effect on the increase in blood pressure or on plasma ACE activity, but also prevented LVH after aortic banding.4+ off

Amino Acid Sequence↗
PubMed1994

Release of angiotensin in the paraventricular nucleus in response to hyperosmotic stimulation in conscious rats: a microdialysis study.

Angiotensin peptides are thought to act as neurotransmitters or neuromodulators in central osmoregulation. We tested the hypothesis that angiotensin peptides are released in the paraventricular nucleus (PVN) of the hypothalamus upon local osmotic stimulation. Brain microdialysis and radioimmunoassay (RIA) techniques were used to measure the release of immunoreactive angiotensin II (irANG II) in the PVN following direct stimulation of this area with hyperosmotic solutions. In conscious rats, perfusion of the PVN with 0.3 M and 0.6 M NaCl in artificial cerebrospinal fluid (aCSF) elicited concentration-dependent increases in irANG II release to 5.52 +/- 0.53, (P < 0.01, n = 8) and 9.01 +/- 1.03 pg/100 microliters, (P < 0.001, n = 7), respectively, from basal values of 3.04 +/- 0.46 pg/100 microliters. Local perfusion of the PVN with 1.2 M glucose in aCSF also resulted in an increased release of irANG II from 3.07 +/- 0.87 to 6.24 +/- 0.45 pg/100 microliters (P < 0.05, n = 5). Fractionization of angiotensin peptides by HPLC followed by RIA revealed that ANG II (1-8) and ANG III (2-8) were released in similar amounts in the perfusate collected during 0.6 M NaCl stimulation (4.79 +/- 0.69 and 3.45 +/- 0.76 pg/100 microliters, respectively). Our results show that both, ANG II and ANG III are released in the PVN in response to local hyperosmotic stimulation. They support the concept that angiotensin peptides in the PVN are involved as neurotransmitters in central osmotic control.

Angiotensin II↗
PubMed1994

Effect of low-dose treatment with perindopril on cardiac function in stroke-prone spontaneously hypertensive rats: role of bradykinin.

Angiotensin-converting enzyme (ACE) inhibitors can improve cardiac function independent of their blood pressure (BP)-lowering actions. We investigated the effect of chronic subantihypertensive ACE inhibitor treatment on functional and biochemical cardiac parameters in stroke-prone spontaneously hypertensive rats (SHRSP). Animals were treated in utero and subsequently to age 20 weeks with the ACE inhibitor perindopril (0.01 mg/kg/day). The contribution of endogenous bradykinin (BK) potentiation to the actions of the ACE inhibitor was assessed by cotreatment with the BK beta 2-receptor antagonist Hoe 140 (500 micrograms/kg/day subcutaneously, s.c.) from age 6 to 20 weeks and by measurement of myocardial prostacyclin and cyclic GMP concentrations. Chronic low-dose perindopril treatment had no effect on development of hypertension and left ventricular hypertrophy (LVH), but perindopril improved cardiac function, as demonstrated by increased LV pressure (LVP) (19.4%) and LVdp/dtmax (27.8%) but no change in heart rate (HR). The activities of lactate dehydrogenase (LDH) and creatine kinase (CK) as well as lactate concentrations in the coronary venous effluent were reduced by 39.3, 50, and 60.6%, respectively. Myocardial tissue concentrations of glycogen and the energy-rich phosphates ATP and CK were increased by 16.3, 33.1, and 28.2%, respectively. All ACE inhibitor-induced effects on cardiac function and metabolism were abolished by concomitant chronic BK receptor blockade. Cardiac prostacyclin concentrations were threefold elevated in perindopril-treated animals whereas cardiac cyclic GMP concentration remained unchanged as compared with that of controls. Our data demonstrate that chronic low-dose ACE inhibitor treatment can improve cardiac function and metabolism by potentiating endogenous BK.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1994

Angiotensin converting enzyme inhibition prevents the increase in aortic collagen in rats.

Four groups of 4-week-old spontaneously hypertensive rats were treated during 4 months with the angiotensin converting enzyme inhibitor quinapril at 1 mg/kg per day (Q1) or 10 mg/kg per day (Q10), hydralazine at 15 mg/kg per day (H), or placebo (P). In the first set of experiments, blood pressure was measured in conscious rats, and plasma and aortic angiotensin converting enzyme activities were evaluated. In the second set of experiments, histomorphometric parameters of the thoracic aorta were evaluated. Mean blood pressure was lower in the Q10 and H groups (136 +/- 16 and 149 +/- 11 mm Hg) compared with the P group (190 +/- 23 mm Hg) (P < .01). The Q1 group showed mean blood pressure values (171 +/- 15 mm Hg) lower than the P group (P < .05) but significantly higher than the Q10 and H groups (P < .01 and P < .05, respectively). Aortic medial cross-sectional area was significantly lower in the H and Q10 groups (455 +/- 61 and 487 +/- 57 x 10(3) microns 2) than in the P group (636 +/- 72 x 10(3) microns 2) (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Angiotensin-converting enzyme inhibition improves cardiac function. Role of bradykinin.

The effect of chronic low- and high-dose treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril (0.01 and 1 mg/kg per day) on the development of hypertension and left ventricular hypertrophy as well as on functional and biochemical alterations of the heart was studied in stroke-prone spontaneously hypertensive rats treated prenatally and subsequently up to the age of 20 weeks. The contribution of endogenous bradykinin potentiation to the ACE inhibitor actions was assessed by cotreatment of rats with the bradykinin B2-receptor antagonist Hoe 140 (500 micrograms/kg per day SC) from 6 to 20 weeks of age. High- but not low-dose ACE inhibitor treatment prevented the development of hypertension and left ventricular hypertrophy. Chronic bradykinin receptor blockade did not attenuate the antihypertensive and antihypertrophic actions of ramipril. High-dose ramipril treatment improved cardiac function, as demonstrated by an increase in left ventricular pressure (29.9%), dP/dtmax (34.9%), and coronary flow (22.1%), without a change in heart rate. The activities of lactate dehydrogenase and creatine kinase and lactate concentration in the coronary effluent were reduced by 39.3%, 55.5%, and 66.7%, respectively. Myocardial tissue concentrations of glycogen and the energy-rich phosphates ATP and creatine phosphate were increased by 31.3%, 39.9%, and 73.7%, respectively, whereas lactate was decreased by 20.8%. Chronic low-dose ACE inhibitor treatment led to a pattern of changes in cardiodynamics and cardiac metabolism similar to that observed with the high dose. All ACE inhibitor-induced effects on cardiac function and metabolism were abolished by chronic bradykinin receptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1994

[Cardioprotective effects by ramipril after ischemia and reperfusion in animal experiment studies].

ACE inhibitors induce an increase in kinin levels with subsequent release of nitric oxide (NO) and prostacyclin, as shown in cultured endothelial cells and isolated rat hearts. Isolated perfused working rat hearts continuously release kinins and prostacyclin. During ischemia after ligation of the left coronary artery kinin and prostacyclin concentrations in the venous effluent of the hearts are increased. ACE inhibition with ramiprilat increases kinin concentrations during normoxia, ischemia and reperfusion, whereas deendothelialization markedly reduces kinin and prostacyclin outflow in controls as well as in ACE inhibitor-treated hearts. Rat hearts with postischemic reperfusion arrhythmias are protected by ramiprilat- and bradykinin perfusion, cardiodynamics and metabolism of treated hearts are improved. These effects are observed in concentrations too low to increase coronary flow. The cardioprotective effects of ramiprilat and bradykinin are abolished by the specific B2-kinin receptor antagonist icatibant and by an inhibitor of NO-synthase. Long-term treatment (20 weeks) with ramipril in a blood-pressure-lowering dose (1 mg/kg/day) and a subantihypertensive dose (10 micromg/kg/day) protects spontaneously hypertensive rats (stroke prone) against hypertension and left ventricular hypertrophy in the high dose. In addition, both treatment regimens induce myocardial capillary growth. Isolated hearts of these animals show increased myocardial contractility and coronary flow, reduced release of cytosolic enzymes into the coronary effluent, and improved myocardial metabolism. These changes are observed even at a dose of ramipril which does not affect blood pressure and left ventricular hypertrophy. They are abolished by chronic blockade of kinin receptors with icatibant.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗