Marcel Gerold

Genetically hypertensive rats: relationship between the development of hypertension and the changes in norepinephrine turnover of peripheral and central adrenergic neurons.

SummaryIn genetically hypertensive rats, the norepinephrine turnover of peripheral and central adrenergic neurons was determined either by the decline in endogenous norepinephrine after inhibition of tyrosine hydroxylase or by the decay in the specific activity of norepinephrine after labelling the stores by intravenous or intraventricular injection of3H-norepinephrine.In the periphery (heart and submaxillary gland), the norepinephrine turnover of genetically hypertensive rats was reduced in proportion to the rise in systolic blood pressure. In the hypothalamus, medulla-pons and the residual parts of the brain, the turnover was unchanged both in the prehypertensive and the hypertensive state. The results indicate that the central adrenergic neurons, involved in the control of blood pressure, may act independently from the activity of peripheral baroreceptors. The elevated blood pressure resulting from an enhanced peripheral vascular reactivity to the physiological neurotransmitter norepinephrine may induce a compensatory inhibition of the activity of the peripheral adrenergic neurons. In the genetically hypertensive rats, neither the peripheral nor the central adrenergic nervous system seems to play a primary role in the development of hypertension.

Cardiovascular effects of 6-hydroxydopamine injected into a lateral brain ventricle of the rat

Summary6-Hydroxydopamine (6-OH-DA) was injected into the left lateral brain ventricle of normotensive, DOCA/NaCl or spontaneously hypertensive rats, and its effect on heart rate and blood pressure was studied. A single injection of 250 μg 6-OH-DA or 3 successive administrations of the same dose caused a reduction of noradrenaline content and tyrosine hydroxylase activity in several parts of the brain to 10–50% of the control values, indicating a considerable destruction of central adrenergic neurons. Heart rate and blood pressure decreased within 10 to 20 min after a single intraventricular injection of 6-OH-DA and both parameters returned to normal after 7 h. This effect was equally observed in normotensive and both types of hypertensive rats and regardless of whether the animals were conscious or anaesthetized. It was prevented by a prior intraventricular injection of phentolamine; this suggests that it is mediated by central alpha-adrenoceptors. The 6-OH-DA-induced bradycardia and hypotension were not influenced by a blockade of peripheral muscarinic receptors with scopolamine methylbromide; however, they were accompanied by a decrease of spontaneous discharges in the splanchnic nerve and, therefore, seem to be due to a reduction in peripheral sympathetic tone.The early cardiovascular effects of 6-OH-DA were sometimes followed by a second phase of bradycardia and hypotension. It occurred in normotensive rats 1–2 days after the second or third intraventricular injection of 6-OH-DA, and in spontaneously hypertensive rats already after a single injection. The hypotension of the second phase lasted 5–6 days, the bradycardia showed no recovery during the observation period which was limited to 3 weeks. Such long term cardiovascular effects of intraventricular 6-OH-DA were never observed in DOCA/NaCl hypertensive rats even after repeated administrations of the compound. The results provide evidence for the existence of a central adrenergic regulation of blood pressure and heart rate which seems to differ in normotensive and hypertensive rats.

α2-adrenoceptors in rat resistance vessels

SummaryIn pithed rats increases in blood pressure were induced by i.v. injections of the α1-agonist methoxamine and the α2-agonists clonidine, oxymetazoline and B-HT 920. The pressor responses were further analyzed by repeated measurements of cardiac output with the thermodilution technique and by calculation of total peripheral vascular resistance. During the pressor phase both vascular resistance and cardiac output were found to be elevated. This indicates that increases in both haemodynamic variables contributed to the pressure rise. Under the assumption that elevated vascular resistance reflected constriction of arterioles and elevated cardiac output constriction of capacitance vessels via increased venous return to the heart, and considering that the magnitude of the increase of both haemodynamic parameters was similar for all three agonists, the results suggest the existence of both α1- and α2-adrenoceptors in resistance as well as in capaticance vessels of rats. For α2-adrenoceptors in resistance vessels this conclusion was supported by the finding that the calcium antagonists verapamil and/or tiapamil virtually abolished the increases of blood pressure and vascular resistance in response to clonidine, oxymetazoline or B-HT 920, but not to methoxamine. The calcium antagonists did not affect the increases in cardiac output, irrespective of which type of α-agonist was administered. While the present results support the existence of α2-adrenoceptors in resistance vessels of the rat, they do not allow a firm conclusion as to their occurrence in rat capacitance vessels.

Cilazapril prevents hypertension in spontaneously hypertensive rats

Summary: Chronic daily administration of cilazapril (1 x 10 mg/kg/day p.o., from age 4 to 14 weeks) to young spontaneously hypertensive rats (SHR) prevented the development of hypertension. The antihypertensive effect of a single dose of cilazapril persisted >24 h. Discontinuation of long-term treatment resulted in an increase of systolic arterial blood pressure (SAP) to control hypertensive levels within 4 days. Following 10 weeks of drug administration, comparative hemodynamic studies were carried out on age-matched (14 weeks) control SHR and cilazapril-treated SHR. Cilazapril-treated SHR had a significantly lower mean arterial blood pressure (MAP) and total peripheral vascular resistance than did control SHR. The antihypertensive effect of cilazapril was not associated with changes in heart rate (HR). The myocardial performance parameters, cardiac output, and stroke volume, were similar in treated and control SHR, suggesting that the antihypertensive effect of cilazapril following chronic administration to SHR is mainly due to a reduction in peripheral vascular resistance. Vasopressor responses to angiotensin I were significantly lower in cilazapril-treated SHR than in control SHR. By contrast, pressor responses to angiotensin II and a high dose of norepinephrine (1.0 μg/kg i.v.) were significantly enhanced. Isoproterenol elicited a fall in blood pressure in both groups, the extent of which was dependent upon the magnitude of basal blood pressure levels. Chronic cilazapril treatment resulted in a reduction of heart weight, suggesting that the drug may prevent development of cardiac hypertrophy in SHR. Kidney and adrenal weights were unaffected by the chronic treatment. Specific renin activities (SRA) in tissues of SHR were increased by factors of 20 (plasma) or 2 (kidney and adrenal) following cilazapril administration. Five weeks after discontinuation of drug treatment, near normal values of SRA were reached, suggesting that chronic administration of cilazapril is associated with reversible changes in the renin-angiotensin system (RAS) of SHR.

Increased levels of prostaglandin-like material in the canine blood during arterial hypotension produced by hydralazine, dihydralazine and minoxidil.

Summary1.Indomethacin completely reversed within 15 min the hypotension produced by hydralazine or dihydralazine in anaesthetized dogs. Acetylsalicylic acid, diclofenac sodium and flufenamic acid inhibitors of prostaglandin synthesis structurally dissimilar to indomethacin — had the same effect. Pretreatment of anaesthetized dogs with indomethacin prevented in part the hypotension in response to a subsequent injection of hydralazine.2.The development of hypotension in response to hydralazine or dihydralazine was paralleled by an increase in the concentration of prostaglandin-like (PG-like) material in the renal venous blood as determined with the blood bathed organ technique. PG-like material increased to a lesser extent, also in the femoral venous and in the aortic blood. Subsequent injection of indomethacin reduced PG-like material in the blood to levels no longer detectable by bioassay and reversed the hypotension produced by either of the two vaso-active antihypertensives.3.Hydralazine and dihydralazine raised also the blood levels of angiotensin II. While there was no decrease in the elevated concentrations of PG-like material at 3 h after the injection of hydralazine, angiotensin II levels started to fall after 1 h and at 2 h an increase was no longer detected.4.Pretreatment of the dogs with the betaadrenoceptor blocking agent propranolol had no major influence on the hydralazine-induced hypotension and on the induced appearance of PG-like material in the renal venous blood.5.Although hydralazine raised the levels of PG-like material in the renal venous blood more than in femoral venous or aortic blood, exclusion of both kidneys from the circulation did not modify the hypotensive effect of the drug.6.While the infusion of neither PGE2 nor PGI2 into the aorta was able to mimic the actions of hydralazine and dihydralazine on both blood pressure and the responses of the blood bathed assay organs, a combined infusion of PGE2 and PGI2 at a ratio of 4:1 was able to do so.7.The hypotension in response to minoxidil —another vasoactive antihypertensive — was also accompagnied by the appearance of PG-like material in the renal venous blood. The increase in PG-like material was, however, smaller than that after hydralazine and dihydralazine in spite of a similar fall in blood pressure, and the hypotensive effect of minoxidil was only partially antagonized by indomethacin. The hypotension in response to the alpha-adrenoceptor blocking drug prazosin, to the adrenergic neurone blocking drug guanethidine, and to the centrally acting clonidine were neither accompagnied by the appearance of PG-like material in the renal venous blood nor influenced by indomethacin.8.In the conscious dog and in the anaesthetized guinea pig indomethacin antagonized the hypotensive action of dihydralazine only partially and in other species such as the rat, the rabbit and the cat — all studied under anaesthesia — failed to affect the drug-induced hypotension.9.The present results suggest that in the anaesthetized dog the hypotensive effects of hydralazine and dihydralazine — and in part of minoxidil — are mediated through vasodilator prostaglandins.

Cardiovascular Effects of the New Angiotensin-Converting-Enzyme Inhibitor, Cilazapril, in Anesthetized and Conscious Dogs

Summary: Cilazapril is a new angiotensin-converting-enzyme inhibitor. In conscious renal-hypertensive dogs, cilazapril (2 × 10 mg/kg/day p.o.) caused a long-lasting (>24 h) decrease in systolic arterial blood pressure, the magnitude of which was potentiated by pretreatment with furosemide. A maximal fall in systolic blood pressure of 39 ± 6 mm Hg (from 145 ± 5 to 106 ± 7 mm Hg) was recorded. The antihypertensive effect did not decline with repeated administration and was accompanied by only a slight increase in heart rate. Cilazapril also reduced systolic blood pressure in furosemide-pretreated normotensive dogs. Hemodynamic studies in anesthetized dogs revealed that cilazapril (0.03–1 mg/kg i.v.) caused a fall in mean arterial and left ventricular systolic pressures. At the highest dose of 1 mg/kg i.v., the blood-pressure-lowering effect (−27%) was due to a decrease in total peripheral resistance (−12%) and cardiac output (−16%). Intravenous administration of cilazapril to anesthetized dogs resulted in a rise in plasma renin activity and a significant fall in plasma angiotensin II levels. In conscious normotensive dogs, cilazapril (0.3–10 mg/kg p.o.) exerted diuretic and saluretic effects, which were accompanied by a significant increase in renal plasma flow (46%), but only a slight rise in the glomerular filtration rate. These results characterize cilazapril as an effective and long-lasting antihypertensive drug, with diuretic activity and, possibly, preload- as well as afterload-reducing properties.

Cardiovascular profile of Ro 13-6438, a novel positive inotropic agent with vasodilating properties

The cardiovascular properties of Ro 13–6438 (R-6-chloro-l,5-dihydro-3-methylimidazo-[2,l b]quinazolin-2[3 H]-one), a novel nonglycoside, noncatechol cardiotonic agent, were investigated in vitro and in vivo by both intravenous and oral administration. Ro 13–6438 increased tension development of isolated guinea pig left atria in a concentration-dependent manner with an ECS50 of 30 μM, but had no stimulant effect on the spontaneous rate of right atria. The positive inotropic effect of Ro 13–6438 was additive to that of ouabain (0.1 μM); Ro 13–6438 suppressed the arrhythmogenic activity of high concentrations of ouabain (10 μM). In anesthetized open-chest dogs 10–300 μg/kg Ro 13–6438 i.v. produced a significant and dose-dependent increase in myocardial contractile force, with a duration of action exceeding 60 min following the highest dose. It also slightly increased heart rate, cardiac output, and coronary blood flow. Ro 13–6438 decreased systolic and diastolic blood pressure, left ventricular end-diastolic pressure, and total peripheral resistance. Thus, the direct positive inotropic effects of Ro 13–6438 were supported by a decrease in preload and afterload. In chronically instrumented, conscious dogs Ro 13–6438 increased myocardial contractility after administration of 0.03–0.3 mg/kg i.v. or 3–10 mg/kg p.o. The effects persisted for >8 h after oral administration of 10 mg/kg. The inotropic effects were accompanied by a modest increase in heart rate, which, however, had a clearly shorter duration of action than the former. The present investigations characterize Ro 13–6438 as a positive inotropic agent with additional vasodilating properties, oral activity, and only weak chronotropic effects. No tachyphylaxis or cumulation was observed.

Cardiovascular effects of tiapamil (Ro 11-1781), a new calcium-entry blocker.

We studied the hemodynamic effects of the new calcium antagonist tiapamil (Ro 11–1781) in anesthetized open-chest dogs and compared them with those of verapamil. Increasing doses of tiapamil injected intravenously caused the following hemodynamic effects: increase in coronary flow and decrease in coronary vascular resistance, followed by decreases in heart rate, blood pressure, and total peripheral resistance. Tiapamil did not depress myocardial contractility over a rather wide dose range, while verapamil did. Tiapamil was more effective in increasing coronary flow than verapamil. Cardiac autonomic denervation did not modify the tiapamil-induced decrease in coronary vascular resistance and did not cause tiapamil to display negative inotropism. Both tiapamil and verapamil reduced the extent of S-T segment elevation in the epicardial electrocardiogram produced by transient occlusion of the left anterior descending coronary artery. Neither drug had this effect when heart rate was kept constant by atrial pacing. In contrast to nitroglycerin. tiapamil dilated small but not large coronary arteries. Tiapamil raised Po2 relatively more in the subendocardial than in the subepicardial layers of the myocardium. The hemodynamic and electrocardiographic effects of tiapamil were not changed by diphenylhydantoin and disopyramide or by pindolol, a β-adrenoceptor blocking agent with intrinsic sympathomimetic activity. However, the decreases in heart rate and blood pressure in response to propranolol were enhanced by tiapamil.

Analysis of cradiac chromotropic responses to diazepam and bromazepam in conscious trained dogs

In conscious trained dogs, administration of bromazepam (0.3 mg/kg p.o.) or diazepam (0.3 and 1.0 mg/kg p.o.) had no influence on heart rate. A higher dose (10 mg/kg p.o.) of two benzodiazepines elicited a positive chronotropic effect which was rapid in onset and of long duration. The beta-adrenoceptor blocking agent practolol (2.5 mg/kg i.v.) did not revert heart rate after the benzodiazepines to the same level as in controls, indicating that the tachycardia was not produced by an increase in sympathetic outflow to the heart. For diazepam, a sympathetic--parasympathetic interaction cannot be excluded. However, diazepam and bromazepam significantly reduced the tachycardia which is normally observed after administration of methylatropine (0.5 mg/kg i.v.) alone or in combination with practolol. In anaesthetized dogs, bromazepam failed to modify the heart rate responses to electrical stimulation of cardiac vagal or sympathetic nerves, excluding an action on this compound on ganglionic transmission and cardiac cholinoceptors and adrenoceptors. It is concluded that high doses of diazepam and bromazepam influence the heart rate of conscious dogs in a biphasic way. Firstly, they cause a central reduction of vagal tone to the heart resulting in tachycardia. Secondly, the two drugs decrease the cardiac pacemaker rate directly. Since the overall effect is tachycardia, the central action is more pronounced.

Implantable Blood Pressure Telemetry System

A telemetry system for long-term monitoring of the blood pressure of unrestrained animals is described. The wholly implantable transmitter is equipped with a pressure transducer suitable for chronic intravascular use. To achieve high performance and long battery life, a greater number of components were used than in conventional implantable devices. Pulse interval modulation is used with a mean sampling rate significantly higher than twice the maximum signal frequency. Together with a controlled pulse window in the receiver, an effective reduction of ignition spark interferences with the weak transmitted signal could therewith be achieved.