Hydrochlorothiazide, administered at 1, 3 and 9 mg/kg/day p.o. for 4 days, produced a dose-dependent lowering of plasma potassium and an elevation in plasma renin activity in unanesthetized dogs. When plasma renin activity was suppressed in diuretic-treated dogs by the potent beta-adrenergic receptor-blocking drug, timolol (0.5, 2 mg/kg/day p.o. for 4 days), the hypokalemia and hyperreninemia were significantly less pronounced. The data suggest that beta-adrenergic blocking drugs can be used to antagonize these side effects of diuretics.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

Use of losartan in the treatment of hypertensive patients with a history of cough induced by angiotensin-converting enzyme inhibitors.

The objective of this study was to determine the incidence of dry cough in hypertensive patients with a history of angiotensin-converting enzyme (ACE) inhibitor-induced cough after treatment with losartan (an angiotensin II-receptor antagonist), lisinopril (an ACE inhibitor), or placebo. One hundred patients from 16 outpatient treatment centers in the United States were included in this double-masked, randomized, parallel-group, active- and placebo-controlled study, with stratification according to sex. After a challenge phase with lisinopril and a placebo washout phase, patients were randomly allocated to receive losartan 50 mg once daily, lisinopril 20 mg once daily, or placebo for a maximum of 8 weeks. The primary efficacy end point of the study was the presence or absence of dry cough during the double-masked period, as rated by the patient at each visit using a validated symptom assessment questionnaire. A secondary end point was the frequency of dry cough, as measured at each visit using a visual analogue scale (VAS). The incidence of dry cough was significantly higher in the lisinopril group than in the losartan and placebo groups (87.5% vs 36.7% and 31.4%, respectively) at the end of the double-masked treatment period; there was no statistically significant difference between the losartan and placebo groups. Mean VAS scores showed that patients treated with lisinopril rated themselves as having a significantly higher frequency of cough than did patients treated with losartan or placebo (4.0 vs 1.2 and 1.5, respectively). Again, the difference between the losartan and placebo groups was not statistically significant. All treatments were otherwise well tolerated, and no serious clinical or laboratory adverse events were reported during the double-masked phase of the study. These results demonstrate that the incidence, severity, and frequency of dry cough in patients with a history of ACE inhibitor-induced dry cough are significantly lower in those treated with losartan than in those treated with lisinopril and are similar to the incidence, severity, and frequency of dry cough in those receiving placebo.

Adult↗

PubMedDate not supplied

Responses to amrinone in isolated cardiac muscles from cat, rabbit, and guinea pig.

Amrinone (10(-5)-10(-2) M) produced a positive inotropic response in several electrically stimulated, isolated cardiac muscle preparations. The order of potencies for amrinone in the tissues studied was: cat papillary muscle greater than rabbit papillary muscle greater than muscle strips from rabbit left atria = guinea pig papillary muscle greater than guinea pig left atria. Amrinone also restored contractility to cat and rabbit papillary muscles which had been partially depolarized with 20 mM K+. The beta-adrenergic antagonists timolol and propranolol partially inhibited these responses in rabbit but not cat papillary muscles. Reserpine pretreatment did not influence the responses to amrinone in any of the preparations studied. In conclusion, (a) the cat papillary muscle was the most sensitive preparation to the inotropic effect of amrinone, and (b) in the rabbit papillary muscle, beta-adrenoceptors contribute to the amrinone response but are not solely responsible for the enhanced inotropy.

Aminopyridines↗

PubMedDate not supplied

Comparison of cardiovascular responses to the bradycardic drugs, alinidine, AQ-A 39, and mixidine, in the anesthetized dog.

Cardiovascular responses to three bradycardic drugs, alinidine, AQ-A 39, and mixidine, were studied in open-chest, anesthetized dogs. All three drugs produced a dose-related decrease in heart rate at 0.3-10 mg/kg i.v. At 2.5 mg/kg i.v., spontaneous heart rates were decreased by 59 +/- 7, 52 +/- 6, and 39 +/- 6 beats/min with alinidine, AQ-A 39, and mixidine, respectively. The sinus node was an important site of action, because direct injection of alinidine, AQ-A 39, or mixidine to the sinus node via the sinus node artery (50 micrograms) elicited a negative chronotropic response. On systemic administration, total peripheral resistance was significantly increased with alinidine, significantly decreased with AQ-A 39, and not affected with mixidine. Increases in stroke volume accompanied bradycardic responses to AQ-A 39 and mixidine, and were prevented when heart rate was held constant by electrical pacing. Despite the production of similar effects on heart rate, AQ-A 39 differed from alinidine and mixidine in that it did not depress cardiac contractility in dogs with spontaneous heart rates. Therefore, all three drugs were effective and relatively selective in reducing heart rate; however, responses at the systemic vasculature and myocardium differed.

Anesthesia↗

PubMedDate not supplied

New centrally acting antihypertensive drugs related to methyldopa and clonidine.

It has been well established that the antihypertensive drugs clonidine and methyldopa lower blood pressure by acting on postsynaptic alpha 2-adrenergic receptors within cardiovascular control centers of the brain. A number of novel agents designed as lipophilic and highly selective alpha 2-adrenergic stimulants have been synthesized and in general the pharmacological features of these agents resemble clonidine or alpha-methylnorepinephrine, the principal metabolite of methyldopa. The clonidine analogs, ICI-106,270, UK-14,304, piclonidine (LR-99,853), and the bridge analogs (ST-1913, ST-1966,ST-1967) exhibit varying activity on the central cardiovascular control centers. ICI-106,270 is of interest because relative to clonidine it appears to exert fewer CNS side effects. Azepexole (BHT-933) is also of interest because, although structurally unrelated to clonidine, it appears to interact with central alpha-adrenergic receptors in a manner similar to that of clonidine. In contrast, central administration of ST-1966, a monoatomic bridge analog of clonidine, lowers blood pressure in animals treated with an alpha 2-antagonist, which suggests other mechanisms may be involved in its action. Novel antihypertensive agents structurally similar to methyldopa have not been described, although viable pro-drugs of methyldopa such as 2-oxo-1,3-dioxol-4-yl-methyl and pivaloyloxyethyl esters have been shown to have greater oral activity than methyldopa, presumably because they are more lipophilic than the parent moiety.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Comparison of renin and converting enzyme inhibition in sodium-deficient dogs.

While renin is a highly specific protease, converting enzyme has at least two principal substrates, angiotensin I and bradykinin. Changes in the rate of formation of angiotensin II or degradation of bradykinin can influence the hypotensive action of angiotensin converting enzyme inhibitors. The present study was designed to determine if there were differences in the maximal blood pressure reduction in Na-deficient dogs after angiotensin converting enzyme or renin inhibitor treatment. Five conscious dogs received 0.1, 0.5, and 1.0 mg/kg of i.v. enalaprilat, a potent angiotensin converting enzyme inhibitor, which reduced blood pressure to 75 +/- 4, 71 +/- 5, and 71 +/- 5 mm Hg. Plasma immunoreactive angiotensin II levels were reduced in a dose-related fashion to 35% of control level at the highest dose. Infusion of a maximally effective dose of a statine-containing renin inhibitor (SCRIP) with the high dose of enalaprilat produced no further fall in blood pressure (68 +/- 7 mm Hg), but immunoreactive angiotensin II levels fell to essentially zero in four of five dogs. The order of drug administration was reversed in another experiment in a group of nine dogs in which SCRIP reduced plasma immunoreactive angiotensin II to 25% of control at 0.04 mg/kg/minute (n = 5), with reduction to near zero levels at higher doses. Maximal blood pressure reduction was achieved at 0.32 to 0.64 mg/kg/minute (76 +/- 4 mm Hg); 1 mg/kg of enalaprilat lowered blood pressure an additional 11 +/- 2 mm Hg (p less than 0.01) while not further decreasing immunoreactive angiotensin II levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

PubMedDate not supplied

Comparative hemodynamic effects of MK-422, a converting enzyme inhibitor, and a renin inhibitor in dogs with acute left ventricular failure.

The angiotensin-converting enzyme (ACE) inhibitor MK-422 (enalaprilat) was compared with the potent renin inhibitor SCRIP for its ability to improve left ventricular function in closed-chest dogs. Acute left ventricular failure (ALVF) was induced by repeated embolization (EMB) of the left coronary arterial vasculature with 50-micron plastic microspheres. Baseline stability data were obtained in 30 dogs in which the evolution of ALVF was monitored over time. Guided by a progressive rise in left ventricular end-diastolic pressure (LVEDP), a stepwise perturbation of the coronary circulation with microspheres over 30 min caused reductions in left ventricular dP/dt and cardiac output, averaging 47 and 40%, respectively. EMB reduced heart rate (20 beats/min) and mean arterial pressure by approximately 20 mm Hg which, along with other hemodynamic variables remained stable after induction of heart failure. MK-422 (100 micrograms/kg i.v.) given 45 min after ALVF was induced, decreased mean arterial pressure by 20 mm Hg (p less than 0.05) and reduced total peripheral resistance (TPR) from 5,453 to 4,150 dyne X s X cm-5 (p less than 0.05). The decline in LVEDP (from 14 +/- 1 to 11 +/- 1 mm Hg) and TPR suggests that MK-422 dilates resistance and, conceivably, capacitance vessels. In dogs with sham EMB (vehicle injections into coronary circulation), MK-422 reduced arterial pressure but had no important effects on the other hemodynamic indices.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗