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Biomedical subjects

P Gohlke

Publications and source records attributed to P Gohlke.

60 records · Page 4Linked to original sources
PubMed1989

Converting enzyme inhibitors and their effects on the renin-angiotensin system of the blood vessel wall.

A local vascular tissue renin-angiotensin system (RAS) may contribute to blood pressure control and the maintenance of high blood pressure in some forms of hypertension, independently of the plasma RAS. Vascular converting enzyme (CE), present mainly in the endothelial layer of arteries and veins, can be altered in hypertension. Locally generated vascular angiotensin II (ANG II) may exert a number of actions on vascular tone and function, including directly and sympathetically mediated vasoconstriction, changes in vascular compliance in larger vessels, influence on vascular reactions to inflammation and injury, and alterations in vascular texture. Orally administered CE inhibitors have been shown to block not only the plasma RAS but also CE in the vasculature, leading to decreased vascular ANG II concentrations and possibly to an accumulation of locally generated vasodilator peptides and prostaglandins in the vascular wall. In spontaneously hypertensive rats, the slow recovery of CE activity in the vasculature on drug withdrawal was more closely associated with the slow return of blood pressure to hypertensive levels than the fast recovery of the plasma RAS. These and other experimental data discussed in this article favor the hypothesis that local CE inhibition in the vascular wall of resistance vessels, large arteries and veins contributes to the beneficial therapeutic effects of CE inhibitors in cardiovascular disorders such as hypertension and congestive heart failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Inhibition of converting enzyme in brain tissue and cerebrospinal fluid of rats following chronic oral treatment with the converting enzyme inhibitors ramipril and Hoe 288.

A direct central nervous system (CNS)-related component of the cardiovascular actions of converting enzyme (CE) inhibitors will be governed by the ability of these drugs to gain access to the brain. We investigated the inhibitory effect of the two CE inhibitors ramipril and Hoe 288 on CE activity in different brain regions and in the cerebrospinal fluid of rats. One-week oral gavage treatment with ramipril (10 mg/kg/day) and Hoe 288 (10 mg/kg/day) resulted in a marked inhibition of CE activity in the brain cortex (90 and 91%, respectively), the hypothalamus (78 and 82%, respectively), and in the brainstem (67 and 66%, respectively). The complete blockade of plasma CE activity was paralleled by a 84% inhibition of CE activity in cerebrospinal fluid. Both CE inhibitors failed significantly to inhibit CE activity in the striatum. Our results demonstrate that the CE inhibitors Hoe 288 and ramipril were able to pass the blood-brain barrier (BBB) to inhibit central CE activity. The penetration of CE inhibitors into the CNS appears to depend on the lipophilicity of the drugs and on the mode of drug application. The possibility that an inhibition of CE activity in circumventricular organs outside the BBB such as the subfornical organ and the organum vasculosum of the lamina terminalis may be sufficient to explain the central effects of orally applied CE inhibitors is discussed.

Administration, Oral↗
PubMed1989

Inhibition of converting enzyme in the cerebrospinal fluid of rats after oral treatment with converting enzyme inhibitors.

Inhibition of brain converting enzyme (CE) has been implicated in the antihypertensive action of some CE inhibitors. However, it is still a matter of debate whether these drugs gain access to the central nervous system upon systemic administration. In this study in rats we investigated the ability of p.o. applied CE inhibitors to penetrate from blood into cerebrospinal fluid (CSF) by analyzing the inhibition of CE activity in the CSF after acute bolus and after 1 week overnight treatment with enalapril, ramipril and Hoe 288. Penetration into the CSF closely paralleled the lipid solubility of the drugs. The most lipophilic drug, Hoe 288 (10 mg/kg), inhibited CE activity in the CSF after acute (66%) and after chronic (30%) p.o. treatment. Ramipril (10 mg/kg), being less lipophilic than Hoe 288, was only effective after acute bolus administration (59% inhibition), whereas the most hydrophilic drug, enalapril (30 mg/kg), did not reduce CE activity in the CSF after either regimen. The CE inhibition in the CSF after acute p.o. treatment with ramipril and Hoe 288 was dose-dependent with threshold doses of 3 to 10 mg/kg (ramipril) and less than 1 mg/kg (Hoe 288). The presence of ramipril and Hoe 288 in the CSF was also demonstrated by the inhibitory effect of heat-inactivated CSF from CE inhibitor-treated rats on purified CE from rabbit lung. A comparison of the in vitro activities of the three prodrugs and their parent diacids against CE in plasma and in CSF and against purified CE revealed hydrolysis of the prodrugs to their parent diacids in plasma and CSF.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1988

[The renin-angiotensin system: systemic and local function].

The renin-angiotensin system (RAS) has long been known as a hormonal system, which is important for the maintenance of volume homeostasis, and which contributes under certain circumstances to the pathogenesis of hypertension and cardiac failure. More recent findings have demonstrated that the individual components of this system can also be synthesized locally in tissue, e.g. in the brain, the vascular wall, the kidney, the adrenals, and the heart. Although the role of locally generated angiotensin within cardiovascular- and body volume regulation needs to be further investigated, it has already become clear that the mechanism of action of drugs interfering with the RAS is not confined to the circulating RAS, but also includes an interaction with local renin-angiotensin systems. These agents, particularly the converting enzyme inhibitors, have proved to be indispensible tools for elucidating the function of local renin-angiotensin systems, in addition to being therapeutically useful in the treatment of cardiovascular diseases.

Angiotensin II↗
PubMedDate not supplied

Angiotensin converting enzyme inhibitors, left ventricular hypertrophy and fibrosis.

From pharmacological investigations and clinical studies, it is known that angiotensin converting enzyme (ACE) inhibitors exhibit additional local actions, which are not related to hemodynamic changes and which cannot be explained only by interference with the renin angiotensin system (RAS) by means of an inhibition of angiotensin II (ANG II) formation. Since ACE is identical to kininase II, which inactivates the nonapeptide bradykinin (BK) and related kinins, potentiation of kinins might be responsible for these additional effects of ACE inhibitors. a) In rats made hypertensive by aortic banding, the effect of ramipril in left ventricular hypertrophy (LVH) was investigated. Ramipril in the antihypertensive dose of 1 mg/kg/day for 6 weeks prevented the increase in blood pressure and the development of LVH. The low dose of ramipril (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. The antihypertrophic effect of the higher and lower doses of ramipril, as well as the antihypertensive action of the higher dose of ramipril, was abolished by coadministration of the kinin receptor antagonist icatibant. In the regression study the antihypertrophic actions of ramipril were not blocked by the kinin receptor antagonist. Chronic administration of BK had similar beneficial effects in a prevention study which were abolished by icatibant and NG-nitro-L-arginine (L-NNA). In a one year study the high and low dose of ramipril prevented LVH and fibrosis. Ramipril had an early direct effect in hypertensive rats on the mRNA expression for myocardial collagen I and III, unrelated to its blood pressure lowering effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗