Renal Hypertensive Dogs Research Articles

P-280) - Antihypertensive effects of RS-4045 in renal hypertensive dogs

P-280) - Antihypertensive effects of RS-4045 in renal hypertensive dogs

Basal and maximal inotropic state in renal hypertensive dogs with cardiac hypertrophy.

We studied three isovolumic indexes of contractility, i.e., dP/dtmax, dP/dtDP40, and (dP/dt)/TPmax, in normal dogs and in a matched group of chronically hypertensive dogs with left ventricular hypertrophy (LVH) [DP40, developed LV pressure of 40 mmHg; TP, total LV pressure above atmospheric]. The LVH was moderate in degree with the LV-to-body weight ratio 50% greater than in normal dogs. The experiments were performed under pentobarbital with open chest, autonomic blockade, and independent control of mean left atrial pressure (LAP) and mean aortic pressure (MAP). We found that dP/dtmax provided the most consistent comparison of inotropic state in the two groups under both basal conditions and with norepinephrine (NE). The other indexes occurred too early in systole to reflect complete LV activation, particularly during the infusion with NE. Under controlled conditions basal dP/dtmax of LVH dogs was 1.28 times the value of normal dogs, with the increase accounted for by the amplifier effect of the increase in LV mass. But with moderate lowering of aortic pressure, inotropic state was more easily compromised in LVH than in normal dogs. With steady-state stimulation by infusing increasing amounts of NE, dP/dtmax rose by 10 times basal in both LVH and normal dogs at maximum stimulation. The absolute value of the index was 1.31 times higher in the LVH group, with the amplifier effect thus the same as under basal conditions. The results suggest that basal and maximal inotropic states are normal in LVH under optimum loading conditions.

Echocardiographic evidence for increased cardiac performance during early renal hypertension in dogs.

Cardiac function early (less than 4 weeks) in the course of experimental renal hypertension was investigated. In 11 male mongrel dogs, one kidney was wrapped in silk to produce two-kidney, one-wrapped hypertension. Two weeks later, the contralateral kidney was removed. Five sham-wrapped and then contralaterally-nephrectomized dogs served as controls. M-mode left ventricular (LV) echocardiograms were recorded twice weekly in all dogs for 4 weeks before and for 2 weeks after wrapping (or sham-wrapping) and for 4 weeks after nephrectomy. In the 11 hypertensive dogs, mean arterial pressure (MAP) rose from 127 mm Hg (mean) to 143 two weeks after wrapping (p less than 0.05) and to 185 two weeks after nephrectomy (p less than 0.001). The fractional shortening of the left ventricle (% delta D) of hypertensive dogs was increased (9% maximum, mean, p less than 0.01) for 2 weeks after wrapping and for one week after nephrectomy. Two weeks after wrapping, LV end-systolic wall stress calculated from femoral artery peak systolic pressure, end-systolic dimension and wall thickness was unchanged, suggesting that increased myocardial contractility accounted for the findings. In normotensive control dogs, there were no echocardiographic changes during the study.

Effects of Nadolol, a new beta-adrenoceptor blocking agent, on blood pressure and renal function in experimental hypertensive animals.

Nadolol, 2,3-cis-1,2,3,4-tetrahydro-5-{2-hydroxy-3-(tert-butylamino) propoxy}-2,3-naphthalenediol, is a non-selective β-adrenergic blocking agent without intrinsic sympathomimetic and membrane stabilizing activity. The effects of Nadolol on blood pressure and renal function in renal hypertensive dogs(RHDogs, two-kidney two-clip, at 2-3 months after the clipping) and spontaneously hypertensive rats(SHR) were compared with those of other β-blocking agents(Propranolol, Alprenolol and Pindolol). 1) In RHDogs, Nadolol(3 or 10mg/kg/day p.o. for 10 days) showed a long lasting antihypertensive effect and β-blocking activity. Nadolol did not decrease the renal blood flow(RBF), glomerular filtration rate(GFR), urine flow(UF) and urinary Na+ and K+ excretion. However, Alprenolol(20mg/kg/day) and Pindolol (1 or 3mg/kg/day) decreased significantly the RBF and urinary Na+ excretion at 5 hour after administration. 2) In SHR(16 weeks old), Nadolol did not show an antihypertensive activity as with other β-blocking agents. On the other hand, in the SHR provided a low-sodium diet(Na 0.0014%), Nadolol(30 mg/kg p.o.) decreased significantly the blood pressure after single or repeated administration for 4-7 days, the same as other β- blocking agents. 3) With immature SHR(4 weeks old), chronic oral administration of Nadolol (3 or 10mg/kg/day for 8 weeks) suppressed the development of hypertension, but did not influence urinary Na+ and K+ excretion. These results indicated that Nadolol appeared to be a long lasting antihypertensive drug without adverse effects on renal function, and Na-depleted SHR was a suitable model for the evaluation of antihypertensive activity of β-blocking agents.

Cardiovascular effects of methamphetamine in dogs treated chronically with the amine.

Methamphetamine is one of a group of sympathomimetic amines that lower blood pressure upon chronic administration to hypertensive dogs. To determine whether tolerance to the cardiovascular effects of these drugs could play a role in their antihypertensive action, acute blood pressure responses to oral d-methamphetamine were determined in trained conscious renal hypertensive dogs at weekly intervals during treatment with the drug for 2 months. Responses were also obtained in similarly treated normotensive dogs and in normotensive and hypertensive animals receiving l-methamphetamine. Pressor responses to d-methamphetamine in hypertensive dogs remained unchanged throughout treatment, while in all other cases they diminished gradually. Only the dextro isomer reduced blood pressure chronically in the hypertensive group. It was concluded that tolerance is not involved in the antihypertensive effect of methamphetamine and that, considering the stereo specificity of this effect, residual lowering of blood pressure might involve formation of a false mediator metabolite of the amine.

Echocardiographic assessment of left ventricular hypertrophy and function in renal hypertensive dogs.

To investigate the performance of the hypertrophied left ventricle, M-mode echocardiographic measurements were performed 2 to 3 times weekly on 8 unanesthetized dogs for several weeks before and for 6 months after the induction of perinephritic hypertension. Four dogs with sham-wrapping and contralateral nephrectomy served as the controls. From a baseline value of 7.7 +/- 0.4 mm (mean +/- SD), left ventricular wall thickness increased to 9.0 +/- 0.6 mm (p less than 0.001) by the 4th week after the induction of hypertension and reached a plateau of 10.2 +/- 1.2 mm (p less than 0.001) by week 10. Fractional shortening of left ventricular dimension (% delta D) increased during early left ventricular hypertrophy and remained elevated for 6 months in the surviving 6 hypertensive dogs. In hypertensive dogs, left ventricular concentric hypertrophy became detectable by week 6 of hypertension. Control dogs did not show these changes. At autopsy, the left ventricular weight of hypertensive and normotensive control dogs was (6.2 +/- 1.4 g/kg and 4.3 +/- 0.5 g/kg (p less than 0.05). In summary, during the early stage of left ventricular hypertrophy in renal hypertensive dogs cardiac performance increased. There is no evidence for deterioration of left ventricular performance as concentric left ventricular hypertrophy develops and becomes chronic.

Baroreflex control of heart interval in conscious renal hypertensive dogs.

The purpose of this study is to determine if baroreflex control of heart interval is abnormal in conscious dogs with renal hypertension. Changes in heart interval in response to transient nitroglycerin-induced decreases in arterial pressure and transient phenylephrine-induced increases in arterial pressure were determined in nine normotensive [mean arterial pressure 92 +/- 4 (SE) mmHg] and nine renal hypertensive conscious dogs (mean arterial pressure 139 +/- 10 mmHg). Data were acquired before and after beta-adrenergic blockade with 2 mg/kg iv propranolol and before and after parasympathetic blockade with 0.5 mg/kg iv atropine. Control heart rates for the normotensive and hypertensive dogs were not different (91 +/- 4 and 93 +/- 7 beats/min, respectively). Before autonomic blockade, the responses of normotensive and hypertensive dogs to nitroglycerin were not different. However, prolongation of the heart interval in response to phenylephrine in hypertensive dogs was significantly less than in normotensive dogs. In both groups, atropine nearly abolished the decrease in heart interval in response to nitroglycerin and the increase in heart interval in response to phenylephrine, although there were small but significant residual responses. Propranolol was without significant effect on heart interval responses to nitroglycerin and phenylephrine. We conclude that the baroreflex control of heart interval during transient decreases in arterial pressure is preserved in hypertensive dogs and is mediated mainly by decreases in parasympathetic outflow to the heart. In contrast, baroreflex control of heart interval during transient increases in arterial pressure is impaired in hypertension and is mediated mainly by activation of parasympathetic cholinergic mechanisms.

Pharmacological studies on cadralazine: a new antihypertensive vasodilator drug.

Cadralazine is a new, orally effective antihypertensive vasodilator. Acute experiments indicate that the compound reduces blood pressure and increases heart rate. The doses which reduce systolic blood pressure by 25% (ED25) are very similar after oral and intravenous administration (spontaneously hypertensive rats, 1.8 mg/kg, p.o.; 2.3 mg/kg, i.v.; renal hypertensive dogs, 0.26 mg/kg, p.o.; 0.24 mg/kg, i.v.; awake normotensive dogs, 0.98 mg/kg, p.o.; 1.01 mg/kg, i.v.). By both routes the peak effect is reached after 3-5 hr, and the activity lasts more than 24 hr. Repeated oral administration in spontaneously hypertensive rats reduces blood pressure with no evidence of tolerance. Cadralazine reverses hypertensive responses to epinephrine in awake normotensive dogs and anesthetized cats. The inhibition of the increase in blood pressure induced by sympathetic outflow activation in pithed rats parallels the antihypertensive activity in onset, intensity, and duration. The effects of cadralazine are not due to a blockade of alpha-adrenoceptors, sympathetic neurons, or ganglionic transmission. Cadralazine has no antihistaminic, anticholinergic, or spasmolytic activity and no specific effect on behavioral tests. In comparison with hydralazine, cadralazine has less acute toxicity and a greater activity by the oral route.

ChemInform Abstract: ANTIHYPERTENSIVE (2‐AMINOETHYL)THIOUREA DERIVATIVES. 1

AbstractDargestellt werden die Verbindungen (III) und (IV), von denen der Vertreter (III) (R1, R4=Cl, R2, R3=H) sedative und antihypertensive Wirkung besitzt.

Hemodynamic profile of a new antihypertensive agent D,L-3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine (SK&F 92657).

The properties of a new antihypertensive agent, SK&F 92657, D,L-3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine, have been studied. The compound, given intravenously, subcutaneously, or orally, caused a sustained fall in systemic blood pressure of conscious genetically hypertensive rats, normotensive cats, and renal hypertensive dogs. The fall in blood pressure of genetically hypertensive rats was maintained during 52 days of chronic dosing with no development of tolerance. The hemodynamic effects and mechanism of action of SK&F 92657 were investigated in anesthetized cats and dogs using a variety of techniques. Blood pressure was lowered by a direct vasodilator effect on precapillary blood vessels (arteries, arterioles), particularly in the renal, coronary, and skeletal muscle vasculatures, giving an overall decrease in total peripheral resistance with no significant change in cardiac output. In contrast, SK&F 92657 had no significant effect on capacitance blood vessel (veins, venules) tone or on vascular reactivity to vasoconstrictors and consequently did not cause postural hypotension. The beta-adrenoceptor-blocking actions of the drug prevented reflex increases in heart rate and cardiac output, except in the conscious dog, where vagal control of heart rate was predominant. It was also concluded that SK&F 92657 was not acting by alpha-adrenoceptor blockade, ganglion blockade, or inhibition of angiotensin II responses. A "central" action was unlikely, as SK&F 92657 caused vasodilatation in denervated autoperfused vascular beds.

Echocardiographic evidence for early left ventricular hypertrophy in renal hypertensive dogs

Echocardiographic evidence for early left ventricular hypertrophy in renal hypertensive dogs

Synthesis and antihypertensive activity of 5-amino-2-pyridinecarboxylic acid derivatives.

The synthesis of various substituted 5-amino-2-pyridinecarboxylic acids and their derivatives is described by three general methods: (1) reductive alkylation of methyl 5-amino-2-pyridinecarboxylates (2) and subsequent hydrolysis; (2) alkylation of the urethane (9), followed by hydrolysis; and (3) selective NaBH4 reduction of the appropriate amide of (2), followed by hydrolysis. A more specific process was used for the 5-(phenylamino) compound, i.e., nucleophilic displacement of nitrite from methyl 5-nitro-2-pyridinecarboxylate by sodioformanilide and subsequent hydrolysis. Many of these 2-pyridinecarboxylic acid derivatives were potent antihypertensive agents in the spontaneously hypertensive rat (SHR). Optimization of structural parameters for this activity yielded compounds 54, 55, 34, 65, and 22, which were selected for further study in the renal hypertensive dog (RHD). Based on these studies, one compound, 5-[(4-fluorobenzyl)amino]-2-pyridinecarboxylic acid (65), was selected for preclinical toxicity evaluation. Based on the toxicological findings, it was decided not to pursue compound 65 clinically.

Antihypertensive (2-aminoethyl)thiourea derivatives. 1.

Structure-activity studies were carried out on a series of antihypertensive 1-(2-aminoethyl)-3-(substituted phenyl)thioureas. From this class of compounds, the 2,6-dichlorophenyl analogue 2 was found to have potent oral antihypertensive activity in two hypertensive rat models and the renal hypertensive dog. In addition to its effect on blood pressure, 2 displayed sedative effects which had a marked species specificity.

Antihypertensive activity of 16,16-dimethyl-oxa-alkyl-prostaglandins of the PGA 2, PGE 2 and trans-Δ 2-11-deoxy-PGE 1 series: Structure-activity relationships

Utilizing Corey's synthesis, a variety of prostaglandins (PGs) with a modified ω-side chain were prepared. The 16,16-dimethyl-oxa-alkyl analogues of PGA 2 had potent antihypertensive activity. HR 466 (16,16-dimethyl-18-oxa-PGA 2), the best compound out of this series was active for 5–6 hours after oral administration of 0,1 mg/kg to conscious renal hypertensive dogs. The corresponding analogues of PGE 2 were also potent antihypertensive compounds, but were much more spasmogenic. Structural variations within the trans-Δ2-11-deoxy-PGE 1-series, in both side chains, gave HR 601 (trans-Δ2-15α-acetoxy-16,16-dimethyl-18-oxa-11-deoxy-PGE 1-methylester) which was orally active in the hypertensive dog with similar activity to HR 466.

β-adrenoceptor and cardiovascular effects of MJ 13105 (Bucindolol) in anesthetized dogs and rats

This report describes the β-adrenoceptor blocking and cardiovascular activity of MJ 13105 (Bucindolol), an indolyl-tert-butyl substituted phenoxypropanolamine. Increases in heart rate elicited by (a) isoproterenol, (b) stellate ganglion stimulation, and (c) bilateral carotid occlusion were antagonized to the same extent (80%) by a dose as low as 30 μg/kg, i.v. MJ 13105 blocked isoproterenol-induced vasodilator responses in the canine hindlimb. Intra-arterial infusions of MJ 13105 effected dose-dependent decreases in perfusion pressure, which persisted even in the presence of prior β-adrenoceptor blockade. Intravenous administration of MJ 13105 lowered mean arterial blood pressure and total peripheral resistance, and increased heart rate and right ventricular contractile force in the open chest, anesthetized dog. The vasodilator response to MJ 13105 persisted and may have been enhanced following propranolol. In vivo, MJ 13105 demonstrated weak α-adrenoceptor blocking activity in both rat and dog. Inhibition of the α-mediated vasoconstriction was more apparent if phenylephrine, rather than norepinephrine was the agonist. MJ 13105 exhibited intrinsic sympathomimetic activity at β 1-receptors, although its maximum capacity to increase heart rate was less than that of pindolol. Plasma renin activity of anesthetized dogs was elevated following administration of MJ 13105, an effect that was attenuated by propranolol. Oral administration lowered blood pressure of SHR and DOCA-salt hypertensive rats and renal hypertensive dogs, with a concomitant decrease in heart rate of rats and an increase in heart rate of dogs.

Angiotensin II and renal hypertension in dog, rat and man: effect of converting enzyme inhibition.

The role of the renin-angiotensin system in the pathogenesis of one-clip, two-kidney hypertension has been studied in man, dog and rat. Particular attention has been paid to peripheral plasma concentrations of angiotensin II in different circumstances; angiotensin II infusion has been combined with radioimmunoassay to construct angiotensin II/blood pressure dose-response curves. The effect of converting enzyme inhibitors has been studied, precautions being taken to avoid obtaining falsely high values for plasma angiotensin II because of cross-reaction with angiotensin I in these circumstances. The initial phase of one-clip, two-kidney hypertension is attributable to the direct pressor effect of the immediate rise in plasma angiotensin II. Subsequently, plasma angiotensin II is relatively lower, although blood pressure remains high. This upward resetting of the plasma angiotensin II/blood pressure relationship can be mimicked by infusing angiotensin II chronically at low dose. After reconstruction of a stenosed renal artery, or excision of a post-stenotic kidney, the angiotensin II/blood pressure relationship returns slowly to normal. In this second phase of one-clip, two-kidney hypertension, the long-term administration of saralasin, or of converting enzyme inhibitor, can also return arterial pressure to normal; brief administration of these drugs is less effective or ineffective. The results are compatible with, although they do not conclusively establish, an important slow pressor action of the renin-angiotensin system in the second phase of one-clip, two-kidney hypertension. This provides a rational basis for the use of captopril clinically in this condition.

Hemodynamic, fluid, and electrolyte changes in sodium-depleted, one-kidney, renal hypertensive dogs.

HomeCirculation ResearchVol. 44, No. 3Hemodynamic, fluid, and electrolyte changes in sodium-depleted, one-kidney, renal hypertensive dogs. Free AccessAbstractPDF/EPUBAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessAbstractPDF/EPUBHemodynamic, fluid, and electrolyte changes in sodium-depleted, one-kidney, renal hypertensive dogs. G A Stephens, J O Davis, R H Freeman, J M DeForrest and D M Early G A StephensG A Stephens Search for more papers by this author , J O DavisJ O Davis Search for more papers by this author , R H FreemanR H Freeman Search for more papers by this author , J M DeForrestJ M DeForrest Search for more papers by this author and D M EarlyD M Early Search for more papers by this author Originally published1 Mar 1979https://doi.org/10.1161/01.RES.44.3.316Circulation Research. 1979;44:316–321 Previous Back to top Next FiguresReferencesRelatedDetails March 1, 1979Vol 44, Issue 3Article InformationMetrics Download: 73 Copyright © 1979 by American Heart Associationhttps://doi.org/10.1161/01.RES.44.3.316 Originally publishedMarch 1, 1979 PDF download Advertisement

Antihypertensive Effects of a Combination of a Diuretic and a β-Adrenoceptor Blocking Agent in Conscious, Renal Hypertensive Dogs

The influence of a diuretic, clorexolone and a β-adrenoceptor blocking agent, alprenolol, alone and in combination, on blood pressure, heart rate and serum angiotensin II and aldosterone levels were examined in 5 conscious renal hypertensive dogs. Clorexolone (10 mg/kg p.o., twice a day) caused a slight increase in heart rate, and a gradual decrease in blood pressure which became significant after the second day of treatment (p<0.05). The mean reduction in systolic blood pressure by clorexolone alone was about 15 mm Hg. Addition of alprenolol (10 mg/kg p.o., twice a day) induced a further rapid decrease in arterial blood pressure and there was a tendency toward decrease in the increased heart rate. The mean decrease in systolic blood pressure was about 26 mm Hg and such was highly significant in comparison with that exerted by clorexolone alone (p<0.025). After withdrawal of clorexolone and final replacement of alprenolol with lactose, the decreased blood pressure gradually returned to the initial value. Increases in serum angiotensin II and aldosterone levels seen after clorexolone alone declined to the initial value when alprenolol was given in combination with clorexolone. The antihypertensive effect of this combination is attributed mainly to the inhibition of renin-angiotensin-aldosterone system, to decrease in circulating blood volume, and in part to decrease in the heart rate.

Characteristics of single carotid sinus baroreceptor fibers and whole nerve activity in the normotensive and the renal hypertensive dog.

SUMMARY Carotid sinus baroreceptor nerve activity was examined in eight renal hypertensive dogs with a duration of hypertension of 5 to 82 days and a mean blood pressure of 148 ± 0.5 mm Hg. These results were compared with those from 13 normotensive dogs. Whole carotid sinus nerve activity and single fiber activity were recorded in the isolated carotid sinus preparation in response to controlled static and pulsatile pressures. Stimulusresponse curves were constructed. Single fiber adapted (5-second) threshold pressure under static pressure conditions increased from 104 ± 3.2 mm Hg in the normotensive dogs to 128 ± 3.9 mm Hg in the hypertensive dogs. Inflection pressure and plateau pressure also were higher in hypertension. Impulse frequency at the inflection pressure was reduced from 39 ± 2.3 impulses/sec in normotensive dogs to 32 ± 1.7 impulses/sec in hypertensive dogs and, at the plateau pressure, from 43 ± 2.1 impulses/sec to 34 ± 1.9 impulses/sec. Whole nerve recordings also showed significantly higher threshold, inflection, and plateau pressures in the hypertensive dog. In response to pulsatile pressure, the single fiber sensitivity decreased from 0.17 ± 0.01 to 0.11 ± 0.01 impulses/cycle per mm Hg. Continuous nerve activity under these conditions occurred at a mean pressure of 166 ±3. 5 mm Hg for the normotensive dogs, compared with 188 ± 0.4 mm Hg for the hypertensive dogs. Hypertensive dogs showed an impulse frequency identical to that of normotensive dogs at pressures equivalent to each dog's unanesthetized mean blood pressure. Baroreceptor resetting was not seen before 5 days of hypertension. It was possible to reverse the resetting by lowering the blood pressure in one dog which had been hypertensive for 47 days.

Studies on renal hypertension. Significance of ratio of K to Na concentration in divided urine in experimental hypertension produced by coarctation of the aorta (author's transl)

Divided renal function studies were performed in experimental unilateral renal hypertension in dogs. Renal ischemia of the left side was produced by coarctation of the aorta between the ramification of renal arteries with a modified Galen's technique.1. In the condition of a 27 to 68 per cent decrease of systolic blood pressure in the femoral artery by aortic coarctation, significant hypertensive state was induced in 3 to 4 weeks postoperatively and sustained up to 8 weeks.2. Results of divided renal function studies were as follows. Decreases of GFR, urine volume, Na concentration and TRF-Na were observed, as well as increases of PAH, creatinine and K concentrations, and osmolarity in urine of the ischemic kidney.3. Ratio of K/Na urinary concentration in the right to left kidney (U-K/Na Index). The value of this index was 0.35±0.14 and a highly significant correlation between this Index and TRFR was found (r=0.892, p<0.001).4. U-K/Na Index is valuable as a clinical examination in the diagnosis of unilateral renal artery stenosis.