Hypertension or high blood pressure is considered globally as an important risk factor for cardiovascular diseases, including myocardial infarction, stroke and premature death [1]. Blood pressure is the product of peripheral vascular resistance (PVR), and cardiac output (CO) is the product of stroke volume (SV) and heart rate (HR). Hence, the blood pressure could be modified by the factors affecting PVR, SV and/or HR [2]. Hypertension may occur due to various factors, including up-regulation of renin-angiotensin-aldosterone-system (RAAS), overactive sympathetic system, increased peripheral vascular resistance, psycho-emotional stress, oxidative stress, endothelial dysfunction, and some genetic factors [3].
The incidence of hypertension among the global population has been estimated as 972 million (26%) in 2000 [4] and 1.13 billion in 2015 [5]. Moreover, adults living in low and middle-income countries had more prevalence of hypertension (1.04 billion) than those from high-income countries (349 million) [6].
The modern antihypertensive medications include angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), diuretics, beta-adrenergic blockers, direct renin inhibitors, direct-acting vasodilators, alpha-adrenergic blockers and centrally acting drugs [7] and the first-line antihypertensive drugs include ACEIs, ARBs, CCBs, or thiazide diuretics as per the recommendation from the eighth joint national committee (JNC 8) and American college of cardiology/American heart association task force [8].
The use of herbal medicine to manage chronic conditions such as hypertension, diabetes, etc., is popular among the global population as modern medicines are associated with many harmful and undesirable side effects [9]. Moreover, the patients may consider traditional herbal medicines as a good strategy to manage chronic conditions due to the reasons such as perceived failure of allopathic medicines, relatively high cost of allopathic medicines, social-cultural practices and/or herbal knowledge, poor accessibility to medical facilities and safety concerns about allopathic medicines [10].
Nigella sativa (Black seeds or Black cumin seeds) is a miracle herb, and it has been used to treat various conditions, including hypertension, obesity, diabetes, cancer, etc [11]. Above all, Prophet Muhammad (PBUH) stated that “In the black cumin, there is a cure for every illness except death” [12]. Hence, the antihypertensive potential of N. sativa is analyzed in this review. The major active constituents of N. sativa include thymoquinone (TQ), thymohydroquinone (THQ), dithymoquinone, d-limonene, d-citronellol, p- cymene and 2-(2-methoxypropyl)-5-methyl-1,4-benzenediol [13-15]. Moreover, it also contains alkaloids such as nigellidine, nigellicine, nigellicimine, nigellicimine N-oxide and nigellone, along with other constituents [16-18].
The pharmacokinetics aspects of oral thymoquinone (the prominent active constituent of N. sativa) have been studied in animals, which revealed that the estimated clearance was 12.30 ± 0.30 ml/min/kg, the volume of distribution was 5,109.46 ± 196.08 ml/kg, the elimination half-life (t1/2) was 274.61 ± 8.48 min and the protein binding was found to be 99% [19].
The acute toxicity study of N. sativa oil in mice determined that the lethal dose 50 (LD50) value for oral N. sativa oil was 28.8 ml/kg, and intraperitoneal N. sativa oil was 2.06 ml/kg. Moreover, the chronic toxicity study of N. sativa oil in rats revealed that the oral administration of 2 ml/kg of N. sativa oil for 12 weeks resulted in stability of key hepatic enzymes and integrity of organs. Hence, the use of N. sativa is considered safe as it has very high LD50 values and no chronic toxicity potentials [20].
This review article provides justification/information to use of N. sativa seed for hypertension along with conventional antihypertensive medications from the evidence of various clinical studies.
The literature was searched in databases including Medline/PMC/PubMed, Google Scholar, sciencedirect, Directory of Open Access Journals (DOAJ) and reference lists in this review, using keywords such as hypertension, high blood pressure, Nigella sativa, black seeds, black cumin seeds, and kalonji. The publications written in the English language were included in this review, while the duplicate publications were excluded.
Numerous randomized controlled clinical trials (RCTs) have been performed to observe the antihypertensive effects of N. sativa Table (11). A significant reduction of blood pressure was noticed almost in every patient who participated in those RCTs, which indicate that the stage 1 hypertension could be managed effectively using N. sativa, and the patients using allopathic antihypertensive medications could reduce the incidence of undesirable effects by decreasing their doses through the addition of N. sativa into their regimen as adjuvant therapy.
Clinical studies supporting the use of N. sativa to manage hypertension.
| S.No | Type of Study | Findings |
|---|---|---|
| 1 | Randomized, double-blind, placebo-controlled clinical trial [21] | Significant reduction of SBP, DBP, and LDL-cholesterol. |
| 2 | Randomized, double-blind, placebo-controlled clinical trial [22] | Improvement in BP, FBG, serum lipids, BMI, waist-hip ratio, ALT and creatinine. |
| 3 | Randomized, double-blind, placebo-controlled clinical trial [23] | Significant decline in SBP, body weight, and waist circumference. |
| 4 | Clinical study [24] | Improvement in BP, FBG, waist circumference, LDL, HDL and triglycerides. |
| 5 | Open labeled study [25] | Significant improvement in SBP, DBP, LDL. |
| 6 | Randomized, double-blind, placebo-controlled clinical trial [26] | Significant decrease in SBP, and DBP. |
| 7 | Randomized, double-blind, placebo-controlled clinical trial [27] | Significant lowering of SBP and significant increase in HDL. |
| 8 | Single-blind, nonrandomized controlled clinical trial [28] | Significant reduction of SBP. DBP, MAP, TC, LDL, TC/HDL, LDL/HDL and significant elevation of HDL. |
| 9 | Randomized, double-blind, controlled clinical trial [29] | Slight decrease in SBP and DBP. |
A randomized, double-blind, placebo-controlled clinical trial accomplished through Dehkordi FR et al. reported a significant reduction of systolic blood pressure (SBP) and diastolic blood pressure (DBP) in a dose-dependent manner in individuals with mild hypertension who were supplemented with 100 and 200 mg of N. sativa extract two times daily for 8 weeks. In addition, the administration of N. sativa extract also resulted in a significant reduction of low-density-lipoprotein (LDL)-cholesterol, and the study did no longer find any complications, which imply more secure use of N. sativa to treat sufferers of high blood pressure [21] and another randomized, double-blind, placebo-controlled clinical trial of 123 patients, reported a favorable impact of capsules containing powdered N. sativa seeds on blood pressure along with fasting blood glucose (FBG), serum lipids, body- mass index (BMI), waist-hip ratio, serum alanine aminotransferase (ALT) and serum creatinine [22].
Similarly, a double-blind, placebo-controlled trial of central obese men revealed that the supplementation of N. sativa leads to a significant decline in SBP, body weight, and waist circumference [23] and a clinical study of patients receiving drugs such as atenolol 50 mg once a day, metformin 500 mg twice daily, simvastatin 10 mg once a day, and clopidogrel 75 mg once daily demonstrated that the adjuvant therapy of 250 mg twice daily of N. sativa for 6 weeks resulted in improvement in blood pressure, waist circumference, fasting blood sugar, LDL, HDL and triglycerides compared to the standard group [24].
An open-labeled study of 90 patients with metabolic syndrome reported a significant improvement in systolic blood pressure, diastolic blood pressure and low-density-lipoprotein (LDL)-cholesterol by the administration of N. sativa for 8 weeks [25].
Fallah Huseini H et al. carried out a randomized, double-blind, placebo-controlled clinical trial of 70 healthy volunteers who received 5 ml of N. sativa oil, observed a significant decrease in systolic blood pressure (SBP) and diastolic blood pressure (DBP). However, the study did not find any significant modifications in different parameters including body mass index and blood levels of creatinine, blood urea nitrogen (BUN), aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase [26] and a randomized, double-blind, placebo-controlled clinical trial of 20 patients of stage 1 hypertension and who received 1000 mg of powdered N. sativa seeds 2 times daily for 50 days, revealed that there was a significant lowering of systolic blood pressure (SBP) in N. sativa treated group. It has also been stated that N. sativa treated group shown a significant increase in high-density-lipoprotein (HDL)-cholesterol [27].
A single-blind, nonrandomized controlled trial of 57 patients with type 2 diabetes demonstrated that 2 g daily supplementation of N. sativa for 1 year resulted in a significant reduction of systolic blood pressure, diastolic blood pressure, mean arterial pressure and heart rate along with a significant elevation of high-density-lipoprotein (HDL)-cholesterol and a significant decrease in total cholesterol (TC), low-density-lipoprotein (LDL)-cholesterol, TC/HDL and LDL-C/HDL-C ratios [28] and a double-blind, randomized controlled trial of 76 elderly patients with hypertension demonstrated a slight decrease in systolic blood pressure and diastolic blood pressure by the administration of 300 mg of N. sativa seed extract 2 times of daily for 4 weeks [29
