Jean-François Giudicelli

Influence of Chronic Angiotensin-converting Enzyme Inhibition on Anesthetic Induction

BackgroundSeveral cases of hypotension have been reported in patients who received angiotensin-converting enzyme inhibitors (ACEIs) before a surgical procedure, suggesting that interactions between ACEIs and anesthesia may be neither beneficial nor predictable. To determine if continuation of ACEI therapy until the morning of surgery leads to an unacceptable decrease in blood pressure on induction, we investigated 51 vascular surgical patients that were chronically treated for hypertension with either captopril or enalapril. MethodsAfter randomization, ACEI therapy was either continued until the morning of surgery or stopped at the time of the preanesthetic visit, at least 12 h (captopril) or 24 h (enalapril) before surgery. Each patient received a standardized anesthetic induction. If systolic blood pressure (monitored using a radial artery cannula) decreased to less than 90 mmHg in response to induction, ephedrine was administered. ResultsA marked decrease in plasma converting-enzyme activity was found in patients who received enalapril until the morning of the surgical procedure, and 100% of them required ephedrine after induction. In patients who received their usual dose of captopril on the morning of surgery, plasma converting-enzyme activity was reduced to a lesser extent (when compared with patients who received enalapril). Finally, in the patients in whom ACEI therapy, either enalapril or captopril, was stopped of the evening before surgery, the incidence of induction-induced hypotension was significantly less when enalapril or captopril therapy has been discontinued. ConclusionsThese data indicate that in hypertensive patients chronically treated with ACEIs, maintenance of therapy until the day of surgery may increase the probability of hypotension at induction.

Cardiovascular effects of 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (ST 115): II. Central sympathetic structures

Abstract In order to discover whether 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (ST 155) has a central site of action, the influence of the drug on spontaneous discharges of sympathetic nerves, and on evoked discharges elicited by chemostimulant drugs or electrical stimulation of sympathetic structures of the brain stem was investigated. In dogs, ST 155 induced bradycardia and hypertension which was usually followed by hypotension. Discharges in splanchnic and inferior cardiac nerves were strikingly reduced or even abolished by ST 155, recovery appearing sometimes after three hours. The site of action appeared to be central because the phenomenon was also observed in debuffered dogs. However, activity in sympathetic nerves could still be evoked by chemo receptor stimulating drugs. Injected intracisternally, ST 155 induced a decrease in blood pressure and a reduction in sympathetic discharges. In cats, the same reduction of spontaneous electrical activity of sympathetic nerves was observed. In addition, increase in blood pressure and evoked discharges induced by hypothalamic and medullary pressor areas stimulation were decreased, but the effects of supramaximal stimulation were not modified. In rats, action potentials in the splanchnic nerve, as well as the evoked discharges elicited by hypothalamic and medullary stimulations were reduced by ST 155. ST 155 appears to be a very potent inhibitor of the spontaneous sympathetic centre in the brain stem, but is less effective on reflexly or centrally evoked discharges.

Centrally mediated decrease in sympathetic tone induced by 2(2,6-dichlorophenylamino)-2 imidazoline (S.T. 155, Catapresan)

Abstract 2(2, 6-dichlorophenylamino)-2 imidazoline hydrochloride (S.T. 155) induced in dogs a long lasting hypotension following a brief increase in blood pressure. At low doses, S.T. 155 decreased strikingly the discharges in the splanchnic and inferior cardiac nerves; this was also obtained in debuffered animals. This reduced sympathetic tone appeared to be the cause of the fall in blood pressure.

Cardiovascular effects of 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (ST 155): I. Peripheral sympathetic system

Abstract The effects of 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (ST 155) have been investigated on the peripheral sympathetic system. ST 155 induced an initial rise in blood pressure in normal and reserpinized or adrenalectomized animals, a contraction of the nictitating membrane of cats and isolated seminal vesicles of guinea pigs and a vasoconstriction in isolated ears of rabbits: all these actions were abolished by phentolamine, suggesting that ST 155 exerts these effects by direct stimulation of α-adrenergic receptors. No β-adrenergic blocking properties could be demonstrated. Low doses of ST 155 potentiated but higher doses decreased or even reversed the hypertensive actions of adrenaline and noradrenaline. The effects of the stimulation of the whole sympathetic system in pithed rats were reduced by ST 155, but the preganglionic stimulation of the nictitating membrane remained unaltered. These results are discussed and it is concluded that although ST 155 induced a certain degree of α-adrenergic blockade, this effect is not sufficient to account for the hypotensive action of the drug.

Effects of long-term angiotensin II AT1 receptor blockade on survival, hemodynamics and cardiac remodeling in chronic heart failure in rats

OBJECTIVE The beneficial effect of chronic angiotensin I converting enzyme (ACE) inhibition on survival has for long been established in the rat post-infarction model of chronic heart failure (CHF) and has subsequently been confirmed in humans. This study investigates in rats whether chronic angiotensin II AT1 receptor blockade shares with ACE inhibition the same beneficial effect. METHODS Rats we subjected to coronary artery ligation and, from 7 days later, orally treated for 7.5 months with placebo or irbesartan (5 or 50 mg/kg/day). RESULTS Irbesartan dose-dependently increased survival (placebo: 27%, low dose: 52%, high dose: 82%, sham-ligated: 100%; high dose vs placebo: P < 0.001 and vs low dose: P < 0.05; low dose vs placebo: P = 0.11). Irbesartan also dose-dependently decreased urinary cyclic GMP excretion throughout the study. At 7.5 months, it dose-dependently decreased left ventricular (LV) end diastolic pressure. normalized LV pressure maximal rate of rise (dP/dt) and cardiac index values and improved LV and right ventricular regional blood flows (radioactive microspheres) and resistances. At 7.5 months, irbesartan markedly decreased myocardial hypertrophy but had almost no effect on LV dilatation and subendocardial fibrosis. CONCLUSIONS Long-term angiotensin II AT1 receptor blockade with irbesartan strongly and dose-dependently increases survival in the rat model of coronary ligation-induced CHF. This effect is due to the combination of the beneficial effects that the drug exerts on systemic and coronary hemodynamics, on cardiac pump function and vs cardiac hypertrophy development. Long-term AT1 receptor blockade might thus prove useful and prolong survival in human CHF.

Role of tissue kallikrein in the cardioprotective effects of ischemic and pharmacological preconditioning in myocardial ischemia

Tissue kallikrein (TK), a major kinin‐forming enzyme, is synthesized in the heart and arteries. We tested the hypothesis that TK plays a protective role in myocardial ischemia by performing ischemia‐reperfusion (IR) injury, with and without ischemic preconditioning (IPC) or ACE inhibitor (ramiprilat) pretreatment, in vivo in littermate wild‐type (WT) or TK‐deficient (TK−/−) mice. IR induced similar infarcts in WT and TK−/−. IPC reduced infarct size by 65% in WT, and by 40% in TK−/− (P<0.05, TK−/− vs WT). Ramiprilat also reduced infarct size by 29% in WT, but in TK−/− its effect was completely suppressed. Pretreatment of WT with a B2, but not a B1, kinin receptor antagonist reproduced the effects of TK deficiency. However, B2 receptor‐deficient mice (B2−/−) unexpectedly responded to IPC or ramiprilat like WT mice. But pretreatment of the B2−/− mice with a B1 antagonist suppressed the cardioprotective effects of IPC and ramiprilat. In B2−/−, B1 receptor gene expression was constitutively high. In WT and TK−/− mice, both B2 and B1 mRNA levels increased several fold during IR, and even more during IPC+IR. Thus TK and the B2 receptor play a critical role in the cardioprotection afforded by two experimental maneuvers of potential clinical relevance, IPC and ACE inhibition, during ischemia.

Losartan's protective effects in stroke-prone spontaneously hypertensive rats persist durably after treatment withdrawal.

Summary: The effects of long-term oral administration of losartan on the occurrence of stroke and on mortality were investigated in young salt-loaded stroke-prone spontaneously hypertensive rats (SHR-SPs) during the treatment period (5–20 weeks of age) and up to 8 weeks thereafter. Two doses of losartan, 1 and 10 mg/kg/day, were investigated, which afforded no and only moderate antihypertensive effects, respectively. During the treatment period, losartan at both doses completely suppressed stroke and mortality and strongly opposed (low dose) or abolished (high dose) the increases in saline intake, diuresis, and proteinuria observed in controls. It markedly limited (low dose) or abolished (high dose) vascular fibrinoid necrosis formation in the brain, kidneys, and heart. Finally, losartan, especially at the high dose, reduced arterial thickening and glomerular and tubulo-interstitial lesions in the kidneys, as well as arterial thickening, infarction, and fibrosis in the heart. Eight weeks after treatment discontinuation, all animals but one (low dose) were still alive. Vascular fibrinoid necrosis development remained strongly prevented (low dose) or fully suppressed (high dose) in all investigated organs. Finally, cardiac and renal lesions tended to worsen, and proteinuria was noted only in the low-dose group. We conclude that in SHR-SPs, angiotensin II, through AT, receptor stimulation, most likely plays a major role in fibrinoid necrosis formation, vascular proliferative changes, and stroke occurrence and that losartan, most likely independently of its effect on blood pressure, affords a full and long-lasting protection against stroke and mortality both during and after the treatment period.

Vascular reactivity in acromegalic patients: preliminary evidence for regional endothelial dysfunction and increased sympathetic vasoconstriction

Hypertension is found in one‐third of acromegalic patients. An heterogenous distribution of cardiac output has been recently demonstrated in acromegalic patients with an increased blood flow at the level of the upper limb, suggesting that acromegalic patients may have some degree of endothelial dysfunction. Elsewhere, studies involving hypopituitary GH‐deficient adults have shown that GH and/or IGF‐I may have direct effect on endothelial function.

Role of microvascular rarefaction in the increased arterial pressure in mice lacking for the endothelial nitric oxide synthase gene (eNOS3pt

Objectives Mechanisms involved in hypertension in homozygous mice for the defective endothelial nitric oxide synthase gene (eNOS−/−) have not been fully elucidated. As NO is a potent vasodilator agent and possibly promotes angiogenesis, we investigated whether vasoconstriction and/or microvascular rarefaction could explain hypertension in these mice. Methods Immunohistochemistry with mouse monoclonal smooth muscle α-actin antibody was used to detect arterioles, and quantification of arteriolar density was performed in the left ventricle and in the gracilis muscle of 12-week-old male eNOS+/+ and eNOS−/− mice. Haemodynamic parameters – mean arterial pressure (MAP), cardiac index (CI), total peripheral résistance (TPR), myocardial blood flow, muscular blood flow and corresponding resistances – were measured or calculated using the fluorescent microsphere method in basal conditions and after infusion of sodium nitroprusside (SNP) (5 to 150 μg/kg per min) in eNOS−/− mice, compared with eNOS+/+ mice. Results We evidenced a significant decrease in arteriolar density in the heart (−16%, P < 0.02) and in the gracilis muscle (−22%, P < 0.05) in eNOS−/− mice. In basal conditions, eNOS−/− mice developed significant hypertension (MAP = 127 ± 14 versus 77 ± 14 mmHg, P < 0.001) associated with decreased CI (−29%, P < 0.001) and increased TPR (+ 125%, P < 0.001). Coronary and gracilis muscular resistances were increased (by 75 and 89% respectively, P < 0.001) compared with eNOS+/+ mice, whereas myocardial and skeletal muscle tissue blood flows were not affected. After SNP administration (10 μg/kg per min), a dose that did not significantly modify haemodynamic parameters in eNOS+/+ mice, MAP, TPR and regional resistances were normalized in eNOS−/− mice, showing that vasodilation may correct hypertension in eNOS−/− mice. However, under maximal vasodilating conditions, TPR and regional resistances remained significantly higher in eNOS−/− mice than those of eNOS+/+ mice. Conclusion Anatomical and functional results show that both vasoconstriction and arteriolar rarefaction are involved in hypertension of eNOS−/− mice. Indeed, under maximal vasodilation, arterial pressure and TPR remained significantly higher in eNOS−/− mice than in eNOS+/+ mice, evidencing a major role of microvascular rarefaction in this model of hypertension.

Long-term treatment with trandolapril opposes cardiac remodeling and prolongs survival after myocardial infarction in rats

Summary: Long-term treatment with angiotensin I converting enzyme inhibitors (ACEIs) prolongs survival in rats developing congestive heart failure after myocardial infarction (MI). In this experimental model, we investigated at regular intervals the effects of a 1-year oral treatment with trandolapril, a new ACEI, on (a) survival rate and duration and (b) hemodynamic, biological, and cardiac and vascular histomorphological parameters. Control MI rats and sham-operated trandolapril-treated and control rats were simultaneously studied. In MI rats, trandolapril significantly increased the survival rate and duration, increasing the life expectancy by approximately 6 months. It also significantly decreased the arterial blood pressure and increased diuresis. These effects occurred as soon as the treatment was started and persisted throughout the study. Trandolapril significantly limited the development of myocardial hypertrophy, decreasing the heart weight and left ventricular hypertrophic area and increasing the left ventricular myocyte nuclear density, but these effects, starting after 3–6 months, were delayed compared to the hemodynamic ones. Finally, trandolapril limited the development of myocardial (both subendocardial and subepicardial) and aortic fibrosis. It is concluded that the early pre- and afterload effects of trandolapril are initially responsible for its beneficial action on survival, whereas later the drugs antihypertrophic and antifibrotic properties together with persistent hemodynamic effects account for the prolonged survival improvement.